Oral Mucosal Drug Delivery

DRUG DELIVERY SYSTEMS Clin Pharmacokinet 2002; 41 (9): 661-680 0312-5963/02/0009-0661/$25.00/0 © Adis International Limited. All rights reserved. Or...
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DRUG DELIVERY SYSTEMS

Clin Pharmacokinet 2002; 41 (9): 661-680 0312-5963/02/0009-0661/$25.00/0 © Adis International Limited. All rights reserved.

Oral Mucosal Drug Delivery Clinical Pharmacokinetics and Therapeutic Applications Hao Zhang,1 Jie Zhang2 and James B. Streisand 3 1 Cephalon, Inc., Salt Lake City, Utah, USA 2 Department of Anesthesiology, University of Utah, Salt Lake City, Utah, USA 3 Genzyme Corporation, Cambridge, Massachusetts, USA

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Principles of Drug Absorption Via the Oral Mucosa . . . 1.1 The Oral Mucosa . . . . . . . . . . . . . . . . . . . . 1.2 Principles of Drug Absorption . . . . . . . . . . . . . 2. Oral Transmucosal Dosage Forms . . . . . . . . . . . . . 2.1 Solid Forms . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Gum . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Patches . . . . . . . . . . . . . . . . . . . . . . . . . 3. Clinical Application of Oral Transmucosal Drug Delivery 3.1 Cardiovascular System . . . . . . . . . . . . . . . . . 3.1.1 Nitroglycerin . . . . . . . . . . . . . . . . . . . . 3.1.2 Captopril . . . . . . . . . . . . . . . . . . . . . 3.1.3 Verapamil . . . . . . . . . . . . . . . . . . . . . 3.1.4 Nifedipine . . . . . . . . . . . . . . . . . . . . . 3.1.5 Propafenone . . . . . . . . . . . . . . . . . . . 3.2 Analgesia . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1 Fentanyl . . . . . . . . . . . . . . . . . . . . . . 3.2.2 Morphine . . . . . . . . . . . . . . . . . . . . . 3.2.3 Buprenorphine . . . . . . . . . . . . . . . . . . 3.2.4 Butorphanol . . . . . . . . . . . . . . . . . . . . 3.2.5 Piroxicam . . . . . . . . . . . . . . . . . . . . . 3.3 Sedation . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.1 Midazolam . . . . . . . . . . . . . . . . . . . . 3.3.2 Triazolam and Other Benzodiazepines . . . . . 3.3.3 Etomidate . . . . . . . . . . . . . . . . . . . . . 3.4 Antiemetics . . . . . . . . . . . . . . . . . . . . . . . 3.4.1 Scopolamine . . . . . . . . . . . . . . . . . . . 3.4.2 Prochlorperazine . . . . . . . . . . . . . . . . . 3.5 Erectile Dysfunction . . . . . . . . . . . . . . . . . . 3.5.1 Apomorphine . . . . . . . . . . . . . . . . . . . 3.5.2 Phentolamine Mesylate . . . . . . . . . . . . . 3.6 Hormonal Therapy . . . . . . . . . . . . . . . . . . . 3.6.1 Testosterone . . . . . . . . . . . . . . . . . . . . 3.6.2 Estrogen . . . . . . . . . . . . . . . . . . . . . . 3.7 Smoking Cessation . . . . . . . . . . . . . . . . . . . 3.8 Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . 3.8.1 Glucagon-Like Peptide . . . . . . . . . . . . . 3.8.2 Insulin . . . . . . . . . . . . . . . . . . . . . . . . 3.8.3 Vasopressin . . . . . . . . . . . . . . . . . . . . 4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract

Zhang et al.

Oral mucosal drug delivery is an alternative method of systemic drug delivery that offers several advantages over both injectable and enteral methods. Because the oral mucosa is highly vascularised, drugs that are absorbed through the oral mucosa directly enter the systemic circulation, bypassing the gastrointestinal tract and first-pass metabolism in the liver. For some drugs, this results in rapid onset of action via a more comfortable and convenient delivery route than the intravenous route. Not all drugs, however, can be administered through the oral mucosa because of the characteristics of the oral mucosa and the physicochemical properties of the drug. Several cardiovascular drugs administered transmucosally have been studied extensively. Nitroglycerin is one of the most common drugs delivered through the oral mucosa. Research on other cardiovascular drugs, such as captopril, verapamil and propafenone, has proven promising. Oral transmucosal delivery of analgesics has received considerable attention. Oral transmucosal fentanyl is designed to deliver rapid analgesia for breakthrough pain, providing patients with a noninvasive, easy to use and nonintimidating option. For analgesics that are used to treat mild to moderate pain, rapid onset has relatively little benefit and oral mucosal delivery is a poor option. Oral mucosal delivery of sedatives such as midazolam, triazolam and etomidate has shown favourable results with clinical advantages over other routes of administration. Oral mucosal delivery of the antinausea drugs scopolamine and prochlorperazine has received some attention, as has oral mucosal delivery of drugs for erectile dysfunction. Oral transmucosal formulations of testosterone and estrogen have been developed. In clinical studies, sublingual testosterone has been shown to result in increases in lean muscle mass and muscle strength, improvement in positive mood parameters, and increases in genital responsiveness in women. Short-term administration of estrogen to menopausal women with cardiovascular disease has been shown to produce coronary and peripheral vasodilation, reduction of vascular resistance and improvement in endothelial function. Studies of sublingual administration of estrogen are needed to clarify the most beneficial regimen. Although many drugs have been evaluated for oral transmucosal delivery, few are commercially available. The clinical need for oral transmucosal delivery of a drug must be high enough to offset the high costs associated with developing this type of product. Drugs considered for oral transmucosal delivery are limited to existing products, and until there is a change in the selection and development process for new drugs, candidates for oral transmucosal delivery will be limited.

Drug delivery via the oral mucosal route is an alternative method of systemic administration for several classes of pharmaceutical agents. The oral mucosal route of administration is well established for various drugs such as nitroglycerin, which has been administered sublingually for over 100 years. Other drugs have undergone extensive evaluation over the past decade, and a substantial body of literature has accumulated regarding the pharmacokinetics and therapeutic effects of these drugs  Adis International Limited. All rights reserved.

when administered transmucosally. Examples of these drugs include potent analgesics such as oral transmucosal fentanyl citrate and buprenorphine, ACE inhibitors such as captopril, and benzodiazepines such as midazolam and triazolam. Oral mucosal drug delivery offers several advantages over both injectable and enteral delivery. Drugs absorbed via the oral mucosa avoid the fate of enterically administered drugs: low gastric pH and proteases, and first-pass hepatic degradation. Clin Pharmacokinet 2002; 41 (9)

Oral Mucosal Drug Delivery

Absorption of certain drugs across the oral mucosa provides patients with a rapid onset of action, approaching that seen with intravenous administration. Additionally, oral mucosal drug delivery offers an alternative when enteral administration is impractical (e.g. in patients who have difficulty in swallowing, nausea or vomiting, or intestinal failure). Oral mucosal delivery is noninvasive and less intimidating for many patients compared with other routes of administration (e.g. intravenous, intramuscular). Finally, drugs administered via the oral mucosa do not require technical equipment (e.g. infusion pumps) and expertise and thus are more cost-effective than invasive therapies. Not all drugs, however, can be efficiently absorbed through the oral mucosa. For example, the systemic bioavailabilities of peptides and proteins are typically less than 5% of administered dose with transmucosal delivery due to the physicochemical barrier of the oral mucosa, which contains enzymes that break down peptides.[1] Recent technological advances, however, have resulted in the development of absorption enhancers that may allow successful mucosal delivery of these and other molecules. Another limitation of oral mucosal delivery is that absorption may be more variable than with other routes. In addition, the barrier properties of the epithelium result in the oral mucosa being an efficient barrier to drug penetration, allowing only small quantities of a drug to penetrate. Therefore, oral mucosal delivery is suitable only for drugs with a high potency. Finally, oral mucosal delivery may be difficult in certain pathological conditions that affect the integrity of the mucosa, such as blisters or mucositis. The clinical pharmacokinetics of drugs administered buccally and sublingually have been reviewed previously in Clinical Pharmacokinetics.[2] However, since the publication of that review, the pharmacokinetic profiles of several other buccal and sublingual drugs have been evaluated, and new oral mucosal delivery forms have been developed. The primary focus of this review is the recent literature, although key information from the earlier  Adis International Limited. All rights reserved.

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review is also mentioned, where appropriate, for completeness. 1. Principles of Drug Absorption Via the Oral Mucosa 1.1 The Oral Mucosa

A thorough description of the oral mucosa and its function is available elsewhere.[3] We have only included those details relevant to the oral mucosal delivery of drugs. The oral cavity comprises the lips, cheek (buccal), tongue, hard palate, soft palate and floor of the mouth. The lining of the oral cavity is referred to as the oral mucosa, and includes the buccal, sublingual, gingival, palatal and labial mucosae. The mucosal tissues in the cheeks (buccal), the floor of the mouth (sublingual) and the ventral surface of the tongue account for about 60% of the oral mucosal surface area. The buccal and sublingual tissues are the primary focus for drug delivery via the oral mucosa because they are more permeable than the tissues in other regions of the mouth. The surface area of the oral mucosa (200 cm2)[4] is relatively small compared with the gastrointestinal tract (350 000 cm2)[5] and skin (20 000 cm2).[6] However, the oral mucosa is highly vascularised, and therefore any drug diffusing into the oral mucosa membranes has direct access to the systemic circulation via capillaries and venous drainage. Thus, drugs that are absorbed through the oral mucosa directly enter the systemic circulation, bypassing the gastrointestinal tract and first-pass metabolism in the liver. The rate of blood flow through the oral mucosa is substantial, and is generally not considered to be the rate-limiting factor in the absorption of drugs by this route.[7] The oral mucosa is made up of closely compacted epithelial cells, which comprise the top quarter to one-third of the epithelium.[8-10] The primary function of the oral epithelium is to protect the underlying tissue against potential harmful agents in the oral environment and from fluid loss.[11] In order for a drug to pass through the oral mucosa, it must first diffuse through the lipophilic Clin Pharmacokinet 2002; 41 (9)

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Zhang et al.

cell membrane, then pass through the hydrophilic interior of the cells of the oral epithelium. Thus, the oral mucosa provides both hydrophilic and hydrophobic barriers that must be overcome for efficient mucosal delivery. An enzymatic barrier also exists at the mucosa, which causes rapid degradation of peptides and proteins, limiting their transport across the oral mucosa. Although these layers provide a unique challenge for drug delivery via the oral mucosa, several different approaches in the design and formulation of suitable delivery systems have been developed to circumvent these barriers. 1.2 Principles of Drug Absorption

Drug absorption via the oral mucosa is a passive diffusion process. By simplifying the oral mucosa into a hydrophobic membrane, Fick’s first law can be used to describe the drug absorption process (equations 1 and 2): P=

D • Kp h

A = P• C •S • t =

D • Kp h

• C •S • t

where P is permeability coefficient, A is the amount of drug absorbed, D is the diffusion coefficient of the drug in the oral mucosa, Kp is the partition coefficient of the drug between delivery medium and the oral mucosa, h is the thickness of the oral mucosa, C is the free drug concentration in the delivery medium, S is the surface area of the delivery site on the oral mucosa and t is the duration of drug contacting the oral mucosa. Parameters such as diffusion coefficient, partition coefficient and thickness of the tissue are inherent properties of the drug and the mucosa. Other parameters, such as surface area, duration of drug delivery and concentration are controlled by the dosage form and formulation. Free drug concentration is a key issue in terms of developing transmucosal drug delivery dosage forms. The effective formulation must not only release the drug to the  Adis International Limited. All rights reserved.

mucosal surface, but do so with the drug in its free form. If the drug is bound to other components in the formulation, it is not available for transmucosal delivery and the bioavailability will be greatly reduced. The unique properties of the oral mucosa have also imposed unique drug delivery challenges for formulation scientists. In general, lipophilic compounds have much higher permeability coefficients than hydrophilic compounds. However, the aqueous solubilities of lipophilic compounds are usually much lower than those of hydrophilic compounds. Thus, the amount of drug absorbed may not be high for lipophilic compounds if their hydrophobicity is too high. There is a fine balance between partition coefficient and solubility for a drug to be suitable for oral mucosal delivery. Due to these constraints, the potency of the drug is important for selecting appropriate candidates. The amount of drug that can be delivered via the oral mucosa is limited to a few milligrams. Occasionally, permeation enhancers are used to promote drug absorption, especially for hydrophilic drugs. Their exact mechanism of action is unknown, and may be different for different types of enhancers. It is believed that the enhancers form aqueous pores on the cell surfaces, thereby increasing the permeability of hydrophilic compounds. The use of permeation enhancers, however, must consider issues such as local tissue irritation, longterm tissue toxicity and enhanced permeability to pathological micro-organisms. Despite considerable research on oral mucosal permeation with enhancers, no product has yet to be commercially developed using a permeation enhancer. 2. Oral Transmucosal Dosage Forms To improve oral transmucosal delivery of drugs, several new dosage forms have been developed: solutions, tablets/lozenges (including lyophilised and bioadhesive), chewing gum, solution sprays, laminated systems and patches, hydrogels, adhesive films, hollow fibres and microspheres. Advances in oral mucosal drug delivery have focused on the development of drug delivery systems that Clin Pharmacokinet 2002; 41 (9)

Oral Mucosal Drug Delivery

not only achieve the therapeutic aims of delivery but also overcome the unfavourable environmental conditions found in the oral cavity. Modern formulations have used creative approaches that incorporate a combination of these strategies to create a balance between patient convenience and clinical benefits. 2.1 Solid Forms

Several solid lozenge formulations have been developed and are commercially available, including nitroglycerin sublingual tablet, fentanyl lozenge on a handle and prochlorperazine buccal tablets. Although these formulations vary in shape and size, they share many common characteristics. This method of delivery is simple for patients to use. The solid formulations dissolve in the oral cavity. The drugs are released and exposed to the entire mucosa and the top third of the oesophageal mucosa. As shown in equation 2, the amount of drug delivered is directly proportional to the surface area. The limitation of this delivery form is the short residence time. Depending on the size and formulation, the lozenge or tablet is usually dissolved within 30 minutes, thus limiting the total amount of drug that can be delivered. The dissolution or disintegration is usually controlled by the patient, i.e. how hard they suck the unit. Increased sucking and saliva production causes swallowing and loss of drug down the oesophagus and into the gastrointestinal tract. Thus, solid dosage forms generally have a much higher inter- and intra-individual variation in absorption and bioavailability. In addition, since these formulations are open systems, the delivery medium is not well controlled. Although the formulation offers some control, it is difficult to control drug or other ingredient concentrations because the media is constantly diluted by saliva. This makes it difficult to effectively use permeation enhancers in this type of system. Taste of the drug is another hurdle for this delivery system. Unless the drug is tasteless or the taste can be masked by sweetening and flavouring  Adis International Limited. All rights reserved.

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agents, it is difficult to achieve high patient acceptability of this type of product. 2.2 Gum

Chewing gum is one of the more modern approaches to oral transmucosal drug delivery and is a useful means for systemic drug delivery. The advantages of chewing gum over other oral mucosal drug delivery systems are the possibility of controlled drug release over an extended time and the potential to improve the variability in drug release and retention times. One of the advantages of chewing gum is convenience. Furthermore, an individual may be able to control the drug intake by simply changing the rate and vigour of chewing, or expelling the gum altogether. Since chewing gum is also an open system, it shares many of the same limitations of the other solid formulations. 2.3 Patches

Flexible adhesive patches have been developed in an effort to overcome some of the drawbacks of other dosage forms. Transmucosal delivery patches have unique characteristics, including relatively rapid onset of drug delivery, sustained drug release and rapid decline in the serum drug concentration when the patch is removed. Also, a buccal patch is confined to the buccal area over which it is attached and therefore the absorption profile may have less inter- and intra-individual variability. In general, oral mucosal patches can be classified into three categories: patches with a dissolvable matrix, patches with a non-dissolvable backing, and patches with a dissolvable backing. Patches with a dissolvable matrix are designed to release drug into the oral cavity. They work similarly to, and share many of the limitations of, the solid dose form. The mucoadhesive layer, either in the drug matrix or attached to drug matrix as an additional layer, prolongs the duration of drug matrix in the oral cavity. Therefore, compared with other open dosage forms, these types of patches are longer acting and can potentially deliver more drug. They also use the entire oral cavity mucosa as compared with other closed systems that typiClin Pharmacokinet 2002; 41 (9)

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cally use smaller areas. These types of patches are also suitable for treating local diseases such as candidiasis or mucositis. Patches with non-dissolvable backing are usually designed for systemic delivery. Since they are closed systems and the formulations are protected from saliva, the drug concentrations are controlled and drug is continuously delivered for up to 10 to 15 hours. The disadvantages of these systems are that they use only a small mucosal area and the backings have to be removed by the patient after drug administration. Patches with dissolvable backing share many characteristics of patches with non-dissolvable backing, but they have the advantage of the entire patch dissolving in the oral cavity. Nonetheless, patches with dissolvable backings are shorteracting than patches with non-dissolvable backing. Oral mucosal dosage forms are convenient, easy to use, and have the potential to offer a low-cost and painless alternative to more invasive routes of administration. Each delivery form offers very distinct delivery characteristics that can be used in a broad range of therapies. 3. Clinical Application of Oral Transmucosal Drug Delivery

3.1 Cardiovascular System 3.1.1 Nitroglycerin

Sublingual nitroglycerin (glyceryl trinitrate) has been used successfully for over a century in the treatment of acute angina pectoris. The pharmacokinetics and pharmacology of sublingually administered nitroglycerin are well established. The drug exerts its effect primarily through peripheral venodilation and coronary vasodilatation. Due to extensive first-pass hepatic metabolism, oral tablets have limited effectiveness. On the contrary, sublingual tablet formulations and liquid aerosol formulations have proven to be highly effective. The pharmacokinetics of the nitrates are reviewed elsewhere.[12,13]  Adis International Limited. All rights reserved.

Zhang et al.

3.1.2 Captopril

Over the past decade, ACE inhibitors have become a routine part of treatment for congestive heart failure. In addition, the sublingual route of administration of captopril has been shown to be effective for hypertensive crisis, and is reviewed by Motwani and Lipworth.[2] A clinical trial that compared sublingual captopril with placebo for acute pulmonary oedema found that the addition of sublingual captopril to the standard therapeutic regimen (oxygen, nitrates, morphine and furosemide) produced more rapid clinical improvement than did the standard regimen alone.[14] A recent pharmacokinetic study in healthy volunteers reported that sublingual captopril administration produced a more rapid attainment of plasma captopril concentrations than did oral administration (45 versus 75 minutes) [table I]. In addition, sublingual administration produced a more rapid pharmacological effect, as shown by a reduction in time to maximal response of plasma renin activity (86 versus 113 minutes).[15] McElnay and coworkers[16] compared the sublingual administration of captopril under optimised pH conditions (pH 7, as determined from buccal partitioning data). Peak concentration (Cmax) occurred slightly earlier (tmax) after buffered versus unbuffered sublingual administration (40 versus 51 minutes) and total absorption [area under the concentration-time curve (AUC)] increased by about 30% with the buffered administration. The magnitude of these differences, however, was small and little therapeutic advantage would be expected with buffered administration. Similar results were obtained in patients with congestive heart failure – buffered sublingual captopril was absorbed more rapidly than oral, but the extent of absorption was the same, suggesting a modest therapeutic advantage when rapid attainment of pharmacological effect is desirable.[17] 3.1.3 Verapamil

Verapamil is a calcium channel antagonist that is used for the management of angina, hypertension and certain supraventricular arrhythmias. After oral administration, verapamil undergoes extensive first-pass metabolism. Table I presents pharClin Pharmacokinet 2002; 41 (9)

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Table I. Absorption characteristics of captopril and verapamil administered buccally or sublingually in volunteers or patients Study Captopril 15 16 17

Verapamil 18

Dose (mg) [no. of evaluable study participants]

F (%)

Mean Cmax (µg/L)

Mean tmax

Mean AUC

Sublingual tablet 25 (8)

NA

234

45 min

15.1 mg • min/La

Oral tablet 25 (8)

NA

228

75 min

17.0 mg • min/La

Buffered (pH 7) sublingual solution 25 (8)

NA

220

40 min

13.8 mg • min/Lb

Unbuffered sublingual solution 25 (8)

NA

197

51 min

12.9 mg • min/Lb

Buffered sublingual tablet 12.5 (6c)

NA

108.2

40 mind

881 µg • min/Le

Oral tablet 12.5 (6c)

NA

94.0

90 mind

366 µg • min/Le 9.3 µg • min/L

Buccal tablet 20 (7)

37.8

48.0

59 min

Oral capsules 80-120 (7)f

33.3

335.6

69 min

9.4 µg • min/L

Intravenous 5 (7)

NA

NR

NR

26.8 µg • min/L

19

Sublingual 80 (7)g

NAh

153.3

1.21h

NA

20

Sublingual crushed tablet 40 (6)

NA

59.2

0.58h

310 µg • h/Lh

Oral 40 (6)

NA

48.6

1.13h

234 µg • h/Lh

Sublingual tablet 40 (7)

57.2

72.3

1.50h

NR

21

Sublingual tablet 60 (7)

59.5

107.0

1.02h

NR

Intravenous 5 (7)

NA

39.1

NR

NR

a

AUC3h.

b

AUC180min.

c

Patients with chronic cardiac failure.

d

Median.

e

AUC40min.

f

Two patients received a dose of 80mg because their bodyweights were at the lower end of normal, five patients received the 120mg dose; results are presented for all seven patients combined.

g

Two patients with atrial flutter, five patients with atrial fibrillation.

h

AUC8h.

AUCt = area under the plasma or serum concentration-time curve from zero to time t; Cmax = peak plasma or serum concentration; F = bioavailability; NA = not applicable; NR = not reported; tmax = time to Cmax.

macokinetic data for intravenous, oral and sublingual verapamil.[18-21] An early study in healthy volunteers indicated that the rate of absorption of the buccal tablet was not significantly different from that of the oral capsule. The absolute bioavailability was slightly higher with the buccal tablet (38%) compared with the oral capsule (33%), but the difference was not significant.[18] Interestingly, the difference in biological effect, PQ interval of the electrocardiogram, was significant between buccal and oral administration. This suggests the possibility that the difference in drug delivery route may contribute to differences in metabolism or active metabolites, which may cause differences in biological effect apart from the pharmacokinetic sim Adis International Limited. All rights reserved.

ilarity of the oral and buccal routes of administration. In contrast, a more recent study in healthy volunteers revealed that sublingual administration of verapamil produced a significantly higher Cmax, a faster rate of absorption and greater bioavailability than oral administration.[19] In seven patients with acute fast atrial flutter or fibrillation, Fort et al.[20] reported that sublingual verapamil produced a rapid and significant reduction in ventricular rate. Verapamil was detected in the blood 12.6 minutes after administration. The effectiveness of sublingual verapamil tablets for severe hypertension was recently compared with the effectiveness of sublingual nifedipine in 90 patients. In this study, nifedipine 10mg Clin Pharmacokinet 2002; 41 (9)

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caused rapid lowering of elevated blood pressure to less than 150/90mm Hg in 22 of 30 patients. It also caused elevation of heart rate in 22 of 30 patients and headache in 8 of 30 patients. Verapamil reduced blood pressure in 18 of 30 patients and reduced heart rate in 21 of 30 patients. It alleviated headache in eight of the patients.[22] Because of the safety concerns associated with sublingual nifedipine (see section 3.1.4), sublingual verapamil offers another alternative for treating the severely hypertensive patient with tachycardia or tachyarrythmia or with symptomatic headache. 3.1.4 Nifedipine

Nifedipine, another calcium channel antagonist, is commonly administered sublingually for treatment of severe hypertension. Motwani and Lipworth[2] concluded that sublingual absorption of nifedipine is poor, with the intestinal mucosa being responsible for the majority of absorption. In 1995, the Cardiorenal Advisory Committee of the US Food and Drug Administration (FDA) unanimously decided that sublingual nifedipine should not be marketed for the treatment of hypertensive emergencies. A review of the literature had revealed numerous reports of serious adverse events when the drug was given for treatment of severe hypertension. These adverse events included cerebrovascular ischaemia, stroke, numerous instances of severe hypotension, acute myocardial infarction, conduction disturbances, fetal distress, and death.[23] 3.1.5 Propafenone

Propafenone is a sodium channel blocker used as long-term oral therapy to maintain normal sinus rhythm in patients with supraventricular tachycardias. Although intravenous loading of propafenone is an effective treatment for paroxysmal arrhythmias, intravenous administration is costly and requires hospitalisation. Rapid absorption after buccal administration of propafenone may provide a more convenient, cost-effective means to deliver propafenone in this indication. Sasaki et al.[24] recently reported a comparison of buccal and oral administration of propafenone in eight healthy volunteers. Following a single buc Adis International Limited. All rights reserved.

Zhang et al.

cal dose of propafenone 150mg, the mean Cmax was 30.4 ± 1.4 µg/L and tmax was 16.9 ± 2.3 min. The tmax for oral administration was notably longer, 1.8 ± 0.1 hours. Cmax following oral administration was 27.9 ± 2.5 µg/L. The results of this study appear promising and warrant further evaluation of this drug. 3.2 Analgesia 3.2.1 Fentanyl

Oral transmucosal delivery of fentanyl has undergone extensive evaluation over the past decade. In the early 1990s, oral transmucosal fentanyl citrate (OTFC) was cleared for marketing by the FDA for premedication prior to surgery or prior to painful procedures in children and adults. The clinical pharmacology of OTFC in volunteers, paediatric patients and acute pain management spurred the investigation of OTFC for treating breakthrough pain in cancer patients. In 1998, OTFC was approved by the FDA for marketing for breakthrough cancer pain. OTFC incorporates a sugar-based lozenge on a handle, which allows patients or caregivers to remove the dosage unit and stop transmucosal absorption once a desired effect is achieved or an adverse effect begins. This technology is noninvasive, easy to use, and less intimidating for many patients with cancer than intravenous patientcontrolled analgesia with an electronic pump. Patients attain rapid relief from their breakthrough cancer pain with OTFC.[25-27] Fentanyl from OTFC is absorbed rapidly through the oral mucosa, with Cmax (3.0 ± 1.0 µg/L) occurring 22 minutes after administration of a 15 µg/kg dose.[28] Analgesic plasma concentrations (about 1 µg/L) are usually reached within 15 minutes of administration (figure 1). Absorption from swallowed fentanyl contributes little to Cmax. However, intestinal absorption is responsible for prolonging the distribution phase and maintaining fentanyl concentrations above 1 µg/L for about 2 hours after administration. The terminal elimination half-life (t1⁄2β) after single-unit OTFC administration is no different than after intravenous Clin Pharmacokinet 2002; 41 (9)

Oral Mucosal Drug Delivery

669

Fentanyl concentration (µg/L)

100

OTFC IV Oral solution

10

1

0.1 0

4

8

12

16

Time (h)

Fig. 1. Plasma concentrations of fentanyl (mean ± standard error) after administration of a 15 µ g/kg dose of fentanyl via the buccal

(OTFC; n = 10), oral (n = 8) and intravenous (IV; n = 10) routes in healthy volunteers (reproduced from Streisand et al.,[28] with permission). OTFC = oral transmucosal fentanyl citrate.

administration, unlike the prolonged elimination seen with transdermal fentanyl administration.[28] Repeated doses of OTFC administered every 6 hours to adult volunteers (800 µg/dose) did not lead to any differences between peak or trough fentanyl concentrations following each administered dose.[29] Over the dose range of 200 to 1600µg, OTFC exhibits dose-proportional pharmacokinetics.[30] In an acute pain model, 200 and 800µg doses of OTFC produced rapid pain relief (within 5 minutes) similar to intravenous morphine at doses of 2 or 10mg, respectively, when administered for post-hysterectomy pain.[31] OTFC is useful for treating breakthrough cancer pain because the pharmacokinetic profile of fentanyl conforms to the characteristics of breakthrough pain. Its rapid onset of action and short duration of analgesic effect match the rapid onset and short duration of breakthrough pain. Several studies have supported the utility of OTFC for effectively managing breakthrough cancer pain.[25-27]  Adis International Limited. All rights reserved.

A recent study directly compared OTFC with oral morphine (morphine sulphate immediate release) in a randomised, double-blind, crossover design.[32] This study reported that OTFC produced a statistically significant increase in pain relief relative to oral morphine at 15 minutes, the first time point evaluated. Global medication performance scores were also significantly better with OTFC than with oral morphine, and 94% of patients chose to continue using OTFC rather than oral morphine during an extension trial. 3.2.2 Morphine

Although some clinicians believe that the sublingual route for delivery of morphine produces rapid absorption, pharmacological data do not support this contention. Coluzzi[33] recently reviewed evidence for the lack of efficacy of sublingual morphine. The physicochemical properties of morphine are not favourable for mucosal absorption. Indeed, as shown in figure 2, morphine is one of the least hydrophobic opioids.[34] It should be Clin Pharmacokinet 2002; 41 (9)

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noted that the Weinberg et al.[34] study from which this figure was derived used a technique whereby participants held 1ml of solution under their tongue for 10 minutes without swallowing, then expectorated the solution. Bioavailability was calculated from the amount of drug in the solution before and after the 10-minute period. Consequently, this study only provides information on the relative mucosal absorption among various opioids, not the absolute bioavailability of the opioids. Morphine is also one of the least potent opioids. Two studies conducted in the past decade in patients with cancer demonstrated the lack of mucosal absorption with sublingual morphine and suggest that morphine delivered sublingually is actually absorbed through the gastrointestinal tract. In one study, the relative bioavailability of oral and sublingual morphine was 25 and 23% of intramuscular morphine.[35] In another study, plasma morphine concentrations were slightly higher following oral administration compared with sublingual administration.[36] A study of aerosolised morphine administered sublingually to volunteers reported a tmax of 0.80 ± 1.9 hours.[37] The low bioavailability and long tmax in these studies indicate that the morphine following buccal administration was absorbed in the gastrointestinal tract, rather than in the oral cavity.

3.2.3 Buprenorphine

Buprenorphine is a synthetic, lipophilic, potent opioid analgesic that is used in the treatment of moderate to severe pain. Recent studies have also shown higher doses of buprenorphine (up to about 45mg) to be an effective treatment for suppressing heroin withdrawal.[38,39] Because of its partial agonist profile, buprenorphine produces limited respiratory depression, even with high doses.[39] The low oral bioavailability resulting from hepatic first-pass metabolism makes sublingual administration an attractive option for buprenorphine, especially because the large doses required for oral administration can be costly. An evaluation of nine different opioids (figure 2) showed that sublingual absorption of buprenorphine is relatively high compared with that of most opioids.[34] The pharmacokinetics of sublingually and buccally administered buprenorphine have been evaluated extensively over the past decade (table II). Systemic bioavailability of buprenorphine ranged from 28 to 58% at doses between 0.2 and 0.8mg.[40-44] Although Weinberg et al.[34] reported relatively high sublingual absorption, the tmax reported for the majority of sublingual or buccal doses was greater than 1 hour (table II). This long tmax indicates that most of the absorption was probably not through the oral mucosa, but rather was through the gastrointestinal system. 3.2.4 Butorphanol

xy e c ( Le odo 5.0 ) H vor ne yd p ( ro ha 2.5 n ) m or ol ( ph 1. on 0) N e al ox (1. M on 0) et ha e (1 D ia don .0) m or e (5 M phin .0) et ha e (2 do . ne 5) Bu Fen (0 .8 ta pr ) en ny l( or 0 ph .5 ) in e (0 .1 )

O

M

or

ph

in

Mean absorbed (%)

80 70 60 50 40 30 20 10 0

Opioid (mg)

Fig. 2. Mean absorption of opioids after 10 minutes in the oral

cavity of healthy volunteers (n = 10 for each test condition). The pH of the solution was 6.5 (reproduced from Weinberg et al.,[34] with permission).

 Adis International Limited. All rights reserved.

Butorphanol delivery through nasal spray for use in migraine headaches is commercially available. This has encouraged evaluation of butorphanol delivery through the oral mucosa. The pharmacokinetics of sublingual tablet and buccal disk formulations of butorphanol have been evaluated. The mean bioavailabilities of the sublingual and buccal formulations were 19 and 29%, respectively, versus