Encyclopedia of Pharmaceutical Technology, Third Edition

Drug Delivery: Buccal Route
James C. McElnay
Queens University Belfast, Belfast, U.K.
Carmel M. Hughes
School of Pharmacy, Medical Biology Centre, The Queens University of Belfast, Belfast, U.K.
INTRODUCTION A drug can be administered via many different routes to produce a systemic pharmacologic effect. The most common method of drug administration is via the peroral route, in which the drug is swallowed and enters the systemic circulation primarily through the membranes of the small intestine. Although this type of drug administration is commonly termed oral, peroral is a better term because oral administration more accurately describes drug absorption from the mouth itself. The mouth is lined with a mucous membrane and among the least known of its functions is its capability of serving as a site for the absorption of drugs.[1] In general, drugs penetrate the mucous membrane by simple diffusion and are carried in the blood, which richly supplies the salivary glands and their ducts, into the systemic circulation via the jugular vein. Active transport, pinocytosis, and passage through aqueous pores usually play only insignicant roles in moving drugs across the oral mucosa.[2] The administration of drugs by the buccal route has several main advantages over peroral administration, including the following: 1. The drug is not subjected to the destructive acidic environment of the stomach. 2. Therapeutic serum concentrations of the drug can be achieved more rapidly. 3. The drug enters the general circulation without rst passing through the liver. This last phenomenon is important for drugs that are highly metabolized during their rst passage through the liver. This metabolism (governed by the hepatic extraction ratio) can lead to a dramatic reduction in the amount of drug available systemically from a given peroral dose but is avoided by buccal absorption. Two sites within the buccal cavity have been used for drug administration. Using the sublingual route, as for glyceryl trinitrate (GTN), the medicament is placed under the tongue, usually in the form of a
rapidly dissolving tablet. The second anatomic site for drug administration is between the cheek and gingiva. Although this second application site is itself known as buccal absorption, the absorption from all areas within the buccal or oral cavity are considered in this article. Of the range of pharmaceutic preparations available for administration into the oral cavity, the most popular form is that of a rapidly dissolving tablet that releases its drug contents for absorption across the oral mucosa. Alternatively, a tablet or capsule can be chewed to release its contents. This latter method is less successful because mastication tends to produce a large volume of saliva that increases the probability of premature swallowing. The same problem occurs in the administration of drug in the form of a chewing gum. The aim of the present article is to review the published literature on the absorption of drugs through the oral mucosa. Special attention is given to the prevention of presystemic metabolism via drug administration by the buccal and sublingual routes. Consideration is also given to the types of pharmaceutical preparations that are commercially available for drug administration into the mouth. Before progressing to drug absorption, however, the structure and blood supply of the oral mucosa are discussed because of the important role they play in the transfer of drugs from the mouth into the systemic circulation.
STRUCTURE AND SECRETIONS OF THE ORAL MUCOSA Epithelial Lining The major function of the oral epithelium is to provide a protective surface layer between the oral environment and the deeper tissues. The oral epithelium has a squamous epithelium of tightly packed cells that form distinct layers by a process of maturation from the deeper layers to the surface.[3] The pattern of maturation differs in different regions of the oral mucosa
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Encyclopedia of Pharmaceutical Technology DOI: 10.1081/E-EPT-100001050 Copyright # 2007 by Informa Healthcare USA, Inc. All rights reserved.
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due to the variation in the specic function of the tissues. The surface layer of the hard palate and tongue forms keratin to yield a tough, non-exible epithelial surface resistant to abrasion, but the epithelium of the cheek, oor of the mouth, and soft palate is nonkeratinized and facilitates distensibility. The major features of the keratinized and non-keratinized oral epithelium have been extensively investigated by Squier and Rooney.[4] Together with the presence or absence of keratin, the second main feature likely to inuence regional differences in drug absorption is the epithelial thickness. This varies in different regions of the mouth: the hard palate, buccal mucosa, lip mucosa, and oor of the mouth have been found to have thicknesses of 100120 mm, 500600 mm, 500600 mm, and 100200 mm, respectively.[5,6] Secretion of Saliva In addition to the protective function afforded by the oral mucosa, it also has the ability to maintain a moist surface, which enhances permeability of the membrane to drugs.[3] Although the mucous membrane lining in the mouth contains many minute glands called buccal glands, which pour their secretions into the mouth, the chief secretion is supplied by three pairs of glands, namely, the parotid (under and in front of the ear), the submaxillary (below the jaw), and the sublingual (under the tongue) glands. Blood is richly supplied to the salivary glands and their ducts by branches of the external carotid artery and afterwards, travelling through the many branch arteries and capillaries, returns to the systemic circulation via the jugular veins.[1] The presence of saliva in the mouth is important to drug absorption for two main reasons: 1. Drug permeation across moist (mucous) membranes occurs much more readily than across nonmucous membranes. 2. Drugs are commonly administered to the mouth in the clinical setting in a solid form. The drug must, therefore, rst dissolve in saliva before it can be absorbed across the oral mucosa; that is, the drug cannot be absorbed directly from a tablet.
This latter publication also includes denitive documentation of the blood supply and drainage from the mouth. The blood supply to the mouth is delivered principally via the external carotid artery. The maxillary artery is the major branch, and the two minor branches are the lingual and facial arteries. The lingual artery and its branch, the sublingual artery, supply the tongue, the oor of the mouth, and the gingiva, and the facial artery supplies blood to the lips and soft palate. The maxillary artery supplies the main cheek, hard palate, and the maxillary and mandibular gingiva.[7,9] The internal jugular vein eventually receives almost all of the blood derived from the mouth and pharynx.[8] Drugs diffusing across the membranes have easy access to the systemic circulation via the internal jugular vein.
FACTORS INFLUENCING DRUG ABSORPTION FROM THE ORAL CAVITY Because the oral mucosa is a highly vascular tissue, the two main factors that inuence drug absorption from the mouth are the permeability of the oral mucosa to the drug and the physicochemical characteristics of the drug that is presented at the site of absorption.
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BuccalMono
Permeability of the Oral Mucosa to Drugs The lipid membranes of the oral mucosa are resistant to the passage of large macromolecules; however, small un-ionized molecules tend to cross the membrane with relative ease. This passage is in either direction, and indeed passage of drugs from the circulation into the mouth can be used in therapeutic drug monitoring by measuring drug concentrations in saliva. The permeability of the oral mucosa has been comprehensively reviewed by Siegel.[10] Mechanisms involved in drug absorption across the oral mucosa The mechanisms by which drugs cross biologic lipid membranes are passive diffusion, facilitated diffusion, active transport, and pinocytosis. Small, water-soluble molecules may pass through small, water-lled pores. The main mechanism involved in drug transfer across the oral mucosa, common with all regions of the gastrointestinal tract, is passive diffusion, although facilitated diffusion has also been shown to take place, primarily with nutrients. Passive diffusion involves the movement of a solute from a region of high concentration in the mouth to a region of low concentration within the buccal tissues. Further diffusion then takes
VASCULAR SYSTEM OF THE ORAL MUCOSA The vascular system and blood supply to the oral mucosa have been clearly described by Stablein and Meyer.[7] Netters excellent drawings of the blood supply to the mouth and pharynx, venous drainage of the mouth and pharynx, and lymphatic drainage of the mouth and pharynx have been published by Ciba.[8]
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place into the venous capillary system, with the drug eventually reaching the systemic circulation via the jugular vein. The physicochemical characteristics of a drug are very important for this diffusion process. Although passive diffusion is undoubtedly the major transport mechanism for drugs, the absorption of nutrients from the mouth has been shown to involve carrier systems (facilitated diffusion), which lead to a more rapid absorption than the concentration gradient would promote. Such a carrier system, unlike passive diffusion, exhibits stereospecicity, and indeed the absorption of D-glucose and L-arabinose across the buccal mucosa has been shown to be stereospecic.[11] The same authors also showed that the absorption of D-glucose, galactose, and 3-0-methyl-D-glucose was at least partially dependent on the presence of sodium ions in the luminal uids. Furthermore, the transport of D-glucose was inhibited by galactose and 3-0methyl- D-glucose, suggesting at least one common carrier system. Similarly, Kurosaki et al.[12] demonstrated that the absorption of cefadroxil (a cephalosporin antibiotic) from the human oral cavity occurs through a carrier-mediated mechanism; this absorption was inhibited by the presence of cephalexin, which shares a common carrier-mediated process with cefadroxil in the small intestine of rat.
Regional differences in mucosal permeability The epithelial lining of the mouth differs in both composition (keratinized and non-keratinized) and thickness in different regions of the mouth. Therefore, drug absorption may vary from different oral sites. This site-dependent absorption has been shown to take place by Pimlott and Addy,[15] who measured the absorption of isosorbide dinitrate into the systemic circulation after applying tablets to the buccal, palatal, or sublingual mucosa in six healthy volunteer subjects. Serum levels of drug were detected from the buccal and sublingual sites after 1 min. The drug concentration progressively increased, peaking at 5 min, and then decreased during the 30 min sampling period. At most of the time periods, serum concentrations were higher from sublingual sites than from buccal sites (Fig. 2). The drug was not detected in the serum of any subject after application to the palatal mucosa. These authors concluded that the keratinized layer of the oral mucosa may be an important barrier to drug absorption because the palatal epithelium is keratinized, but the buccal and sublingual mucosa are not.[16] Absorption across the sublingual epithelium is likely to be greater than across the buccal epithelium because the former is thinner and is immersed in a larger volume of saliva. Rapid absorption from the sublingual mucosa was also demonstrated through work by Al-Furaih et al.,[17] who reported that sublingual administration
Membrane storage during buccal absorption of drugs The absorption of a drug from the mouth is not synonymous with drug entry into the systemic circulation. Instead, the drug appears to be stored in the buccal membranes, sometimes known as the membrane reservoir effect.[13] Due to this phenomenon, buccal partitioning has been suggested as a more accurate term to describe the diffusion of drugs across the oral mucosa.[14] Although several authors have devised schematic representations of the kinetics of oral drug absorption (Fig. 1)[1,14] the mucosal constituents responsible for drug binding have not been identied.
Drug in lymphatic circulation
3.2 Buccal 2.8 2.4 Sublingual
Plasma ISDN ng/ml
2 1.6 1.2 0.8 0.4 0 0
Solid drug powder or tablet
Dissolved drug in buccal fluids
Dissolved drug in buccal membrane
Drug removed from oral cavity by swallowing
Drug in blood circulation
5 Tablet removed
10
15
20
25
30
Time (mins)
* Pathway to account for back-partitioning into buccal fluids of drug absorbed by membrane.
Fig. 1 Schematic representation of the absorption kinetics of buccally presented drugs. (From Ref.[10].)
Fig. 2 Mean plasma isosorbide dinitrate concentrations after application of isosorbide dinitrate (5 mg) to the buccal and sublingual mucosa in six healthy male volunteer subjects. (Redrawn from Ref.[15].)
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of captopril led to a more rapid attainment of plasma captopril concentrations and had a more rapid pharmacological effect (i.e., lower systolic blood pressure) compared to peroral administration of the drug.
Percentage of dose absorbed
100 90 80 70 60 50 40 30 20 10 0 0 1 2 3
Chloroquine Phenobarbitone
Physicochemical Characteristics of the Drug Various experimental techniques have demonstrated that cell membranes have a large lipid component,[18] and most drugs cross such membranes by simple passive diffusion. In order to cross these lipid membranes, a drug should be in the lipid-soluble or un-ionized form and also be in solution. The various physicochemical characteristics of the drug are, therefore, of paramount importance as far as drug penetration across the oral mucosa is concerned. Molecular weight In general, molecules penetrate the oral mucosa more rapidly than ions, and smaller molecules penetrate more rapidly than larger molecules. However, this rule is not absolute because dextrans with a molecular weight of up to 70,000 cross keratinized rabbit oral mucosa,[19] but horseradish peroxidase (molecular weight 40,000) does not.[20] High-molecular-weight mucopolysaccarides such as heparin are not well absorbed,[21] although inclusion of penentration enhancers in some insulin formulations have improved bioavailability.[22] Degree of ionization The average pH of saliva is 6.4. Because the un-ionized form of a drug is the lipid-soluble-diffusible form, the pKa of the drug plays an important role in its absorption across the lipid membranes of the oral mucosa. The degree of ionization of a drug at a specied pH can be calculated using the HendersonHasselbalch equation as follows: For an acid: pH pKa log10 For a base: pH pKa log The importance of pH on drug absorption from the mouth has been extensively studied using the buccal absorption model, in which loss of drug from buffered drug solutions placed in the mouth is monitored.[23] The inuence of pH on the absorption of the weak base chloroquine and of the weak acid phenobarbitone is shown in Fig. 3.[24] un-ionized species ionized species
10
pH
Fig. 3 The inuence of pH on the absorption of the weak acid phenobarbitone and the weak base chloroquine from the buccal cavity in three healthy volunteer subjects. (Redrawn from Ref.[24].)
However, pH does not always inuence the rate or extent of absorption. For example, McElnay et al.[25] found that captopril pharmacodynamic parameters (blood pressure, heart rate, and plasma renin activity) did not differ signicantly between buffered and unbuffered sublingual administration, suggesting that manipulation of pH had little effect. It was, therefore, proposed that a mechanism other than passive diffusion was involved in the buccal absorption of this drug. Although many studies illustrate the importance of ionization on drug absorption, the pH of saliva is relatively constant, and in the absence of a buffer, the pKa of the drug plays the deciding role as to the state of drug ionization. Also, due to the relatively large surface area available for absorption and to the maintenance of an equilibrium between ionized and un-ionized drug, only a small percentage of drug has to be present in the un-ionized form before signicant absorption can take place. Lipid solubility Although the undissociated (un-ionized) form of a drug has the higher lipid solubility, the un-ionized moieties themselves have differing lipid solubilities. A common way of assessing the lipid solubility of a drug is to measure its oilwater partition coefcient. As with pH, buccal absorption has been shown to be positively correlated with a drugs oilwater partition coefcient.
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Beckett and Moffat,[26] for example, found a correlation of partition coefcients in n-heptane/aqueous systems with buccal absorption data for a series of amines and acids when the degree of ionization was held constant. In conclusion, to penetrate the oral mucosa to a signicant degree, a drug should have a relatively low molecular weight and exhibit biphasic solubility patterns, that is, be soluble in both the aqueous salivary uid and the lipid membrane barrier to penetration. A signicant amount of the drug should be un-ionized at salivary pH, and the drug should also not bind strongly to the oral mucosa. BUCCAL ADMINISTRATION AS A METHOD OF PREVENTING PRESYSTEMIC METABOLISM The systemic availability of a drug is a measure of the fraction of the administered amount of drug that is absorbed into the general circulation in an unchanged form from its site of administration. Disregarding pharmaceutical reasons (e.g., poor tablet disintegration) and inappropriate physicochemical properties of the drug, the two main reasons for poor bioavailability after peroral administration are drug destruction by stomach acid and drug modication by metabolic enzyme systems prior to its entry into the systemic circulation. The principal organs involved in presystemic elimination are the gut wall, the liver, and the lung.[27] Drug metabolism of this type is known as rst-pass metabolism. A number of drugs have high afnities for the enzyme systems in these organs and are, therefore, highly extracted during their ow through the organs. These drugs, which are said to have a high extraction ratio (Fig. 4), include propranolol, terbutaline, levodopa, imipramine, aspirin, morphine, pentazocine, nitroglycerin, lignocaine, hydralazine, verapamil, and methyldopa. The main metabolizing organ in the body is the liver. Because blood draining from the gut via the portal vein must pass through the liver prior to entry into the general circulation, the total drug absorbed from the gut must pass through the liver before it can reach its site
CA CV
DRUGS AND PHARMACEUTICAL FORMULATIONS FOR ADMINISTRATION BY THE BUCCAL AND SUBLINGUAL ROUTES Although the data produced using the buccal partitioning model of drug absorption[23] have shown that numerous drugs are absorbed efciently from the oral cavity, few drugs have been assessed clinically after administration by this route, and not all drugs that have given encouraging clinical data have specic formulations available for intraoral administration. Drugs within the cardiovascular and strong analgesic pharmacologic classes have received the most attention. Cardiovascular Drugs Glyceryl trinitrate (GTN) This vasodilator has been used for over 100 years in the treatment of angina pectoris, and today, many
ORGAN
CA CV extraction ratio = CA
Fig. 4 Diagrammatic representation of the extraction ratio of a drug. The extraction ratio is a measure of the tendency of a drug to be removed from the blood during its passage through an organ such as the liver. In the diagram, CA is the arterial drug concentration and CV is the venous drug concentration.
Drug Delivery
of action. Once the drug has entered the systemic circulation, it is distributed to other areas of the body (depending on its volume distribution); although the extraction ratio remains constant, the proportion of the total drug in the body that is metabolized on subsequent passes through the liver is reduced due to a lowered drug concentration in the plasma after distribution has taken place. The liver receives only 20% of the cardiac output (as compared with 100% from the portal vein), which also protects the drug that has already been absorbed from the metabolic systems of this organ. Presystemic elimination can, therefore, be avoided by choosing a site of administration from which the drug enters the systemic circulation directly, without rst passing through the liver, lung, or gut wall. Because blood draining from the oral cavity enters the general circulation via the internal jugular vein, oral administration by the buccal or sublingual routes provides a useful strategy for improving bioavailability of drugs that are susceptible to extensive rst-pass metabolism. A high rst-pass effect does not, however, mean that drugs with a high extraction ratio cannot be given perorally. If a sufcient dose of the drug is given, an adequate amount of drug (to produce the required therapeutic effect) often remains intact during its rst passage through the liver. Also, a high peroral dose of drug or, indeed, serum levels of the drug from previous doses may saturate the high-afnity metabolizing systems in the liver and, thereby, decrease the rst-pass effect and increase bioavailability. With some drugs, moreover, the metabolites themselves may have good pharmacologic activity.
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clinicians consider it the most effective drug despite exhaustive efforts to nd alternatives. It is also used in the treatment of congestive heart failure. This drug is rapidly absorbed from the mouth, with much of the drug bypassing the liver. The liver has a high metabolic capacity for organic nitrates by virtue of the enzyme glutathione reductase.[28] Sublingual administration of GTN is the most appropriate action to alleviate the pain of an acute angina attack because of its rapid action, its long-established efcacy, and its low cost.[29] The traditional pharmaceutical formulation of the drug is a rapidly dissolving tablet for administration under the tongue. This approach, however, has two main disadvantages: 1. The time taken for the tablet to disintegrate and dissolve may vary from person to person. A delayed and varied onset of action may result. 2. The tablets of GTN lose signicant potency after only 8 weeks of the initial opening of the manufacturers bottle and should be discarded after that period because exposure to moisture and to the atmosphere accelerates nitrate breakdown. Heat also accelerates drug deterioration. In an attempt to overcome the previously noted problems with the sublingual tablet formulations, GTN is now widely available in metered-dose aerosol preparations. The sprays usually contain 0.4 mg GTN per unit dose. The manufacturers suggest that 1 or 2 metered doses be sprayed on the oral mucosa (preferably under the tongue) and then the mouth should be closed. A slightly different approach has been taken by Pharmax, the manufacturer of Suscard Buccal tablets. Instead of the traditional 300-, 500-, and 600-mg sublingual tablets, the Pharmax tablets contain 1, 2, 3, or 5 mg of GTN and are placed between the upper lip and the gum on either side of the front teeth. During the dissolution phase, the tablet softens and adheres to the gum, after which dissolution continues in a uniform and gradual manner. Because this is a prolongedrelease dosage form, the patient should not increase the tablets dissolution rate by moving it around the mouth. The tablet should be replaced if accidentally swallowed, and the placement of successive tablets should be alternated on either side of the mouth. As well as an effective prophylactic in angina, this formulation has been shown to be effective in congestive heart failure.[30] Isosorbide dinitrate This nitrate is also active sublingually and is a more chemically stable drug for those who require nitrates only infrequently. It is a longer-acting drug than GTN. The activity of isosorbide dinitrate may depend on the
production of active metabolites, the most important of which is isosorbide 5-mononitriate. Isosorbide mononitrate is also available for angina prophylaxis, though the advantages over isosorbide dinitrate have not yet been rmly established.[31] The general consensus is that the activity of the dinitrate is also longer than that of GTN Kattus et al.,[32] for example, found that sublingual isosorbide dinitrate offered protection against angina for 2.53 h compared to 1 h relief with GTN The nding of equal bioavailability of chewable (buccal absorption) and slow-release capsules (intestinal absorption) infers that buccal or sublingual absorption does not circumvent the rst pass effect, that presystemic metabolism occurs in the buccal mucosa, that buccal absorption is not as effective as believed or that isosorbide dinitrate is swallowed and not absorbed by the buccal mucosa. The identical pattern of metabolites after buccal and intestinal administration favours the theory that buccal absorption is slow and that isosorbide dinitrate is swallowed with the saliva in which it is dissolved.[33] Current knowledge concerning the buccal absorption route supports this theory. The main advantage of sublingual and buccal dosing may be the rapid disintegration and dissolution of the tablet in saliva. Present knowledge suggests using the drug buccally for the treatment of acute attacks of angina and using a sustained-release formulation for prophylactic purposes. Iga and Ogawa[34] demonstrated that a sustained release buccal formulation of both GTN and isosorbide dinitrate increased the bioavailability of both drugs when administered to dogs, compared to oral administration. A number of isosorbide dinitrate preparations are available for administration by the buccal or sublingual routes, the usual strengths being 5 or 10 mg. Although chewable preparations are available, the more traditional quick-disintegrating tablets predominate. Because mastication tends to increase saliva production, in order to prevent premature swallowing of the drug, the traditional tablet type may also be preferable. Sublingual rather than buccal administration may also be preferable because higher plasma concentrations have been found in healthy volunteers when the former route was used (Fig. 2).[15] Nifedipine In the past, the difculties presented in the administration of drugs in the treatment of hypertensive emergencies were largely overcome with the use of nifedipine administered sublingually.[35] The onset of action was rapid, and the drug was also used sublingually for the treatment of acute attacks of angina pectoris. Presently, two types of formulation of nifedipine are available, both intended primarily for peroral administration. The sustained-release formulation is
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Captopril conc. (ng/ml)
150 100 50 0 0 30 60 90 120 Time (min) 150 180
105 100 95 90
Captopril have indicated the usefulness of Two studies sublingual captopril in the treatment of severe hypertension. The hypertensive patients thus treated showed a marked decrease in systolic and diastolic blood pressure, with the onset of action being 25 min and the peak effect at 10 min.[37] Perorally administered captopril takes 12 h to achieve a maximal therapeutic effect[39] and, therefore, is unsuitable for the treatment of hypertensive crisis. Al-Furaih et al.[17] reported that sublingual administration of captopril (followed by plasma monitoring of drug levels) led to a more rapid attainment of plasma captopril concentrations and had a more rapid pharmacological effect (i.e., lower systolic blood pressure) compared to peroral administration of the drug as shown in Fig. 5. Iscan et al.[40] compared a number of parameters of a specially formulated buccal bioadhesive captopril tablet with that of a conventional tablet. The buccal formulation provided controlled release of captopril with a smooth plasma level prole and a long duration of action; however, its bioavailability was 40% via the buccal route as compared to 65% following an oral dose. This was attributed to the intestinal mucosa being more permeable than the buccal mucosa, and it was concluded that further work was required to improve its bioavailability. Analgesics Buprenorphine In common with other phenolic opiate analgesics, buprenorphine shows low peroral potency, suggesting a high rst-pass metabolism effect; indeed, work in rats has shown this to be the case.[27] Intravenous studies have estimated that the extraction ratio of buprenorphine is 85% and that peroral systemic availability is consequently expected to be 15% or less.[41] Although absorption from the mouth is slow and, therefore, not as useful as parenteral administration in the treatment of acute pain, it offers a major bioavailability advantage over the peroral route for this drug.[42] If required, the patient can be given a parenteral dose of buprenorphine to achieve rapid pain relief and
[37,38]
B 300 Captopril conc. 250 200 150 100 50 0 0 30 60 90 120 Time (min) 150 180 Systolic BP 120 115 110 105 100 95 90
Captopril conc. (ng/ml)
Systolic BP
Systolic BP
solely used perorally; however, the rapid-release capsule, which contains nifedipine in solution form, was formerly administered to the buccal cavity. However, the manufacturers now state in their literature that nifedipine should not be used for the treatment of acute attacks of angina as it has been associated with large variations in blood pressure and reex tachycardia.[36]
A 300 Captopril conc. 250 200 Systolic BP 115 110 120
Fig. 5 Correlation over time of systolic blood pressure (c) with plasma unchanged captopril concentration ( ) after sublingual (A) and peroral (B) administration of 25 mg of captopril. (From Ref.[17].)
thereafter be maintained on sublingual drug. The drug is available as a sublingual tablet containing 200 or 400 mg of buprenorphine hydrocholoride for the treatment of moderate to severe pain. Morphine Although not routinely given by the buccal or sublingual routes, several research studies have shown that absorption of morphine from the mouth gives rise to effective analgesia and that these routes may provide suitable alternatives to parenteral administration.[43] Clinical studies have suggested that the bioavailability of morphine is 4050% greater after buccal than intramuscular administration; as plasma morphine
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concentrations decline more slowly after buccal administration, buccal morphine may be associated with enhanced analgesia.[44] Anlar et al.[45] administered buccoadhesive morphine sulphate tablets to six healthy volunteers, resulting in up to 30% of active drug being absorbed; this is in contrast to absolute bioavailability of a morphine sulphate solution of 23%.[46] Christrup et al.[47] found that buccal delivery of morphine sulphate could be enhanced further by using ester prodrugs with higher lipophilicity than the parent drug itself. Ketobemidone Ketobemidone is a narcotic analgesic that has been used clinically in Scandinavia and other European countries. The mean bioavailability in humans has been reported to be approximately 35% following oral administration, but this can be substantially improved when administered by the sublingual or buccal route.[48] To date, in vitro work has focussed on the use of the ketobemidone prodrugs (largely esters), and published results suggest that, as with morphine sulfate, buccal mucosa permeation is greatly improved.[49,50] Flurbiprofen Studies have suggested that this nonsteroidal antiinammatory drug may be useful in the treatment of peridontal disease. Manipulation of pH was shown to inuence the amount of drug absorbed; an increase in pH resulted in a reduction of drug absorbed, thus resulting in a poor local effect.[51] Gonzalez-Younes et al.[52] reported that the drug was tightly bound to the membrane of the tissues in the mouth. Peptide Drugs The oral mucosa has been cited as a route of administration for peptide drugs as a way of avoiding parenteral delivery, although permeability is low, which reduces its value as a viable option.[22] However, modications to drug formulation may offer greater success. The addition of penetration enhancers to dosage forms appears to improve bioavailability to the greatest extent, by improving the permeability of the epithelium and/or affecting the nature of the drug.[53] To date, much of the experimental work has been conducted in animals. Insulin To achieve hypoglycemia with insulin, the traditional route of administration has been via subcutaneous
injection. Peroral preparations are not feasible due to the degradation of insulin by gastric acid and enzymes. However, studies carried out in animals utilising buccal formulations have been more successful. Ritschel et al.[54] administered insulin to beagle dogs using solutions of different pHs. Bioavailability (22.3%) was maximized at pH 7.5, and the addition of penetration enhancers (bile salts) did not increase this further. Experimental work in rabbits found that in the absence of penetration enhancers, insulin solutions over a range of pHs did not show any signicant hypoglycaemic response, indicating that insulin was not absorbed to a signicant degree through the buccal mucosa.[55] Buserelin This luteinizing hormone-releasing hormone has been used in the treatment of endometriosis and hormonedependent tumors. Modes of administration have included injections, nasal sprays and subcutaneous implantations. One study, conducted in pigs, demonstrated the value of glycodeoxycholate (a penetration enhancer) in improving the bioavailability of buserelin by up to ve-fold after buccal delivery.[56] a-Interferon a-Interferon has broad antiviral and antiproliferative activity and has been used in HIV and certain forms of hepatitis. As with other peptide drugs, ways have been sought to improve the buccal delivery of a-interferon to avoid gastro-intestinal degradation and rst-pass metabolism. Using a range of penetration enhancers, Stewart, Bayley, and Howes[57] noted improved bioavailability, particularly with sodium taurocholate, in rats. As with all of the studies reviewed under the category of peptide drugs, extrapolation to the human situation should be done with caution. Miscellaneous Drugs Nicotine The absorption of nicotine from chewing tobacco has been widely used for many years. Buccal absorption of nicotine is also the route of absorption for pipe and cigar smokers if the smoke is not inhaled. Nicotine replacement therapy has been used in smoking cessation strategies. Nicotine in the form of chewing gum carries no cancer risk and is a useful part of a smoking cessation strategy.[58] A recent innovation has been the development of a sublingual tablet (available in 2 mg); a clinical trial has shown that this formulation is a safe form of administration,[59] and patients may use one tablet every 12 h.
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Zinc Zinc gluconate in the form of a lozenge has been marketed for the treatment of the common cold; there has been no denitive conclusion as to whether it is effective in treating cold symptoms, although differences in study methodology may partially explain the conicting results that have been reported.[60,61] Midazolam Midazolam administered bucally in solution has been shown to be rapidly absorbed and produces changes in EEG readings.[62] The authors suggested that this may offer an alternative to rectal administration of diazepam in the emergency treatment of seizures.
existing drugs. The main advantages of the buccal route of administration over the traditional peroral route are that drug degradation in the stomach is avoided, rst-pass metabolism is avoided, and therapeutic blood levels of drug can be achieved rapidly. Clearly these advantages are presently clinically relevant for only a limited number of drugs. However, with the recent developments of formulation types, such as mucoadhesive preparations and the use of peptides as drugs, this number may increase in the future. The main disadvantage of the buccal route is that the drug may have an unwanted local effect in the mouth, such as bad taste, or may be absorbed slowly and, therefore, be swallowed prior to sufcient absorption taking place. The buccal route, like the rectal and intranasal routes, has been largely neglected by clinicians and manufacturing companies in the past and clearly merits further intensive research.
CONCLUSIONS The buccal cavity provides a highly vascular mucous membrane site for the administration of drugs. The epithelial lining of the oral cavity differs both in type (keratinized and nonkeratinized) and in thickness in different areas, and the differences give rise to regional variations in permeability to drugs. Although some macromolecules have been shown to cross the absorption barrier (lipid membrane), the absorption of smaller drug molecules occurs more reproducibly and rapidly. The main absorption mechanism is passive diffusion of the un-ionized (lipid-soluble) form of the drug. Facilitated diffusion has also been shown to take place with nutrients. Drugs are often stored or bound to the buccal mucosa prior to entry into the bloodstream. The blood drainage from the mouth enters the general circulation directly without rst passing through the liver. This feature enhances the bioavailability of certain drugs as compared with peroral administration because rst-pass metabolism is avoided. To ensure adequate absorption from the mouth, a drug administered as a solid dosage form must exhibit biphasic solubility, that is, be soluble in saliva and in the lipid membranes of the buccal cavity. The major drugs currently available for buccal administration fall within the vasodilator and strong analgesic pharmacologic classes. Although the main type of formulation available for buccal absorption is rapidly disintegrating tablets, new approaches include mucoadhesive tablets and spray formulations. Much of the current knowledge on the mechanism and characteristics of drug absorption from the buccal cavity has been gained from volunteer studies in which buffered drug solutions are placed in the mouth (buccal absorption model) rather than from clinical pharmacologic studies in patients. This former method provides useful information on the bioavailability of new and
REFERENCES
1. Harris, D.; Robinson, J.R. Drug delivery via the mucous membranes of the oral cavity. J. Pharm. Sci. 1992, 81, 110. 2. Beckett, A.H.; Hossie, R.D. Buccal absorption of drugs. In Handbuch der Experimentellen Pharmakologie; Gillette, T.R., Ackermann, H.S., Eds.; Springer-Verlag: Berlin, 1971; 28, 160. 3. Feldman, R.S.; Szabo, G. Comparative microanatomy of skin and oral mucosa. In Textbook of Oral Biology, 1st Ed.; Shaw, J.H., Sweeney, E.A., Cappuccino, C.C., Meller, S.M., Eds.; W.B. Saunders: Philadelphia, 1978; 166167. 4. Squier, C.A.; Rooney, L. The permeability of keratinized and non-keratinized oral epithelium to lanthanum in vivo. J. Ultrastruct. Res. 1976, 54, 286295. 5. Schroeder, H.E. Classication of stratied epithelia. In Differentiation of Human Oral Stratied Epithelia; Karger: Basel, 1981; 33. 6. Chen, S.Y.; Squier, C.A. The ultrastructure of the oral epithelium. In The Structure and Function of Oral Mucosa; Meyer, J., Squier, C.A., Gerson, S.J., Eds.; Pergamon Press: Oxford, 1984; 730. 7. Stablein, M.J.; Meyer, J. The vascular system and blood supply. In The Structure and Function of Oral Mucosa; Meyer, J., Squier, C.A., Gerson, S.J., Eds.; Pergamon Press: Oxford, 1984; 237256. 8. Netter, F.H. Upper digestive tract. In The Digestive System, Part 1: The Ciba Collection of Medical Illustrations; Oppenheimer, E., Ed.; Ciba: New York, 1959; 3, 2428. 9. Boyer, C.C.; Neptune, C.M. Patterns of blood supply to teeth and adjacent tissue. J. Dent. Res. 1962, 41, 158171. 10. Siegal, I.A. Permeability of the oral mucosa. In The Structure and Function of Oral Mucosa; Meyer, J., Squier, C.A., Gerson, S.J., Eds.; Pergamon Press: Oxford, 1984; 95108. 11. Manning, A.S.; Evered, D.F. The absorption of sugars from the human buccal cavity. Clin. Sci. Mol. Med. 1976, 51, 127132. 12. Kurosaki, Y.; Nishimura, H.; Terao, K.; Nakayama, T.; Kimura, T. Existence of a specialised absorption mechanism for cefadroxil, an aminocaphalosporin antibiotic, in the human oral cavity. Int. J. Pharm. 1992, 82, 165169. 13. Ho, H.F.H. Biophysical kinetic modeling of buccal absorption. Adv. Drug Del. Rev. 1993, 12, 6197.
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14. Henry, J.A.; Ohashi, K.; Wadsworth, J.; Turner, P. Drug recovery following buccal absorption of propranolol. Br. J. Clin. Pharmacol. 1980, 10, 6165. 15. Pimlott, S.J.; Addy, M. A study into the mucosal absorption of isosorbide dinitrate at different intra-oral sites. Oral Surg. Oral Med. Oral Pathol. 1985, 59, 145148. 16. Squier, C.A.; Johnson, N.W.; Hopps, R.M. The human oral mucosa: innervation of the oral mucosa. In Human Oral Mucosa; Blackwell Scientic Publications: Oxford, 1975; 63. 17. Al-Furaih, T.A.; McElnay, J.C.; Elborn, J.S.; Rusk, R.; Scott, M.G.; McMahon, J.; Nicholls, D.P. Sublingual captoprila pharmacokinetic and pharmacodynamic evaluation. Eur. J. Clin. Pharmacol. 1991, 40, 393398. 18. Gurr, M.I.; Harwood, J.L. Lipids in cellular structure: membrane structure. In Lipid Biochemistry; Chapman and Hall: London, 1991; 265281. 19. Squier, C.A.; Johnston, N.W. Permeability of oral mucosa. Br. Med. Bull. 1975, 31, 169175. 20. Squier, C.A. The permeability of keratinized and nonkeratinized oral epithelium to horseradish peroxidase. J. Ultrastruct. Res. 1973, 43, 160177. 21. Fuller, H.L. Effect of sublingual heparin on lipemia clearing and on recurrence of myocardial infarction. Angiology 1960, 11, 200206. 22. Merkle, H.P.; Wolany, G. Buccal delivery for peptide drugs. J. Controlled Release 1992, 21, 155164. 23. Beckett, A.H.; Triggs, E.F. Buccal absorption of basic drugs and its application as an in vivo model of passive drug transfer through lipid membranes. J. Pharm. Pharmacol. 1967, 19, 31S41S. 24. McElnay, J.C.; Sidahmed, A.M.; DArcy, P.F. Experimental modeling of drug absorption and drug absorption interactions. Int. J. Pharm. 1986, 31, 107117. 25. McElnay, J.C.; Al-Furaih, T.A.; Hughes, C.M.; Scott, M.G.; Elborn, J.S.; Nicholls, D.P. The effect of pH on the buccal and sublingual absorption of captopril. Eur. J. Clin. Pharmacol. 1995, 48, 373379. 26. Beckett, A.H.; Moffat, A.C. Correlation of partition coefcients in n-heptane-aqueous systems with buccal absorption data for a series of amines and acids. J. Pharm. Pharmacol. 1969, 21, 144S150S. 27. Brewster, D.; Humphrey, M.J.; McLeavy, M.A. The systemic bioavailability of buprenorphine by various routes of administration. J. Pharm. Pharmacol. 1981, 33, 500506. 28. Needleman, P.; Hunter, F.E. The transformation of glyceryl trinitrate and other nitrates by glutathione-organic nitrate reductase. Mol. Pharmacol. 1965, 1, 7786. 29. Goldstein, R.E.; Rosing, D.R.; Redwood, D.R.; Beiser, F.D.; Epstein, S.E. Clinical and circulatory effects of isosorbide dinitrate comparison with nitroglycerin. Circulation 1971, 43, 629639. 30. Sanghera, S.S.; Goldberg, A.A.J.; Parson, D.F. Buccal nitroglycerin in elderly patients with congestive heart failure. Practitioner 1985, 229, 10541055. 31. British national formulary No. 40, british medical association and the pharmaceutical society of great britain. The Pharmaceutical Press: London, 2000. 32. Kattus, A.A.; Alvaro, A.B.; Zohman, L.R.; Coulson, A. Comparison of placebo, nitroglycerin, and isosorbide dinitrate for effectiveness of relief of angina and duration of action. Chest 1979, 75, 1721. 33. Galeazzi, R.L.; Platzer, R.; Reuteman, G. Plasma isosorbide dinitrate concentrations and effect after chewable and high-dose sustained-release formulations. Int. J. Clin. Pharmacol. Ther. 1983, 21, 393397. 34. Iga, K.; Ogawa, Y. Sustained-Release buccal dosage forms for nitroglycerin and isosorbide dinitrate: increased bioavailability and extended time of absorption when administered to dogs. J. Controlled Release 1997, 49, 105113. 35. Mathur, M.M.; Chaturvedi, M.K.; Rai, R.R.; Das Khatri, T. Role of nifedipine sublingually in accelerated hypertension. J. Assoc. Phys. India 1986, 34, 137138.
36. A., B.P.I. Compendium of Data Sheets and Summaries of Product Characteristics 19992000; Datapharm Publications: London, 1999. 37. Tschollar, W.; Belz, G.G. Sublingual captopril in hypertensive crisis. Lancet 1985, 2, 3435. 38. Hauger-Klevene, J.H. Comparison of sublingual captopril and nifedipine. Lancet 1986, 1, 219. 39. Ohman, K.P.; Kagedal, B.; Larsson, R.; Karlberg, B.E. Pharmacokinetics of captopril and its effects on blood pressure during acute and chronic administration and in relation to food intake. J. Cardiovasc. Pharmacol. 1985, 7 (Suppl. 1), 2024. 40. Iscan, Y.Y.; Capan, Y.; Senel, S.; Sahin, M.F.; Kes, S.; Duchene, D.; Hincal, A.A. Formulation and in vitro/ in vivo evaluation of buccal bioadhesive captopril tablets. STP Pharma. Sci. 1998, 8, 357363. 41. Bullingham, R.E.S.; McQuay, H.J.; Moore, R.A.; Bennett, M.R.D. Buprenorphine kinetics. Clin. Pharmacol. Ther. 1980, 28, 667672. 42. Cassidy, J.P.; Landzert, N.M.; Quadros, E. Controlled buccal delivery of buprenorphine. J. Controlled Release 1993, 25, 2129. 43. Whitman, H.H. Sublingual morphine: a novel route of narcotic administration. Am. J. Nursing 1984, 84, 939 44. Bell, M.D.D.; Murray, G.R.; Mishra, P.; Calvey, T.N.; Weldon, B.D.; Williams, N.E. Buccal morphinea new route for analgesia. Lancet 1985, 1, 7173. 45. Anlar, S.; Capan, Y.; Guven, O.; Gogus, A.; Dalkara, T.; Hincal, A.A. Formulation and in vitroin vivo evaluation of buccoadhesive morphine sulphate tablets. Pharm. Res. 1994, 11, 231236. 46. Hoskin, P.J.; Hanks, G.W.; Aheme, G.W.; Chapman, D.; Littleton, P.; Filshie, J. The bioavailability and pharmacokinetics of morphine after intravenous, oral and buccal administration in healthy volunteers. Br. J. Clin. Pharmacol. 1989, 27, 499505. 47. Christrup, L.L.; Christensen, C.B.; Friis, G.J.; Jorgensen, A. Improvement of buccal delivery of morphine using the prodrug approach. Int. J. Pharm. 1997, 154, 157165. 48. Hansen, L.B.; Christrup, L.L.; Bundgaard, H. Ketobemidone prodrugs for buccal delivery. Acta Pharma. Nord. 1991, 3, 7782. 49. Hansen, L.B.; Christrup, L.L.; Bundgaard, H. Enhanced delivery of ketobemidone through porcine buccal mucosa in vitro via more lipophilic ester prodrugs. Int. J. Pharm. 1992, 88, 237242. 50. Hansen, L.B.; Jorgensen, A.; Rasmussen, S.N.; Christrup, L.L.; Bundgaard, H. Buccal absorption of ketobemidone and various ester prodrugs in the rat. Int. J. Pharm. 1992, 88, 243250. 51. Barsuhn, C.L.; Olanoff, L.S.; Gleason, D.D.; Adkins, E.L.; Ho, N.F.H. Human buccal absorption of urbiprofen. Clin. Pharmacol. Ther. 1988, 44, 225231. 52. Gonzalez-Younes, I.; Wagner, J.G.; Gaines, D.A.; Ferry, J.J.; Hageman, J.M. Absorption of urbiprofen through human buccal mucosa. J. Pharm. Sci. 1991, 80, 820823. 53. Hoogstraate, A.J.; Bodde, H.E. Methods for assessing the buccal mucosa as a route of drug delivery. Adv. Drug Del. Rev. 1993, 12, 99125. 54. Ritschel, W.A.; Ritschel, G.B.; Forusz, H.; Kraeling, M. Buccal absorption of insulin in the dog. Res. Comm. Chem. Path. Pharmacol. 1989, 63, 5367. 55. Oh, C.K.; Ritschel, W.A. Biopharmaceutic aspects of buccal absorption of insulin. Meth. Find. Exp. Clin. Pharmacol. 1990, 12, 205212. 56. Hoogstraate, A.J.; Verhoef, J.C.; Pijpers, A.; van Leengoed, L.A.M.G.; Verheijden, J.H.M.; Junginger, H.E.; Bodde, H.E. In vivo buccal delivery of the peptide drug buserelin with glycodeoxycholate as an absorption enhancer in pigs. Pharm. Res. 1996, 13, 12331237. 57. Steward, A.; Bayley, D.L.; Howes, C. The effect of enhancers on the buccal absorption of hybrid (BDBB) a-interferon. Int. J. Pharm. 1994, 104, 145149.
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58. Henningeld, J.E. Nicotine medications for smoking cessation. N. Engl. J. Med. 1995, 333, 11961203. 59. Wallstrom, M.; Sand, L.; Nilsson, F.; Hirsch, J.M. The long-term effect of nicotine on the oral mucosa. Addiction 1999, 94, 417423. 60. Mossad, S.B.; Macknin, M.L.; Medendorp, S.V.; Mason, P. Zinc gluconate lozenges for treating the common colda randomized double-blind, placebo-controlled study. Ann. Intern. Med. 1996, 125, 8189. 61. Macknin, ML.; Piedmonte, M.; Calendine, C.; Janosky, J.; Wald, E. Zinc gluconate lozenges for treating the common cold in childrena randomized controlled trial. JAMA 1998, 279, 19621967. 62. Scott, R.C.; Besag, F.M.C.; Boyd, S.G.; Berry, D.; Neville, B.G.R. Buccal absorption of midazolam: pharmacokinetics and EEG pharmacodynamics. Epilepsia 1998, 39, 290294.
BIBLIOGRAPHY
Chidambaran, N.; Srivatsava, A.K. Buccal drug delivery systems. Drug Dev. Indust. Pharm. 1995, 21, 10091036. Gandhi, R.B.; Robinson, J.R. Oral cavity as a site for bioadhesive drug delivery. Adv. Drug Del. Rev. 1994, 13, 4374. Harris, D.; Robinson, J.R. Drug delivery via the mucous membranes of the oral cavity. J. Pharm. Sci. 1992, 81, 110. Meyer, J.; Squier, C.A.; Gerson, S.J. The Structure and Function of the Oral Mucosa; Pergamon Press: Oxford, 1984. Rathbone, M.J.; Tucker, I.G. Mechanisms, barriers and pathways of oral mucosal drug permeation. Adv. Drug Del. Rev. 1993, 12, 4160. Rathbone, M.J.; Drummond, B.K.; Tucker, I.G. The oral cavity as a site for systemic drug delivery. Adv. Drug Del. Rev. 1994, 13, 122.
Drug Delivery
Drug Delivery: Controlled Release

Yie W. Chien
Research and Development, Kaohsiung Medical University, Kaohsiung, Taiwan
Senshang Lin
College of Pharmacy and Allied Health Professions, St. Johns University, Jamaica, New York, U.S.A.
INTRODUCTION Over the past decades, the treatment of illness has been accomplished by administering drugs to the human body via various pharmaceutical dosage forms, like tablets. These traditional pharmaceutical products are still commonly seen today in the prescription and over-the-counter drug marketplace. To achieve and maintain the drug concentration in the body within the therapeutic range required for a medication, it is often necessary to take this type of drug delivery system several times a day. This yields an undesirable seesaw drug level in the body (Fig. 1). A number of advancements have been made recently in the development of new techniques for drug delivery. These techniques are capable of regulating the rate of drug delivery, sustaining the duration of therapeutic action, and/or targeting the delivery of drug to a specic tissue.[16] These advancements have already led to the development of several novel drug delivery systems that could provide one or more of the following benets: 1. Controlled administration of a therapeutic dose at a desirable rate of delivery. 2. Maintenance of drug concentration within an optimal therapeutic range for prolonged duration of treatment. 3. Maximization of efcacy-dose relationship. 4. Reduction of adverse side effects. 5. Minimization of the needs for frequent dose intake. 6. Enhancement of patient compliance. Based on the technical sophistication of the controlled-release drug delivery systems (CrDDSs) that have been marketed so far, or that are under active development, the CrDDSs can be classied (Fig. 2) as follows: 1. Rate-preprogrammed drug delivery systems. 2. Activation-modulated drug delivery systems.
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3. Feedback-regulated drug delivery systems. 4. Site-targeting drug delivery systems. In this article, the scientic concepts and technical principles behind the development of this new generation of drug-delivery systems are outlined and discussed.
RATE-PREPROGRAMMED DRUG DELIVERY SYSTEMS In this group of CrDDSs, the release of drug molecules from the delivery systems has been preprogrammed at a specic rate prole. This is accomplished by system design, which controls the molecular diffusion of drug molecules in and/or across the barrier medium within or surrounding the delivery system. Ficks laws of diffusion are often followed. These CrDDSs can further be classied as follows: 1. Polymer membrane permeation-controlled drug delivery systems. 2. Polymer matrix diffusion-controlled drug delivery systems. 3. Polymer (membrane/matrix) hybrid-type drug delivery systems. 4. Microreservoir partition-controlled drug delivery systems. Polymer Membrane Permeation-Controlled Drug Delivery Systems In this type of CrDDS, a drug formulation is either totally or partially encapsulated in a drug reservoir compartment whose drug-releasing surface is covered by a rate-controlling polymeric membrane. The drug reservoir can be drug solid particles, a dispersion of drug solid particles, or a concentrated drug solution in a liquid- or solid-type dispersing medium. The polymeric membrane can be fabricated from a homogeneous
Drug Delivery
BuccalMono
1083
A
A4 Adverse side effects Toxic level A2 A1 A3 B Therapeutic range Minimum effective concentration No therapeutic effects
C Sphere Polymer coating Sheet Drug reservoir Pore Drug release Drug reservoir Nonporous membrane Diffusion layer Cp
Cp Pd Pm Cm Cb Sink Cs Dm Da Elution medium hd hm
Drug concentration
B Cylinder
Drug impermeable barrier
Porous membrane
Frequencies of dosing
Fig. 1 Drug concentration proles in the systemic circulation as a result of taking a series of multiple doses of a conventional drug-delivery system (A1, A2, . . . ) in comparison with the ideal drug concentration prole (B). (Adapted from Ref.[6].)
Km=r Ka=m Dd Dm Q CR t Km=r Dm hd Ka=m Dd hm
where Km/r and Ka/m are, respectively, the partitioncoefcients for the interfacial partitioning of drug molecules from the reservoir to the membrane and from the membrane to the aqueous diffusion layer;
A
Drug reservoir Rate-controlling surface
B
C
D
Drug
Drug
Drug Sitetargeting moiety
Drug
Energy sensor
Biochemical responsive/ Energy sensor
Biochemical responsive/ Energy sensor
Fig. 2 The four major classes of controlled-release drug delivery systems: (A) Rate-preprogrammed DDS; (B) Activation-modulated DDS; (C) Feedback-regulated DDS and (D) Site-trageting DDS.
Drug Delivery
or a heterogeneous non-porous polymeric material or a microporous or semipermeable membrane. The encapsulation of drug formulation inside the reservoir compartment can be accomplished by molding, capsulation, microencapsulation, or other techniques. Different shapes and sizes of drug delivery systems can be fabricated (Fig. 3). The release of drug from this type of CrDDSs should be at a constant rate (Q/t), which is dened by the following general equation:
Fig. 3 Release of drug from various shapes of polymer membrane permeation-controlled drug-delivery systems: (A) sphere-type, (B) cylinder-type, and (C) sheet-type. In (D), the drug concentration gradients across the rate-controlling polymeric membrane and hydrodynamic diffusion layer exist in series. Both the polymer membrane, which is either porous or non-porous, and the diffusion layer have a controlled thickness (hm and hd, respectively).
Dm, and Dd are, respectively, the diffusion coefcients in the rate-controlling membrane with a thickness of hm, and in the aqueous diffusion layer with a thickness of hd. For microporous membrane, the porosity, and tortuosity of the pores in the membrane should be included in the estimation of Dm and hm. CR is the drug concentration in the reservoir compartment. The release of drug molecules from this type of CrDDS is controlled at a preprogrammed rate by modulating the partition coefcient and the diffusivity of drug molecule and the rate-controlling membrane and the thickness of the membrane. Several CrDDSs
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5.7mm
of this type have been successfully marketed for therapeutical uses and some representatives are outlined later for illustration. Progestasert IUD In this controlled-release intrauterine device, the drug reservoir exists as a dispersion of progesterone crystals in silicone (medical grade) uid encapsulated in the vertical limb of a T-shaped device walled by a nonporous membrane of ethylenevinyl acetate copolymer (Fig. 4). It is engineered to release continuously a daily dose of 65 mg progesterone inside the uterine cavity to achieve contraception for one year.[6] The same technology has been utilized in the development of the Mirena system, a plastic T-shaped frame with a steroid reservoir containing 52 mg levonorgestrel, which is designed to release a daily dose of levonorgestrel at 20 mg/day for achieving effective contraception for ve years.[79] Ocusert system In this controlled-release ocular insert, the drug reservoir is a thin disc of pilocarpinealginate complex sandwiched between two transparent discs of microporous membrane fabricated from ethylenevinyl acetate copolymer (Fig. 5). The microporous membranes permit the tear uid to penetrate into the drug
13.4mm
305 74 Ethylene / vinyl acetate membrane Pilocarpine-core reservoir Titanium dioxide-white ring
60
Pilocarpine release rate (mcg/hr)
40
20
0 0 1 2 3 4 5 6 7 8 9
Time (days)
Fig. 5 Diagrammatic illustration of a unit of Ocusert system, showing various structural components, and the ocular release rate prole of pilocarpine from the Ocusert pilo-20 system. (From Ref.[11].)
reservoir compartment to dissolve pilocarpine from the complex. Pilocarpine molecules are then released at a constant rate of 20 or 40 mg/h for a 4- to 7-day management of glaucoma.[1,6,10,11] Transderm-Nitro system In this controlled-release transdermal therapeutic system, the drug reservoir, which is a dispersion of nitroglycerinlactose triturate in a silicone (medical grade) uid, is encapsulated in an ellipsoid-shaped thin patch. The drug reservoir is sandwiched between a drugimpermeable metallic plastic laminate, as the backing membrane, and a constant surface of drug-permeable, rate-controlling membrane of ethylenevinyl acetate copolymer (Fig. 6). This device is fabricated by an injection-molding process. A thin layer of silicone adhesive is further coated on the drug-permeable membrane in order that an intimate contact of the drug-releasing surface with the skin surface is achieved and maintained. It is engineered to have nitroglycerin delivered transdermally at a rate of 0.5 (mg/cm2)/day for a daily relief of angina.[2,3] The same technology has been utilized in the development of the following: 1) the Estraderm system, which administers a controlled dose of estradiol transdermally over 34 days for the relief of postmenopausal syndrome and osteoporosis;[1214] 2) the Duragesic system, which provides a transdermal-controlled administration of fentanyl, a potent narcotic analgesic, for 72-h relief of chronic pain;[14] and 3) the Androderm system, which provides a transdermal-controlled delivery of
Drug Delivery
g/day
BuccalMono
A Polyethylene
Ethylene vinylacetate copolymer 38 mg of progesterone microcrystals (and barium sulfate) suspended in silicone oil B In Vitro 100 80 60 40 20 0 0 100 200 300 400 100 80 60 40 20 0 0 In Vivo
95% Confidence Level
100
200 300 400
Days
Days
Fig. 4 Diagrammatic illustration of a unit of Progestasert IUD, showing various structural components (A) and the in vitro and in vivo delivery rate proles of progesterone for up to 400 days (B).
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Drug reservoir
Drug-impermeable metallic plastic laminate
Rate-controlling polymeric membrane Adhesive layer
0.25
Plasma nitroglycerin conc. (ng/ml SD)
0.20
by either 1) blending a dose of nely ground drug particles with a viscous liquid (or a semisolid) polymer, followed by a crosslinking of polymer chains or 2) mixing drug solids with a melted polymer at an elevated temperature. The resultant drug-polymer dispersion is then molded or extruded to form drugdelivery devices of various shapes and sizes designed for a specic application (Fig. 8). It can also be fabricated by dissolving the drug and the polymer in a common solvent, followed by solvent evaporation, at an elevated temperature and/or under a vacuum, in a mold. The release prole of drug from this matrix diffusion-controlled CrDDS is not constant, because the rate of drug release is time dependent as dened by: Q t1=2 2ACR DP 1=2 2
0.15 Night Period 0.10
0.05
0 0 5 10 15 20 25
Time (h)
Fig. 6 Cross-sectional view of a unit of Transderm-Nitro system, showing various structural components, and plasma concentration proles of nitroglycerin in 14 human volunteers, each receiving one unit of Transderm-Nitro system (20 cm2, with a delivery rate of 10 mg/day) for 24 h. (From Refs.[11,55].)
testosterone, through non-scrotal skin, for the 24 h replacement therapy of testosterone-decient patients.[14] Norplant subdermal implant The controlled-release subdermal implant is fabricated from a non-porous silicone (medical-grade) tubing, by sealing both ends with silicone (medical-grade) adhesive to encapsulate either levonorgestrel crystals alone (generation I) or a solid dispersion of levonorgestrel in silicone elastomer matrix (generation II). It is designed to attain a continuous release of levonorgestrel, at a daily dosage rate of 30 mg, to each subject (following the subcutaneous implantation of either 6 units of I or 2 units of II); (Fig. 7) for up to 7 years.[1518]
Nitro-Dur system This controlled-release transdermal therapeutic system is fabricated by rst heating an aqueous solution of water-soluble polymer, glycerol, and polyvinyl alcohol and then lowering the temperature of the mixture to form a polymer gel. Nitroglycerin/lactose triturate is dispersed in the gel, and the mixture is then solidied at room temperature to form a medicated polymer disc by a molding and slicing technique. After assembly onto a drug-impermeable metallic plastic laminate, a patch-type transdermal therapeutic system is produced with an adhesive rim surrounding the medicated disc (Fig. 9). It is designed for application onto an intact skin to provide a continuous transdermal infusion of nitroglycerin, at a daily dose of 0.5 mg/cm2, for the prevention of angina pectoris.[2,19] The drug reservoir can also be formulated by directly dispersing the drug in an adhesive polymer, such as poly(isobutylene) or poly(acrylate) adhesive, and then spreading the medicated adhesive by solvent casting or hot melt, onto a at sheet of drug-impermeable backing support to form a single- or multiple-layer drug reservoir. This type of transdermal CrDDS (TDD)
Polymer Matrix Diffusion-Controlled Drug Delivery Systems In this type of CrDDS, the drug reservoir is produced from the homogeneous dispersion of drug particles in either a lipophilic or a hydrophilic polymer matrix. The drug dispersion in the polymer matrix is accomplished
Drug Delivery
where A is the initial loading dose of drug dispersed in the polymer matrix; CR is the drug solubility in the polymer, which is also the drug reservoir concentration in the polymer matrix; and Dp is the diffusivity of the drug molecules in the polymer matrix. The release of drug molecules from this type of CrDDSs may be controlled at a preprogrammed rate by controlling the loading level and the polymer solubility of the drug and its diffusivity in the polymer matrix. Several CrDDSs of this type have been successfully marketed for therapeutical uses, and some representatives are outlined later for illustration.
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Milligrams 216 ~ ~ 90 70 50 30 10 1 2
total load of levonorgestrel daily dose 30 g
Milligrams 216 ~ ~ 90 70 50 30 10
Years of use
Concentration of Levonorgestrel in plasma
ORAL
1.00
Peak (mean)
0.75 0.50 0.25

Trough (mean)
NONPLANT SUBCERNAL INPLANTS Mean value and 95% confidence intervals
2.4 mm 34 mm
24 hr
Time of use (years)

Fig. 7 Diagrammatic illustration of the subcutaneous implantation of Norplant implants. The subcutaneous release prole of levonorgestrel in female volunteers for up to 6 years and the resultant plasma prole as compared to those obtained by oral administration. (Adapted from Refs.[1518].)
Drug Delivery
BuccalMono
is best illustrated by the development and marketing of an isosorbide dinitrate-releasing TDD system, named Frandol tape, by Toaeiyo/Yamanouchi in Japan, and of a nitroglycerin-releasing TDD system, named Nitro-Dur II system by Key in the United States, for once-a-day medication for angina pectoris. This second generation of TDD system (NitroDur II) has also received FDA approval for marketing. NitroDur II compares favorably with Nitro-Dur (Fig. 10) and has gradually replaced the rst-generation Nitro-Dur from the marketplace. The same technical basis has been also utilized in the development of the following: 1) Habitrol and Nicotrol systems, which provide a controlled dose of nicotine transdermally over 24 h for smoking cessation;[14] 2) Minitran system, which administers a controlled dose of nitroglycerin transdermally over 24 h for the relief of anginal attacks;[14] 3) Testoderm system, which administers a controlled delivery of testosterone for transdermal permeation through a scrotal skin[14] for the replacement therapy of testosterone-decient patients for 24 h; and 4) Climara system, which provides a controlled
delivery of 17b-estradiol for transdermal permeation for once-weekly treatment of vasomotor systems[14] associated with menopause. Compudose implant This controlled-release subdermal implant is fabricated by dispersing micronized estradiol crystals in a viscous mixture of silicone elastomer and catalyst and then coating the estradiol-polymer dispersion around a rigid (drug-free) silicone rod by an extrusion technique to form a cylinder-shaped implant (Fig. 11). This implant is designed for subcutaneous implantation in the steers ear ap for a duration of 200 or 400 days, during which a controlled quantity of estradiol is released daily for growth promotion.[20] To improve the Q versus t1/2 drug release proles [Eq. (2)], this polymer matrix diffusion-controlled CrDDS can be modied to have the drug-loading level varied, in an incremental manner, to form a gradient of drug reservoir along the diffusional path in the polymer matrix. A constant drug release prole is thus
1087
B Drug reservoir (Dispersion) Drug release
Furthermore, it was recently demonstrated that the release of a drug, such as propranolol, from the multilaminate adhesive-based TDD system can be maintained at zero-order kinetics by controlling the particle size distribution of drug crystals in the various laminates of adhesive matrix.[22] Polymer (Membrane/Matrix) Hybrid-Type Drug Delivery Systems This type of CrDDS is developed with the objective of combining the constant drug release kinetics of polymer membrane permeation-controlled drug delivery systems with the mechanical superiority of polymer matrix diffusion-controlled drug delivery systems. The release prole of drug from a sandwich-type drug delivery system (Fig. 13) is constant, and the instantaneous rate of drug release is dened by: ACp Dp dQ 2 dt Dp Km 1=Pm 1=Pd 4ACp Dp t1=2 4
Drug depletion zone Drug release
Gel layer
C Drug reservoir Receding boundary depletion zone Diffusion layer A CR Matrix Dp Perfect sink hd hp + dhp Elution medium
Fig. 8 Release of drug from the polymer matrix diffusioncontrolled drug delivery systems with drug reservoir exists as a homogeneous dispersion in (A) lipophilic, non-swellable polymer matrix, with a growing thickness of drug depletion zone, or (B) a hydrophilic, swellable polymer matrix, with a growing thickness of drug-depleted gel layer. In (C), the drug concentration gradients across the time-dependent drug depletion zone, with a growing thickness (hp dhp), and the hydrodynamic diffusion layer, with a controlled thickness (hd), are shown in series.
achieved, and the rate of drug release from this drug reservoir gradient-controlled drug delivery system is dened by: Ka=r Da dQ Cp ha ha t dt 3
where A is the initial amount of drug solid impregnated in a unit volume of polyer matrix with solubility Cp and diffusivity Dp; Km is the partition coefcient for the interfacial partitioning of drug molecules from polymer matrix toward polymer coating membrane; Pm is the permeability coefcient of the polymer coating membrane with thickness hm; and Pd is the permeability coefcient of the hydrodynamic diffusion layer with thickness hd. The hybrid system is exemplied by the development of clonidine-releasing and scopolamine-releasing transdermal therapeutic systems (Catapres-TTS and Transderm-Scop) (Fig. 14), in which a ratecontrolling non-medicated polymeric membrane is added to coat the surface of the drug-dispersing polymer matrix, and the release of drug molecules thus becomes controlled by membrane permeation instead of matrix diffusion. The same technology has been utilized in the development of levonorgestrel-releasing subdermal implants (Norplant II). Microreservoir Partition-Controlled Drug Delivery Systems In this type of CrDDS, the drug reservoir is a suspension of drug solid particles in an aqueous solution of a water-miscible polymer, like polyethylene glycols. This forms a homogeneous dispersion of many discrete, unleachable, microscopic drug reservoirs in a biocompatible polymer, like silicone elastomers (Fig. 15). The microdispersion is achieved by applying a high-energy dispersion technique.[13,23] Different shapes and sizes of drug-delivery devices can be fabricated from this
in which the time-dependent thickness [ha(t)] of the diffusional path for drug molecules to diffuse through, which is increasing with time, is compensated by the proportional increase in the drug-loading level [Cp(ha)], and a constant drug release prole is thus obtained. This type of CrDDS is best illustrated by the nitroglycerinreleasing Deponit system (Fig. 12), rst marketed by Pharma-Schwartz/Lohmann in Europe.[21] WyethAyerst has received FDA approval for marketing this system in the United States.
Drug Delivery
1088
Absorbent pad Occlusive baseplate (aluminum foil) Impermeable backing (polyethylene coverstrip)
Adhesive rim (microporous acrylic polymer tape)
Drug reservoir (drug/hydrophilic polymer matrix)
0.8
Plasma nitroglycerin conc. (ng/ml SEM)
0.6
Night Period
0.4
off
0.2
Drug Delivery
BuccalMono
10
15
20
25
Time (h)
Fig. 9 Cross-sectional view of a unit of Nitro-Dur system, showing various structural components, and the plasma nitroglycerin concentration proles in six human volunteers, each receiving 1 unit of Nitro-Dur system (20 cm2, with a delivery rate of 10 mg/day) for 24 h. (From Refs.[5556].)
microreservoir-type CrDDS by molding or extrusion techniques. Depending upon the physicochemical properties of drugs and the desired rate of drug release, the device can be further coated with a layer of biocompatible polymer to modify the mechanism and the rate of drug release. The rate of drug release (dQ/dt) from this type of CrDDS is dened by: Dp Dd mKp dQ dt Dp hd Dd hp mKp ! Dl Sl 1 n 1 1 nSp ht Kl Km 5
where m a/b and n is the ratio of drug concentration at the inner edge of the interfacial barrier over the drug solubility in the polymer matrix,[1,6] in which a is the ratio of drug concentration in the bulk of elution solution over drug solubility in the same medium and b is the ratio of drug concentration at the outer edge of
the polymer coating membrane over drug solubility in the same polymer. Kl, Km, and Kp are, respectively, the partition coefcients for the interfacial partitioning of drug from the liquid compartments to the polymer matrix, from the polymer matrix to the polymer coating membrane, and from the polymer coating membrane to the elution solution, whereas Dl, Dp, and Dd are, respectively, the diffusivities of the drug in the liquid layer surrounding the drug particles, the polymer coating membrane enveloping the polymer matrix, and the hydrodynamic diffusion layer surrounding the polymer coating membrane with respective thicknesses of hl, hp, and hd (Fig. 15); and Sl and Sp are the solubilities of the drug in the liquid compartments and in the polymer matrix, respectively. The release of drug from the microreservoir-type CrDDS can follow either a dissolution- or a matrix diffusion-control process, depending upon the relative magnitude of Sl and Sp.[24] Representatives of this type of CrDDS is outlined below.
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Drug-loaded adhesive
Impermeable film
Silicone rod
Release liner 1000 500
Estradiol-releasing polymer matrix
Nitroglycerin (pg/ml)
250
1.0
100 50
75% 40%
0.8
Q (mg/cm2)
25 10
20%
0.6
10
15
20
25
Time (h)
Fig. 10 Cross-sectional view of Nitro-Dur II, showing various structural components, and the comparative 24 h plasma nitroglycerin concentration proles in 24 healthy male volunteers, each receiving randomly 1 unit of NitroDur II (open circle) or Nitro-Dur (closed circle), 20 cm2 each, with a delivery rate of 10 mg/day, over the chest for 24 h (the arrow indicates unit removal). (From Ref.[56].)
0.4
0.2
0.0 0 1 2 3 4
Nitrodisc system In this transdermal CrDDS (Fig. 16), the drug reservoir is a suspension of nitroglycerin/lactose triturate in an aqueous solution of 40% polyethylene glycol 400. It is dispersed homogeneously by a high-energy mixing technique, with isopropyl palmitate, a skin permeation enhancer, in a mixture of viscous silicone elastomer and catalyst.[25] The resultant drug-polymer dispersion is then formed in situ into a solid medicated disc on a drug-impermeable metallic plastic laminate, with an adhesive rim, by an injection-molding technique and application of an instantaneous heating. It is engineered to provide a transdermal administration of nitroglycerin at a daily rate of 0.5 mg/cm2 for once-a-day medication of angina pectoris.[2,26] AQ versus t1/2 (matrix diffusion-controlled) release prole is obtained. Syncro-Mate-C implant This subdermal controlled-release implant is fabricated by dispersing the drug reservoir, which is a suspension of norgestomet in an aqueous solution of PEG 400, in a viscous mixture of silicone elastomers by a highenergy dispersion technique.[24] After adding catalyst,
Fig. 11 Diagrammatic illustration of a unit of Compudose subdermal implant and in vitro release proles of estradiol from the implants immersed in aqueous solution containing various volume fractions of polyethylene glycol 400.
the suspension is delivered into a silicone medical-grade tubing, which serves as the mold as well as the coating membrane, and then polymerized in situ. The polymerized drug-polymer composition is then cut into a cylinder-shaped implant with its ends staying open (Fig. 17). This tiny cylindrical implant is designed to be inserted into the subcutaneous tissue of the livestocks ear ap; norgestomet is released continuously into the subcutaneous tissue for up to 20 days for the control and synchronization of estrus and ovulation and up to 160 days for growth promotion. A constant Q versus t (dissolution-controlled) release prole has been achieved, as compared to the Q versus t1/2 release prole (matrix diffusion-controlled drug release) for the Syncro-Mate-B implant and the Nitrodisc system discussed above. Transdermal contraceptive device The transdermal contraceptive device is based on a patentable micro-drug-reservoir technique[26] to achieve
Drug Delivery
(Days)
1090
Drug-impermeable metallic plastic laminate
R1 R2 R3 Drug reservoir gradient layers (R1 > R2 > R3)
chemical, or biochemical processes and/or facilitated by an energy supplied externally (Fig. 2). The rate of drug release is then controlled by regulating the process applied or energy input. Based on the nature of the process applied or the type of energy used, these activation-modulated CrDDSs can be classied into the following categories: 1. Physical means a. Osmotic pressure-activated drug delivery systems b. Hydrodynamic pressure-activated drug delivery systems c. Vapor pressure-activated drug delivery systems d. Mechanical force-activated drug delivery systems e. Magnetics-activated drug delivery systems f. Sonophoresis-activated drug delivery systems g. Iontophoresis-activated drug delivery systems h. Hydration-activated drug delivery systems 2. Chemical means
Adhesive layer 400
Plasma nitroglycerin conc. (pg/ml)
Cmax = 255 151 pg/ml (tmax = 3.6 3.5 h) Css = 125 50 pg/ml (8-24 h) AUC = 3.3 1.6 ngh/ml 200
100 80 60 Dose =5.0 0.7 mg/day (n=6) 4.5 0.8 mg/day (n=17)
40
12
16
20
24
a. b. c. d.
pH-activated drug delivery systems pH-activated drug delivery systems Ion-activated drug delivery systems Hydrolysis-activated drug delivery systems
Drug Delivery
BuccalMono
Duration of Device/Skin contact (h)

Fig. 12 Cross-sectional view of a unit of Deponit system, showing various structural components, and the plasma nitroglycerin concentration proles in six human volunteers, each receiving 1 unit of Deponit system (16 cm2, with a delivery rate of 5 mg/day) for 24 h. (Plasma proles are plotted from data from Ref.[21].)
3. Biochemical means a. Enzyme-activated drug delivery systems b. Biochemical-activated drug delivery systems Several CrDDSs have been successfully developed and applied clinically to the controlled delivery of pharmaceuticals and biopharmaceuticals. These are outlined and discussed below.
a dual-controlled release of levonorgestrel, a potent synthetic progestin, and estradiol, a natural estrogen, at constant and enhanced rates, continuously, for a period of 7 days.[5] By applying 1 unit (10 or 20 cm2) of transdermal contraceptive device per week, beginning on day 5 of an individuals menstrual cycle, for 3 consecutive weeks (3 weeks on and 1 week off), steadystate serum levels of levonorgestrel have been obtained, and the secretion of gonadotropins and progesterone have been effectively suppressed.
Osmotic Pressure-Activated Drug Delivery Systems In this type of CrDDSs, the drug reservoir, which can be either a solution or a solid formulation, is contained within a semipermeable housing with a controlled water permeability. The drug in solution is released through a special laser-drilled delivery orice at a constant rate under a controlled gradient of osmotic pressure. For a solution-type osmotic pressure-activated CrDDS, the intrinsic rate of drug delivery (Q/t) is dened by: Q Pw Am ps pe t hm
ACTIVATION-MODULATED DRUG DELIVERY SYSTEMS In this group of CrDDSs, the release of drug molecules from the delivery systems is activated by some physical,
1091
Sphere
Cylinder
hp(t)
hm
hd
Drug reservoir
Dp
Dm pm
Dd pd
CR
Perfect sink (Cb = 0) Solution bulk
Polymer matrix
Drug depletion zone
Polymer coating membrane
Diffusion layer
Fig. 13 The controlled release of drug molecules from a (membrane-matrix) hybrid-type drug delivery system in which solid drug is homogeneously dispersed in a polymer matrix, which is then encapsulated inside a polymeric membrane, where D, P, and h are the diffusivity, permeability, and thickness, respectively, and the subscripts p, m, and d denote the drug depletion zone in the polymer matrix, polymer coating membrane, and diffusion layer, respectively.
For a solid-type osmotic pressure-activated CrDDS, the intrinsic rate of drug delivery should also be a constant and is dened by:
DRUG-DISPERSING ADHESIVE LAYERS
DRUG-IMPERMEABLE BACKING LAMINATE
Q P w Am ps pe Sd t hm
where Pw, Am, and hm are, respectively, the water permeability, the effective surface area, and the thickness of the semipermeable housing; (ps pe) is the differential osmotic pressure between the drug-delivery system with an osmotic pressure of ps and the environment
DRUG MOLECULES
Fig. 14 Cross-section view of various structural components in the Transderm-Scop and Catapres-TTS systems.
MICROPOROUS MEMBRANE
Drug Delivery
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Polymer matrix (cross-linked, solid)
Drug reservoir (microscopic liquid compartments)
Coating membrane
Polymer/Solution interface
Drug Delivery
BuccalMono
Interfacial barrier
Liquid layer
Polymer matrix Dp
Dm
Ds Solution sink
Cp Dl Drug particle Sl Cl ' Cp
' Cp
Cm
Cd Cm' Cb = O
Polymer Diffusion coating layer membrane
Fig. 15 Microscopic view of a microreservoir-type drug-delivery system, which shows the microscopic structure of various components, and the physical model developed for the mechanistic analysis of the controlled release of drug. (Adapted from Refs.[1,57].)
with an osmotic pressure of pe; and Sd is the aqueous solubility of the drug component in the solid reservoir. The release of drug molecules from this type of CrDDS is activated by osmotic pressure and controlled at a rate determined by the water permeability and the
effective surface area of the semipermeable housing as well as the osmotic pressure gradient. Several CrDDSs of this type have been successfully marketed for therapeutical uses and some representatives are outlined later.
1093
Occlusive baseplate (aluminum foil disc)
Adhesive foam pad (flexible polyurethane)
Polymer coating membrane
Drug reservoir
Adhesive rim (acrylic polymer coating)
Microscopic drug reservoirs (drug/co-solvents) Polymer matrix (silicone elastomer)
Open ends 100
Medicated MDD core
Fraction of drug released (%)
0.6
Plasma nitroglycerin conc. (ng/ml SEM)
0.5 0.4 0.3 0.2 0.1 0.0 0 4 8 12

(C plasma)ss Night Period
80 60 40 20 0
16
20
24
28
32
Time (h)
Fig. 16 Cross-sectional view of a unit of Nitrodisc system, showing various structural components, and the plasma nitroglycerin concentration proles in 12 human volunteers, each receiving 1 unit of Nitrodisc system (16 cm2, with a delivery rate of 10 mg/day) for 32 h. (From Ref.[23].)
10
15
20
25
30
Days of implantation
Fig. 17 Syncro-Mate-C implant, a subdermal implant fabricated from the microreservoir dissolution-controlled drugdelivery system, and subcutaneous controlled release of norgestomet, a potent synthetic progestin, at constant rate for 20 days. The open ends on the implant do not affect the zeroorder in vivo drug release prole. (Adapted from Ref.[57].)
Alzet osmotic pump Acutrim tablet In this implantable or insertable CrDDS, the drug reservoir, which is normally a solution formulation, is contained within a collapsible, impermeable polyester bag whose external surface is coated with a layer of osmotically active salt, for example, sodium chloride. This reservoir compartment is then totally sealed inside a rigid housing walled with a semipermeable membrane (Fig. 19). At an implantation site, the water content in the tissue uid will penetrate through the semipermeable membrane at a controlled rate and dissolve the osmotically active salt. This creates an osmotic pressure in the narrow spacing between the exible reservoir wall and the rigid semipermeable housing. Under the osmotic pressure created [Eq. (6)], the reservoir compartment is thus reduced in volume and the drug solution is forced to release through the ow moderator at a controlled rate.[27,28] By varying the drug concentration in the solution, different doses of drug can be delivered at a constant rate for a period of 14 weeks. In addition to its application in the subcutaneous controlled administration of drugs for pharmacological studies, this technology has recently been extended to the controlled administration of drugs in the rectum by zero-order kinetics. The hepatic rst-pass metabolism of drugs is thus bypassed.[29] In this oral CrDDS, the drug reservoir, which is a solid tablet of water-soluble and osmotically-active phenylpropanolamine (PPA) HCl, is enclosed within a semipermeable membrane of cellulose triacetate.[2,30] The surface of the semipermeable membrane is further coated with a thin layer of immediately releasable PPA dose (Fig. 20). In the alimentary tract, the gastrointestinal uid will dissolve away the immediate release layer of PPA to provide an initial dose of PPA and then penetrate through the semipermeable membrane to dissolve the sustained-release dose of PPA. Under the osmotic pressure created [Eq. (7)], the PPA solution is released continuously at a controlled rate, through an orice pre-drilled by a laser beam.[2,30,31] It is designed to provide a controlled delivery of PPA over a duration of 16 h for appetite suppression in a weightcontrol program.[31] The same delivery system has also been utilized for the oral controlled delivery of indomethacin. An extension of this technology is the development of a push-pull type osmotic pressureactivated CrDDS for the oral controlled delivery of nifedipine and metroprolol.[27] It has been further extended to the delayed-onset and controlled oral delivery of verapamil[14] to produce a maximum plasma concentration in the morning hours.
Drug Delivery
1094
A 288
Concentration (pg/ml S.E.)
10 Sq. cm - Patch (n=6)
240 192 144 96 48 0
20 Sq. cm - Patch (n=6)
hydrophilic polymer layer is sandwiched between the drug reservoir compartment and the housing. In the gastrointestinal tract, the laminate will imbibe the gastrointestinal uid through the annular openings at the lower end of the housing and become swollen. This generates a hydrodynamic pressure in the system. The hydrodynamic pressure, thus created, forces the drug reservoir compartment to reduce in volume and causes the liquid drug formulation to release through the delivery orice.[32] The drug release rate is dened by:
504 m p 672 p
0 m
168 mm
336 mm
Q Pf Am ys ye t hm
Duration of study (h)

B 30
Subject Code MM (Group A: 1 TCD patch) Pretreatment Treatment Subject Code MG (Group B: 2 TCD patch) Pretreatment Treatment
Serum progesterone (ng/ml)
25 20 15 10 5 0 0
Tmax
Tmax
where Pf, Am, and hm are the uid permeability, the effective surface area, and the thickness of the wall with annular openings, respectively; and ys ye, is the difference in hydrodynamic pressure between the drug delivery system (ys) and the environment (ye). The release of drug molecules from this type of CrDDS is activated by hydrodynamic pressure and controlled at a rate determined by the uid permeability and effective surface area of the wall with annular openings as well as by the hydrodynamic pressure gradient. Vapor Pressure-Activated Drug Delivery Systems In this type of CrDDS, the drug reservoir, which is a solution formulation, is contained inside the infusion compartment. It is physically separated from the pumping compartment by a freely movable partition (Fig. 21). The pumping compartment contains a vaporizable uid, such as uorocarbon, which vaporizes at body temperature and creates a vapor pressure. Under the vapor pressure created, the partition moves upward and forces the drug solution in the infusion compartment to be delivered, through a series of ow regulator and delivery cannula, into the blood circulation at a constant ow rate.[1,6,33] The process is dened by: Q d4 dP t 40:74ml 9
Drug Delivery
BuccalMono
10
20
30
40 0
10
20
30
40
Day of menstrual cycle

Fig. 18 (Upper panel) The 4week serum levonorgestrel proles in 12 human volunteers, each receiving 1 or 2 units of a transdermal contraceptive system (10 cm2, with daily dosage of 28.3 mg/day) once a week, consecutively for 3 weeks, and the same size of placebo on week 4. (Lower panel) Comparative serum concentration proles of progesterone during the pretreatment and treatment cycles in two subjects, each as the representative for group A (receiving 10 cm2) and group B (receiving 20 cm2), respectively. The suppression of progesterone peak during the treatment cycle is an indication of effective fertility control.
Hydrodynamic Pressure-Activated Drug Delivery Systems In addition to the osmotic pressure systems discussed above, hydrodynamic pressure has also been explored as the potential source of energy to modulate the delivery of therapeutic agents.[2] A hydrodynamic pressure-activated drug-delivery system can be fabricated by placing a liquid drug formulation inside a collapsible, impermeable container to form a drug reservoir compartment. This is then contained inside a rigid, shape-retaining housing. A laminate of an absorbent layer and a swellable,
where d and l are, respectively, the inner diameter and thelength of the delivery cannula; Dp is the pressure difference between the vapor pressure in the pumping compartment and the pressure at the implantation site; and m is the viscosity of the drug formulation. The delivery of drug from this type of CrDDS is activated by vapor pressure and controlled at a rate determined by the differential vapor pressure, the formulation viscosity, and the size of the delivery cannula.
1095
B 200 175 150 125 100 75 50 25 0 0 3 6 9 12 15 Flexible impermeable reservoir wall Osmotic agent Neck Plug
Pump implanted Pump removed Urine volume
Daily urine volume (% of Pretreatment control + S.D.)
Drug solution leaving via delivery portal Removable cap Flange Flow moderator
3000
Urine osmolality
Urine osmolalilty (mOsm/ kg H2O + S.D.)
2500 2000 1500 1000

Pump implanted Pump removed
Semipermeable membrane Water entering semipermeable membrane Reservoir
500 0
6 Time (day)
12
15
Fig. 19 (A) Cross-sectional view of the Alzet osmotic pump, an osmotic pressure-activated drug-delivery system. (B) The effect of 7 days of subcutaneous delivery of antidiuretic hormone (vasopressin) on the daily volume of urinary excretion and urine osmolality in the Brattleboro rats with diabetes insipidus.
A typical example is the development of Infusaid, an implantable infusion pump by Metal Bellows, for the constant infusion of heparin in anticoagulation treatment,[34] of insulin in the normoglycermic control of diabetics,[33] and of morphine for patients suffering from the intensive pain of a terminal cancer.[35] Mechanical Force-Activated Drug Delivery Systems In this type of CrDDS, the drug reservoir is a solution formulation in a container equipped with a mechanically activated pumping system. A metered dose of drug formulation can be reproducibly delivered into a body cavity, such as the nose, through the spray head upon manual activation of the drug-delivery pumping system. The volume of solution delivered is xed and is independent of the force and duration of activation. A typical example of this type of drug-delivery system is the development of a metered-dose nebulizer for the intranasal administration of a precision dose of luteinizing hormone-releasing hormone (LHRH) and
its synthetic analogs, such as buserelin. Through nasal absorption, the hepatic rst-pass elimination of these peptide drugs is thus avoided.[24] Magnetic-Activated Drug Delivery Systems Macromolecular drugs, such as peptides, have been known to release only at a relatively low rate from a polymer-controlled drug-delivery system. This low rate of release can be improved by incorporating an electromagnetism-triggering vibration mechanism into the polymeric delivery device. With a hemispheric-shaped design, a zero-order drug-release prole is achieved.[36] By combining these two approaches, a subdermally implantable, magnetic-activated hemispheric drugdelivery device is developed. It is fabricated by rst positioning a tiny doughnut-shaped magnet at the center of a drug-dispersing biocompatible polymer matrix and then coating the external surface of the medicated polymer matrix, with the exception of one cavity at the center of the at surface, with a pure polymer, for instance, ethylenevinyl acetate copolymer or silicone
Drug Delivery
1096
Delivery orifice Drug reservoir/ osmotically active solutes Controlled-release dose Semi-permeable coating Immediate releasing layer (initial dose)
Cumulative % loading dose released
100 80 60 40 20 0
12.16 atm 30.16 atm 54.16 atm 114.0 atm
molecule across a biological membrane, such as the skin, in a manner similar to passive diffusion under a concentration gradient but at a much facilitated rate. The iontophoresis-facilitated skin permeation rate of a charged molecule i consists of three components and is expressed by: Jiisp J p J e J c dC Zi Di Fi dE Ci Ks Ds kCs Id RT hs hs
10
12
16
20
24
Time (h)
Fig. 20 Cross-sectional view of a unit of Acutrim tablet, a solid-type osmotic pressure-activated drug delivery system, and the effect of increased osmotic pressure in the dissolution medium on the release proles of phenylpropanolamine HCl from the Acutrim tablet at intestinal condition. (Adapted from Refs.[31,58].)
elastomers. This uncoated cavity is designed for allowing a peptide drug to release. The hemispheric magnetic delivery device produced can release macromolecular drugs, like bovine serum albumin, at a low basal rate, by diffusion process, and under a non-triggering condition, or it can release the same drug at a much higher rate, when the magnet is activated, to vibrate by an external electromagnetic eld. Sonophoresis-Activated Drug Delivery Systems This type of activation-controlled drug delivery system utilizes ultrasonic energy to activate (or trigger) the delivery of drugs from a polymeric drug delivery device. The system can be fabricated from either a non-degradable polymer, such as ethylenevinyl acetate copolymer, or a bioerodible polymer, such as poly [bis(p-carboxyphenoxy)alkane anhydride].[37] The potential application of sonophoresis (or phonophoresis) to regulate the delivery of drugs was recently reviewed.[38] Iontophoresis-Activated Drug Delivery Systems This type of CrDDS use electrical current to activate and to modulate the diffusion of a charged drug
where J p, J e, and J c represent, respectively, the ux for the skin permeation by passive diffusion, for the electrical current-driven permeation, and for the convective ow-driven skin permeation; Ks is the partition coefcient for interfacial partitioning from the donor solution to the stratum comeum; Ds and Di are, respectively, the diffusivity across the skin and the diffusivity of ionic species i in the skin; Ci and Cs are, respectively, the donor concentration of ionic species i and the concentration in the skin tissue; dE/hs is the electrical potential gradient across the skin; dC/hs is the concentration gradientacross the skin; Zi is the electrical valence of ionic species i; Id is thecurrent density applied; F, k, and R are, respectively, the faraday, proportionality, and gas constant; and T is the absolute temperature. A typical example of this type of activationcontrolled CrDDS is the development of an iontophoretic drug delivery system, named Phoresor by Motion Control, to facilitate the percutaneous penetration of antiinammatory drugs, such as dexamethasone sodium phosphate,[3941] to surface tissues. Further development of the iontophoresis-activated drug delivery technique has yielded a new design of iontophoretic drug delivery systemthe transdermal periodic iontotherapeutic system (TPIS). This new system, which is capable of delivering a physiologicallyacceptable pulsed direct current, in a periodic manner, with a special combination of waveform, intensity, frequency, and on/off ratio, for a specic duration, has signicantly improved the efciency of transdermal delivery of peptide and protein drugs.[4] A typical example is the iontophoretic transdermal delivery of insulin, a protein drug, in the control of hyperglycemia in diabetic animals.
Drug Delivery
BuccalMono
Hydration-Activated Drug Delivery Systems In this type of CrDDS, the drug reservoir is homogeneously dispersed in a swellable polymer matrix fabricated from a hydrophilic polymer. The release of drug is activated and modulated by hydration-induced
1097
Bacterial filter assembly Fluorocarbon fluid filling tube 2.4 cm
Inlet septum
Needle stop
Flow regulator Silicone polymer coating
Empty weight = 181g
Infusate chamber
Bellows Fluorocarbon fluid chamber 8.6 cm
1000 A 800 600 400

Pump implanted
Dose units/kg per day
n=7
200 0 1000 800 600 400

n = 25
200 0 0 8 16 24 32 40 48 56
Weeks of infusion
Fig. 21 Cross-sectional view of a unit of Infusaid system, a vapor pressure-activated drug-delivery system, and daily heparin dose (mean S.E.) delivered to 25 dogs for 6 months and to 7 dogs for 12 months. (Adapted from Ref.[34].)
swelling of the polymer matrix. Representatives of this type of CrDDS are outlined below. Syncro-Male-B implant This subcutaneous CrDDS is fabricated by dissolving norgestomet, a potent progestin for estrus synchronization, in an alcoholic solution of linear ethylene glycomethacrylate polymer (Hydron S). The drugpolymer mixture is then cross-linked by adding ethylene dimethacrylate, in the presence of an oxidizing catalyst, to form a cylinder-shaped subdermally implantable implant.[1,6] This tiny subdermal implant can be activated by tissue uid to swell and can be
engineered to deliver norgestomet, at a rate of 504 mg/cm2/day1/2, in the subcutaneous tissue for up to 16 days for the control and synchronization of estrus in livestock.[13] Valrelease tablet This oral CrDDS is prepared by granulating Valium, an antidepression drug, with hydrocolloids (2075 wt%) and pharmaceutical excipients. The granules are then compressed to form an oral tablet. After oral intake, the hydrocolloids absorb the gastric uid and are activated to form a colloid gel matrix surrounding the tablet surface (Fig. 22). The release of Valium molecules
Drug Delivery
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is then controlled by diffusion through the gel barrier, while the tablet remains buoyant in the stomach, due to a density difference between the gastric uid (d > 1) and the gelling tablet (d < 1).[2,3]
pH-Activated Drug Delivery Systems For a drug labile to gastric uid or irritating to gastric mucosa, this type of CrDDS has been developed to target the delivery of the drug only in the intestinal tract, not in the stomach.[2] It is fabricated by coating a core tablet ofthe gastric uid-sensitive drug with a combination of intestinal uid-insoluble polymer, like ethyl cellulose, and intestinal uid-soluble polymer, like hydroxylmethyl cellulose phthalate (Fig. 23). In the stomach, the coating membrane resists the degrading action of gastric uid (pH <3), and the drug molecules are thus protected from the acidic degradation. After gastric emptying, the CrDDS travels to the small
A Hydrocolloids (2075% w/w) Gastric fluid (d>1)
intestine, and the intestinal uid-soluble component in the coating membrane is dissolved away by the intestinal uid (pH >7.5). This produces a microporous membrane of intestinal uid-insoluble polymer to control the release of drug from the core tablet. The drug is thus delivered in a controlled manner in the intestine by a combination of drug dissolution in the core and diffusion through the pore channels. By adjusting the ratio of the intestinal uid-soluble polymer to the intestinal uid-insoluble polymer in the membrane, the rate of drug delivery can be regulated. Representative application of this type of CrDDS is in the oral controlled delivery of potassium chloride, which is highly irritating to gastric epithelium.
Ion-Activated Drug Delivery Systems For controlling the delivery of an ionic or an ionizable drug, this type of CrDDS has been developed.[2] Because the gastrointestinal uid has regularly maintained a relatively constant level of ions, the delivery of drug by this type of CrDDS can be modulated, theoretically, at a constant rate. Such a CrDDS is prepared by rst complexing an ionizable drug with an ion-exchange resin, such as
Stomach (pH < 3)
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Colloid gel barrier d<1
Gastric emptying
Coating of Gastric fluidlabile drug Intestinal fluid-insoluble polymer Intestinal fluid-soluble polymer
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Valium (Placebo)
Valrelease (Placebo)
Intestinal fluid (pH > 7.5)
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100
Gastric fluidlabile drug
Microporous membrane of intestinal fluidinsoluble polymer
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Fig. 22 (A) Schematic illustration of Valrelease tablet, a swelling-activated drug-delivery system, and the hydrationinduced formation of colloid gel barrier. (B) Comparison in the gastric residence prole between Valrelease with the conventional Valium capsule. (From Ref.[58].)
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Fig. 23 Schematic illustration of a pH-activated drugdelivery system and the pH-dependent formation of microporous membrane in the intestinal tract.
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complexing a cationic drug with a resin containing SO3 group or an anionic drug with a resin containing N(CH3)3 group. The granules of the drugresin complex are further treated with an impregnating agent, like polyethylene glycol 4000, for reducing the rate of swelling upon contact with an aqueous medium. They are then coated by an air-suspension coating technique with a water-insoluble but water-permeable polymeric membrane, such as ethylcellulose. This membrane serves as a rate-controlling barrier to modulate the release of drug from the CrDDS. In the GI tract, hydronium and chloride ions diffuse into the CrDDS and interact with the drugresin complex to trigger the dissociation and release of ionic drug (Fig. 24). This type of CrDDS is exemplied by the development of Pennkinetic system (by Pennwalt Pharmaceuticals), which permits the formulation of oral liquid-type dosage forms with sustained release of a combination of hydrocodone and chlorpheniramine (Tussionex).[14,4244] Hydrolysis-Activated Drug Delivery Systems This type of CrDDS depends on the hydrolysis process to activate the release of drug molecules. In this system, the drug reservoir is either encapsulated in microcapsules or homogeneously dispersed in microspheres or nanoparticles. It can also be fabricated as an implantable device. All these systems are prepared from a bioerodible or biodegradable polymer, such as polylactide, poly(lactideglycolide) copolymer, poly (orthoester), or poly(anhydride). The release of a drug from the polymer matrix is activated by the hydrolysisinduced degradation of polymer chains, and the rate of drug delivery is controlled by polymer degradation rate.[45] A typical example is the development of Lupron Depot, an injectable microspheres for the subcutaneous controlled delivery of luprolide, a potent biosynthetic analog of gonadotropin-releasing hormone (GnRH) for the treatment of gonadotropin-dependent cancers, such as prostate carcinoma in men and endometriosis in the females, for up to 4 months. Another example is the development of Zoladex system, an implantable cylinder for the subcutaneous controlled delivery of goserelin, also a potent biosynthetic analog of GnRH for the treatment of patients with prostate cancer (Fig. 25) for up to 3 months.[14] Enzyme-Activated Drug Delivery Systems In this type of CrDDS, the drug reservoir is either physically entrapped in microspheres or chemically bound to polymer chains fabricated from biopolymers, such as albumins or polypeptides. The release of drugs is
made possible by the enzymatic hydrolysis of biopolymers by a specic enzyme in the target tissue.[4648] A typical example is the development of albumin microspheres, which release 5-uorouracil, in a controlled manner, by protease-activated biodegradation.
FEEDBACK-REGULATED DRUG DELIVERY SYSTEMS In this group of CrDDSs, the release of drug molecules is activated by a triggering agent, such as a biochemical substance, in the body via some feedback mechanisms (Fig. 2). The rate of drug release is regulated by the concentration of a triggering agent detected by a sensor built into the CrDDS. Bioerosion-Regulated Drug Delivery Systems The feedback-regulated drug delivery concept has been applied to the development of a bioerosion-regulated CrDDS by Heller and Trescony.[49] This CrDDS consists of a drug-dispersed bioerodible matrix fabricated from poly(vinyl methyl ether) half-ester, which was coated with a layer of immobilized urease (Fig. 26). In a solution with near neutral pH, the polymer only erodes very slowly. In the presence of urea, urease at
Drug-resin complex particles Resin SO3 Drug+ Resin [N(CH3)3+ ]Drug Polyethylene glycol treatment Ethyl cellulose coating
Blood Gut wall Polymer Drug
Ion Coating membrane H + + Resin SO3 Drug+ CI + Resin [N(CH3)3 + ] Drug ResinSO3 H + + Drug + Resin [N(CH3)3+ ] CI + Drug
Fig. 24 Cross-sectional view of an ion-activated drugdelivery system, showing various structural components, and diagrammatic illustration of ion-activated drug release. (Adapted from Ref.[58].)
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Drug-dispersed polymer matrix Hydrolytic erosion Phase I: surface erosion Phase II: bulk erosion goserelin Glp His Trp Ser Tyr
(D) Ser
u u Micropores u u u Leu Arg Pro Azgly NH
u u
Poly (vinyl methyl ether) half-ester (monolithic matrix) u u Urease (Immobilized)
Hydrocortisone
u urea
t-Bu
Serum Testosterone (nmol/L)
urease + 2NH4 + HCO3 + OH H2O alkaline polymer erosion pH
Serum LH (lU/L)
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20 0 0 4 8 12
30
15 0 0 4 8 12
Hydrocortisone
Hydrocortisone released (%)
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urea (0.1 M)
Weeks
Weeks
Fig. 25 Amino acid sequence of goserelin, a biosynthetic analog of gonadotropin-releasing hormone, and the effect of subcutaneous controlled release of goserelin from the biodegradable poly(lactide-glycolide) implant on the serum levels of luteinizing hormone and testosterone.
the surface of the drug delivery system metabolizes urea to form ammonia. This causes the pH to increase and activates a rapid degradation of polymer matrix as well as the release of drug molecules.
20
40
60
80
100
120
140
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Time (h)
Fig. 26 Cross-sectional view of a bioerosion-regulated hydrocortisone delivery system, a feedback-regulated drug delivery system, showing the drug-dispersed monolithic bioerodible polymer matrix with surface-immobilized ureases. The mechanism of release and time course for the urea-activated release of hydrocortisone are also shown. (From Ref.[49].)
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Bioresponsive Drug Delivery Systems The feedback-regulated drug delivery concept has also been applied to the development of a bioresponsive CrDDS by Horbett et al.[50]. In this CrDDS, the drug reservoir is contained in a device enclosed by a bioresponsive polymeric membrane whose permeability to drug molecules is controlled by the concentration of a biochemical agent in the tissue where the CrDDS is located. A typical example of this bioresponsive CrDDS is the development of a glucose-triggered insulin delivery system, in which the insulin reservoir is encapsulated within a hydrogel membrane containing pendant NR2 groups (Fig. 27). In an alkaline solution, the NR2 groups exist at neutral state and the membrane is unswollen and thus impermeable to insulin. As glucose penetrates into the membrane, it is oxidized enzymatically by the glucose oxidase entrapped in the membrane to form gluconic acid. This process triggers the protonation of NR2 groups to form NR2H, and the hydrogel membrane becomes swollen and is thus permeable to insulin molecules (Fig. 27). The amount of insulin delivered is bioresponsive to the concentration of glucose penetrating into the CrDDS.
Self-Regulating Drug Delivery Systems This type of feedback-regulated CrDDS depends on a reversible and competitive binding mechanism to activate and to regulate the release of drug. In this CrDDS, the drug reservoir is a drug complex encapsulated within a semipermeable polymeric membrane. The release of drug from the CrDDS is activated by the membrane permeation of a biochemical agent from the tissue where the CrDDS is located. Kim et al. rst applied the mechanism of reversible binding of sugar molecules with lectin into the design of self-regulating CrDDS.[51] For this CrDDS, a biologically-active insulin derivative, in which insulin is coupled with a sugar (e.g., maltose), was rst prepared and then conjugated with lectin to form an insulin sugarlectin complex. The complex is then encapsulated within a semipermeable membrane to produce CrDDS. As blood glucose diffuses into the CrDDS, it binds, competitively, with the binding sites in the lectin
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molecules and activates the release of the insulinsugar derivatives from the binding sites. The released insulinsugar derivatives diffuse out of the CrDDS, and the amount of insulin-sugar derivatives released depends on the concentration of glucose. Thus, a self-regulating drug delivery is achieved. However, a potential problem has remained to be resolved: that is, the release of insulin is non-linear in response to the changes in glucose level.[52] Further development of the self-regulating insulin delivery system has utilized the complex of glycosylated insulinconcanavalin A, which is encapsulated inside a polymer membrane.[53] As glucose penetrates into the system, it activates the release of glycosylated insulin from the complex for a controlled release from the system (Fig. 28). The amount of insulin released is thus self-regulated by the concentration of glucose that has penetrated into the insulin delivery system.
Self-Regulating Insulin Delivery Systems (Biochemical Approach) Concanavalin A Polymer membrane + Glycosylated (G) insulin Glucose in G-Insulin out
Pancreatectomized dogs
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200
100 F F F F F
Normoglycemic level F = Feeding
SITE-TARGETING DRUG DELIVERY SYSTEMS Delivery of a drug to a target tissue that needs medication is known to be a complex process that consists
9am 3pm 9pm 3am 9am 3am 9pm
Time of day
Fig. 28 Various components of a self-regulating insulin delivery system, a feedback-regulated drug delivery system, and its control of blood glucose level in the pancreatectomized dogs. (From Ref.[53].)
Glucose oxidase NR2 .... . ..... ..... .. .. NR NR2 . 2 ....... .. NR2 . .... .... NR . 2 Glucose
Insulin reservoir
Glucose NR2
Oxidase
Gluconic acid + N R2H
H+ Acidic pH
Hydrogel membrane swells N Enzyme + N R2 ..... . ......... . H .. + . .......... N R2 .. H + N R2 H Insulin + N R2 .... H ..... . + .. N R2 H Swollen membrane
Fig. 27 Cross-sectional view of a bioresponsive insulin delivery system, a feedback-regulated drug delivery system, showing the glucose oxidase-entrapped hydrogel membrane constructed from amine-containing hydrophilic polymer. The mechanism of insulin release, in response to the inux of glucose, is also illustrated. (From Ref.[50].)
of multiple steps of diffusion and partitioning. The CrDDSs outlined above generally address only the rst step of this complex process. Essentially, these CrDDSs have been designed to control the rate of drug release from the delivery systems, but the path for the transport of drug molecules from the delivery system to the target tissue remains largely uncontrolled. Ideally, the path of drug transport should also be under control. Then, the ultimate goal of optimal treatment with maximal safety can be achieved. This can be reasonably accomplished by the development of a CrDDS with a site-targeting specicity (Fig. 2). An ideal site-targeting CrDDS has been proposed by Ringsdorf.[54] A model, which is shown in Fig. 29, is constructed from a non-immunogenic and biodegradable polymer and acts as the backbone to contain three types of attachments: 1) a site-specic targeting moiety, which is capable of leading the drug delivery system to the vicinity of a target tissue (or cell); 2) a solubilizer, which enables the drug delivery system to be transported to and preferentially taken up by a target tissue; and 3) a drug moiety, which is convalently bonded to the backbone, through a spacer, and contains a linkage that is cleavable only by a specic enzyme(s) at the target tissue.
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Amine-containing hydrogel membrane
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Polymer backbone (nonimmunogenic and blodegradable)
4.
Site-specific targeting moiety
Spacer Cleavable group
Solubilizer
5.
Facilitate systemic distribution and tissue uptake
6. 7.
Enzyme (at target tissue) Cell of target tissue
Drug
Drug
8.
Drug Cell membrane
9.
10. 11. 12.
Fig. 29 An ideal site-targeting controlled-release drug delivery. (From Ref.[54].)
13. 14. 15. 16.
Unfortunately, this ideal site-targeting CrDDS is only in the conceptual stage. Its construction remains largely unresolved and is still a challenging task in the biomedical and pharmaceutical sciences. CONCLUSIONS The controlled-release drug delivery systems outlined here have been steadily introduced into the biomedical community since the middle of the 1970s. There is a growing belief that many more of the conventional drug delivery systems we have been using for decades will be gradually replaced in the coming years by these CrDDSs.
17. 18.
19. 20. 21.
REFERENCES
1. Chien, Y.W. Novel Drug Delivery Systems: Fundamental, Developmental Concepts and Biomedical Assessments; Marcel Dekker, Inc.: New York, 1982. 2. Chien, Y.W. Industrial Pharmaceutical R&D Symposium on Transdermal Controlled Release Medication. Piscataway, New Jersey, Jan 14&15, 1982; Rutgers University, College of Pharmacy, Proceedings Published in Drug Develop. & Ind. Pharm. 1983; 9, 497744. 3. Chien, Y.W. Industrial Pharmaceutical R&D Symposium on Oral Controlled Drug Administrations. Piscataway, New Jersey, Jan 19&20, 1983; Rutgers University, College
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of Pharmacy, Proceedings Published in Drug Develop. & Ind. Pharm. 1983; 9, 10771396. Chien, Y.W. International Pharmaceutical R&D Symposium on Advances in Transdermal Controlled Drug Administration for Systemic Medication. Piscataway, New Jersey, June 20&21, 1985; Rutgers University, College of Pharmacy, Proceedings Published in Transdermal Controlled Systemic Medications; Chien, Y.W., Ed.; Marcel Dekker, Inc.: New York, 1987. Chien, Y.W. Rate-control drug delivery systems: controlled release vs. sustained release. Med. Prog. Technol. 1989, 15 (12), 2146. Chien, Y.W. Novel Drug Delivery Systems: Second Edition, Revised and Expanded; Marcel Dekker, Inc.: New York, 1992. Luukkainen, T.; Allonen, H.; Haukkamaa, M.; Lahteenmaki, P.; Nilsson, C.G.; Toivonen, J. Five years experience with levonorgestrel-releasing IUDs. Contraception 1986, 33 (2), 139148. Andersson, K.; Odlind, V.; Rybo, G. Levonorgestrelreleasing and copper-releasing (Nova T) IUDs during ve years of use: a randomized comparative trial. Contraception 1994, 49 (1), 5672. Sivin, I.; Stern, J. Health during prolonged use of levonorgestrel 20 micrograms/d and the copper TCu 380Ag intrauterine contraceptive devices: a multicenter study. International committee for contraception research (ICCR). Fertil. Steril. 1994, 61 (1), 7077. Robinson, J.R. Sustained and Controlled Release Drug Delivery Systems; Marcel Dekker, Inc.: New York, 1978. Baker, R.W.; Lonsdale, H.K. Controlled deliveryan emerging use for membranes. Chemtech. 1975, 5, 668. Chien, Y.W. Methods to achieve sustained drug delivery. The physical approach: implants. In Sustained and Controlled Release Drug Delivery Systems; Robinson, J.R., Ed.; Marcel Dekker, Inc.: New York, 1978. Chien, Y.W. Microsealed Pharmaceutical Delivery Device. US Patent 3,992,518, Nov 16, 1976. Physicians Desk Reference, 53rd Ed.; Medical Economics Company. Montvale, 1999. Segal, S.J. The development of NORPLANT implants. Stud. Fam. Plann. 1983, 14 (67), 159163. Diaz, S.; Pavez, M.; Miranda, P.; Robertson, D.N.; Sivin, I.; Croxatto, H.B. A ve-year clinical trial of levonorgestrel silastic implants (Norplant2). Contraception 1982, 25 (5), 447456. Weiner, E.; Victor, A.; Johansson, E.D. Plasma levels of Dnorgestrel after oral administration. Contraception 1976, 14 (5), 563570. Croxatto, H.B.; Diaz, S.; Miranda, P.; Elamsson, K.; Johansson, E.D. Plasma levels of levonorgestrel in women during longterm use of Norplant. Contraception 1981, 23 (2), 197209. Keith, A.D. Polymer matrix considerations for transdermal devices. Drug Develop. & Ind. Pharm. 1983, 9, 605625. Hsieh, D.S.T. Subcutaneous controlled delivery of estradiol by compudose implants: in vitro and in vivo evaluations. Drug Develop. & Ind. Pharm. 1987, 13, 26512666. Wolff, M.; Cordes, G.; Luckow, V. In vitro and in vivo release of nitroglycerin from a new transdermal therapeutic system. Pharm. Res. 1985, 1, 2329. Corbo, M.; Liu, J.C.; Chien, Y.W. Transdermal controlled delivery of propranolol from a multilaminate adhesive device. Pharm. Res. 1989, 6 (9), 753758. Microsealed Pharmaceutical Delivery device. US Patent 4,053,580, Oct 11, 1977. Chien, Y.W. Microsealed drug delivery systems: Fabrication and performance. In Methods in Enzymology; Widder, K.J., Green, R., Eds.; Academic Press: New York, 1985; 461470. Sanvordeker, D.R.; Cooney, J.G.; Wester, R.C. Transdermal Nitroglycerin Pad. US Patent 4,336,243, June 22, 1982. Karim, A. Transdermal absorption: a unique opportunity for constant delivery of nitroglycerin. Drug Develop. & Ind. Pharm. 1983, 9, 671.
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27. Theeuwes, F.; Yum, S.I. Principles of the design and operation of generic osmotic pumps for the delivery of semisolid or liquid drug formulations. Ann. Biomed. Eng. 1976, 4 (4), 343353. 28. Theeuwes, F. Elementary osmotic pump. J. Pharm. Sci. 1975, 64 (12), 19871991. 29. De Leede, L.G.J. Rate-Controlled and Site-Specied Rectal Drug Delivery; Ph.D. Thesis; State University of Leiden: Leiden, The Netherlands, 1983. 30. Theeuwes, F. Oros-osmotic system development. Drug Develop. & Ind. Pharm. 1983, 9, 13311357. 31. Liu, J.-C.; Farber, M.; Chien, Y.W. Comparative release of phenylpropranolamine HCL for long-acting appetite suppressant products: acutrim vs. dexatrim. Drug Develop. & Ind. Pharm. 1984, 10, 16391661. 32. Michaels, A.S. Device for Delivering Drug to Biological Environment. US Patent 4,180,073, Dec. 25, 1979. 33. Blackshear, P.J.; Rohde, T.D.; Grotting, J.C.; Dorman, F.D.; Perkins, P.R.; Varco, R.L.; Buchwald, H. Control of blood glucose in experimental diabetes by means of a totally implantable insulin infusion device. Diabetes 1979, 28 (7), 634639. 34. Blackshear, P.J.; Rohde, T.D.; Varco, R.L.; Buchwald, H. One year of continuous heparinization in the dog using a totally implantable infusion pump. Surg. Gynecol. Obstet. 1975, 141 (2), 176186. 35. American pharmacy, implantable pump for morphine. NS24:20 1984. 36. Hsieh, D.S.T.; Langer, R. Zero-order drug delivery systems with magnetic control. In Controlled Release Delivery Systems; Roseman, T.J., Mansdorf, S.Z., Eds.; Marcel Dekker, Inc.: New York, 1983. 37. Kost, J. Ultrasound for controlled delivery of therapeutics. Clin. Mater. 1993, 13 (14), 155161. 38. Tyle, P.; Agrawala, P. Drug delivery by phonophoresis. Pharm. Res. 1989, 6 (5), 355361. 39. Bertolucci, L.E. Introduction of anti-inammatory drugs by iontophophoresis: double blind study. J. Orthopaed. & Sports Phys. Ther. 1982, 4, 103. 40. Glass, J.M.; Stephen, R.L.; Jacobson, S.C. The quantity and distribution of radiolabeled dexamethasone delivered to tissue by iontophoresis. Int. J. Dermatol. 1980, 19 (9), 519525. 41. Harris, P.R. Iontophoresis: clinical research in musculoskeletal inammatory conditions. J. Orthopaed. & Sports Phys. Ther. 1982, 4, 109. 42. Controlled Release Suspensions, APhA/APS Midwest Reg. Meet, Chicago, Illinois, April, 1984. 43. Raghunathan, Y. Prolonged Release Pharmaceutical Preparations. US Patent 4,221,778, Sept 9, 1980.
44. Raghunathan, Y.; Amsel, L.; Hinsvark, O.; Bryant, W. Sustained-release drug delivery system I: coated ionexchange resin system for phenylpropanolamine and other drugs. J. Pharm. Sci. 1981, 70 (4), 379384. 45. Heller, J. Biodegradable polymers in controlled drug delivery. Crit. Rev. Ther. Drug Carrier Syst. 1984, 1 (1), 3990. 46. Morimoto, Y.; Fujimoto, S. Albumin microspheres as drug carriers. Crit. Rev. Ther. Drug Carrier Syst. 1985, 2 (1), 1963. 47. Sezaki, H.; Hashida, M. Macromolecule-drug conjugates in targeted cancer chemotherapy. Crit. Rev. Ther. Drug Carrier Syst. 1984, 1 (1), 138. 48. Heller, J.; Pengburn, S.H. A triggered bioerodible naltrexone delivery system. Proc. Int. Symp. Control. Rel. Bioact. Mater. 1986, 13, 3536. 49. Heller, J.; Trescony, P.V. Controlled drug release by polymer dissolution. II: Enzyme-mediated delivery device. J. Pharm. Sci. 1979, 68 (7), 919921. 50. Horbett, T.A.; Ratner, B.D.; Kost, J.; Singh, M. A bioresponsive membrane for insulin delivery. In Recent Advances in Drug Delivery Systems; Anderson, J.M., Kim, S.W., Eds.; Plenum Press: New York, 1984; 209220. 51. Kim, S.W.; Jeong, S.Y.; Sato, S.; McRea, J.C.; Feijan, J. Self-regulating insulin delivery systemaa chemical approach. In Recent Advances in Drug Delivery Systems; Anderson, J.M., Kim, S.W., Eds.; Plenum Press: New York, 1983; 123. 52. Baker, R.W. Controlled release of biologically active agents; J. Wiley & Sons: New York, 1987. 53. Jeong, S.Y.; Kim, S.W.; Eenink, M.J.D.; Feijen, J. Selfregulating insulin delivery systems. I. Synthesis and characterization of glycosylated insulin. J. Controlled Release 1984, 1, 5766. 54. Ringsdorf, H. Synthetic polymeric drugs. In Polymeric Delivery Systems; Kostelnik, R.J., Ed.; Gordon and Brech: New York, 1978. 55. Chien, Y.W. Logics of transdermal controlled drug administration. Drug Develop. & Ind. Pharm. 1983, 9, 497520. 56. Noonan, P.K.; Gonzalez, M.A.; Ruggirello, D.; Tomlinson, J.; Babcock-Atkinson, E.; Ray, M.; Golub, A.; Cohen, A. Relative bioavailability of a new transdermal nitroglycerin delivery system. J. Pharm. Sci. 1986, 75 (7), 688691. 57. Chien, Y.W. Microsealed drug delivery systems: theoretical aspects and biomedical assessments. In Recent Advances in Drug Delivery Systems; Anderson, J.M., Kim, S.W., Eds.; Plenum Press: New York, 1984; 367387. 58. Chien, Y.W. Potential developments and new approaches in oral controlled release drug delivery systems. Drug Develop. & Ind. Pharm. 1983, 9, 12911330.
Drug Delivery
Drug Delivery: Fast-Dissolve Systems

Vikas Agarwal Bhavesh H. Kothari Derek V. Moe Rajendra K. Khankari
CIMA Labs, Inc., Brooklyn Park, Minnesota, U.S.A.
INTRODUCTION Orally disintegrating tablets (ODTs) rapidly disintegrate in the mouth without chewing upon oral administration and without the need for water, unlike other drug delivery systems and conventional oral solid immediate-release dosage form.[1] ODT dosage forms, also commonly known as fast melt, quick melts, fast disintegrating, and orodispersible systems have the unique property of disintegrating the tablet in the mouth in seconds. For acute conditions, this dosage form is easier for patients to take anytime, anywhere those symptoms occur. For chronic conditions, it is assumed to improve compliance. Some important advantages of ODT drug delivery over others are ease of swallowing for patients and convenience of taking the medication anytime without the need of water. Some limitations include difculty in developing extremely high doses (typically in excess of 500 mg), and sometimes-extensive taste masking of bitter tasting actives. Orally disintegrating dosage forms are often formulated for existing drugs with an intention to extend the patent life of the drug through product differentiation. They are evaluated against the innovator drug in a bioequivalence study in humans to establish comparability of pharmacokinetic parameters. Although intuitive, at the present time no data exists that ODTs improve compliance over solid oral dosage forms.
differentiation, and patient compliance. Owing to the increased costs of getting a product to market and focus on clinical advancement, new chemical entities (NCEs) typically do not go through an extensive evaluation of DDT. The goal is to get the product through the clinical studies with a stable formulation that can achieve the safety and efcacy required for Food and Drug Administration (FDA) approval. The time to get the NCE to the market eats up a majority of the patent life cycle of the drug. Drug delivery technologies are very helpful in adding value/timeline to the patent. They offer additional benets such as patient compliance and ease of administration. Market data suggests that sales of DDT-based products are increasing in general and will continue to increase.
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DRUG DELIVERY MARKET Drug delivery systems are technologies that transport the active drug into the bodys circulatory system. Drug can be delivered into the body by various means, depending on its physical and chemical properties. Some may alter the method of taking the drug, others alter the desired therapeutic activity. The advent of new drug delivery systems can clearly differentiate a drug product in todays highly competitive pharmaceutical market. To better understand the concept of the drug delivery system, one needs to know how a drug delivery system can be a valuable and costeffective life cycle management resource. Pharmaceutical companies worldwide have recognized various drug delivery systems as powerful marketing tools to differentiate products, extend product life cycles, and even improve the efcacy of a drug. Several examples
MARKET NEEDS The application of a drug delivery technology (DDT) to any molecule is based on market needs, product
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include Claritin ODTs, Actiq (transmucosal dosage form for patient compliance), and Cardiazem XL (osmotic dosage form for extended release). The drug delivery market encompasses a wide array of technologies that cover various routes of administration such as oral, nasal, transdermal, and inhalation. The oral route remains most popular owing to the ease of administration, manufacturing, and regulatory strategy. The oral drug delivery market encompasses technologies such as sustained and controlled release dosage forms, oral transmucosal technologies, targeted technologies, pH-specic dosage forms, and orally disintegrating dosage forms. The increasing popularity of orally disintegrating dosage forms is in part owing to various factors such as patient preference and life cycle management.[2] Some reasons for patient preference include fast disintegration, good mouth-feel, easy to handle, easy to swallow, and effective taste masking (for tablet based technologies). A perceived benet for ODT is the ease of administration to elderly and pediatric populations and other patient populations that have difculty swallowing traditional tablets or capsules. A customer study funded by CIMA was done to measure consumer/patient reactions to fast dissolve. The population size was 5000 and spanned across a diverse age group. Patients were given a conventional tablet and an ODT and asked various questions. A signicant majority of the patients said they would or might prefer a fast dissolve dosage form over a regular tablet or liquid. Only 12% of the patients rejected fast dissolve tablets. Most of the patients also indicated that they would ask their doctor for a fast dissolve version and would purchase a fast dissolve if available. Life cycle management allows for differentiation of product in the market. According to datamonitor, drugs worth $37 billion will loose patent protection between 2000 and 2010. Development of an ODT formulation within the patent expiration period can add signicant patent life to the formulation as it cannot be substituted at the pharmacy counter until an equivalent ODT is available in the market.
specic needs of the product. Each technology utilizes one or more combinations of processes described below to develop ODT drug delivery systems. ODT development consists of three parts: 1. Evaluating the need to taste mask the drug. 2. Incorporating the taste masked/non-tastemasked drug into the tablet matrix. 3. Packaging.
TASTE-MASKING PRINCIPLE Taste masking of drug may be achieved with preventing the exposure of drug to the tongue through processing or adding competing taste-masking agents. Exposure of solubilized drug to the oral cavity can be prevented by encapsulation in polymer systems or complexation.[5] The approaches are as follows: Layering the drug onto inert beads using a binder followed by coating with a taste-masking polymer. Granulating the drug and coating with a tastemasking polymer. Spray drying the drug dispersed or dissolved in a polymeric solution to get taste-masked particles. Complexation by the use of inclusion in cyclodextrins. Psychological modulation of bitterness. Coacervation to form microencapsulated drug within a polymer. Formation of pellets by extrusion spheronization. Layer/Coat Process The layering process involves deposition of successive layers of an active compound onto the granules of the inert starter seeds such as sugar spheres or microcrystalline cellulose beads. Sugar spheres (Non Pareil) or microcrystalline spheres (Celpheres) can be used as initial substrate in the preparation of beads by the layering process. In the layering process, the bitter drug is dissolved or dispersed in an aqueous or non-aqueous solvent, depending on its solubility characteristics and ease of processing. Binder is added to the solution to form liquid bridges between the primary particles. Most commonly used binders are gelatin, povidone, carboxymethyl cellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), and maltodextrin.[6] In solution form, the drug is completely soluble in the solvent, while in dispersed form, the drug is either micronized before adding into the solvent or the solvent containing dispersed drug is subjected to wet milling using a high-shear mixer to micronize in solution. It is desirable that the ratio of
MANUFACTURING PROCESSES FOR ORALLY DISINTEGRATING SOLID DOSAGE FORMS This part of the article describes the main processes, which can be used to develop an ODT drug delivery system.[3,4] The processes described hereunder are utilized to develop ODTs, depending on its capabilities and limitations, in addition to developing the product within an acceptable period of time satisfying all the
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particle size of the drug to the size of the beads is about 1 : 10. In the layering process, drug layering up to 100150% in weight is achievable, beyond which drug layering may cause excessive grittiness because of increased particle size of the granules when incorporated into a dosage form. A potential disadvantage encountered during drug layering process is the possibility of drug recrystallizing into different polymorphs upon completion of the process. After the drug is layered over an inert starting material, it is then coated with a polymer that retards dissolution in the oral cavity. Two mechanisms to prevent dissolution are predominantly used, either a polymer that slows down dissolution across all pHs or a polymer that does not dissolve in the pH of the saliva but dissolves rapidly in the gastric uid of the stomach. The various polymers used for taste-masking purpose are Eudragit E 100, ethylcellulose, HPMC, HPC polyvinyl alcohol, and polyvinyl acetate. The polymer is dissolved in an aqueous or non-aqueous solvent depending on its solubility characteristic and antitack agents such as talc, magnesium stearate, and cab-o-sil are added to improve processing and prevent agglomeration. Sometimes taste masking is possible by combining layer/coat in a single process, i.e., incorporating the drug in solution/suspension form containing a polymer that serves both as a binder and as a taste-masking agent and then depositing the drug onto beads.
Spray Drying For taste-masking application, the drug is either dissolved or dispersed along with bulking agent (polymer) and, occasionally, a binding agent is also added if required, in a suitable solvent. Spray drying consists of four stages: atomization of feed into a spray, sprayair contact (mixing and ow), drying of spray (moisture/volatiles evaporation), and separation of dried product from the air.[7] The solvent used for spray drying process may be aqueous or non-aqueous. Product obtained upon spray drying yields highporosity granules or beads containing encapsulated drug. Some unintended effects include formation of solid dispersions of the drug owing to recrystallization and thermal degradation for temperature-sensitive drugs. Complexation Taste masking by inclusion complexation is possible by physically entrapping the drug in cone-shaped structures called cyclodextrins.[8] Cyclodextrins are bucketshaped oligosaccharides produced from starch. Owing to their peculiar structure and shape, they possess the ability to entrap guest molecules in their internal cavity. Drug inclusion complexes can be formed by a variety of techniques that depend on the property of the drug, the equilibrium kinetics, other formulation ingredients, processes, and the nal dosage form desired. In all these processes, a small amount of water is required to achieve thermodynamic equilibrium. The initial equilibrium to form the complex is very rapid, the nal equilibrium takes a longer time. The drug, once inside the cyclodextrin cavity, makes conformational changes to itself so as to attach itself to the complex and to take maximum advantage of the weak van der waals forces. Complexation is also possible through the use of ion-exchange resins. Both anionic and cationic types are available.[9] The preparation of the taste-masked complex involves suspending the resin in a solvent in which the drug is dissolved. For liquid preparations, the drugresin complex can be used as is. For solid dosage forms, the complex may be processed by ltration or direct drying. Drug loading up to 50% is possible with this process. Some commercially available ion-exchange resins that may be used for taste masking are based on methacrylic acid and divinyl benzene and styrene divinyl benzene polymer.[10] Psychological Modulation of Bitterness Taste masking with addition of competing agents involves modulating the psychological perception of
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Granulation Taste masking by granulation is achieved by decreasing the surface area of the drug by increasing its particle size. The additional benet obtained is ease of processing for tablet compression as the majority of drugs have a low bulk density. Additionally, polymers that serve as binders and taste-masking agents may be incorporated, which reduce the perception of taste. Granulation may be achieved with or without the use of a solvent. Dry granulation involves the use of forming compacts/slugs that are milled for blending. Wet granulation can be achieved by using the uid bed process or high-shear granulation. In the uid bed process, the drug is suspended in the bed with air, and a binder is sprayed from the top. The granules formed are porous and not amenable to further processing like coating. In high-shear granulation, the granule formation occurs by spraying a liquid binder onto drug/mixture of drugs with excipients that are being agitated by combined action of an impeller and chopper. The granules obtained are dense and may be used directly or coated further in a uid bed. This approach is suitable for high-dose drugs (>50 mg) with unpleasant taste.
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bitterness. To understand this better, the theory of perception of taste is in order. The biochemical and physiological basis of bitterness has been summarized recently.[11,12] There are two theories. One theory contends that receptors for common taste stimuli such as salt, bitter, and sweet are present in specic locations of the tongue. The second theory contends that taste buds respond to all stimuli to a different extent. Regardless of the mechanism, taste masking is achieved by the addition of specic inhibitors to suppress the stimuli. This approach is likely to involve the use of an inhibitor specic to the taste masking of the drug in question. In the authors knowledge, there is no specic universal inhibitor available, which will mask all the taste stimuli.
form of the drug; however, the appropriate choice of polymers could lend itself to taste masking. The advantage touted for this is better control of particle size of the pellets and absence of the use of solvents.
INCORPORATION OF TASTE-MASKED DRUG/NON-TASTE-MASKED DRUG INTO THE TABLET MATRIX After evaluating the need to taste mask the drug, the drug is then incorporated in the nal dosage form. Final dosage forms for ODTs can be achieved using freeze drying, molding, and direct compression. Freeze drying based ODT technology is a single-step process. Taste masking, if achieved, and formation of the matrix can be achieved in one step. Alternatively, the drug may be incorporated in the freeze-drying process in a taste-masked form. Molding and compressionbased technologies mostly involve taste masking as a separate processing step. Each process has its own advantages and disadvantages and are discussed below.
Coacervation Coacervation leads to formation of a microencapsulated form of drug. The process primarily consists of formation of three immiscible phases, formation of the coat, and deposition of the coat. The formation of the three immiscible phases is accomplished by dispersing the core particles in a polymer solution. A phase separation is then induced by changing the temperature of the polymer solution, addition of a salt and nonsolvent, or by inducing a polymerpolymer interaction. This leads to deposition of the polymer coat on the core material under constant stirring. The core particles coated by the polymer are then separated from the liquid phase by thermal, cross-linking, or desolvation techniques leading to rigidization of the coat.[13]
TABLET MATRIX PRINCIPLE
Extrusion Spheronization The process begins with the blending of dry powders followed by granulation. The granulation is different from conventional granulation as the end point is determined by the consistency of the paste suitable for passing through an extruder. After passing through the extruder, the granulate is in the form of rods. The rods can then be passed through a spheronizer to form pellets, which are then dried. An advantage touted for extrusion spheronization is the formation of more spherical pellets compared to wet granulation.[14] Hot-melt extrusion involves passing a molten solid dispersion of the drug through a extruder to obtain pellets. The hot-melt extrudate consists of drug dispersed in a molten hydrophilic matrix, which is then passed through an orice in the extruder. The extruder paste can then be passed through a spheronizer to obtain pellets that are subsequently cooled. This process is primarily used for increasing the solubility of poorly soluble drugs as it leads to formation of amorphous
Freeze drying, also known as lyophilization, is a process in which water is sublimated from the product after freezing. This process can be used in many different ways to achieve the same end point. In one of the freeze-drying formulation methods, drug is physically trapped in a water-soluble matrix (water-soluble mixture of saccharide and polymer, formulated to provide rapid dispersion, and physical strength), which is freeze dried to produce a product that dissolves rapidly when placed in the mouth. The ideal candidate for this kind of manufacturing method would be a molecule that is chemically stable and water insoluble, with a particle size lower than 50 mm.[15] In another method, lyophilization of an oil-in-water emulsion (porous solid galenic form) is placed directly in the blister alveolus.[16] One other method for ODT manufacture using freeze drying involves the formation of a porous solid form obtained by freezing an aqueous dispersion or solution of the active containing matrix, then drying the matrix by removing the water using an excess of alcohol (solvent extraction). The ideal candidates for this kind of method should be insoluble in the extraction of solvent. The advantage of this process is that drug substances that are thermolabile in nature can be formulated at non-elevated temperature, thereby eliminating adverse thermal effects, and stored in a dry state with few shelf life stability problems.[17]
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Molding Compression molding is a process in which tablets are prepared from soluble ingredients such as sugars by compressing a powder mixture previously moistened with solvent (usually ethanol or water) into mold plates to form a wetted mass.[18] In hot-melt molding, molded forms are prepared directly from a molten matrix in which drug is dissolved or dispersed (heat molding) or by evaporating the solvent from a drug solution or suspension in the presence of nitrogen gas at standard pressure (novacuum lyophilization). Tablets produced by this type of molding are solid dispersions categorized as hot melt. In molding, the drugs physical characteristic depend on whether its dissolves or disperse in the molten carrier. The drug can exist as discrete particles dispersed all over the matrix or dissolved in the matrix. When the drug is dissolved in the matrix, it forms a solid solution. The characteristic of the tablets (such as disintegration time, drug dissolution rate, and mouth feel) will depend on the state of the drug whether dispersion or dissolution. As the molded tablets dispersion matrix in which the drug gets dispersed or dissolved are made of water-soluble sugars, tablet disintegration is more rapid when tablets are more porous.
Direct Compression A direct compression method uses conventional equipment, commonly available excipients, and a limited number of process steps. This process may involve granulation prior to nal blend. The direct compression tablets disintegration and solubilization are based on the single or combined action of super disintegrants, water-soluble excipients, and effervescent agents.[19] In many cases, the disintegrants have a major role in the disintegration and dissolution process of ODT technology made by direct compression. The choice of a suitable type and an optimal amount of disintegrants is paramount for ensuring a rapid disintegration rate. Several different formulation routes are followed to achieve an optimal disintegration time in ODT drug delivery systems made by direct compression.
PACKAGING Upon prototype selection, selection of a packaging conguration is a crucial part of an ODT dosage form. Unlike conventional tablets, where packaging provides a means of administration/transport, ODTs may require specialized packaging congurations owing to their relative high moisture sensitivity and fragility.
In fact, the cost of packaging can be signicant for commercialization. One approach used to overcome the moisture and physical issues with ODTs is to select a rigid, multilayer foil-based barrier material to protect the dosage form, with the blister actually forming during the tablet formulation process. In many cases, ODT are very fragile, and regular push through blister packaging may break the tablet upon removing from the blister, so the packaging requires a peelable closure. Packaging made from formable and exible material can offer protection from water, oxygen, or ultraviolet barrier, as well as providing some physical protection. The most common packaging conguration includes blister packaging and bottle packaging. Blisterpackaged ODTs require specialized packaging equipment. In case of CIMAs PakSolv Technology, tablets are picked and placed in individual blister pockets one at a time using a robotic hand. In the case of freeze drying technology, each blister needs to be lled individually with the solution or suspension before subjecting it to freeze drying. The nal packaged dosage form has to be evaluated to verify packaging integrity. One way to perform this is by immersing blisters in water and subjecting them to a vacuum for a specied period of time. The blisters are then opened manually and checked for presence of water droplets. Additionally, blisters and bottles should be monitored in simulated shipping tests according to American Society for Testing Materials (ASTM) standards. An additional issue with blister packaging is the evaluation of child resistance. The Consumer Product Safety Commission regulates this. The blisters are evaluated for F value, and appropriate designs need to be in place for child resistance and senior friendliness. The F requirement is determined from the toxicity of the drug. In the case of tablets, this would be the number of tablets that when ingested may produce a serious injury or serious illness based on a 25-pound child. A package passes a certain F rating, if 90% of the children from an initial 50-child test are not successful in accessing the required F number of tablets. As an example, if it is determined that an F 3 package is required and during testing with 50 children, 4 children are able to access three or more cells during the test, an F 3 rating is obtained at 92%. Commercialization of ODTs have to go through the nal evaluation of long-term stability of the tablet matrix and packaging components per International Conference on Harmonisation guidelines. As the majority of ODT dosage forms on the market are sensitive to moisture, evaluation of moisture vapor transmission rate is an important parameter for assessing the shelf life of the product.
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Some ODTs are sensitive to moisture to such an extent that, even during processing or formulation development stages, temperature and humidity have to be controlled to avoid long-term stability issues and may require special packaging. Long-term stability studies done with several ODT products have indicated that the foilfoil blister PakSolv blister design leads to a mere 0.1% increase in moisture level compared to start over six months at 40 C/75% RH. The increase in moisture level for high density polyethylene (HDPE) bottles is about 0.5% under the same stability conditions at the end of six months based on CIMA in-house experience on all bottled products.
attempt to mimic in vivo performance. As with many analytical methods, there is no denite correlation between in vitro and in vivo data. In vitro disintegration tests serve as an important quality control test throughout the development of the product. A disintegration time specication is considered standard on nal product specication for ODTs, unlike conventional tablets.
Hardness and Friability Many ODTs, in an effort to decrease disintegration time, are highly porous soft-molded tablets compressed at low compression force.[24] Sometimes if the formulation and processing parameters are not optimized, the tablets can exhibit higher friability irrespective of any hardness changes. Also, problems like capping, picking, and chipping are observed during formulation development if the formulation and processing parameters are not optimized. Several of the compressed ODTs are more robust and can withstand the rigors of bottling. Dissolution Dissolution testing of ODTs has been reviewed recently.[25] As ODTs sometimes contain taste-masked active, it adds an added layer of complexity to the development of a dissolution method for tablets. The taste masking plays a signicant role in dissolution method development, specications, and testing. The USP 2 paddle apparatus is the most suitable and common choice for ODTs. USP 1 is not appropriate owing to rapid disintegration in the screen, leaving signicantly less perturbation of the product in the media. Discriminating, robust dissolution methods has value in monitoring process optimization, changes during scale-up of taste-masked bulk drug and tablet manufacture and routine quality control testing. This is important as the barrier properties of the scaled-up taste-masked product may change, leading to leaching of the drug in the oral cavity that may effect taste or even bioequivalence. Upon selection of a prototype based on the evaluation techniques described above, the individual processes are scaled up against FDA guidelines and evaluated for stability and bioequivalence.
IN PROCESS CHALLENGES The nal product containing taste-masked drug, and matrix is typically evaluated for sensory characteristics, disintegration time, and compared for dissolution. Sensory characteristics of prototypes include evaluation in taste panels in humans. Some of the characteristics tested are avor acceptance, bitterness perception, sweetness, and after taste. Evaluation in human panels is not entirely possible all the time owing to the cost and timing associated with human testing. Some alternate methods include dissolution testing in small volume[20] and electronic evaluation of taste referred to as an electronic tongue.[21] It consists of coated probes that are immersed in a liquid-containing dissolved solids. The potentiometric response of the probe is compared for the active and placebo using principal component analysis mapping. The response of the product containing the active that is closest to placebo is regarded as the best formulation.
Disintegration Disintegration is an important characteristic of an ODT. According to the Center for Drug Evaluation and Research Data Standards Manual, the denition of an ODT is A solid dosage form containing medicinal substances which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue.[22] According to the European Pharmacopoeia (EP), Orodispersible tablets are uncoated tablets intended to be placed in the mouth where they disperse rapidly before being swallowed.[23] The test criteria outlined by EP is Orodispersible tablets should disintegrate within 3 min when examined by the test for disintegration of tablets and capsules. In vitro disintegration testing is sometimes performed by the standard United States Pharmacopoeia (USP) method and often times by more discriminating methods in an
REGULATORY The FDAs approval process for any application whether it is a new drug application (NDA), abbreviated new drug application, or over-the-counter is a closely
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monitored government activity. The FDA has set regulations for ling a petition of a Supplemental NDA for a drug that has the same strength and route of administration as a drug listed in the FDAs publication entitled Approved Drug Products with Therapeutic Equivalence Evaluations, but differ in dosage form. This petition generally can be led pursuant to section 505(b) (2) of the Federal Food, Drug and Cosmetic Act and 21 CFR x 314.93. Most of the ODT drug delivery systems fall under this category. Depending on the bioequivalence study, certain products can get approval under this clause or otherwise will need to establish safety and efcacy of the product by conducting further clinical trials. As ODT products do not require administration of water, it may be required to perform bioequivalence studies with and without water depending upon the nature of the drug. This will depend upon the difference of absorption of drug in the fed and fasted state and in addition may lead to a fed and fasted study.
Lyoc Lyoc technology is owned by Cephalon Corporation. CIMA is a subsidiary of Cephalon, and currently manages the Lyoc R&D efforts. This was the rst freezedrying-based technology introduced for ODTs. The process involves preparation of a liquid solution or suspension of the drug containing llers, thickening agents, surfactants, non-volatile avoring agents, and sweeteners.[29] This homogenous liquid is then deposited in blister cavities and subjected to freeze drying. Advantages of Lyoc compared to other freezedried dosage forms include absence of preservatives. Zydis Zydis technology is owned by RP Scherer, a subsidiary of Cardinal Health. This drug delivery system consists of freeze-dried tablets having active drug designed to rapidly disintegrate in the mouth.[30] The freeze-dried tablet is made by lyophilizing a suspension or solution of drug containing various excipients such as polymer, polysaccharides, preservatives, pH adjusters, avors, sweeteners, and colors, which is then lled in blisters. Freeze drying occurs in the blisters, which are then sealed and further packaged. Some of the advantages of the Zydis system include fast disintegration time. Some of the disadvantages include low throughput, high cost of goods, and limited taste masking. Flashtab Flashtab tablet matrix consists of a swellable agent (modied starch or microcrystalline cellulose) and a super disintegrant (crospovidone or croscarmellose). The system may also contain, depending on the need, a highly water-soluble polyol with binding properties such as mannitol, sorbitol, maltitol, or xylitol, instead of the swellable agent as mentioned before.[31] The active is taste masked by direct coating. Tablets manufactured using this technology produce durable tablets in which the excipients are rst granulated using wet or dry granulation process, then the coated drug is mixed with the excipient granules and compressed into tablets that can be handled and packaged using conventional processing equipment. Tablets for blister packaging can withstand the pressure used to push the tablet out of the lidding foil of the blister card. Tablets containing hygroscopic material can also be blister packaged, by using high-quality polyvinyl chloride or aluminum foils, which provide a higher degree of moisture protection than ordinary polyvinyl chloride or polypropylene foils.
ORALLY DISINTEGRATING TECHNOLOGIES OraSolv, DuraSolv, and PakSolv OraSolv and DuraSolv are CIMAs core ODT tabletbased technologies. The ingredients contained in the technology include polyols as llers, disintegrant, which may include an effervescence couple, avor, sweetener, and lubricant. The drug may be taste masked if required typically utilizing a uid bed coating process. The tabletting process includes direct compression, and can accommodate a wide range of potency from less than 1 mg to as high as 500 mg. Tablets manufactured with OraSolv technology should contain an effervescence couple along with microparticles of drug within a rupturable coat.[26] The tablets manufactured are compressed at a low hardness that promotes fast disintegration. The dosage forms need to be packaged in foilfoil aluminum blisters with a dome shape that impact physical protection and impermeability to moisture. This constitutes the PakSolv Techonology.[27] Tablets manufactured with DuraSolv technology contain a non-directly compressible ller and a lubricant. They may or may not contain effervescence, and the drug need not be taste masked.[28] DuraSolv tablets are compressed at higher hardness compared to OraSolv that allows for packaging in bottles or push through blisters. The advantages of tablet-based technology include low cost of goods, standard manufacturing technology, standard packaging format and materials, and lowdevelopment costs and risks. Disadvantages include slightly longer disintegration time.
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FlashDose Fuisz technologies is the inventor of the FlashDosetechnology.[32] It is now owned by Biovail. FlashDose tablets are manufactured utilizing SHEARFORM matrix in which material containing substantial amounts of brous polysaccharides, which are processed by simultaneous action of ash melting and centrifugal force, are compressed to form ne sugar bers. FlashDose tablets containing a matrix of these sugar bers disintegrates very rapidly upon contact with saliva, with disintegration times of a few seconds. The tablets produced by FlashDose are hydrophilic and highly porous, owing to relatively low compression during the pressing of the tablets. For taste masking, Fuisz uses its own patented, single-step, solvent-free process, termed CEFORMTM technology, which produces uniform microspheres with a very narrow particle size distribution. The resulting tablets produced by this process are soft, friable, and highly moisture sensitive. They require specialized packaging materials and processes to protect them from external humidity and mechanical abrasion. WOWTAB WOWTAB tablets are developed by Yamanouchi Pharma Technologies.[33] The main ingredients in the tablets include low- and high-moldable sugars. The low-moldable sugars promote quick dissolution and include mannitol, lactose, and glucose. High-moldable sugars promote good hardness upon compaction and include maltose, sorbitol, and maltitol. The active and other excipients are granulated with a solution containing both the sugars in a uid bed granulator. The granules obtained are blended with lubricants and avors and then compressed to form tablets. The tablets are then stored in a controlled humidity and temperature system for conditioning and then packaged in blisters or bottles. Taste masking of the active may be achieved by the use of cyclodextrins.
technology, the unit doses are not initially formed from liquid dispersions, but from the tabletted article subjected to freeze drying. The water needed to be removed during freeze drying is introduced into the tablets in the form of ice particles and mixed along with excipients and active and subsequently compressed at low temperature. The porosity in the tablet is determined and controlled by the number and size of ice particles. Microencapsulated liquid or gelled binder is incorporated in the tabletting mixture to obtain rigid tablets with high tensile strength. During compression, the microcapsules disintegrate and release the binder, which improves the adhesion between the compressed drug and excipient particles OraQuickTM KV Pharmaceuticals two proprietary taste-masking technologies, FlavorTech and MicroMask, are utilized for developing OraQuick tablets. MicroMask provides taste masking by incorporating a drug into matrix microspheres. The rst step involved in formulating the tablet include dissolving the sugar (sucrose, mannitol, sorbitol, xylose, dextrose, fructose, or mannose), and protein (albumin or gelatin) in a suitable solvent, such as water, ethanol, isopropyl alcohol, and ethanolwater mixture.[35] The porosity of the product is determined by the quantity of solvent used in the formulation. The solution of the matrix is then spray dried, yielding highly porous granules. The matrix granules are mixed with other excipients such as binder, lubricant, sweeteners, avors, coloring agent, llers, disintegrants, surfactants, etc. The drug can be added at this stage in the form of taste-masked granules, other wise added rst in the matrix granule. The granules or powder obtained is then compressed at low compression force to form tablets that are soft and friable but highly porous. After the tablets are compressed, they are subjected to a sintering step. Tablets are sintered in an oven, typically at temperature of about 50 C to 100 C for few minutes to several hours or at 90 C for about 10 min. During this step, the compressed tablets containing binder (polyethylene glycol) in the earlier step melts and binds particles to form stronger tablet.
ODT Technologies in Development KryotabTM Biotron designs and develops freeze-dried tablets and microparticles using low-temperature and cryogenicprocessing technologies.[34] The products developed may be used for different dosage forms such as oral, parenteral, pulmonary, and transdermal delivery. Kryotab technologys two version used to develop different dosage form are Kryotab-MIM and KryotabCD. Unlike RP Scherers Zydis technology, in this
Quick-DisTM Lavipharm Laboratories is the inventor of Quick-Dis technology. Quick-Dis technology refers to thin, easily dispensed, exible, and rapidly dissolving lms for the local or systemic delivery orally.[36] Quick-Dis disintegrates rapidly upon wetting when placed under the tongue. This drug delivery of Lavipharm has the
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capability of being printable, non-tacky in nature while dry, with a low-residual water content, easy to process. The lm thickness ranges from 1 to 10 mils, and surface area can be 120 cm2 for any geometry. Lavipharm manufactures its oral lms by a solvent-casting process, using water as the preferred solvent followed by a drying step. The coating thickness range is typically from 5 to 20 mils with aerated oven drying. The lms can also be processed alternatively using cold- or hot-melt extrusion technique.
handle high drug loading and coated particles, can be packed in both bottles and pushed through blisters. QdisTM Phoqus owns the Qdis technology. The dosage forms comprises of ODTs containing agglomerates greater than 50 mm in size that comprises at least 10% or more of superdisintegrants without drug. The agglomerates are blended with excipients, and drug particle size ranging in size from 50 to 300 mm. The resulting soft tablets are coated using an electrostatic dry-powder deposition technology. This coating strengthens the tablet while still providing rapid disintegration.[38] FrostaTM Akina owns Frosta technology. The technology incorporates manufacture of highly plastic granules using a plastic material, a material enhancing water penetration, and a wet binder.[39] These granules can then be compressed into tablets at low pressure, thus enabling fast disintegration upon administration.
AdvatabTM Eurand is the owner of Advatab drug delivery system. Eurand is known for its Microcaps technology, which involve taste-masking drug particles using microencapsulation process based on coacervation/phase separation technique.[37] Eurand applied Microcaps technology to design ODTs (Advatab), which contains taste-masked active ingredients. The primary ingredients in the dosage form include sugar alcohols and saccharide with particle size less than 30 mm along with disintegrant and lubricant. The lubricant used in the formulation is added as an external lubricant compared to conventional formulations, which contain an internal lubricant. The company claims that this allows the tablets to be stronger compared to conventional tablets as internal lubricants are hypothesized to decrease binding of the drug particles. The dosage forms are manufactured using conventional tabletting and packaging equipments. The tablets, which can
Miscellaneous Owing to the increasing popularity of ODTs, some recent trends are of notable mention. One of them is the use of highly plastic granules to compress into tablets at low pressure to enable it to melt faster,
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Table 1 ODT technologies and corresponding commercial products Technologies DuraSolv , OraSolv

Company name CIMA
Products on market Tempra Quicklet/Tempra FirsTabs, Trimainic Softchews (several formulations), Remeron SolTabs, Zomig Rapimelt, Nulev, Alavert, FazaClo, Parcopa, Niravam, Clarinex Redi Tabs Neruofen Nurofen None None Film none None Film none Benadryl Fastmelt None Maxalt MLT, Claritin Reditabs, Zyprexa Zydis, Zofran ODT Proxalyoc (piroxicam), Paralyoc (paracetamol), SpasponLyoc (loperamide)
FlashDose Flashtab Kryotab OraQuick Quick-Dis RapitrolTM Slow-DisTM WOWTAB Advatab Zydis Lyoc
Biovail Ethypharm Biotron KV Pharmaceutical Lavipharm Lab Shire Lab Lavipharm Lab Yamanouchi Eurand Cardinal Health Cephalon
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CONCLUSIONS As discussed in this article, drugs can be administered into humans by various drug delivery systems. A large number of companies are in the ODT drug delivery market, which is evident from the number of products launched as ODT and patents approved. Amongst other drug delivery companies, those in the ODT market possess tremendous potential of extending the drug product life cycle, reducing the attrition rate during the drug development stage, and extending the protability of existing products. Owing to its exible nature, molecules of a wide variety of doses and chemical characteristics can be incorporated into an ODT. The different technologies such as ne particle layering/ coating or adding avors/sweeteners into tablet matrix for taste masking, spray drying, granulation, freeze drying, molding are now widely accepted applications in the industry for developing an ODT. As pharmaceutical companies are now starting to recognize the need for more technological advances to meet the new challenges in the future, DDT continues to have
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thereby enhancing the dissolution prole. The plastic granules are made of three components namely: a plastic material, a material enhancing water penetration, and a wet binder.[39] Excipient manufacturers are now supplying excipients specically geared toward manufacture of ODTs. One of them is spray-dried mannitol. The properties of this excipient suitable for ODTs include good compressibility at low hardness and fast disintegration, desirable properties for the manufacture of ODTs. The two brands commercially available include Pharmaburst by SPI Pharma[40] and Pearlitol by Roquette.[41] The hope is that it will stimulate the development of ODTs in house for pharmaceutical companies not traditionally involved with manufacture of ODTs. Companies are offering taste-masking capabilities for drugs. Some of them are Particle Dynamics,[42] The Coating Place,[43] and Particle and Coating Technologies.[44] The rationale here is outsourcing of taste-masking abilities of drugs, which can then be combined, with the use of excipients such as spray-dried mannitol to develop ODTs in-house. One company has gone a step further. SPI Pharma has a business agreement with Particle and Coating Technologies to taste mask drugs for their clients or offer the ability for manufacture of free-dried ODTs through their agreement with Oregon Freeze Dry Company.[45] This allows developments of an ODT of both compressed or freeze-dried dosage form for a client without having any in-house resources. Table 1 outlines some of the ODT technologies and corresponding commercial products, if any.
a signicant impact and contribution in meeting those demands and challenges.
ARTICLE OF FURTHER INTEREST Hot Melt Extrusion Technology, p. 2004.
REFERENCES
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Drug Delivery: Buccal Route

Drug Delivery: Buccal Route

Drug Delivery: Buccal Route

3.2 Buccal 2.8 2.4 Sublingual

Plasma ISDN ng/ml

2 1.6 1.2 0.8 0.4 0 0

Solid drug powder or tablet

Dissolved drug in buccal fluids

Dissolved drug in buccal membrane

Drug removed from oral cavity by swallowing

Drug in blood circulation

Drug Delivery: Buccal Route

Drug Delivery: Buccal Route

Drug Delivery: Buccal Route

Drug Delivery: Buccal Route

Captopril conc. (ng/ml)

150 100 50 0 0 30 60 90 120 Time (min) 150 180

Captopril conc. (ng/ml)

A 300 Captopril conc. 250 200 Systolic BP 115 110 120

Drug Delivery: Buccal Route

Drug Delivery: Buccal Route

Drug Delivery: Buccal Route

Drug Delivery: Buccal Route

Drug Delivery: Controlled Release

Drug Delivery: Controlled Release

Drug impermeable barrier

Km=r Ka=m Dd Dm Q CR t Km=r Dm hd Ka=m Dd hm

Drug Sitetargeting moiety

Biochemical responsive/ Energy sensor

Biochemical responsive/ Energy sensor

Drug Delivery: Controlled Release

Pilocarpine release rate (mcg/hr)

200 300 400

Drug Delivery: Controlled Release

Drug-impermeable metallic plastic laminate

Rate-controlling polymeric membrane Adhesive layer

Plasma nitroglycerin conc. (ng/ml SD)

0.15 Night Period 0.10

Drug Delivery: Controlled Release

total load of levonorgestrel daily dose 30 g

0.75 0.50 0.25

NONPLANT SUBCERNAL INPLANTS Mean value and 95% confidence intervals

Time of use (years)

Drug Delivery: Controlled Release

B Drug reservoir (Dispersion) Drug release

Drug depletion zone Drug release

Drug Delivery: Controlled Release

Adhesive rim (microporous acrylic polymer tape)

Drug reservoir (drug/hydrophilic polymer matrix)

Plasma nitroglycerin conc. (ng/ml SEM)

Drug Delivery: Controlled Release

Release liner 1000 500

Estradiol-releasing polymer matrix

Drug Delivery: Controlled Release

Drug-impermeable metallic plastic laminate

R1 R2 R3 Drug reservoir gradient layers (R1 > R2 > R3)

Adhesive layer 400

Plasma nitroglycerin conc. (pg/ml)

Duration of Device/Skin contact (h)

Drug Delivery: Controlled Release

Perfect sink (Cb = 0) Solution bulk

Drug depletion zone

Polymer coating membrane

DRUG-IMPERMEABLE BACKING LAMINATE