Encyclopediaof
`
`Pharmaceutical Technology
`
`Second Edition
`
`Volume 1
`A—D
`
`Pages 1-1032
`
`edited by
`
`James Swarbrick
`
`President
`
`PharmaceiiTech, Inc., Pinehurst, North Carolina
`and
`
`Vice President for Scientific Afiairs, aaiPharma, Inc.
`Wilmington, North Carolina, U.S.A.
`
`and
`
`James C. Boylan
`
`Pharmaceutical Consultant
`
`Gurnee, Illinois, U.S.A.
`
`
`
`MARCEL DEKKER, INC.
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`NEW YORK ° BASEL
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`Amgen Ex. 2006
`
`Complex Innovations v. Amgen
`
`|PR2016-00085
`
`Amgen Ex. 2006
`Complex Innovations v. Amgen
`IPR2016-00085
`
`

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`Cover Art: Leigh A. Rondano, Boehringer angelheim Pharmaceuticals, Inc.
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`ISBN: Volume 1:
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`Copyright © 2002 by Marcel Dekker, Inc. except as occasionally noted on the opening page of each article. All Rights Reserved.
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`

`
`colon cancers. Oral drug delivery systems (DD
`S) can ,_
`classified into three categories:
`immediate—re1
`preparations, control1ed—release (CR) preparations’ a
`F
`targeted-release preparations. This chapter describes “I
`recent technological advances in oral drug delivery an‘
`various physicochemical and biological barriers, and als
`provides some insight on future strategies to improve or 1-
`drug delivery.
`-
`
`
`
`ANATOMICAL AND PHYSIOLOGICAL
`CHARACTERISTICS OF THE GI TRACT
`
`Mechanisms and Pathways of Drug Absorption
`Orally administered drugs are mainly absorbed in th
`small intestine (duodenum, jejunum, and ileum) and int a‘.
`large intestine (colon); however, other regions, such ‘._
`buccal cavity, stomach, and rectum, also can be considered
`potential sites for drug absorption. The various anatomica
`and physiological characteristics of each segment at
`briefly described in Table 1.
`Once at the surface of intestinal epithelium, a drug c Ir_
`be absorbed across by one or a combination of th
`following mechanisms: passive transcellular, passiv
`paracellular, and carrier— and receptor—mediated transpol;
`systems. Paracellular transport involves the passage '|'
`drug molecules through aqueous pores created 0'
`epithelial tight junctions, and is the most likely route '1-
`polar, hydrophilic drugs since they exhibit poor rnembfl ‘I’
`partitioning. In the human small intestine, the averag‘3 5‘ ‘
`of these water—filled pores is approximately 7-9 A "'
`jejunum and 3-4
`for ileum (2).
`In the colon,
`f‘
`estimated pore radii are about 8-9 A, albeit this Value
`"
`obtained from rat colon (3). Nevertheless, the extent "
`paracellular transport is limited as tight junctions C0mP_ _‘
`only about 0.01% of the total absorptive surface area of
`intestine (villi) (4). Transcellular absorption inV0_IVeS I
`transport of drugs through the intestinal epithelial c :
`(enterocytes) and requires partitioning of drugs across I‘,
`the apical and the basolateral membranes. Obvi0lJS1Y’ :.'
`route is mainly limited to the transport of relatiV513f
`molecular weight lipophilic drugs. Furthermore, Stud”
`
`
`
`h 01 '
`.
`Encyclopedia ofPharn1aceutzcfll Tecesrgr
`,
`.
`Copyright © 2002 by Marcel Dekker, Inc. All rights r
`
`DRUG DELIVERY—ORAL ROUTE
`
`Kwon H. Kim
`
`Brahma N. Singh
`St. John's University, Jamaica, New York
`
`INTRODUCTION
`
`Oral drug delivery is the most desirable and preferred
`method of administering therapeutic agents for their
`systemic effects. In addition, the oral medication is generally
`considered as the first avenue investigated in the discovery
`and development of new drug entities and pharmaceutical
`formulations, mainly because of patient acceptance,
`convenience in administration, and cost—effective manu-
`facturing process. For many drug substances, conventional
`immediate—release formulations provide clinically effective
`therapy while maintaining the required balance of
`pharmacokinetic and pharmacodynamic profiles with an
`acceptable level of safety to the patient.
`However, the potential for oral dosage form develop-
`ment is sometimes limited for therapeutic agents that are
`poorly absorbed in the gastrointestinal
`(GI)
`tract and
`unstable to various enzymes, in particular, to proteolytic
`enzymes, such as peptide and protein drugs. The overall
`process of oral delivery is frequently impaired by several
`physiological and pharmaceutical challenges that are
`associated with the inherent physicochemical nature of the
`drugs and/or the variability in GI conditions, such as pH,
`presence of
`food,
`transit
`times,
`expression of
`P—Glycoprotein (P-Gp) and CYP3A, as well as enzymatic
`activity in the alimentary canal. Manipulation of these
`problems and challenges is considered an important
`strategy for improving oral drug delivery, and requires
`thorough understanding and appropriate integration of
`physicochemical principles, GI physiology and biochem-
`istry, polymer science, pharmacokinetics, and pharmaco-
`dynamics. Over the last 3 decades, much research effort
`has been made in this area to address various biological
`and technological issues. Research has opened many novel
`avenues for
`the more effective,
`sustained, or
`rate-
`controlled oral delivery of both existing and new
`therapeutic agents,
`including peptide and protein drugs
`emerging from the biotechnology arena.
`Furthermore,
`the oral
`route offers an attractive
`approach of drug targeting at the specific sites within GI
`tract for the treatment of certain pathological conditions,
`such as gastroesophageal reflux "disorder, gastroduodenal
`ulcers,
`inflammatory bowel disease, and stomach and
`
`886
`
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`
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`
`2.3.see
`
`

`
`Drllg Del1ve1.y\or
`
`
`
`phases (11, 12). Phase I (basal state) is a quiesce
`mp
`about 45-60 min without any contractions, exc
`occasions. Phase II (preburst state) is a periodept ‘u_-.
`duration (30-45 min)
`that consists of imof
`"
`peristaltic contractions that gradually increasfi ins‘ ._..
`and frequency. Phase III (burst state) is a Short
`“_l
`consists of large, intense peristaltic C0HtI‘aQtiQl:1:I‘1
`about 5 - 15 min. This phase serves to sweep the unadt,
`materials out of the stomach and for this reason
`:~.
`contractions are known as “housekeeper” waves’ p '
`As phase III of one cycle reaches the end Ofith
`ileum (ileocecal junction), phase I of the next cycle...
`in the stomach (proximal) or esophagus (lower es0p;,_
`sphincter). However, sometimes MMC may or-lgi In
`the duodenum or jejunum and some MMC may “__
`action potentials strong enough to traverse throu
`entire small intestine (12). Phase IV is a brief transi .1,
`phase (0-5 min) that occurs between phase III and p
`of two consecutive cycles.
`In the fed state, the onset of MMC is delayed. In .3.
`words, feeding results into delayed gastric emptying .
`duration of this delay is mainly dependent on the size (L.
`or heavy) and composition (fatty or fibrous) of the
`Consequently, the fate of pharmaceutical dosage in
`mainly subject to the pattern of GI motility in faste
`fed) state at the time of dosage administration.
`
`,
`
`PROBLEMS AND BARRIERS TO
`ORAL DRUG DELIVERY
`
`
`
`The biggest problem in oral drug delivery is low
`erratic bioavailability, which mainly results from on
`more factors
`such as poor aqueous
`solubility,
`s .-
`dissolution rate, low intestinal permeability, instabili-
`GI milieu, high first—pass metabolism through liver -Fr
`intestine variable GI transit, and P-gp mediated ill-
`This, in turn, may lead to unreproducible clinical resp I‘
`or a therapeutic failure in some cases due to subtherape
`plasma drug levels. Indeed, the incomplete and var -1“
`oral bioavailability will have its most serious imp
`‘
`drugs with a narrow “therapeutic window” (13) (
`theophylline, carbamazepine, quinidine, etc.) From '
`economic point of view, low oral bioavailability F6531
`the wasting of a large portion of an oral dose, and adfi
`the cost of drug therapy, especially when the drug ‘I
`expensive one (14). It is, therefore, extremely W190 L.
`that these issues be considered and a suitable techlllqu
`an animal model) be used while estimatlng
`[ll
`contributions from each factor responsible for 10W a
`variable bioavailability.
`
`888
`
`humans have demonstrated that absorption by the
`in the colon
`transcellular route decreases significantly
`(small intestine > ascending colon > transverse colon),
`which has implications for delayed or sustained release
`formulations, whereas no such gradient exists for the
`paracellular route (5).
`Carrier—mediated transport involves interaction of the
`drug with a specific transporter or carrier, in which drug is
`transferred across the cell membrane or entire cell and then
`released from the basal surface of the enterocyte into the
`circulation (6). The process is saturable and utilized by
`small hydrophilic molecules (7). Drugs that are shown to
`be transported by this mechanism include [3-Lactam
`antibiotics, cephalosporins, and ACE inhibitors (7).
`Receptor-mediated transport involves internalization of
`an external substance, which may be a ligand for which
`there is a surface bound receptor, or a receptor which binds
`to a surface located ligand (8). During this process, a small
`region of the cell invaginates and pinches off, forming a
`vesicle. This process, in general, is known as endocytosis
`and comprises phagocytosis, pinocytosis,
`receptor-
`mediated endocytosis (clathrin—mediated), and potocytosis
`(nonclathrin mediated) (9).
`After a drug is absorbed in the GI tract, it can gain
`access to the systemic circulation via two separate and
`functionally distinct absorption pathways—portal blood
`and the intestinal lymphatics. The relative proportion of
`drug absorbed Via these two pathways is largely dictated
`by physicochemical and metabolic features of the drug,
`and the characteristics of the formulation (10).
`The portal blood represents the major pathway for the
`majority of orally administered drugs as it has higher
`capacity to transport both water soluble and poorly water
`soluble compounds (10). During this process, hydrophilic
`molecules are carried to the liver via the hepatic portal
`vein, and then by the hepatic artery gain across to the
`systemic circulation for subsequent delivery to their sites
`of action. On the other hand, highly lipophilic drugs (log P
`> 5) that cross the same epithelial barrier are transported
`to the intestinal lymphatics, which directly delivers them
`to the vena cava, thereby bypassing the hepatic first—pass
`metabolism (10).
`
`Gastrointestinal Motility
`The process of GI motility occurs both during fasted and fed
`states; however, the pattern differs markedly in the two
`states. In the fasted (interdigestive) state, the pattern is
`characterized by a series of motor activities known as
`interdigestive myoelectric cycle or migrating motor
`complex
`(MMC), which
`usually
`occurs
`every
`80-120 min. Each cycle consists of four consecutive
`
`

`
`889
`
`dispersions, supersaturation is maintained for a long period
`due to better dispersion through particle size reduction.
`
`Lipophilicity
`
`The lipid solubility or lipophilicity of drugs has long been
`recognized as a prerequisite for transcellular diffusion
`across the intestinal membrane. Traditionally,
`the
`lipophilicity of drug substances is expressed as
`the
`apparent partition coefficient or distribution coefficient
`(log P) between n-octanol and an aqueous buffer (pH 7.4),
`which is pH-dependent in the case of ionizable compounds
`(29). In general, compounds with low log P are poorly
`absorbed, whereas compounds with log P > —1 offer
`satisfactory absorption (29). It is important, however, that
`the drug possess an optimum lipophilicity, as too low or
`too high lipophilicity may result in less than optimum oral
`bioavailability. For example, Mori et al.
`(30) did not
`observe any significant improvement in oral absorption of
`disodium cromoglycate (log P < -3) despite the fact that
`lipophilicity was increased by derivatization to a lipophilic
`(diethyl) ester prodrug (log P = 1.78). This observation
`was attributed to a marked decrease in the water solubility
`(from 195.3 mg/mL to 0.0052 mg/mL), which occurred
`simultaneously with increased lipophilicity. Similarly,
`Wils et al.
`(31) reported for the first
`time that high
`lipophilicity (log P > 3.5) decreases drug transport across
`the intestinal epithelial cells and could be accounted for
`loss of in vivo biological activity. The “cut—off” point of P
`value, that is, the P value corresponding to an optimal
`transepithelial passage of drugs,. was found to be around
`3000. Other consequences of high lipophilicity may
`include passive exsorption (32), and increased plasma
`protein binding and biliary excretion; the biliary excretion
`may limit the oral bioavailability of polypeptides.
`
`Aqueous boundary layer
`
`The aqueous boundary layer or the unstirred water layer
`(UWL) is a more or less stagnant layer, about 30— 100 am
`in thickness, composed of water, mucus, and glycocalyx
`adjacent to the intestinal wall that is created by incomplete
`mixing of the lumenal contents near the intestinal mucosal
`surface (33). The glycocalyx is made up of sulfated
`mucopolysaccharides, whereas mucus is composed of
`glycoproteins (mucin), enzymes, and electrolytes. Until
`recently, the resistance of the UWL to intestinal absorption
`was believed to be correlated to the effective intestinal
`
`permeability (Peff) values of the solutes; however,
`considerable evidence suggests instead that the available
`surface of the apical membrane of the intestinal mucosa is
`the main barrier
`for both actively and passively
`absorbed solutes (33). It is also interesting to note that
`coadministration of food and prokinetic (motility inducing)
`
`Defive,-y——Oral Route
`
`:1 S
`
`
`
`‘
`
`.
`
`,
`
`‘
`
`sicochemical Barriers to Oral Drug Delivery
`-V
`..
`eons solubility
`5
`long been recognized that before an orally
`hlflfliswred drug becomes available for absorption at
`fig sites within the GI tract, it must be dissolved in the
`id_ Since both the dissolution rate and the maximum
`01:1, of a drug that can be dissolved are dictated by the
`ability ofthe drug in the medium (15), aqueous solubility
`.
`.
`.
`8 drug could be regarded as a key factor responsible for
`‘ Oral bioavailability of poorly water—soluble drugs,
`‘Why 1imiting their therapeutic potential. Other issues
`"Med to low bioavailability for a sparingly soluble drug
`'
`, lack of dose proportionality, substantial food effect,
`I; intra. and intersubject variability, gastric irritancy, and
`I". onset of action (16). These problems are further
`.acerbated when attempts are made to develop CR dosage
`“ms (17). Unfortunately, many potent compounds,
`.cluding new chemical entities (NCES), possess very low
`ueous solubility at physiological pH, which could be
`fibuted to their high inherent lipophilicity incorporated
`.\ drug design in order to ensure good absorption (18).
`nsequently, various approaches are utilized to improve
`ueous solubility, which mainly include chemical
`odification (19), complexation (17, 20, 21), microniza—
`on (22), solubilization using surfactants, solid dispersion
`3, 24), and design of drug delivery systems. However,
`11 ere may be specific practical limitations to each of these
`pproaches. For instance, the salt formation approach is not
`feasible for neutral compounds, and in many cases also for
`_eakly acidic or weakly basic drugs because of the
`raconversion of salts into aggregates of their corresponding
`tee acid or base forms (23). This precipitation effect would
`:l'ivery is low and
`‘ us lead to slower dissolution rates and may cause failure
`esuns from one or
`—va clinical response or epigastric distress due to change in
`s
`solubility,
`.sl0.W _
`RH (24). Sometimes, the rate of renal excretion may also
`bility, instability Ill
`-
`-M9386, particularly when amine drugs are solubilized as
`;h1~ough liver and/07
`:“°‘d'Sa1.lS(25)-
`gp mediated effl1l>_i--
`_ Similarly, the commercial success of solid dispersion
`ale clinical respoll?
`btien limited due to use of higher temperatures
`tue to subthefapfwtii
`.1 10p C) or harmful organic solvents, such as chloroform
`mplete and Van“? r
`0? dichloromethane, which may result
`in chemical
`;t serious impact 0
`,_?“°0mposition of drugs and carriers or possible toxicity
`window” (13) (°~3"’.'
`{gm the residual solvent. These unacceptable problems
`fine, etc.) From
`flh Scientists to explore novel alternatives, particularly
`availability reslglgsfi
`-— e °°gI‘1nding method, which involves cogrinding of a
`ral dose, and 3 .5
`’when the drug 1531 mily Water-soluble drug with a water-soluble polymer,
`extremely irrtporw
`- £1 as Polyvinyl pyrrolidone, polyethylene glycol (PEG),
`suitable technlquemgl
`pol ml")/PTOPY1 cellulose, hY<1roxYlJroPY1m°thY1 0611111036,
`3'
`yvmyl alcohol (26, 27), or sugars such as D—Mannitol
`2
`)nsible for low 3l‘..._
`E0811)‘ These authors suggest that although the composi-
`°f the coground mixture is similar to that of solid
`
`v
`_
`nzvisf th
`_xtcyc1eebdl"‘
`Wet esoph
`13)’ Originate
`C may ROI .1;
`zrse through .'.
`brief t1‘aI1Sltl0.l
`
`;e III and phas II‘
`
`delayed. In oth_'
`ic emptying.
`i.'.
`L on the size (lig I:
`)us) of the meal
`.1 dosage forms. ’
`ility in fasted (d_ '
`tration.
`
`
`
`

`
`_
`therapeutic system (GITS®, Alza Corpor
`provide zero—order drug absorption, in
`hieh atti ..
`drug absorption from the GI tract is Constanha
`determined by the amount of drug available in tht
`However, none of the CR systems can control thee .
`drug absorption from the GI tract. This is
`to the fact that the extent of drug absorpti
`.0n fmm ii.
`regions of the GI tract is different, wh
`lch in fac .
`constitutes a basis for the biopharmaceutic C1aSS_ \.
`scheme for drugs administered as extended.relea :
`products (41). Thus, indirectly the extent of abs
`,
`determined by the GI transit time (GITT) of the _.
`form rather than its CR properties or deliver
`,_
`(42).
`In general,
`the GITT of most drug pr0I'_
`relatively short (8-12 h), which in tum impe
`'
`formulation of a once daily dosage form (43)_
`From the oral delivery standpoint, both .:.
`emptying time (GET) and small
`intestinal transi
`(SITT) are considered important since the majo
`drugs are preferentially absorbed in the upper pan 5-.
`GI tract (stomach, duodenum, and jejunum)_ ‘_
`the stomach and intestines have a limited site f .'
`absorption. This is known as an “absorption win
`The relatively short GET (1-3 h) and SITT (3-5
`provide limited time for drug absorption throu
`major absorption zone. These problems are
`"I"
`aggravated by the highly variable nature of the
`emptying process, which can vary depending on -...
`physiological factors, such as food, age, posture, -I-~
`body mass index, circadian rhythm, etc.; patholr
`factors, such as stress, diabetes, Crohn’s diseas
`motility disorders; and pharmaceutical factors, «'1
`size and density of formulation and coadministrat
`drugs like anticholinergic and prokinetic agents.
`ll
`apparent
`that GI transit
`is less likely to be a in
`determinant of bioavailability for drugs
`tha
`completely absorbed from the GI
`tract and if _"
`dosage forms reside in the GI tract for a consid
`period of time (~14-18 h).
`Since SITT has been demonstrated to be consta ~_
`
`'
`
`
`
`by gastric emptying. The variability in turn may 1""
`unpredictable plasma drug levels, and could 5° __
`impair the performance of pulsed— or time-releaS6 d°. '
`which are basically designed to deliver drug 3‘
`predetermined time to a specific site of the G1 tfac
`instance, if there is a large intrasubject variation In "Vi
`times,
`then the use of time-release S)/Stems ma
`precluded due to the unintended delivery Of drug
`inappropriate region of the GI tract (45).
`
`890
`
`agents such as cisapride tends to decrease the thickness of
`UWL by increasing segmental and propagative contrac-
`tions respectively, which may have implications for drug
`dissolution in the GI tract (34). The reverse is true for some
`viscous soluble dietary fibers, such as pectin, guar gum and
`sodium carboxymethylcellulose, which may increase the
`thickness of UWL by reducing intraluminal mixing
`(35-37) and could possibly decrease the intestinal exsorp—
`tion of lipophilic drugs like quinidine and thiopental (38).
`
`Biological Barriers to Oral Drug Delivery
`
`intestinal epithelial barrier
`
`lines the GI tract
`layer that
`The intestinal epithelial
`represents the major physical barrier
`to oral drug
`absorption. Structurally, it is made up of a single layer
`of columnar epithelial cells, primarily enterocytes and
`intercalated goblet cells (mucus secreting cells) joined at
`their apical
`surfaces by tight
`junctions or zonula
`occludens. These tight
`junctions are formed by the
`interaction of membrane proteins at the contact surfaces
`between cells and are responsible for restricting the
`passage of hydrophilic molecules during the paracellular
`transport.
`In fact, electrophysiological
`studies have
`suggested that epithelium gets tighter as it progresses
`distally, which has been implicated in a reduced
`paracellular absorption in the colon (39).
`The epithelium is supported underneath by lamina
`propria and a layer of smooth muscle called muscularis
`mucosa (3-10 cells thick). These three layers, i.e., the
`epithelium,
`lamina propria, and muscularis mucosa,
`together constitute the intestinal mucosa (40). On the
`apical surface, the epithelium along with lamina propria
`projects to form villi. The cell membranes of epithelial cells
`that comprise the villi contain uniform microvilli, which
`give the cells a fuzzy border, collectively called a brush
`border. These structures, although greatly increase the
`absorptive surface area of the small intestine, provide an
`additional enzymatic barrier since the intestinal digestive
`enzymes are contained in the brush border. In addition, on
`the top of the epithelial layer lies another layer, the UWL, as
`previously described. The metabolic and biochemical
`components of the epithelial barrier will be discussed.
`
`Gastrointestinal transit
`
`Advanced CR dosage forms can provide a precise control
`over release rates or release patterns for most drugs, which
`is attractive from a clinical point of view, particularly
`minimization of peak and trough variations in plasma drug
`concentration, and chronotherapy. For example,
`the GI
`
`

`
`891
`
`Furthermore, the brush border activity is generally
`greater in the proximal small intestine (duodenum ~
`jejunum > ileum >> colon) and involves enzymes
`such as alkaline phosphatase, sucrase, isomaltase, and
`a considerable number of peptidases (7).
`The intracellular metabolism occurs in the cyto-
`plasm of enterocytes and involves the major class
`of phase I metabolizing enzymes (i.e., cytochrome
`P450s,
`in particular CYP3A4),
`several phase II
`conjugating enzymes, and others such as esterases.
`Important examples of intestinal phase II metabolism
`include sulfation of isoproterenol and terbutaline, and
`glucuronidation of morphine and propofol (52). It
`is obvious that
`intestinal epithelium as a site of
`preabsorptive metabolism may significantly contrib-
`ute to the low bioavailability of therapeutic peptides
`and ester type drugs like aspirin, although it could
`serve as a key site for targeted delivery of ester or
`amide prodrugs (52).
`
`3.
`
`First-pass hepatic metabolism. As an absorbed drug
`reaches the liver through the portal circulation, a
`fraction of the administered dose is biotransformed
`
`before it reaches the systemic circulation. This is
`known as first—pass hepatic metabolism. In comparison
`with intestine, the liver dominates the process of first-
`pass metabolism for most drugs by virtue of its large
`mass, multiplicity of enzyme families present, and its
`unique anatomical position (13). However, this is not
`true for some drugs, such as terbutaline, in which case
`the sulfation occurs predominantly in the small
`intestine, as well as for midazolam, in which first-
`pass extraction by intestinal mucosa and liver appears
`to be comparable (44 i 14% versus 43 i 24%) (52). It
`is also important to emphasize here. that efflciency of
`first—pass metabolism (both hepatic and intestinal)
`varies considerably among different animal species
`and human subjects, which should be taken into
`account when deriving the estimates of oral bioavail-
`ability, particularly in the case of poorly soluble drugs.
`
`P-Glycoprotein and other
`efflux systems
`
`it has been recognized that P—Gp can
`In recent years,
`significantly contribute to the barrier function of the
`intestinal mucosa. P—Gp is an integral membrane protein,
`about 170-180 kDa, encoded by the MDRI gene in
`humans and contains 12 putative transmembrane domains
`and two ATP binding sites (53). In the small intestine and
`colon, P—Gp is expressed almost exclusively within the
`brush border membrane of mature enterocytes, where it
`
`Drug Delivery—Oral Route
`
`Food effect
`
`The coadministration of drugs with food is known to result
`in decreased, delayed,
`increased, or accelerated drug
`absorption, which may have pharmacokinetic and
`pharmacodynamic implications
`(46). Most often,
`the
`food effect is nonspecific and manifested as an interplay
`between physiological effects of food (such as delayed
`gastric emptying, stimulated bile secretion, increased liver
`blood flow, and alterations in gastric and duodenal pH),
`physicochemical characteristics of the drug (e.g., water
`solubility), or
`its
`formulation (e.g.,
`size,
`structural
`organization, and dissolution profiles). In general, drugs
`that are most
`influenced are those that are primarily
`absorbed from the upper regions of the GI tract and/or are
`poorly water—soluble. Apparently, food does not have a
`clinically significant effect on the absorption of moder-
`ately soluble drugs having a pH—independent solubility,
`and those that are completely absorbed (e.g., glipizide,
`isosorbide-5-mononitrate, felodipine, and nifedipine) from
`the GI tract. Furthermore, food may indirectly influence
`the drug absorption by affecting drug release from both
`hydrophilic matrix as well as lipid matrix formulations. In
`the former case, the effect has been attributed to increased
`
`hydrodynamic mechanical stress, which is caused by
`increased gastric motility (47). In the latter, the effect is
`due to increased pancreatic and biliary secretions, which in
`turn affect the integrity of matrix (48).
`Other potential factors that affect oral delivery are pH
`of the upper GI tract (49), which varies as a function of
`age, food and certain disease states, circadian rhythm (50,
`51), various diseases of the GI tract (49), and drug—drug
`interactions (7).
`
`
`
`Metabolic and Biochemical Barriers
`
`to Oral Drug Delivery
`
`Presystemic metabolism
`
`to presystemic
`Orally administered drugs are subject
`metabolism, which is comprised of three subtypes of
`mechanisms:
`
`1- Lumenal metabolism. This may be triggered by
`digestive enzymes
`secreted from the pancreas
`(amylase,
`lipases, and peptidases including trypsin
`and or-chymotrypsin), and those derived from the
`bacterial flora of the gut, especially within the lower
`part of the GI tract.
`
`First-pass intestinal metabolism. This includes brush
`border metabolism and intracellular metabolism. The
`
`former occurs at the surface of the enterocytes by the
`enzymes present within the brush border membrane.
`
`

`
`
`
`Controlled-Release Preparations
`
`The currently employed CR technologies for ora1_
`delivery are diffusion-controlled systems. solven
`vated systems, and chemically controlled system 2.
`Diffusion—controlled systems
`include monolithic}:
`reservoir devices in which diffusion of the drug-1
`rate—limiting step, respectively, through a polymer H
`or a polymeric membrane. Solvent-activated systems" .
`be either osmotically controlled or controlled by po _.,._
`swelling. Chemically controlled systems release drug
`polymeric degradation (surface or bulk matrix erosi
`cleavage of drug from a polymer chain (63).
`-._..
`examples of commercial products that have
`developed based on these CR principles are provid
`Table 3. It is worth mentioning here that the so—c ll
`programmed—release (“tailored—_release”) profile of a ii--
`CR product is rarely the outcome of a single pharma --
`tical principle. Depending on the specific physicoche u -
`properties of the drug in question and desired therap
`objectives, different formulation and CR principles
`-13:
`proportionally combined within the same dosage
`This task appears to be simpler when realized in tar as
`appropriate selection of polymers and excipients -~-~
`incorporate desired principles.
`
`Targeted-Release Preparations
`Site-specific oral drug delivery requires spatial Place
`of a drug delivery device at a desired site within th_
`tract. Although it is virtually possible to localize 3 d '.
`within each part of GI tract, the attainment of site-SP‘
`delivery in the oral cavity and the rectum is fem
`I,
`easier than in the stomach and the small and
`"E
`intestines. The latter
`requires consideration of
`longitudinal and transverse aspects of G1 cons“
`(66). Some of the potential CR and site-specific DDSS A
`be described.
`
`'
`
`‘M
`
`892
`
`Drug Delive
`
`ry§0 '
`
`fast disintegrating tablets and granules th
`at use 4 I
`cent mixtures, such as sodium carbonate
`._
`bicarbonate) and citric acid (or
`tartaric (or 5.
`superdisintegrants,
`such as
`sodium Starch aci
`croscarmellose sodium, and crospovidon El
`.
`technologies in fast-dispersing dosage fore.
`u‘:
`modified tableting systems, floss or Shearfofls
`ogy, which employs application of centrifugainf in
`controlled temperature, and freeze drying 6
`these technologies are briefly described in (fig)-leS
`
`acts as an energy—dependent drug efflux pump. Although
`P-gp appears to be distributed throughout the GI tract,
`its
`levels
`are
`higher
`in more
`distal
`regions
`(stomach < jejunum < colon) (54). Moreover, several
`studies have shown that P—Gp and CYP3A4 have similar
`substrate specificity [reviewed in Ref.
`(55)]. The
`colocalization of P—Gp and CYP3A4 in the mature
`enterocytes and their overlapping substrate specificity
`reasonably suggest that the function of these two pro-
`teins may be synergistic and appear to be coordinately
`regulated (56). Consequently, a greater proportion of the
`drug will be metabolized since the repetitive two-way
`kinetics (drug exsorption from the enterocyte into the
`lumen via P—Gp and reabsorption back into the
`enterocyte) will simply prolong the drug exposure to
`CYP3A4 (57). This mechanism not only limits the
`absorption of a wide variety of drugs, including peptides,
`but also poses a threat for potential drug interactions
`when attempts are made to inhibit CYP3A4 or P—Gp (58).
`Other mechanisms of drug efflux process may involve
`organic cation and anion transporters, which have been
`described elsewhere (32).
`
`CURRENT TECHNOLOGIES IN
`ORAL DRUG DELIVERY
`
`Over the last 3 decades, many novel oral drug therapeutic
`systems have been invented along with the appreciable
`development of drug delivery technology. Although these
`advanced DDS are manufactured or
`fabricated in
`
`traditional pharmaceutical formulations, such as tablets,
`capsules, sachets, suspensions, emulsions, and solutions,
`they are superior to the conventional oral dosage forms in
`terms of their
`therapeutic efficacies,
`toxicities, and
`stabilities (59). Based on the desired therapeutic
`objectives, oral DDS may be assorted into three
`categories:
`immediate—release preparations, controlled-
`release preparations, and targeted—release preparations.
`
`Immediate-Release Preparations
`
`These preparations are primarily intended to achi