IBIT 1021
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`TEVA EXHIBIT 1021
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`
`
`Cover Art‘. Leigh A. R[}l1t.|:lll0. Bochringer angelheim Phatrlnaceutical,-s, lnc,
`
`ISBN: Volume I:
`Volume 2:
`Volume 3:
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`Prepatck:
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`0-8247-2822—X
`U-8247-2823-8
`U-8247-2824-6
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`ISBN: Unline:
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`0-8247-2820-3
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`PRINTEI) IN THE UNITED S'I‘A'l‘l'lS ()1-' AMERICA
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`TEVA EXHIBIT 1021
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`
`
`This material may be protected by Copyright law (Title 17 U_S_ Code}
`
`DRUG DELIVERY-——-BUCCAL ROUTE
`
`James C. Mclflnay
`Carmel M. Hughes
`The Qucen’5 Un.-‘wgrsity of Be.-‘fast, Be.-‘Test, tjniterl Kirigrloiti
`
`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 pemrai
`route,
`in which the drug is swallowed and enters the
`systemic circulation primarily through the mernbranes oi"
`the small
`intestine. Although this type of drug adminis-
`tration is commonly termed o.--oi. _.uemroi' is a better term
`because arm’ atlrninistration more accurately describes
`
`drug absorption from the mouth itsell'. 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 sttpplies the salivary glands and
`their ducts,
`into the systemic circulation via the jugular
`vein. Active transport, pinocytosis. anti passage through
`aqueous pores usually play only insignificant roles in
`moving drugs across the oral mucosa (2).
`The administration of drugs by the huccal route has
`several main advantages over peroral administration,
`including the following:
`
`I. The drug is not subjected to the destructive acidic
`environment of the stolnnclt.
`
`2. Therapeutic serum concentrations of the drug can he
`achieved more rapidly.
`3. The drug enters the general circulation without
`passing through the liver.
`
`first
`
`This last phenomenon is important for drugs that are
`highly metabolized during their lirst passage through the
`liver. This metabolism (governed by the hepatic extraction
`ratio} can lead to a tlramatic reduction in the amount of
`
`drug available systemically from a given pcroral close but
`is avoided by buccal absorption.
`Two sites within the buccai cavity have been used for
`
`drug administration. Using the sublingual route, as for
`giyceryl trinitrate iGTNi. 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 iirmrc.-t’ m';.t'orprioir. the
`
`800
`
`absorption front all areas within the buccal or oral cavity
`are considered in this article.
`
`Of the range of pharmaceutic preparations available for
`admiltistralion 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
`Intleosa. AIlct'—
`nativcly. a tablet or capsule can be chewed to release its
`Contents. This latter tncthotl
`is less successful because
`
`mastication tends to product: a large volume of saliva that
`increases the probability of premature swallowing. The
`satire problem occurs in the administration of drug in the
`form of a chewing gum.
`The aim of the present article is to review the puhlished
`literature on the absorption oi‘ drugs through the oral
`mucosa. Special attention is given to the prevention of
`presystcmic metabolism via drug administration by the
`buccal antlsublinguai routes.Consideration is also given to
`the types of pharmaceutical p|‘cp;|]‘;]ti{}m;
`that are
`conuncrcially available for drug administration into the
`month. Before progressing to drug absorption. however‘, the
`structtlrc and blood supply ol'the oral mucosa are discussed
`because of the important role they play in the transl‘er of
`drugs from the mouth into the systemic circulation.
`
`STRUCTURE AND SECFIETIONS
`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 front the deeper layers to the
`surl'ace (3). The pattern of maturation differs in diilcrent
`regions of the oral mucosa due to the variation in the
`spccilic {traction of the tis.sues. The surface layer of the
`hard palate and tongue forms keratin to yield a tough.
`nonllcxihle epithelial surface resistant to abrasion, but the
`epithelium ofthe check. lioor of the mouth. and soft palate
`is nonkeratinized and facilitates distcnsibility. The major
`features of the keralinizcd and non-keratinizetl oral
`
`f:'ritj\'t‘tr=imlr'n of Platrrrrrir'crrrir‘ri! 'i"r't'»'irir»t'ri,t{t'
`Copyrigltl -1'; 2tltl2 by Marcel i)eltl-tcr. Inc. All rights reserved.
`
`
`
`TEVA EXHIBIT 1021
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`
`
`Drug l)eliver_v—-Buccal Route
`
`80]
`
`epitlteliutn have been extensively investigated by Sqnier
`and Rooney (4). Together with the presence or absence of
`keratin, the second main l’e:tture likely to inlluence regional
`dit't'erences in drug absorption is the epithelial tliickness.
`This varies in t|i|'l’erent regions of the mouth:
`the hard
`palate. httccal mucosa. lip mucosa. and lloor rat" the mouth
`have been found to have thicknesses of lt)(J—l2() p.m.
`50t}—6UU |.t..I!‘l. 500-(100 j.t,tn. and li'l(l—.'Z[)tl p.t'n. respect-
`ively (5. 6}.
`
`Secretion of Saliva
`
`In addition to the protective tuitction at't'orded by the oral
`mucosa. it also has the ability to maintain a moist surface.
`which enhances permeability of the n1eIrIl.‘iI'ane to drugs
`(3). Although the mucous membrane lining in the mouth
`contains many minute glands called lmr'rm" glririds, whiclt
`pottr their secretions into the mottth. the chief secretion is
`
`the prtrutin’
`supplied by three pairs oi’ glands. namely.
`(under and in front of the ear}. the .siil:iiirt_t'rllctr1- (below the
`jaw), and the .riibh'ngtml (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 Ill.
`The presence of saliva in the moutlt is important to drug
`absorption for two main reasons:
`
`I. Drug permeation across moist (mucous) metnbranes
`OCCUTS 'ITIUCiI
`l'l'l(1l‘C readily lilllll.
`l'tCl'0S5 !']Ull.!'I"lUC0l..l.‘-L
`membranes.
`
`Ex.)
`
`Drugs are commonly administered to the mouth in the
`clinical
`setting in a
`solid lornt. The drug must.
`therefore,
`lirst dissolve in saliva before it can be
`
`that
`absorbed across the oral mucosa:
`cannot be absorbed directly from a tablet.
`
`is,
`
`the tlrttg
`
`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).
`Netter‘s excellent drawings of the blood supply to the
`ntottth and pltatytlx. vettotts tlntittatge of the mouth and
`pharynx. and lymphatic drainage of the mouth and
`pharynx have been published by Ciba (8). This latter
`publication also includes definitive documentation of the
`blood sttpply 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 lloor ol‘
`the
`mouth, and the gingiva, and the facial artery supplies
`blood to the lips and soil palate. The maxillary artery
`supplies the main cheek. hard palate. and the maxillary and
`mandibular gingiva (7. 0'). The internal
`jugular vein
`eventually receives almost all of the blood derived lrotn
`the mouth and pharynx (8). Drugs Lliffttsing across the
`membranes have easy access to the systemic Circulation
`via the ittternal jugular vein.
`
`FACTORS INFLUENCING DRUG ABSORPTION
`FROM THE ORAL CAVITY
`
`Because the oral mucosa is a highly vascular tissue. the
`two main t'actors that influence drug absorption from the
`month are the permeability of the oral Inucosa to the drug
`and the pltysieochemieal characteristics of the drug that is
`presented :11 the site of absorption.
`
`Permeability of the Oral llllucosa to Drugs
`
`The lipid membranes of the oral mucosa are resistant to the
`passage of large macroniolecutes: however, small un-
`ionized molecules tettd to cross the membrane with relative
`
`case. This passage is in either direction, and indeed passage
`ol‘ drugs from the t:irculation into the ntouth can be used in
`therapeutic drug monitoring by measuring drug Ct_‘u‘|ccn-
`trations in saliva. The pernteability ol’ the oral mucosa has
`been comprehensively reviewed by Siege] (10).
`
`Mechanisms involved in drug absorption
`across the oral mucosa
`
`The mechanisms by which drugs cross biologic lipid
`membranes are passive dit'l'ttsion.
`lacilitzttetl diffusion.
`active transport. and pinoeytosis. Small. water-soluble
`molecules may pass through small. water—filled pores.
`The tnain mechanism involved in drug transfer across the
`oral
`tttucosa. common with all regions of the gastroint-
`tcstinal
`tract.
`is passive dil'l'ttsion, although facilitated
`ditTusion has also been shown to take place. primarily
`with nutrients. Pns.w'-re o'i_',(i'ii.s-irm involves the movement
`of a solute from a region of high concentration in the
`mouth to -‘1 region of low concentration within the buccal
`tissues. Further diffusion then takes place into the venous
`capillary system. with the drug eventually reaching the
`systemic circulation via the jugular vein. The physico-
`chemical characteristics of a tlrttg are very important for
`this tiiflttsion process. Although passive dit't'usion is
`undoubtedly the major transport mechanism for drugs, the
`
`
`
`TEVA EXHIBIT 1021
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`
`
`802
`
`Drug De|ivery—liucI:al Route
`
`l)rag in lymphatic circulation
`
`Stllitl tirug
`powtler or lahlet
`
`'
`
`Di.sst:|\'L‘tI drug
`in I‘lLIL‘L'.'Ii I'|uitlr-
`
`:1»
`‘T
`
`|)issoIved drug in
`|1uL'i:a| Itletllhrtlni:
`
`l
`Drug I'eInoved l‘I'uIIt oral cavity
`by swallowing
`
`\.
`llrug in blood
`circulation:
`
`-" Patliway to account for haelvt-partitioning into l)|.IL'L'lIi Iluids oldrug ahsorhetl by
`n|embr:tne_
`
`Fig. I
`
`Seheinatic representation oi’ the absorption kinetics of huecally presented drugs. [From Rel’. Ill)
`
`absorption of nutrients from the mouth has been shown to
`involve Carrier systems (fric‘iii.*m‘t*r! rl'i,ff(ii.\'r(JiiJ. which lead
`to a more rapid absorption than the concentration gradient
`would promote. Such a carrier system. unlike passive
`dil"l'usion, exhibits
`stereospccilieity, and indeed the
`
`the
`absorption of o-glucose and 1.-arabinose across
`buccal mucosa has been shown to be stereospeciiic t] I).
`The same authors also showed that
`the absorption ol"
`D—g|ucose. galaetose. and 3-U-inethyl-1)-glucose was at
`least partially dependent on the presence of sodium ions
`in
`the Iuminal
`fluids. Ftirthermore.
`the transport of
`r)-glucose was inhibited by galaetose and 3-(}-mcthy|-
`I)-glucose.
`suggesting at
`least one common carrier
`system. Similarly. Kurosaki et al.
`(I2)
`tlentonstratcd
`that
`the absorption of cefadroxil
`la eephalosporin
`antibiotic) from the human oral cavity occurs through at
`carrier-mediated mechanism:
`this absorption was inhib-
`
`ited by the presence of cephaiexin, which shares a
`common carrier—mediated process with celadroxil in the
`small intestine of rat.
`
`Membrane storage during buceal 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
`
`el'l'ect (I3). Due to this phenomenon. buceal partitioning
`has been suggested as a more accurate term to describe the
`diffusion of drugs across the oral mucosa H4). Although
`several authors have devised schematic representations ol"
`the kinetics oforal drug absorption (Fig. l)and (1, I4) the
`mucosa] constituents responsible for drug binding have not
`been identified.
`
`Regional differences in mucosal permeability
`
`lining of the mouth differs in both
`The epithelial
`composition fkeratinized and nonkeratinizedl
`and
`
`thickness in dilTe:'ent regions of the motith. Therefore.
`drug absorption may vary from tliiterent oral sites. This
`Sllc—Lit.2[Jt.2l‘|tit.‘.llI absorption has been shown to take place by
`Pimlott and Addy (I5), who measured the absorption of
`isosorbide tliriitratc into the systemic circulation after‘
`applying tablets to the huceal. palatal, or sublingual
`mucosa in six healthy volunteer subjt.’.Cts. Serum levels ol"
`drug were detected from the buccal and sublingual sites
`after
`I 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 buceal sites (Fig. 2). The drug was not detected
`in the serum of any stth_ieet alter application to the palatal
`mucosa. These authors eoncludetl
`that
`the keratini:r.ed
`
`layer of the oral mucosa may be an imponant barrier to
`drug absorption because the palatal epithelium is
`keratinized. but
`the huccal and suhlingual mucosa are
`not on). Absorption across the sublingual epithelium is
`likely to be greater than across the buceai epithelium
`because the former is thinner and is immersed in a larger
`volume of saliva.
`
`Rapid absorption from the suhlingual mucosa was also
`demonstrated through work by Al-Furaih et al. (I7), who
`reported that sublingual administration ofcaptopril led to a
`more rapid attainment of plasma captopril concentrations
`and had a more rapid pharmacological effect (i.e., lowe1'
`systolic blood pressure) compared to perornl adminis-
`tration ol‘ the drug.
`
`Physicochemical Characteristics of the Drug
`
`Various experimental techniques have demonstrated that
`cell membranes have a large lipid component (I8), and
`most drugs cross such membranes by simple passive
`tlil‘l‘usion. In order to cross these lipid membranes. a drug
`should he in the lipitl—so|uhle or un—it)nized form and also
`
`
`
`TEVA EXHIBIT 1021
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`
`
`Drug Delivery—Bucca| Route
`
`803
`
`For alt acid I
`
`PH 2 PK" + log'”
`For a base :
`
`pH = PK.-. + he
`
`[on — ionized species]
`[ionized species]
`
`The importance of pH on drug absorption from the mouth
`ltas been extensively studied using the buecal absorption
`model, in which loss of drug front buffered drug solutions
`placed in the mouth is monitored (23). The ittllttence of pH
`on the absorption of the weak base chloroquine and of the
`weak acid pltenobarbitone is shown in Fig. 3 (24).
`However. pl-I does not always inlluenee the rate or
`extent of absorption. For example. MeElnay et al. (25)
`found that captopril pltarmacodyttamic parameters (blood
`pressure. heart rate. attd plasma renin activity) did not
`diI'l"er significantly hetweeit but'tct'ed and unbttffered
`
`sublingual administration, sttggestittg that manipulation
`of pH had little effect. It was. therefore. proposed that a
`mechanism other than passive <.lift'usion 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 oI'a buffer, the pKi, oftlte drug
`plays the deciding role as to the state of drug it)niza[j()n_
`
`—-*-Ci-— Chloroquine
`
`.......-0.........
`
`Phettoharbitotte
`
`mu
`‘)0
`
`till
`
`70
`
`(>0
`
`5!]
`
`40
`
`Ill]
`
`ll}
`
`Ii)
`
`0
`
`fig, 3 The influence of pH on the absorption of the weak acid
`phenobarbitone and the weak base eltloroqttittc front the buecal
`cavity in three ltealthy volunteer suhjeets.
`(Redrawn from
`Rel‘. 2-l.)
`
`i
`
`3.2
`
`2.8
`
`2.4
`
`E
`
`'3
`
`|.()
`
`L2
`
`0.8
`
`0.4
`
`U
`
`EE
`
`3!
`2
`
`EQ
`
`E
`
`
`
`'
`
`(El? Bticcztl
`
`-------
`
`Sultliltgual
`
`O§
`
`=._
`
`U
`
`5
`Tablet
`
`"'~‘"““'I3d
`
`ID
`
`I5
`
`.".{l
`
`15
`
`3|]
`
`Tinte lntins)
`
`Fig. 2 Mean plasnta isosorbide dinitrate cont.-ettlratiotts alter
`application of isosorbide dinitrate [5 mg) to the buecal and
`suhlingttal mucosa itt
`six healthy male volunteer subjects.
`fkedrawn from Ref. I5.)
`
`be in solution. The various physicochemical charactet'-
`istics of the drug are, therefore, of paratnount importance
`as
`far as drug penetration across the oral
`tnttcosa is
`concerned.
`
`Molecular weight
`
`In general. ntoleeules peitetrate tlte oral ntueosa tnore
`rapidly than ions. and smaller molecules penetrate more
`rapidly thatt larger utoleeules. However. this rule is not
`absolute because dextrans with a molecular weight of up to
`'i'0.U0() cross keratinized rabbit oral mucosa H9). but
`
`(1065
`horseradish peroxidase (molecular weight 4{l.U(}0]
`not
`(20). Higlt-tnoleeular-weight
`tnucopolysacearides
`such as hepariit are not well absorbed (21). although
`inclusion of penentration enltancers
`in
`sottte insulin
`formulations ltave itnproved bioavailability (22).
`
`
`
`Percenta:_:eofDoseAbsorbed
`
`Degree of ionization
`
`The '.tve:‘-age pH of saliva is (1.4. Because the un—iotti:r.ed
`form of a drug is the lipid-soluble-diffusible form.
`the
`pK;. of the drug plays an important role in its absorption
`across the lipid ntembranes of the oral ntttcosa. The
`degree of ionization of a drug at a specified pH can be
`calculated using the Henderson—Hasselhalch equation as
`follows:
`
`
`
`TEVA EXHIBIT 1021
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`
`
`804
`
`Drug Delivery—ll-uccal Route
`
`Also, due to the relatively large surface area availabie for
`absorption and to the tttttittlcttttttce of an cqttilibriunt
`between ionized and un—ioni7,ed drug. only a
`small
`percentage ofdrug has to be present in the on-ionized form
`before significant absorption can take place.
`
`Lipid solubility
`
`Altltouglt the undissociatcd tun-ionized} form of a drug
`has the higher lipid solubility,
`the un—ioni7.cd moieties
`themselves have tlil'fet'ittg lipid solubilities. A common
`way ofassessing the lipid solubility ol'a drug is to nteasttre
`its oil—water partition coeflicicnt. As with pH, bttccal
`absorption has been shown to be positively correlated with
`a drug's oil—water partition coefficient. Beckett and
`Mol"fat (26). for example, found a correlation of partition
`coefficients in n—heptane/aqueous systems with buecal
`absorption data for a series of amines and acids when the
`degree of l0l'll?,£llZI{Jl'I was held constant.
`In conclusion.
`to penetrate the oral mucosa to a
`significant degree. a drug should have a relatively low
`molecular weight and exhibit biphasic solubility patterns.
`that is, be soluble in both the aqueous salivary fluid and the
`lipid tnetnbrane barrier to penetration. A significant atnount
`ofthe drug should be un-ionized at sali vary pH, and the drug
`should also not bind strongly to the oral mucosa.
`
`BUCCAL ADMINISTRATION AS A METHOD
`OF PREVENTING PFIESYSTEMIC METABOLISM
`
`The systemic availability of a drug is a measure of the
`fraction oftbe administered amount of drtt g that is absorbed
`
`into the general circulation in an unchanged lornt from its
`site of administration. Disregarding pharmaceutical
`reasons te.g., poor tablet disintegration) attd inappropriate
`physicochemical properties of the drttg,
`the two main
`reasons for poor bioavailability after peroral administration
`are drug destruction by stomach acid and drug modification
`by metabolic enzyme systems prior to its entry into the
`systetnic circulation. The principal organs involved in
`presystemic elimination are the gut wall. the liver, and the
`lung (27). Drug metabolism of tltis type is known as first-
`pris.r metabolisnt. A nttntberofdrugs ltavc high aftinities for
`the enzyme systems it] these organs and are, therefore.
`highly extracted during their flow through the organs. These
`drugs, which are said to have a trig}: writ-rir‘ti‘rm rtiiir; (Fig. 4},
`include propranolol.
`terbutaline,
`lcvodopa.
`imipramine,
`aspirin, tnorphine, pentazocine, nitroglycerin, lignocaine.
`ltydralarzine, verapamil, and methyldopa. The tnain
`metabolizing organ in the body is the liver. Because
`blood draining from the gut via the portal vein must pass
`
`€'.t
`—jr
`
`IJRGAN
`
`‘--'v
`
`cxlrztetititt ratio
`
`(3,
`
`- r.-V
`
`Q,
`
`Fig. 4 Diagramtnittic t'ept'escnttt|ioI1 til’ the cxtractiott ratio of a
`drug. 'l'|te c‘Ktt':tClioI1 ratio is a measure of the tettdency ot' a drug
`to be removed l"t'om the hlootl tlt1t'ing its pttssttgc lftrotlglt an organ
`suclt as the liver.
`In the (litl}._!l‘:I]‘t‘.t,
`("A is
`the arterial drug
`concentration and (‘V is the venous drug conccttttation.
`
`through the iivcr prior to entry into the general circulation.
`the total drug z1bsot'bed l't'om tltc gttt must pass throttglt the
`liver before it can reach its site of action. Once the dt'ug has
`entered the systemic circulation. it
`is distribttted 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 redttced due to it
`lowered drug concentration iii the plasnta after distribution
`has taken place. The liver receives only 20% ofthe cardiac
`output (as compared with [()t}% from the penal vein),
`which also protects the drug that has already been absorbed
`l'rot'n the metabolic systems ol‘ this organ. Prcsysletttit:
`elimination can. therefore. be avoided by choosing a site of
`administration from which the drug enters the systemic
`circulation directly, without tirst passing through the liver.
`lung, or gut wall. Because blood draining from the oral
`cavity enters the general circulation via the intcrnaljuguiar
`vein, oral administration by the bttccal or sublingual routes
`provides a useful strategy for itnpt'oving bioavailabitity ol'
`drugs that are susceptible to extensive lirst—pass metab-
`olistn. A high Iirst-pass effect does not, however, mean that
`drugs with a high extraction ratio cannot be given perorally.
`If a sttlticicnt dose of the drug is given, an adequate ainottnt
`of dt'ttg tto prodttcc the required therapeutic effect) often
`remains intact during its first passage through the liver.
`Also, a high peroral dose ofdrug or, indeed, serttm levels of
`the drttg front previotts doses may saturate the higlt-aflittity
`metabolizing systems in the liver and, thereby. decrease the
`lit'st-pass effect and increase bioavailability. With sortie
`drugs, moreover,
`the metabolites tltcmseivcs may have
`good pharmacologit: activity.
`
`DRUGS AND PHARMACEUTICAL
`FORMULATIONS FOR ADMINISTRATION
`BY THE BUCCAL AND SUBLINGUAL ROUTES
`
`Although the data produced using the buccal partitioning
`model of drug absorption I23) have shown that numerous
`
`
`
`TEVA EXHIBIT 1021
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`
`
`Drug I)elivery—|!uccal Route
`
`805
`
`the oral cavity. few
`drugs are absorbed elificiently |'rottt
`drugs have been assessed clinically ‘.tl"ter adtttinisuation by
`this route. and not all drugs that have given encotnagiag
`Clinical data have specilic lornntlalions available for
`intraoral administration. Drugs within the cardiovascular
`and strong analgesic pharmacologic classes have received
`the Ittost attention.
`
`Cardiovascular Drugs
`
`Glyceryl trinitrate (GTN)
`
`This vasotlilator has been ttsed for over 100 years in the
`treatment of angina pectoris. and today. tnany clinicians
`consider it
`the most eI'|'ective drug despite cxlraustive
`efforts to had alternatives. [1 is also used itt the treatment
`
`ol’ congestive heart l'ai|urc. This drug is rapidly absorbed
`from the mouth. with mttch olthe drug bypassing tlte liver.
`The liver has a high metabolic capacity for organic nitrates
`by virtue of the enzyme glutathionc reductase (23).
`Sublingual administration ol'GTN is the most appropriate
`action.
`to alleviate the pain of an acute angina attack
`because of its rapid action. its lttI1t_1~etitttbliHl1ct.l cflicacy.
`attd its low cost
`(29). The traditional pltatrttlitctillllfldl
`fortnttlation of the drug is a rapidly dissolving tablet for
`administration under the tongue. This approach. however.
`has two main tlisadvantages:
`
`ls.)
`
`to disintegrate and
`l. The time taken for tlte tablet
`dissolve may vary l'ront person to person. A tl'~‘li1)"3d
`and varied onset of action may resuh.
`The tablets of GTN lose signilicant potency alter only
`8 weeks of the initial opening of the tnanul'acturer‘s
`bottle and should be discarded al’ter that period hccdllfic
`exposure to moisture and to the atmosphere accelerates
`nitrate breakdown.
`l-lcat also accelerates drug
`deterioration.
`
`to overcome the previously noted
`In an attempt
`problems witlt
`the suhlingual
`tablet formulations. GTN
`is
`now widely available
`in metered—dose
`aet‘os0l
`preparations. The sprays usually contain 0.4 mg GTN
`per unit dose. The inanufacturers suggest
`that
`I or 2
`ntetcred doses be
`sprayed on the
`oral
`t1tllL‘0-‘til
`(preferably under
`the
`tongue) and then the mouth
`should be closed.
`
`A slightly dil"t”erent approach has been taken by
`Pharmax.
`the ntanufacturer ol' Suscard Buccal
`tablets-
`lnstcad ot'
`the
`traditional 300-, 500-.
`and {tilt}-p.g
`sublingttal
`tablets.
`the Pltartttax tablets I.'ortl£tlt1 l. 3. 3-
`or 5 mg ot‘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. alter which dissolution continues in a ttnitornt and
`gradual manner. Because this
`is a pi‘olonged—re|ease
`dosage form, the patient should not increase the tablet‘s
`dissolution rate by moving it around the mouth. The
`tablet should be replaced it" 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 forntulation has been shown
`to be effective in congestive heart failure (30).
`
`Isosorbide dinitrate
`
`This nitrate is also active sublingualiy and is a more
`
`chemically stable drug for those who require nitrates only
`infrequently.
`It
`is a longer—acting drug than GTN. The
`activity o|'
`isosorbide tlinitrate may depend on the
`production of active metabolites.
`the most important of
`which is isosoi-bide 5-mononitriate. Isosorbide monom-
`
`trate is also available for angina prophylaxis. though the
`advantages over isosorbide dinitrate ltave not yet been
`Iirtnly established l3|). The general consensus is that the
`activity ol‘ the dinitrate is also longer than that of GTN
`Katttts et al. £32).
`for example. found that sublingual
`isosorbide Clinitrate ol't'cretl protection against angina for
`2.5—3 h compared to I h relief with GTN The finding, of
`equal bioavailability of chewable tbuccal ttbSUt'plit)t1]:t[1d
`slow—releasc capsules {intestinal absorption) “infers that
`buccal or sublingual absorption does not circumvent the
`first pass effect.
`that prcsystctnic metabolism occurs in
`the buccal mucosa.
`that huccal 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
`
`auhninistration 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 he the rapid disintegration and dissolution of
`the tablet in saliva. Present knowledge suggests using the
`drug buccally l'or the treatment of acute attacks of angina
`and using a sustaitted-t‘eleasc liorntttlation for prophylactic
`purposes.
`Iga and Ogaw-.1 (34)
`tlenionstrated that
`;.
`sustained release buccal Forraulation of both GTN and
`isosorbide dinitrate increased the bioavailability of both
`drugs when administered to dogs. compared to am]
`administration. A number of isosorlzlide dinitrate prep-
`arations are availabl
`tot‘ administration by the buccal or
`suhlingttal routes. tl-
`ttsual strengths being 5 or I0 mg.
`Although chewable preparations are available. the ntore
`traditional quick-disintegrating tablets predominate.
`Because mastication tends to increase saliva production.
`in order to prevent premature swallowing of the drug. the
`
`
`
`TEVA EXHIBIT 1021
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`
`
`806
`
`Drug Di.-livery—Bucc-al Route
`
`——-EI-—-
`
`(‘aptopril cone.
`
`—‘**
`
`Systolic Bi’
`
`a
`U
`‘-3
`
`in
`
`'
`
`U
`
`10
`
`60
`
`an
`Tiltu: llitilij
`
`no
`
`Iso
`
`use
`
`
`
`tn}
`
`Mill
`
`gin
`
`"E
`‘El Elli)
`
`150
`
`too
`
`St)
`
`0
`
`30!]
`
`35!]
`
`E
`3
`
`E§
`
`-
`is
`U
`
`{I1}
`
`Iii
`-I
`
`g. 3""
`5
`:3
`'5
`u
`‘"5;
`2
`Er
`D
`
`'”“
`
`so
`
`*5'-‘*‘
`
`Cztptopril cone.
`
`'
`
`Systolic Bl’
`
`|'_)_{]
`
`I 15
`
`Ill:
`
`n.
`CG
`3
`ms 3
`
`ca
`
`too
`
`.. 95
`
`so
`
`” "
`(1
`
`ill]
`
`(ill
`
`‘)0
`'l'imc lminj
`
`120
`
`I 50
`
`Jill)
`
`traditional tablet type may also be preferable. Sublingual
`rather than buceal administration may also be preferable
`because higher plasma concentrations have been found in
`healthy volunteers when the former route was used (I5).
`(Fig. 2)
`
`Niteclipine
`
`in the past, the difficulties 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 solely used perorally;
`however.
`the
`rapid-release capsule, which contains
`nifedipine in solution form, was formerly administered
`to the buceal cavity. However,
`the manufacturers now
`state in their literature that "nifedipine should not he used
`for the treatment of acute attacks of angina“ as it has been
`associated with large variations in blood pressure and
`reflex tachycardia (36).
`
`Captopril
`Two studies (37. 38) have indicated the usefulness of
`sublingual eaptopril in the treatment of severe hyperten-
`The hypertensive patients thus treated showed a
`sion.
`marked decrease in systolic and diastolic blood pressure.
`with the onset of action being 2-5 min and the peak effect
`at 10 min (37'). Perorally administered captopril
`takes
`I-2 h to achieve a maximal therapeutic effect (39) and,
`therefore,
`is unsuitable for the treatment of hypertensive
`crisis. Al-Furaih et al.
`ll?) reported that suhlingual
`administration of captopril tfollowed by plasma monitor-
`ing ofdrug levels) led to a more rapid attainment of plasma
`captopril concentrations and had a more rapid pharmaco-
`logical effect
`ti.e.,
`lower systolic blood pressure)
`compared to peroral administration of the drug as shown
`in Fig. 5.
`lsean et al. (40) compared a number of parameters
`of a specially formulated buceal bioadhesivc captopril
`tablet with that of a conventional
`tablet. The buceal
`formulation provided controlled release of captopril
`with a smooth plasma level profile and a long duration
`of action; however,
`its bioavailability was 40% via the
`buccal
`rottte as compared to 65% following an oral
`(lose. 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.
`
`Fig. 5 Comzlation over time of systolic blood pressure (0) with
`plasma unchanged captopril concentration (B) after suhlingual
`la) and peroral {bi administration of 25 mg of captopril. (From
`Ref. 17.}
`
`Analgesics
`
`Buprenorphine
`
`in common with other phenolic opiate analgesics.
`buprenorphine shows low peroral potency, suggesting, a
`high lirst-pass metabolism effect; indeed. work in rats has
`shown this to he the case t2"r'). Intravenous studies have
`estimated that the extraction ratio ofhu