PAHENTEHAL FUNDAMENTALS
`
`Bioavailahility of Parenteral Drugs ll. Parenteral Buses Other Than
`Intravenous and Intramuscular Routes
`
`FRANCIS L. S. TSEA and
`PETER G. WELLING'
`
`A College of Pharmacy
`Rutgers~—The State University
`Piscataway, New Jersey
`
`* School of Pharmacy
`University of Wisconsin
`Madison, Wisconsin
`
`Introduction
`
`In the previous article of this series basic
`pharmacokinetic principles governing drug
`levels in blood were reviewed, and the bio~
`availability of parenteral drug products was
`described with particular reference to intro»
`venous and intramuscular dosage forms (1).
`In this article attention is focused on the bio-
`availability of dosage forms which are ad-
`ministered by other parenteral routes.
`The major drugs and drug groups which
`may be administered by parenteral routes
`other than intravenous and intramuscular are
`
`shown in Table I. In many instances, e..g.,
`subcutaneous insulin and intraarterial or in-
`trathecal administration of anticancer com-
`
`pounds and antibiotics, the parenteral dosage
`route is well established and clinically useful.
`In other instances, such as intradermal vac-
`cines and vaginal administration of estrogens
`for systemic activity, the dosage route is less
`well established but has considerable clinical
`
`potential for some compounds.
`
`Subcutaneous Administration
`
`Many compounds are routinely given by
`subcutaneous injection, in particular insulin
`local anesthetics, and vaccines.
`
`Small volumes (0.5 to 2 ml) of medications
`in solution form may be administered by
`subcutaneous (hypodermie) injection, usually
`into the outer surface of the upper arm, al-
`though the anterior surface of the thigh,
`abdomen, or buttock may also be used. The
`needle is usually inserted at a 45~degree angle
`to the skin, as shown in Fig. l.
`The same factors affecting intramuscular
`drug absorption also govern drug bioavail-
`ability following subcutaneous doses (2). The
`rate of absorption, 12,, of a subcutaneous dose
`of drug from the injection site into the blood
`is proportional to the amount of drug at the
`site. A, as described by liq. l:
`
`R: = Pi/ls)
`
`(Bit 1)
`
`The penetration coefficient, p, depends upon
`the diffusion coefficient of the drug in the
`particular environment, the area of membrane
`exposed to the solution, the distance of diffu-
`sion, and the concentration gradient of drug
`across the absorption membrane. The primary
`absorption membrane in subcutaneous con-
`nective tissue is the capillary wall (3).
`As with intramuscular doses, drug solutions
`injected subcutaneously are influenced by the
`buffer capacity of the subcutaneous tissues
`
`Journal of the Parenteral Drug Association
`
`Astrazeneca Ex. 2119 p. 1
`Mylan Pharms. Inc. V. Astrazeneca AB
`IPR20 16-0 1325
`
`

`
`
`
`Epidermis
`Dennis
`Subcutaneous
`Muscle
`
`Figure I ~.Snbcutan:>ous‘ injection.
`
`which breaks down mucopolysaccharides of
`the connective tissue matrix. has been used to
`
`promote spreading of solutions and to increase
`drug absorption rates (8).
`Drug absorption is increased by rubbing the
`skin around the injection site, and also by ex-
`ercise. Bcrger and associates (9) reported a
`substantial increase in the absorption rate of
`3H-insulin due to leg exercise following sub-
`cutaneous injection leading to markedly ele-
`vated plasma levels of exogenous insulin. The
`effect of exercise on circulating 31-I-insulin
`levels in one patient is shown in Fig. 2. The
`effect is more pronounced when insulin is in-
`jected into an exercised limb than when it is
`injected at another site (10). This is illustrated
`in Fig. 3 which shows a far greater increase in
`hypoglycemic effect due to leg exercise when
`
`TABLE 1. Compounds Which May be
`Administered by Parenteral
`Routes Other Than
`Intravenous and Intramuscular
`
`Route
`
`Subcuta~
`neous
`
`Intraderrnal
`Pcreutaneous
`
`Intraarterial
`
`lritrathecal
`
`Intraperito~
`neal
`inhalation
`
`Vaginal
`
`Compounds
`
`Bethanechol, epinephrine,
`fat-soluble vitamins,
`
`heparin, insulin, local
`anesthetics, vaccines
`Antigens, vaccines
`Nitroglycerin ointment.
`safflower oil
`
`Anticancer agents,
`vasopressin
`Antibiotics, anticancer
`agents. local anesthetics
`Antibiotics, anticancer
`agents, insulin
`Anesthetic gases,
`antibiotics, atropine,
`corticosteroids, cromolyn
`sodium. epinephrine,
`ergotarnine,
`isoproterenol, lidocaine,
`mctaproterenol,
`terbutaline
`
`Estrogens, progesterone,
`prostaglandins
`
`and fluids (4). The rate of absorption of sub-
`cutaneous lidocaine hydrochloride, for ex-
`ample, is affected by pH changes at the in-
`jection site (5). At a pH of 7.4, the lidocaine
`hydrochloride concentration must be lower
`than 0.097% to avoid precipitation.
`Absorption of drugs which are given sub-
`cutaneously is generally slower than after in-
`tramuscular administration because of less
`efficient regional circulation. Prolonged ab-
`sorption of metallic mercury from subcuta-
`neous injections was demonstrated in a recent
`case of metallic mercury poisoning £6).
`Molecules or ions with low molecular
`weights are absorbed primarily via the capil~
`laries, while molecules having high molecular
`weights appear to be absorbed primarily via
`lymph vessels (7). Hyaluronidase, an enzyme
`
`Novemhervficcember. (980, Vol. 34, No. 6
`
`485
`
`on
`E
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`EXERCISE
`3
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`so
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`so
`minutes
`
`12o
`
`:50
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`see
`
`are
`
`3H - insulin injected
`
`Figure 2—Effec: of mild bicycle exercise on plasma
`levels of intact 3H»insu!z'n foliowingsubcmaneous
`injection ofé X 105 cpm 3H-insulin/kg body weight
`into the leg ofa juvenile patient. Reproduced by per-
`mission from Diabetes
`(Suppl.
`1’), 28, 53-57
`(I 979).
`
`Astrazeneca Ex. 2119 p. 2
`
`

`
`EXERCl5E
`
`
`
`
`
`APLASMAGLUCOSE(mg/til)
`
`ABDOWNAL lNdECTl0N
`
`TIME (hr)
`
`Insulin Injection
`
`Figure 3wfnfluence offnjeaion site on plasma glucose
`response to insulin dwing leg exercise. Shaded areas
`represent changes in plasma glucose levels (mean :1:
`SE) following in.ml£n injection during leg exercise
`compared to that obtained with :10 exercise. The area
`above the curve for leg injection is signijimntty greater
`than therefor both arm (p < 0.02) and abdominal (p
`< 0.005) injections. Reproduced by permissionfrom
`N. Engl. J. Med., 298, 79-83 (1978).
`
`insulin is injected subcutaneously into the leg
`compared to the arm, while the effect was
`negligible after abdominal injection. Stimu-
`iation of absorption could be due to changes
`in the interstitial fluid pressure of subt:uta~
`neous tissue owing to contractions of undcr-
`lying musculature or movements of the in-
`jected limb.
`
`Drug action may be prolonged if injection
`is made deep into the subcutaneous tissue, c.g.,
`aqueous solutions of heparin and long-acting
`insulins. Coadministration of epinephrine with
`Iocal anesthetics extends their duration of local
`action by producing vasoconstriction in the
`zone of absorption (1 1). Cooling also causes
`local vasoconstriction and results in prolonged
`drug absorption.
`
`Sustained-Release Subcutaneous Products
`Prolonged release of drug may be obtained
`by implanting pellets under the skin. An ideal
`
`pellet does not disintegrate but slowly dissolves
`in the subcutaneous fluid environment during
`the implantation period. The absorption rate
`of drug can be determined by weighing the
`pellet upon removal (12). For a spherical
`pellet,
`
`= 32-” (D0 - my
`and for a flat disc,
`
`{Eq. 2)
`
`W -—- ¥ (00 ~ knltizo — kt)
`
`(Eq. 3)
`
`where W is the weight of pellet at any time I
`after implantation, p is the apparent density
`of solid, D0 is the initial diameter of the sphere
`or disc, I10 is the initial height of the disc, and
`k is the mean absorption rate constant.
`Subcutaneous implants have been used in
`commercial products for the continuous de-
`livery of certain steroid hormones, e.g., ms»
`tosterone (Oreton), and the delivery of a va-
`riety of drugs, including bcnzyl pcniciliin, goid
`salt, progesterone, and sulfadiazinc,
`from
`subcutaneous implants has been tested in man
`or experimental animals (12,
`I3)k Silastic
`rubber implants have been examined For re-
`
`
`
`
`
`CUMULATIVENICOTINEEFFLUX,%.
`
`INTOpH74BUFFER
`
`2
`TlME lhrl
`
`3
`
`4f_l.6
`
`Figure 4~—Cumu1a!ive percentage of nicotine base
`released from dimezhylpolsitoxane (~04 and di-
`methylpolysiloxane -2- fiuarosilicone-laminated pol-
`ysiloxane (-0-) tubing: into pH 7.4 bujjfer at 37°.
`Reproduced by permission from J. Pharm. Sci, 63,
`18494853 (1974).
`
`Journal of the Pareritcral Drug Association
`
`Astrazeneca Ex. 2119 p. 3
`
`

`
`
`
`
`
`
`
`
`
`
`
`....'...'.,i_._-E.*3‘,_$_M._.P.-,.5-9'..m_.:,gag,e§g;:I_--iié;....s..,«.;~,
`
`
`
`
` ZfimydroxyvitominD(rag/mil 20
`
`100
`
`80
`60
`
`40
`
`CIJMULATWE%RELEASED
`
`i so
`
`I00
`
`I50 200 250 300 350 400 450 500
`TIME (mm)
`
`Figure 6——ln vitro release of pentagastrirl fmm two
`liquidformulations. I (-0-) and I1 (-51-), andfrom
`two crystalline suspensions, III (—A-) and IV (-0-)
`into pH ?.3 isotonic phosphate buffer at 37°. Repro-
`duced by permissionfrom J. Pharm. Pharmacol., 22,
`923-929 (I970).
`
`T
`
`_l-.-.~v4r--r‘
`
`"V
`
`3
`2
`TtME (Weeks)
`
`4
`
`6
`
`T
`
`E0
`
`0 O
`
`l
`
`Figure 5~Serum 25-hydroxyuitamin D levels (:1.-
`SEM) in volunteers who received a 1.00-pg/kg oral
`dose (O-MO). a 2D0—,ug/kg intramuscular dose (0
`~00. or a 200-1&8’,/kg Stzbmtaneous dose (0 .
`.
`. O)
`ofvitamin D, and in control subjects who received no
`uitamtn D (O~ - -O). Reproduced by permissionfrom
`J. CIWK Endocrine]. Memix, 48, 906-91 1 (1979).
`
`lease of progestogens (14), and Gaginella and
`associates have demonstrated marked varia-
`
`tion in the rate of drug release from different
`silicone polymers (15). This is illustrated in
`Fig. 4, in which the in vitro release of nicotine
`base into pH 7.4 buffer from 3. dimethylp0l-
`ysiloxane polymer reaches 75% in 4 hr and
`95% in 16 hr, but the release from a fluornsi1-
`icone-laminated polymer is reduced to 40% in
`4 hr and 65% in 16 hr. The use of polymer
`materials with different release characteristics
`
`is of considerable potential in the design of
`sustained-release drug implants. Alginate
`implants have been shown to provide slow and
`continuous release of fluoride in rats (16),
`while oily depot subcutaneous injections re-
`sulted in prolonged release of vitamin D (17).
`Comparative serum levels of the metabolite
`25-hydroxyvitamin D during a 7-week period
`following oral, depot intramuscular, and depot
`subcutaneous doses of vitamin D, and also in
`control animals who received no vitamin D,
`are show in Fig. 5.
`Marked differences in the in vitro release of
`
`November-%ember. l98l3. Vol. 34‘ No. 6
`
`487
`
`pentagastrin from two solutions (Formulations
`I and ll) and two crystalline suspensions
`(Formulations Ill and IV) designed for sub-
`cutaneous injection are demonstrated in Fig.
`6 (2). Prolonged release of pentagastrin from
`the subcutaneously injected crystalline for-
`mulations is suggested in Fig. 7, in which bil-
`iary excretion of drug was lower but more
`prolonged from Formulations III and IV than
`from Formulations I and I].
`
`Although still in the early stages of devel-
`
`
`
`
`
`DOSEEXCRETEDENTHEBILE(‘Xvi
`
`TIME AFTER lNdECTlON (hr)
`
`Figure 7—B‘il:'ary excretion of radioactivity labelled
`pentagastrin after subcutaneous administration of
`Iiquidformulatiorzs, I (-0-) and II (—|ZI—). and cry.r~
`talline suspensions. I(I (—a—) and I V (-0-) to rats.
`Reproduced by permissionfrom J. Pharm. Pfiarmacoh
`22, 923-929 (I 970).
`
`Astrazeneca Ex. 2119 p.
`
`

`
`opment, liposomes appear promising as po-
`tential vehicles for delivering drugs from the
`site of subcutaneous injection to specific tar-
`gets within the body. Liposornes are hydrated
`liquid crystals formed when phospholipids are
`allowed to swell in aqueous media. In a recent
`study (18) unilamellar vesicles consisting of
`distearoyl phosphatidylcholine, cholesterol,
`and some sugar and amino—sugar derivatives
`of cholesterol were shown to be potentially
`useful in developing liposome systems capable
`of providing controlled release of therapeutic
`agents.
`
`Imradermal Administration
`
`lntradermal injections are used predomi-
`nantly for local effects, but the potential of this
`route for systemic activity, particularly for
`vaccines, has been illustrated in several
`studies.
`
`Intradermal injection is made into the upper
`layers of skin, just beneath the epidermis. A
`usual site for intraderrnal injection is the an-
`terior surface of the forearm. The volume of
`solution that may be administered in this
`manner is only about 0.1 ml.
`Intradermal injection is frequently used for
`administering antigens in tests for allergic
`reactions (19). Alcohol is given by intradermal
`injection for the treatment of pruritus vulvae
`(20), While systemic absorption from an in-
`tradermal injection site is usually slow, this
`route is useful in delivering agents for immu-
`nization (21). An intradermal injection of 0.1
`ml of an Asian influenza vaccine produces a
`rise in antibody titer comparable to that
`achieved with a subcutaneous injection of 1 ml
`of the same vaccine (22, 23). A recent study
`by Halperin at. al. (24) confirmed the supe~
`riority of the immunogenicity of the intra~
`dermal route for A/Victoria/ 75 vaccine, but
`failed to show any difference in intradermal
`and subcutaneous routes for A/New Jer-
`seyf76 (Swine Flu) vaccination. The authors
`concluded that in times of vaccine shortage the
`intradermal route. which involves smaller
`doses, may be important. In addition, less local
`irritation may be associated with intradermal
`than with subcutaneous injections (25).
`
`Percuzaneous Administration
`
`The outermost layers of human skin consist
`of the epidermis and the dermis (see Fig. 1).
`Drugs penetrate the epidermis at rates deter-
`mined largely by their oil/water partition
`coefficients, water—soluble molecules being
`virtually excluded. The underlying dermis
`consists of loosely arranged connective tissue
`and is more freely permeable. Various phar—
`Inacokinetic models have been examined to
`describe the percutaneous absorption of a drug
`from topically applied vehicles (26, 27). The
`percutaneous route is used primarily in sit-
`uations where drug action is to be upon an
`open wound or upon the superficial layers of
`the stratum corneum. If the pathologic con-
`dition is in the deeper layers of the epidermis
`or in the dermis, topical drug therapy may be
`ineffective. For example, antibacterial and
`antifungal agents are often more effective in
`skin infectious when given orally or by injec-
`tion than when applied to the skin.
`Two examples of the use of percutaneous
`absorption for systemic effects are the topical
`application of safflower oil in some patients
`with essential fatty acid deficiency who cannot
`be closed parenterally, and topical nitroglyr»
`erin ointment for the prevention or treatment
`of angina. Accurate titration of the dose of
`nitroglycerin is achieved by adjusting the
`amount of ointment to the patient’s needs. The
`usual dose is 1-2 in., as squeezed from the
`tube, every 3 to 4 hr (28).
`
`Inhalation
`
`The respiratory tract has been used as a
`route of drug administration for centuries and
`the large number of compounds which may be
`administered by this route is indicated in Table
`I. This pathway consists of the mouth or nose,
`pharynx, trachea, bronchi, bronchioles, al-
`veolar ducts. alveolar sacs, and the alveoli.
`Together, they provide an extremely large
`surface area for rapid absorption, most of
`which occurs in the alveolar ducts and alveolar
`
`sacs. For a more complete description of the
`anatomy and physiology of the respiratory
`system, the reader is referred to a review by
`German and Hall (29).
`
`488
`
`Journal of the Parenteral Drug Association
`
`_:
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`Astrazeneca Ex. 2119 p. 5
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`

`
`tr-
`
`‘la.».».
`
`
`
`‘~'%Efi.%=a_—.._.,...W
`
`TABLE I1. Regional Deposition of Unit Density Spheres in Relationship to Particle Size
`(29)
`
`Particle
`Diameter,
`(pm)
`
`Percent Aerosol Deposition for Tidal Volume of 750 ml
`Nasopltaryngeal
`Tracheobmnchial
`Pulmonary
`Region
`Region
`Region
`
`0.01
`0.06
`0.20
`0.60
`1.0
`2.0
`3.0
`4.0
`6.0
`10.0
`
`L
`
`0
`0
`0
`0
`4
`41
`55
`65
`80
`99
`
`31
`7
`3
`2
`3
`5
`7
`8
`9
`0.7
`
`51
`S9
`28
`20
`25
`35
`31
`24
`10
`0.2
`
`Total
`
`82
`66
`31
`22
`32
`81
`93
`97
`99
`100
`
`The alveoli are separated from the capillary
`system by the alveolawsapillary membrane,
`which forms an air-blood barrier of about
`
`0.240 nm in thickness. The proximity of the
`capillary endothelium to the alveoli permits
`very efficient exchange of substances, and a
`rich pulmonary blood supply assures rapid
`removal of any substance that may penetrate
`the alveolar-capillary membrane.
`Drugs can be introduced into the respiratory
`system as gases or as inhalation aerosols. Best
`examples of the former are the general zines»
`thetics such as ether and chloroform. Diffusion
`across the alveolar-capillary niembrane does
`not offer any significant resistance to the
`transfer of gases between the lung and blood,
`and they are almost instantaneously absorbed
`{30. 31).
`Aerosols are fine suspensions or dispersions
`of solid or liquid particles in gases. The active
`ingredient is dissolved or suspended in a li-
`quified propellant system, from which an
`aerosol is produced. Upon inhalation, {i6]){)~
`sition of aerosol particles may occur within the
`respiratory airways by impaction, sedimen-
`tation, or diffusion (32). lmpaction usually
`occurs in the nasal pharynx and tracheal~
`bronchial tree when the airstream in which a
`
`particle is flowing changes direction. For a
`given drug, particle size is the primary factor
`governing the bioavailability of inhalation
`
`Novemher~Deceml;x:r. 1980. Vol. 34. No. 6
`
`489
`
`aerosols. Aerosol particles larger than 10 ;.tm
`are almost completely deposited in the nasa-
`pharyngeal region. Smaller particles penetrate
`deeper in the respiratory tract, with some de-
`position in the passages, resulting in local ac-
`tivity. The regional deposition of different size
`particles in the respiratory tract is shown in
`Table ll (29).
`Most aerosol particles will adsorb moisture
`as they pass through the respiratory tract, and
`the resultant growth in particle size contrib-
`utes to deposition. Systemic absorption occurs
`mainly after the particles reach and deposit in
`the alveoli, dissolve in the alveolar fluid, and
`are transported through the alveolar-capillary
`membrane into the capillary blood system.
`The optimum size for this purpose is about 1-2
`pm.
`The presence of electrical charges on par-
`ticles also has an effect on their deposition.
`Small particles in particular show marked
`increases in deposition in the nasopharynx
`when they are charged (29). Another factor
`which can affect the absorption of substances
`from an aerosol is the density of the suspend-
`ing gas. A denser gas has a greater buoyant
`effect on suspended particles, permitting them
`to penetrate more deeply into the lungs.
`An important consideration in aerosol ad-
`ministration is the respiration rate and tidal
`volume, i.e., the volume of air inspired and
`
`..
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`Astrazeneca Ex. 2119 p. 6
`
`

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`......1
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`
`
`expired with each normal breath. In a normal
`young male adult, the respiratory rate is ca. 12
`breaths per minute and tidal volume is 500 ml
`(33). Any increase in the velocity of inspired
`air would drive the particles deeper into the
`pulmonary tree. On the other hand, reducing
`the respiratory rate would increase the dwell
`time and the retention of aerosol particles in
`the lungs.
`Inhalation aerosols are used both for local
`
`therapy (e.g., isoproterenol in acute asthmatic
`attacks) and for systemic effect (e.g., genta~
`micin, penicillin. and corticosteroids such as
`heclomethasone dipropionate). An obstacle to
`more extensive use of this route is the concern
`
`for dose accuracy (34). Further studies to
`improve inhalation devices are needed in order
`to expand the use of this effective route of drug
`administration.
`
`Intmarteriai Administration
`
`This route is used for the regional delivery
`of drugs to various organs, as often desired in
`cancer chemotherapy or in the use of vaso-
`pressin for gastrointestinal bleeding. Intra-
`arterial infusion increases drug delivery to the
`area supplied by the infused artery, while re-
`ducing the access of drug to the systemic cir-
`culation (35). This advantage is particularly
`evident in the infusion of a highly cytotoxic
`drug into an artery which receives a small
`fraction of the cardiac output. In order to have
`reduced entry of the toxic drug into the sys-
`temic circulation after arterial
`infusion,
`however, there must be loss of drug by me»
`tabolism, excretion, or chemical degradation
`during its passage through the region being
`perfused by the arterial blood.
`Clinical reports have shown intraarterial
`BCNLJ to be effective for the treatment of
`
`metastatic brain tumor from lung carcinoma
`(36), and local (pelvic) intraarterial actino—
`mycin D to be useful for malignant tropho-
`blastic disease (37). Cason and Whaley (38)
`used a head-hunter catheter for intraarterial
`
`hepatic infusion of chemotherapeutic agents,
`which permits direct perfusion of primary and
`secondary liver tumors. Carotid artery infu-
`sion of vinblastine is more satisfactory than
`
`
`venous infusion of the drug in treating oerebra :
`tumor in rats (39). A recent study showed the '
`effectiveness of selective intraarterial tissue
`
`pressin infusion in treating massive upper
`gastrointestinal tract hemorrhage (40).
`Despite the advantages mentioned above,
`use of the intraarterial route of drug admin-
`istration is limited by the potential dangers.
`Complications such as emholization, arterial
`occlusion, and excessive local drug toxicity are
`not uncommon, thus requiring maximum care
`in dose administration.
`
`Intrallzecal Admi’m'strarion
`
`Injection directly into the eerebrospinal
`fluid ensures complete bioavailability of drugs
`which otherwise may have difficulty crossing
`the blood-brain barrier. This dosage route is
`therefore useful in the treatment of serious
`central nervous system (CNS) infections, such
`as meningitis and ventriculitis. lntratheealj
`injection is used also to produce spinal anes»
`thesia, with such agents as mepivacaine and
`prilocaine, and in relieving chronic pain (41).
`Heidrich et al. (42) showed that intrathecal
`administration ofp-aminomethylbenzoic acid
`is effective in treating subarachnoid hemorw
`rhages, while oral or intravenous administra
`tion of the drug fails to produce hemostatieally
`effective concentrations in the eerebrospinall
`fluid.
`In recent years.
`intrathecal chemo-’:
`therapy has gained importance in the treat«
`ment of meningeal neoplasms, which are
`largely CNS metastases from systemic cancer
`(43).
`Drugs administered by the intrathecal route
`are usually injected directly into the lumbar
`spinal suharachnoid space, into the subdural
`space, or into the ventricles. frequently via an
`implanted reservoir. The site of injection has
`a great effect on the availability of drug to.
`various regions of the CNS. This is demon»
`strated in Table III (44). lntraventricular
`administration of 3H-methotrexate in monrf .-
`keys gave rise to significantly higher drug
`levels at 2 hr in whole brain, and cervical and
`thoracic spinal cord, but lower levels in the‘.
`lumbar spinal cord compared to levels ob-
`tained from a spinal catheter. At 4 hr post-
`
`
`
`490
`
`Journal of the Parenteral Drug Association
`
`Astrazeneca Ex. 2119 p. 27
`
`

`
`TABLE III. Mean Levels“ of 3H-Metholrexate in Whole Brain and Spinal Cord Regions
`after lntraventricular and lntrathecal Spinal Catheter Administration to
`Monkeys (44)
`
`Tissue
`
`[VA ll’
`
`Whole brain
`Cervical spinal cord
`Thoracic spinal cord
`' Lumbar spinal cord
`
`4.32
`8.46
`7.92
`5.64
`
`2 hr
`
`SC °
`
`0.15
`0.86
`1.36
`9.57
`
`Time after Injection
`
`[VA/SC
`Ratio
`
`28.8
`9.8
`5.8
`0.6
`
`IVA
`
`8.67
`7.13
`4.29
`1.96
`
`4 hr
`
`SC
`
`0.74
`26.1
`60.2
`121.2
`
`IVA /SC
`Ratio
`
`l 1.7
`0.3
`0.]
`0.02
`
`“ Units are pig/g tissue. 5’ lntraventricular administration. “ Spinal catheter.
`
`
`
`-.‘E-
`"X.
`..,r‘.4
`:.~
`
`‘
`
`\.. .
`ii:E:
`Q.
`s‘....
`
`
`
`
`
`thecal chemotherapy in brain tumors. in order
`to achieve therapeutic levels at the tumor,
`there must be minimal loss ofdrug as it moves
`along the CSF pathways to the target site.
`CSF How may be altered by obstructions (e.g.,
`tumor growths) in the subarachnoid space or
`ventricular pathways. Finally, although CSF
`protein content is much lower than that in
`plasma, the effect of protein binding can be
`significant
`for drugs that are extensively
`bound, such as methotrexate [ca. 95% (50)],
`resulting in a diminished quantity of free drug
`available for transport into the tumor cells.
`
`Intraperitoneal Administration
`In situations where the more common
`
`routes of drug administration are impractical.
`intraperitoneal injeetions may be useful. The
`drug is injected directly into the peritoneal
`space through a locally anesthetized area
`below the umbilicus. Drug absorption from the
`abdominal cavity is slower than from intra-
`venous injection. and the effects are usually
`prolonged. Schade and associates (51) com—
`pared intravenous, intraperitoneal. and sub-
`cutaneous routes of insulin delivery in diabetic
`patients, and showed that
`intraperitoneal
`dosage provided plasma insulin levels that
`were intermediate between the high but
`transient
`levels obtained from intravenous
`
`injection, and the delayed but prolonged levels
`after subcutaneous injection. it is claimed that
`intraperitoneal insulin injection may be an
`attractive alternative to intravenous and sub-
`
`Astrazeneca Ex. 2119 p.
`
`dosing, brain levels from the intraventricular
`administration were still 11.? times greater
`than those obtained from the spinal catheter,
`although drug levels in the spinal cord were
`then significantly higher
`from the spinal
`catheter administration.
`
`Lumbar puncture often results in leakage
`of drug into the epidural or subdural space.
`Also, the drug must ascend the spinal sub-
`arachnoid space against the descending bulk
`flow of cerebrospinal fluid (CSF) (45). re-
`sulting in low. subtherapeutic levels in the
`brain (46). Furthermore,
`intraventricular
`administration is superior to intralumbar in-
`jection as the cerebral ventricles are the site of
`CSF production,
`thus allowing thorough
`mixing and distribution of drug throughout
`the CSF compartments (47).
`Drugs injected intrathecally are distributed
`initially into a much smaller volume (140 ml
`CSF) than those adminstered intravenously
`(3 liters plasma). The former route therefore
`generally provides higher drug concentrations
`in the CNS with less risk of systemic toxicity.
`lntrathecally administered methotrexate
`produces concentrations in the cerehrospinal
`fluid that are lO0~fold higher than simulta-
`neous plasma concentrations (46, 48). How-
`ever, toxic rnethotrexate levels in plasma may
`be more prolonged following intrathecal in-
`jection compared to intravenous or oral doses,
`possibly due to slow release of drug from the
`CNS into the systemic circulation (49).
`Other factors may limit the use of intra-
`
`Novem‘oer-December. 198$}. Vol. 3&1. Mn. 6
`
`491
`
`
`
`

`
`cutaneous dosage routes, since it provides
`relatively fast absorption for systemic activity
`while avoiding the risk of intravascular dosing
`complications such as catheter thrombosis.
`The peritoneal route has been used recently
`to administer antineoplastic agents for the
`management of tumors with extensive peri-
`toneal involvement, e.g., carcinoma of the
`ovary, breast, stomach, and colon. Theoretical
`studies by Dedrick and associates (52) suggest
`that peritoneal permeability of certain hy-
`drophilic anticancer drugs (e.g., methotrexate,
`ara-C) may be considerably less than plasma
`clearance, leading to substantially higher drug
`concentrations in the peritoneal cavity than in
`plasma. The data of Speyer er al. (53) on 5-
`fluorouracil support these predictions, and
`these authors claim that injecting directly into
`the intraperitoneal cavity may offer significant
`pharmacologic advantages over conventional
`dosage routes for some conditions. Drugs ab»
`sorbed from the peritoneum are also subject
`to first—pass metabolism in the liver (54), so
`that systemic availability may be further re-
`duced ibeneiicially) for those compounds
`which undergo hepatic metabolism. However,
`the success of intraperitoneal chemotherapy
`depends on several factors (52). For successful
`treatment, tumors must be of limited size, and
`large volumes of drug—containing solution
`must be used to ensure exposure of the entire
`peritoneal surface. Coadministration of drugs
`which may impair hepatic or renal function
`should be avoided.
`
`Vaginal Administration
`While the vaginal dosage route is used pri-
`marily for local effects, recent studies have
`shown that vaginal administration of some
`drugs may provide rapid and complete sys-
`temic absorption (55, 56). Martin et al. (57)
`studied the effects of two estrogen vaginal
`cream preparations in 29 postmenopausal
`women receiving daily applications, and re-
`ported rapid and efficient vaginal absorption
`of estrogens into the systemic circulation.
`Englund and Johansson (58) compared the
`plasma levels of estrone and estradiol in post-
`menopausal women after equal (1.25 mg) oral
`
`and vaginal doses of conjugated equine es-
`trogens. In four out of five subjects, plasma
`V estrone and estradiol levels were higher after
`vaginal than after oral administration, as in-
`dicated by radioimmunoassay and by cle-
`pression of plasma gonadotropins, follicle-
`stimulating hormone (FSH), and luteinizing
`hormone (LH). The comparative plasma
`levels of estrone and estradiol following oral
`and vaginal doses in one 53-year-old individual
`are shown in Fig. 8 (58). Estrogens given by
`the intravaginal route may be more bioavai-
`lahle than orally administered doses partly
`because the former do not have to pass
`through the hepatic circulation before entering
`the peripheral circulation. lntravaginal dosing.
`appears therefore to be a useful approach to
`estrogen replacement in deficiency states.
`Unfortunately,
`these findings also pose
`potential hazards for the use of vaginal creams
`which are intended only for topical treatment
`of atrophic vaginitis in patients who have had
`estrogen-dependent neoplasms.
`Another class of drugs administered vagi-
`nally for systemic activity are the prosta-
`glandin analogues used to terminate early
`pregnancy (59). Newly developed long-acting
`suppositories
`containing
`l5—methyl-
`PGFgc;r-methyl ester have been shown to be
`effective in terminating first and second tri-
`mester pregnancies fol lowing a single vaginal
`administration (60, 61).
`The effectiveness of vaginal absorption of
`
`
`
`
`
`PLASMAESTRONEAM}ESTRADKIL
`
`_
`vagina,” L 5509;-aesspmal
`In
`
`pmolft
`2000
`I503
`
`TIME (hrl
`
`Figure 8wPtasma estromz (~O-) and eszraalinl (- -
`0- -) levels following l.25—mg era! and vagina)‘ doses
`ofconjugazed equine esrrogens in a 53-year-oldfemale
`patient. Reproduced by permissionfrom Br. J. Obrter.
`GynaecoI., 85, 957-964 (1978).
`
`Journal of the Parenteral Drug Association
`
`Astrazeneca Ex. 2119 p. 9
`
`

`
`
`
`
`
`__,;.,,a,,.5,;.5-gm,.._.::::=:='g,-21.._se-Pg-3"-,;=i-i;_'e'.:";:_,,..,-_..,.Vvi.V-in
`
`4»1:
`
`l .K.,i
`
`..-,
`
`
`
`
`
`
`
`progesterone suppositories has been well
`documented (62). The current goal is to design
`a long-acting drug delivery device which can
`be inserted and removed without difficulty,
`and would function as a drug reservoir to re-
`leasc the contraceptive agent at a controlled
`rate, thus insuring patient compliance. Initial
`studies (63) have demonstrated the suocess of
`this route in providing more constant serum
`contraceptive levels than daily oral doses.
`
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`Wai, K. N., Gorring, B, E. L., and Broad, R. 1).,
`“Formulation and Pharmacological Studies of a
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`Plzarm. Pha1'mrz('01'., 22, 9234929 (1970).
`Schou, 1.. “Absorption of Drugs from Sub-::ut21~
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`Koivisto, V. A., and Felig, P., “Effects of Leg Ex-
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`Luckhardt, A. B., and Knppanyi, T., "Studies o