`
`
`
`352-
`_
`-' “M '
`‘
`ELSEVIER
`
`international Journal of Pharmaceutics 105 (1994) 189—2117
`
`
`
`international
`inurnal of
`pharmaceutics
`
`—-——-—-—-
`
`Invited Review
`
`Release and absorption rates of intramuscularly
`and subcutaneously injected pharmaceuticals (II)
`
`J. Zuidema *, F. Kadir, H.A.C. Titulaer, C. Oussoren
`
`Department of Biopharmeceuti‘c‘s, Facuity of Pharmaty. Department of Br‘opharmecettticr PO Box 80032, Utrecht (JPIlL‘QFJ'lly,
`3508 T3 Utrecht. The Netherlands
`
`(Received 22 July 1993; Accepted 22 November 1993)
`
`Abstract
`
`The rate and extent of intramuscular (i.m.) and subcutaneous (s.e.) drug absorption are very erratic and variable.
`The lipophilicity of the compound plays an important role. Aqueous drug solutions and suspensions of the more
`lipophilie compounds are often absorbed incompletely within the therapeutically relevant time. More hydrophiiic
`compounds are absorbed completely. Injection depth. drug concentration and vehicle volume, pH-pKIi
`relation,
`vehicle, cosolvents and surfactants have strong influences on the absorption profile of lipophilic drugs. Aqueous
`solutions of hydrophilic drugs are less sensitive to these factors. Drug solutions in oil and even suspensions in oil are
`often thought to be sustained release preparations. In fact, rapid absorption has often been observed. Slow release is
`not a property of the oily vehicle but is achieved by a high lipophilicity of the dissolved or suspended compound.
`Liposomal preparations are currently under investigation as i.rn. and s.c. injectable sustained release preparations.
`Factors that induce drug release at the injection sites are the proteins and especially lipoproteins in the interstitial
`fluids, originating from serum filtrate and from turnover of inflammatory cells. Phagocytosis by macmphagcs and fat
`cells may play an important role in the local clearance of liposomal material from the injection site. Sustained
`release of some pharmaceuticals with normal or long half-lives appeared in Specific cases preferable to rapid release.
`In addition, high arterial drug concentrations during the absorption phase may result in undesired effects even when
`venous drug concentrations are within the safe range.
`
`Key words: Drug absorption; Intramuscular administration; Subcutaneous administration; Absorption rate
`
`1. Introduction
`
`The intramuscular and subcutaneous routes of
`drug injection are often used when drugs cannot
`be injected intravenously because of their low
`aqueous solubility and / or when high peak con—
`centrations, resulting in local or systemic side
`
`* Corresponding author,
`
`effects, occur with intravenous injection. More-
`over, additional advantages of these routes in-
`elude greater convenience,
`less problems with
`compatibility of the injection components with
`full blood in the ciculation and often less fre-
`quent administration when compared to intra-
`venous administration.
`Many variables are known to affect drug re-
`lease after intramuscular or subcutaneous injec—
`tion. Factors such as molecular size, pKa, drug
`
`0378-5173/94/307IXI © 1994 Elsevier Science B.V. All rights reserved
`SSDI 0378—5173(93lED348-T
`
`AstraZeneca Exhibit 2114 p. 1
`InnoPharma Licensing LLC V. AstraZeneca AB IPR2017-00904
`Fresenius-Kabi USA LLC V. AstraZeneca AB IPR2017-01910
`
`

`

`
`
`190
`
`J. Zm'rt'trrrm t'r HI. fltrlt’r‘Itlliirtitrri Journal of th'nutt't'ttfit‘s' 1'05 ”994) hW—BUI’
`
`absorbed
`Fraetionnot
`
`injection
`initial drug concentration,
`solubility.
`depth, body movement. blood supply at the injec-
`tion site. injection technique and properties of
`the vehicle in which the drug is formulated have
`been discussed extensively in a previous review
`(Zaidema ct al.. 1988). This article is an update
`with emphasis on factors related to drug trans-
`port
`through the
`tissue.
`the
`role of drug
`lipophilicity. recent technology to modulate drug
`absorption from intramuscalar and subcataneous
`injection sites by carrier systems such as lipo-
`somes. absorptionby the lymphatic system and
`clinical implications.
`Drugs such as antibiotics, anti-asthmatics, anti-
`convulsics, anxioiyties and analgesics are often
`administered intramuscularly in severe disease
`states. A generally held viewpoint is that the drug
`is rapidly and completely absorbed from the in-
`jection site. Previously published data have al~
`ready demonstrated that complete absorption
`during a time relevant for therapy is not true in
`every case. (Ballard.
`i968: Dundee et al..
`[974:
`Kostenbauder et al.. 1975:1‘se and Welling, 198(1).
`however, recognition of their significance is lack-
`ing. Such findings may have important clinical
`implications.
`Consequently. this article is aimed at reviewing
`the relevant literature. in order to provide and to
`discuss material for the rational design of intra-
`muscular and subcutaneous drug formulations
`and to examine the clinical aspects of these types
`of injections.
`in contrast
`to the former
`review
`which was organised in order of the types of
`injection.
`this article is mainly ordered with re—
`spect
`to elements of the mechanism and further
`subdivided in types of injection.
`
`2. Drugs in conventional systems
`
`Conventional systems are solutions. emulsions
`and suspensions in aqueoas or in oily vehicles.
`
`2. 1'. Drugs in rapidly releasing systems
`
`2.1.1. Aqueous injections:
`rate
`
`t‘nriabiiity in absorption
`
`O
`
`30
`
`90
`60
`Time (min)
`I. Fraction remaining to be absorbed at'tcr intramuscular
`Fig.
`injection of 20 mg/kg sodium artciinalc aqueous solution in
`rabbits to = 1m,
`
`120
`
`tion after intramuscular and subcutaneous injec-
`tion is very variable (Gibaldi. 1977). This is first
`illustrated with some aqueous solutions.
`Artelinic acid is a water-soluble derivative of
`
`artcmisinin. an antimalarial drug, of the fast-
`acting schizontocidai
`type. Artemisinin and its
`derivatives are important new drugs. especially
`for the treatment of life~threatcning states of the
`disease. Artclinic acid is even more active than
`
`is very rapidly eliminated
`artemisinin itself. but
`after intravenous injection. Rapid and complete
`absorption is therefore essential. After intramus~
`cular injection in rabbits the absorption rate ap»
`pears to he very variable (Tituiaer ct al.. 1993).
`This is depicted in Fig.
`l where the fractions not
`absorbed are plotted vs time.
`The curves representing the fraction remaining
`to be absorbed suggest an apparent zero—order
`absorption. This
`is
`a
`rather unexpected phe-
`nomenon. since diffusion is characterised by a
`first-order mechanism. A possible explanation is
`a solvent
`tiow dependent paraceilular transport
`of this highly hydrophiiic solute. This transport
`capacity is very variable. at
`least between sub-
`jects. and it appears that it
`is influenced by sev-
`eral factors including muscle activity.
`inflamma-
`tion and flow of the tissue fluid [Zuidema et al..
`i988a). This explanation is supported by the next
`example.
`Relevant information on kinetic behaviour of
`
`It has frequently been reported that absorp—
`
`i.m. and s.c. injections has often originated from
`
`AstraZeneca Exhibit 2114 p. 2
`
`

`

`
`
`J. Zuidcma er al. /IIilemationalermm' of Pharmaceutics 105 (1094} 180—207
`
`19]
`
`veterinary studies. The risk of residual drug at
`injection sites is a considerable problem in meat
`consumption. Fig. 2 shows as a second example
`the large variation in absorption parameters after
`intramuscular and subcutaneous injection,
`in a
`fat-rich region. also referred to as intra—adipose
`injectiOn (Kadir et al., 1990a). Carazolol
`is
`a
`fi-blocking agent which is used in veterinary prac—
`tiCe as a tranquillising agent in cattle and pigs.
`The fraction of carazolol absorbed during the
`first 24 h from an aqueous solution varied from
`24 to 59% after intramuscular and from 25 to
`66% after intra-adipose injection.
`Many factors which influence the variability in
`the rate and extent of absorption can be postu-
`lated. Firstly. a difference between intra- and
`intermuscular injection is postulated and defined
`as injections within and between the muscle fib-
`rils, respectively (Groothuis et al.. 1980). Such a
`supposition must be supported by a bimodal sta—
`tistical distribution in absmption rate. In the lit-
`erature, however, experimental evidence for this
`contention is
`lacking. Secondly. differences in
`drainage and blood flow are possible explana-
`tions. The cause of these differences. however,
`remains unclear. Thirdly, differences in absorp—
`tion rate might also be result from differences in
`osmolality and other formulation factors, how-
`ever. such factors cannot explain variability with
`
`the same preparation and batch. Physiological
`circumstances that vary randomly and physiologi-
`cal reacrions to the injection trauma might influ-
`ence absorption.
`A more likely explanation than those men-
`tioned above is a variation in the Shape of the
`depot. The shape may vary from merely spherical
`to almost needle-shaped in different
`subjects.
`These differences depend on the local cohesion
`between the muscle components and the ten-
`dency to be torn open by the injection procedure.
`Differences in shape are accompanied by differ-
`ences in the depot surface (and therefore in the
`effective permeation area). the interface between
`depot and tissue and the absorption rate.
`
`2.].2. Drug lipophilicity in aqueous systems: extent
`of absorption and absorption rate
`Lipophilic compounds are slowly absorbed
`from intramuscular and subcutaneous injection
`sites (Zuidema et al., 1988). Recent findings show
`that absorption under such conditions often seems
`to be incomplete as well.
`It appeared that the
`apparent half-lives of midazolam in patients after
`intramuscular injection are much longer than af-
`ter intravenous injection, due to rate-limiting sus—
`tained release from the intramuscular injection
`site (Raeder and Nilsen, 1988). In a former study
`by the same group, a reduced apparent bioavail—
`
`lNTHA-ADIPOSE
`
`INTRAMUSCULAFI
`
`500
`
`400
`
`a"
`
`g 300
`g a,
`
`100
`
`0 I
`o
`
`
`
`20
`
`40
`
`so
`
`time (min)
`
`so
`
`
`
`6
`
`20
`
`so
`40
`time (min)
`
`so
`
`100
`
`in the serum of four pigs following intramuscular and subcutaneous
`Fig. 2. Individual concentration-time curves of carazolol
`administration of0.l)25 nag/kg in a fat layer (intra—adipose injection).
`
`AstraZeneca Exhibit 2114 p. 3
`
`

`

`
`
`192
`
`.l. Zuidema emf. / international Journal of Pharmaceutics 105 l .7994) lilo—207
`
`ability of midazolam under these conditions was
`also observed (Raeder and Breivik, 1987).
`Phenobarbital appeared to be completely ab-
`sorbed after
`intramuscular injection in deltoid
`muscle in children, however,
`the bioavailability
`was only 80% relative to oral administration in
`adults (Viswanathan et al., 1978). Nevertheless,
`the number of investigated subjects was too small
`to permit definite and statistically warranted con—
`clusions. A lack of stability of phenobarbital (the
`amide bonds might be hydrolysed at the injection
`site) might be proposed as an explanation for the
`incomplete bioavailability. This possibility cannot
`excluded, however, it does not explain the differ-
`cnce between children and adults nor the find-
`
`ings in the midazolam study. Further information
`is needed for a better understanding of the fac~
`tors which determine bioavailability in these spe-
`cific cases.
`
`The B-blocking agents are an ideal group for
`studying drug lipophilicity and release from intra—
`muscular and subcutaneous injection sites, since
`they have similar molecular weights and 13K“
`values but differ markedly in iipophilicity. Studies
`in pigs using crossover experiments with propra-
`noloi. atenolol, carazolol, metoproiol and al-
`prenolol have recently been published (Kadir et
`al.. l990a,b).
`The curves representing the fraction remaining
`to be absorbed of the B-blocking agents. con-
`structed from intramuscular and subcutaneous
`
`(intra-adipose) plots and using intravenous data
`as references, demunstrate biphasic declines: a
`rapid first phase followed by a very slow second
`phase (Fig. 3). initial release rates appeared to be
`negatively correlated with drug lipophilicity ex-
`pressed as fat-buffer partition coefficients, espe-
`cially after injection in the subcutaneous fat lay-
`ers, also called intra—adipose layers. Propranoiol
`showed greater and faster absorption than ex-
`pected from its lipophilicity only after intramus—
`cular, but not after intra-adipose, injection. Pro-
`pranolol is known to possess irritating properties
`which may improve blood perfusion in the mus-
`cles and account for the deviation in behaviour
`
`after intramuscular injection. The subcutaneous
`fat layer or adipose layer is less sensitive to such
`irritating properties and is less perfused.
`The extent of drug release within the men-
`tioned 24 h also transpired to be dependent on
`the lipophilicity of
`the compound:
`the more
`lipophilic the compound, the lower the bioavail-
`ability at 24 h after injection (the observation
`period) (Fig. 4). The most hydrophilic compound.
`atenolol, was the only one which was completely
`absorbed or bio-available within 8 h after intra-
`
`muscular injection and within 24 h after subcuta—
`neous injection (Fig. 3).
`injected drugs are probably rapidly absorbed,
`provided sufficient vehicle is present to maintain
`the drug in solution or to drive the absorption
`process. After the vehicle has been absorbed the
`
`
`
`lNTRA-ADIPOSE
`
`INTHAMUSCULAR
`
`
`
`O
`
`250
`
`500
`
`1'50
`
`two
`
`1250
`
`
`
`0
`
`250
`
`500
`
`750
`
`"ID
`
`1150
`
`1500
`
`1500
`
`
`
`fractionnotabsorbed
`
`F..
`
`F'N
`
`.9o
`
`time (min)
`time (min)
`Fig. 3. Fraction remaining to be absorbed curves (drug vs time) after intramusCular and intra-adipose administration of a series of
`{J—blocking agents. (El) Propranoiol. (O) alprenoioi. (0) metomoiol, (I) atenolol.
`
`CD
`
`AstraZeneca Exhibit 2114 p. 4
`
`

`

`J. Zuidema er al. [International Journal of Pharmaceutics 105 (1994} [89—207
`
`W3
`
`2
`
`Ma
`
`0-
`
`VI
`
`U
`
`r0
`
`D
`
`
`
`releaserateconst.1103(rnin'1)
`
`Al
`
`PH
`
`:9
`D4
`
`0
`
`2
`
`3
`
`4
`
`fat paniLion coefficient
`Fig. 4. Correlation between the fat-buffer distribution con-
`stants and release rates on intra—adipose administration of
`atenolol (At). metopropo] (Me). alprenolol (All and propru-
`nolol (PI).
`
`absorption rate of the drug decreases rapidly.
`This theory explains the midazolarn studies but is
`also relevant in the case of the rapid absorption
`of artemisinin from an intramusculariy injected
`suspension in oil and the low and erratic absorp-
`tion of artemisinin from a suspension in water as
`shown in the following (Fig. 5).
`
`2.1.3. Oily injections; influence of the lipophilicity
`of the vehicle on the absorption rate
`injection.
`The next
`example
`is
`an
`oily
`Artemisinin is rather lipophilic and not soluble in
`water, however, it is also sufficientiy insoluble in
`oil to allow its preparation as a dissolved injec-
`tion as of a conventional oil system with a suffi-
`ciently high dose.
`Oil systems and suspensions for injection are
`generally considered to be sustained release for-
`mulations. Therefore, the rapid onset of absorp-
`tion shown in Fig. 5a with the artemisinin suspen-
`sion in oil is striking (Titulaer et al., 1990b). The
`oily vehicle is absorbed only very slowly and re—
`mains present at
`the injection site for several
`months. Apparently, artemisinin dissolves rather
`rapidly in the oil phaSe and the dissolved fraction
`is then depleted. by further absorption.
`In the
`case of arternisinin, this depletion is apparently a
`rapid transit process over the oil
`to the water
`interface to the tissue fluids. This is less favoured
`in the case of highly lipophilic substances.
`
`the rate of
`to the 0in system,
`In contrast
`dissolution of artemisinin in the aqueous injec-
`tion is slow and the process appears to cease
`almost‘fiompletely within the first few hours, the
`time during which the aqueous vehicle has been
`absorbed.
`
`In the preceding section, studies have been
`discussed in which the lipophilicity of a drug or
`model compound was the variable in a given
`aqueous medium. Interestingly, a study has ap-
`peared in which the drug was chosen as the
`constant and the lipophilicity of the oily vehicle
`was the variable (Table l) (Al—Hindawi et al.,
`1986). The in vivo release of testosterone propi-
`onate in a number of oily vehicles was investi-
`
`ugl |
`400
`
`300
`
`200
`
`1191'
`400
`
`100
`
`300
`
`200
`
`Fig. 5. Plots of artemisinin concentrations in serum vs time
`01:10) after a dose of 400 mg artemisinin to human volun-
`teers: (a) suspension in oil intramuscularly; (bl suspension in
`an aqueous vehicle intramusculariy.
`
`AstraZeneca Exhibit 2114 p. 5
`
`

`

`
`
`194
`
`J. Zrtizfemn er a]. / International Journal of Pharmaceutics 10.1" {1994} 189—207
`
`Table l
`Testosterondccanoate fatfphosphatehut‘l‘er partition and ab-
`sorption rate expressed as halt‘lil‘e in the muscle
`
`Solvent
`
`(“3 in
`Partition
`coefficient
`muscle
`
`(x In”)
`on
`
`Ethyl oleatc
`Octanol
`Isopropy] myristate
`Light liquid paraffin
`
`{LS
`5.3
`4.3
`1.3
`
`ill”?
`9.7
`7.3
`3.2
`
`gated. Disappearance from the injection site ap-
`peared to he proportionally related to the in vitro
`partition coefficients. This study illustrates and
`emphasises the importance of the vehicle and the
`affinity of the drug to the vehicle for the disap-
`pearance process in the muscles after injection.
`
`2.1.4. Influence of injection volume and drug can—
`centmfion
`
`Data on the influence of injection volume and
`drug concentration seem to he contradictory. They
`can be classified into the following four groups of
`results on: (i) hydrophilic drugs in aqueous sys—
`tems (concentrations are much lower than drug
`saturation in the vehicle);
`(ii)
`lipophilic drugs
`solved in oily systems:
`(iii) lipophilic drugs in
`aqueous systems [concentrations are close to drug
`saturation in the vehicle); and (iv) drugs in sus-
`pension. The latter is discussed in section 2.2.
`since most of the suspensiOn formulations are
`intended to be sustained release formulations.
`The available
`information on the first
`three
`
`groups is summarised below.
`Atropine, sodium chloride, sugars and polyols
`Such as mannitol and sorhitol. all hydrophilic drug
`solutions in aqueous- systems, were reported to be
`absorbed more rapidly when the compounds Were
`administered in smaller injection volumes (War-
`ncr ct al.. 1953: Schriftman and Kondritzer. 1957:
`Sand and Schou. 1964). The common properties
`of these compounds are that
`they are very hy-
`drophilic, readily soluble in water and have low
`molecular weights. Examples of compounds with
`higher molecular weights are the dextrans. which
`appear to behave similarly but have a slower rate
`of absorption. The molecular weight appears to
`be inversely related to the absorption rate. The
`
`higher absorption rate in smaller volumes can he
`explained by the greater diffusion potential. Oh-
`viousiy. the absorption of this type of compound
`is controlled by passive diffusion or by paraccllu—
`iar transport.
`Results With amikacin. an aminoglycosidc. are
`often misinterpreted (Pfeffer and Harken. 1981).
`In the available literature, these results are often
`wrongly discussed together with the first group.
`Amikacin is a hydrophilie compound but with a
`high molecular weight. In aqueous SVStems it is a
`suspension, which is slowly absorbed from a sin—
`gle large depot. It is preferably given in multiple.
`simultaneously administered separate injections.
`in order to provide sufficiently high concentra—
`tions in serum. The solved amikacin fraction is
`constant and concentration is
`therefore not a
`
`useful absorption rate-determining variable vari-
`able. This in contrast
`to the situation with at-
`ropine. sugars and polyols as discussed above.
`The effects of drugs which depress absorption
`rate are illustrated with atr0pine. At higher doses
`it exerts a self-depressive effect on the absorption
`rate by its parasympathicolytic activity. Effects of
`this type have scarcely been investigated and lit-
`erature data are sparse.
`Testosterone and some other model com-
`
`pounds represent examples of the second group.
`lipOphI‘Iic substances in oil. They have been stud-
`ied in several oily vehicles (Tanaka et al.. 1974).
`This typc of compound is absorbed more rapidly
`when it
`is dosed in smaller volumes of an oily
`vehicle. Again the diffusion potential is obviously
`the dominating absorption rate-determining fac-
`tor.
`
`injection volume on the
`The influence of
`bioavailability of fipaphl'lic‘ drugs in aqueous sul-
`r'ents.
`the third group. has been studied in rats
`(Kadir ct al., 1992c). The aforementioned study
`was performed in order to find an explanation for
`the incomplete absorption of the more lipophilic
`fl-blocking agents as described in section 2.I.
`Propranolol was used as the model compound.
`Both the rate and the extent ol' absorption at 8
`b appeared to increase with increasing injection
`volume. thn the vehicle volume is
`increased
`
`the residence time of the vehicle at the injection
`site increases. maintaining the drug in solution
`
`AstraZeneca Exhibit 2114 p. 6
`
`

`

`.l'. Zuirl'cma ('2‘ al. / International Journal of Pharmaceutics 105 {1994) 189-207
`
`195
`
`0.160
`
`030
`
`0.10
`
`0.10
`
`
`
`releaseratemusth'1
`
`0.00
`
`0
`
`50
`
`it]?
`
`2113
`
`injection volume (pl)
`Fig. 6. Individual release rate constants after intramuscular
`injection of 3 mg prtipranolo] HCl
`in 51). 100 and lel) ,til
`aqueous solution in rats. Lines connect the individual values
`for the same rat (12:6).
`
`it
`in other words,
`for a greater length of time;
`remains dissolved over a longer time and absorp—
`tion is faster from the dissolved state (Fig. 6).
`Moreover,
`the increasing volume may increase
`the vehicle flow away from the depot This influ—
`ence is in a certain sense comparable with the
`action of the mobile phase in a chromatographic
`system. in HPLC terms: increasing solvent flow
`diminishes the retention time. This effect may be
`a possible explanation for the greater absorption
`rate during the initial phase.
`
`2.1.5. Influence of pH and /or cosoluents
`Cosolvents such as ethanol. glycerol, propylene
`glycol and also polyethylene glycol 400 are used
`as solvents together with water, in order to en-
`hance the solubility of certain drugs for injection
`(Chen-Der and Kent, 1982). They have varying
`influences on the absorption of drugs. Ethanol is
`better discussed separately in the next survey,
`since the mechanism of its influence deviates
`
`from those of the otherlcosolvents.
`Ethanol is a liquid of very low viscosity and
`exerts only a minor influence on the viscosity of
`the vehicle in mixtures with water. When used at
`
`high concentrations it has a denaturing effect on
`
`proteins at the injection site. It appears to have
`an inhibitory effect on the absorption rate of
`water-soluble ionic as well as non-ionic model
`
`drugs such as isonicotinamide, methylisomcoti-
`nate.
`isonicotinic acid and procaine hydrochlo-
`ride (Kobayashi et al., 1977). This influence could
`be attributed to alterations in the permeability of
`the connective tissue which was significantly de-
`creased‘ In chromatographic terms: ethanol seems
`to change the properties of the ‘stationary phase',
`probably by protein denaturation.
`Other cosolvents such as propylene glycol.
`glycerol and polyethylene glycol 400 have been
`reported contradictorily to diminish and to new
`hance the absorption ratc of model compounds
`(Kakemi et al., 1972; Cheng—Der and Kent1 1982).
`The diminishing effect
`is
`ascribed to the
`viscosity—enhancing influence of these compounds
`on the vehicle.
`Effects of cosolvents may partly be explained
`by a change of the properties of the ‘mobile
`phase”. The dielectric constant and consequently
`the hydro/lipophilicity of the solvent is changed
`to that of water. The enhancing effect of cosol—
`vents and the properties of the systems where
`enhancement occurs are discussed below,
`to-
`gether with the effects of pH-pK“ relationships.
`Additives with high molecular weights known
`as viscosity enhancers, such as cellulose deriva-
`tives, dextrans or long—chain polyethylene glycols
`resulted in a degree of inhibition that was less
`than expected. This suggests that macromolecules
`apparently do not interfere with the absorption
`mechanisms.
`
`The absarption rate of cefonicid has been de-
`scribed as being pH-dependent (Brumfitt et al.,
`1988). However,
`the authors failed to give an
`explanation nor is it possible to analyse their
`results, since the experimental data were lacking
`in detail. Other studies shed more light on the
`pH dependency in Lin. and so. absorption pro-
`cesses.
`
`Salts with an alkaline or acidic reaction which
`can be neutralised by the tissue fluids have the
`potential to precipitate after injection duc to the
`neutralising or buffer capacity of the tissue fluids.
`This has been briefly mentioned in the literature
`for quinidine hydrochloride as well
`(T56 and
`
`AstraZeneca Exhibit 2114 p. 7
`
`

`

`
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`J. Zui'dcma t'! al. /’ International Journal of Pharmaceutics It'll H9941 ESQ—207
`
`is clearly
`Welling. 1980). The effect. however.
`illustrated in the study using human volunteers by
`Kostenbauder et ai.
`(1975} with intramuscular
`phenytoin (see section 1). Phenytoin is absorbed
`over a period of approx. 5 days. Even after 40 h
`211% of the drug remained unabsorbed. Pheny-
`toin is a drug which is dissolved for injection in
`relatively high concentrations at pH ll or higher.
`and also using cosolvents and/or complexing
`agents.
`The authors reported that precipitation and
`slow redissolution of the drug by tissue fluids at
`the injection site could explain their results and
`developed a mathematical model based on this
`concept. The observed drug concentration curves
`in plasma fitted well with this model. Precipita-
`tion probably has two causes. i.e.. the pH neutral-
`ising effect of the tissue components and the
`rapid absorption of some of the solvents.
`The influence of cosolvents on the absorption
`of salts is illustrated by a study of the effect of
`propylene glycol on the absorption of benzimida-
`zole hydrochloride (Cheng—Der and Kent. 1982).
`it appeared that propylene glycol, which appar—
`ently is absorbed more slowly than water. may
`prevent in certain circumstances, at least partly,
`the precipitation of thc free base (or free acid).
`in this manner. it might enhance the absorption
`of the drugs in question.
`'
`
`2.17.6. Influence of surfactants
`The influence of surfactants and injection
`depth on the kinetics of absorption has been
`discussed previously (Zuidema et al., 1988). Non-
`ionic surfactants at
`low concentrations probably
`exert a retaining effect on well-absorbed water-
`solubie drugs. however. the promotion of absorp-
`tion has been reported for a poorly absorbed high
`molecular weight polypeptide. The mechanisms
`underlying this phenomenon are still not well
`understood. Again the model of reversed-phase
`chromatography may be helpful.
`Surfaetants in the mobile phase might have a
`coating effect on the lipophilie stationary phase.
`making the stationary phase more hydrophilic.
`This might explain the retaining effects on hy-
`drophiiic drugs. Such a model predicts the re-
`verse effect on iipophilie drugs.
`
`.2._l.7. Influence of injection depth
`in the articles discussed above. the difference
`
`in absorption rate between deep intramuscular
`injections and shallow subcutaneous or
`intra-
`adiposc injections is shown in Fig. 3 (Kadir ct al..
`1990b). Even the hydrophilic atenolol
`is already
`completely absorbed 8 h after intramuscular in»
`jection whereas this lasts about 24 h after subcu—
`taneous or intra-adipose injection. The fatty sub—
`cutaneous connective tissues and adipose layers
`are more lipophillc and perfused less than muscu-
`lar
`tissues. These phenomena have been dis-
`cussed extensively previously (Zuidema ct al..
`1988).
`
`2.2. Long—acting systems
`
`Long-acting systems consist either of lipophillc
`drugs in aqueOus solvents us suspensions or or
`highly lipOphilic drugs dissolved or suspended in
`oil. In the first case, the release or absorption is
`dissolution rate controlled. while in the latter. the
`compounds with lower molecular weights. which
`are soluble in oil. are ‘phase transfer controlled‘
`released from the system (Zuidema et al.. 19883:
`the compounds with high molecular weights.
`which are not soluble in the oil. are released by
`dissolution and/or phase transfer control. these
`factors alone or in combination.
`
`Another possible absorption mechanism is
`phagocytosis. The participation of direct absorp-
`tion of fine particles by phagocytosis appears to
`be possible in certain cases but the contribution
`to the overall absorption process can mostly be
`neglected. Absorption via the mechanisms of lym—
`phatic transport and inflammation-mediated ap—
`pearance of phagocytosing macrophages (24-48 h
`after injection) have been demonstrated for iron
`complexes (Beresford et al.. 1957}.
`Long-lasting residues after intramuscular in—
`jection or subcutaneous injection. of water-in-
`soluble penicillin derivatives and dihydrostrepto-
`mycin in aqueous vehicle in cattle have been
`detected 30—45 days after administration (Mercer
`ct al.. i97l). Examples of long—acting systems in
`oil are the depot neuroleptics as discussed previ-
`ously (Zuidema et al., 1988).
`Ober et a1. (1958) stated that aggregation in
`
`AstraZeneca Exhibit 2114 p. 8
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`1, Ziu'dema er al. / International Journal ofPhamacemics [05 (1994) 189—207
`
`197
`
`concentrated systems often gives rise to increased
`viscositics, specific rheological features and a di-
`minished rate of dissolution after injection. it is
`known that viscosities and specific rheological
`features such as (pseudo)plastic behaviour in sus-
`pensions and emulsions increase with increasing '
`concentration and with decreasing particle size.
`In fact,
`this process is associated with the
`so-called flocculation phenomenon. This is be—
`cause gel formation consists of aggregation to a
`large viscous aggregate in which vehicle might be
`included (structured water or,
`in oil, structured
`oil}, which is a special case of flocculation of
`lyophilic dispersions. These systems display mostly
`(pseudo)plastic prOperties. This theory is largely
`expounded in the context of colloidal systems but
`is it also valid for systems of small non-colloidal
`particles.
`When either lyophilic or lyophobic systems are
`concentrated by precipitatiOn under gravitational
`forces or by other compression forces, they might
`develop a more compact
`form of aggregation,
`c0mparable with the phenomenon referred to as
`caking.
`This theory, applied to su5pension prepara-
`tions for injection, was provided with a solid and
`mathematical foundation by the work of Hirano
`et al.
`(1981) and Hirano and Yamada (1982,
`19833,b). It is relevant to review this work in a
`little more detail, since it is also pertinent to the
`behaviour of liposomes, as discussed in section 3.
`The authors studied the local clearance of
`suSpensions of practically water-insoluble drugs
`injected intramuscularly or subcutaneously in the
`rat. They used these results to develop or to
`check their mathematical model. This work is of
`
`great importance for understanding the influence
`of the phenomenon of aggregation on the release
`kinetics. The theory is mainly applicable to those
`drugs for which the absorption into blood or
`lymph is controlled by dissolution. Phase transi~
`tion of oily systems and blood supply are not
`thought
`to be relevant. As is clear from the
`former study, this is a simplificatiOn and not true
`for every system (Zuidema et a1., 1988).
`Hirano and co-workers expressed the influ-
`ence of aggregation as a factor e with two limits:
`no aggregation and complete aggregation. In the
`
`first case, the suspension particles behave inde-
`pendently, while in the latter, the aggregate be-
`haves as a single clot with the clot surface acting
`as the effective area for release or in vivo dissolu—
`
`is governed by particle
`tion. The parameter e
`size, concentration, volume, hydrodynamic factors
`such as injection speed and pressure and histolog-
`ical and physiological states at the injection site.
`This means that particle size has two opposite
`influences on the dissolution rate: on the One
`hand, smaller sizes without aggregation lead to a
`greater effective dissolution surface and therefore
`to higher dissolution rates; on the other, smaller
`particle sizes may lead to stronger aggregation
`effects with more compact aggregates and subse-
`quently to a smaller effective dissolution surface.
`A deviation of this pattern occurs for particles
`smaller than about 2—3 pm, especially after sub-
`cutaneous injection. These particles appear to
`pass more easily through the fibrous networks
`accompanying the spreading of the dispersion
`medium during injection and seem to form conse—
`quently looser agglomerate. Differences between
`muscle or subcutaneous networks, however, were
`not investigated and therefore not discussed.
`Dose adjustment can be effected as a change
`in drug concentration for a constant volume or as
`a change in vehicle volume at a constant drug
`concentration. In both cases, the absorption rate
`appears to decrease with increasing dose as a
`result of the aggregation phenome