PHARMACY LIBRARY· ~
`SCHOOL OF PHARMACY .
`
`Narcotic ~ntagonists:
`Naltrexon~ Pharn:~acochemistry and
`Sustai!1e~~~R~Iea~e Preparations
`.
`
`Editors:
`Robert E. Willette, Ph. D.
`Gene Barnett, Ph .. D.
`
`·NIDA Research Monograph 28
`
`1981
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`Public Health Service
`Alcohol, Drug Abuse, and Mental Health Administration
`
`National Jnstitute on Drug Abuse
`Division of Research
`5600 Fishers Lane
`Rockville, Maryland 20857
`
`For sale by the Superintendent of Documents, U.S. Government Printing Ofilce
`Wnslllnjtton, D.C. 20402
`
`AMN1026
`IPR of Patent No. 7,919,499
`
`

`

`Naltrexone: Research Monograph 28
`R. E. Willette and G. Barnett, eds.
`National Institute on Drug Abuse, 1980
`
`Pharmacokinetic
`Quantitation of Naltrexone
`Release From Several
`Sustained-Release Delivery
`Systems
`R. H. Reuning, S. H. T. Liao, and A. E. Staubus
`
`A method designed to quantitate in vivo naltrexone release
`rates from sustained·release systems has been applied to the
`evaluation of seven different naltrexone delivery systems in
`the monkey. The method consists of two phases: a single in·
`travenous bolus dose quantitation of each monkey's phar-
`macokinetic parameters coupled with a delivery system
`study in which plasma naltrexone levels are measured
`throughout the time period of sustained-release. In vivo re-
`lease rates and the total amount released are then calculat-
`ed. It should be noted that these determinations require the
`analysis of unchanged naltrexone in plasma as the only ex-
`perimental measurement. Data from injectable naltrexone
`pamoate microcapsule delivery systems indicate that 1)
`when these microcapsules are suspended in an aqueous ve-
`hicle, a significant part of the dose is released .very rapidly,
`yielding release rate·time data that parallel a non·sus-
`tained·release control; 2) this rapid release for the aqueous
`vehicle is followed by a slow release phase lasting to about
`24 days for the subcutaneous route and to about 45 days for
`the intramuscular route; and 3) when these· microcapsules
`are suspended in an oily vehicle there is no initial rapid re-
`lease, substantial release rates are obtained for at least 60
`days, and an ·average of 89% of the dose is calculated to
`have been released. Data from implantable naltrexone de·
`livery systems show that 1) the Alza system most closely ap-
`172
`
`AMN1026
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`
`

`

`QUA:NTITATION OF NALTREXONE RELEASE
`proximates a zero-order release rate-time profile; 2) the Bat-
`telle system provides a rapid initial release followed by a
`slowly declining release rate; 3) the Dynatech system is
`characterized by a more rapid initial release rate of 3-8% of
`the dose per day over the first 3-5 days followed by a rather
`constant 1-3% per day ... to about day 36; and ,4.) essentially
`complete recovery of the dose was obtained for the Battelle
`and Dynatech systems.
`
`173
`
`INTRODUCTION
`
`The rationale for developing sustained·release narcotic antago.
`nist delivery systems for treatment of opiate addiction has recently
`been reviewed (1,2). One phase of a scheme for evaluating these
`systems consists of a pharmacokinetic quantitation of drug release
`rates in vivo (2). The methodology that has been developed for
`quantitating naltrexone release in monkeys is characterized by two
`phases: 1) calibration of the pharmacokinetics of each individual
`monkey from plasma level-time data obtained after an intravenous
`bolus dose of naltrexone, and 2) measurement of plasma levels of
`unchanged naltrexone over the time period that the sustained-re-
`lease system yields measurable concentrations. Data from 1) and 2)
`above permit calculation of an in vivo release rate-time profile as
`well as the total amount of naltrexone released during the study.
`The purpose of this report is to summarize the naltrexone re-
`lease data for those delivery systems that have been evaluated
`pharmacokinetically in the monkey. In order to obtain an overview
`it was necessary to average the release rate data obtained from the
`several monkeys utilized in evaluating each delivery system. Also,
`data related to the calibration of each monkey's pharmacokinetic
`parameters has been omitted. Both types of data for individual
`monkeys will be included in subsequent manuscripts.
`
`EXPERIMENTAL
`
`Delivery Systems
`The following seven delivery systems have been evaluated:
`I. Naltrexone in a physical blend with 90% <L+ )lactic acid·
`10% glycolic acid copolymer, spherical beads 1.5 nun in di-
`ameter, subcutaneous, Dynatech # 24086;
`TI. Naltrexone pamoate-poly(lactic acid) mictocapsules sus-
`pended in 2% aluminum monostearate·peanut oil and in-
`jected intramuscularly, Thies #GL-1·6·76-1;
`
`AMN1026
`IPR of Patent No. 7,919,499
`
`

`

`17 4
`
`NALTREXONE SUSTAINED-RELEASE PREPARATIONS
`III. Naltrexone pamoate-polyQactic acid) microcapsules sus-
`pended in a medium consisting of 'water, 2% Tween 20,
`0.02% anti-foam silicone and 1:10,000 phemerol and inject-
`ed intramuscularly, Thies #GL-1-6-75-1;
`IV. Naltrexone pamoate-polyQactic acid) microcapsules sus-
`pended in an aqueous medium ofO.l% Tween 80 in Macro-
`dex (6% dextran 70 in 5% dextrose/water for injection)
`and injected subcutaneously, Thies #GL-3-9-77-3;
`V. Micronized naltrexone pamoate (batch #21\f!1869-866-16)
`suspended in 2% aluminum monostearate-peanut oil and
`injected intramuscularly;
`VI. Rods-naltrexone and hydrophobic polymer, Chrohomer,
`Alza, subcutaneous;
`VII. Naltrexone 33% in a dipalmitin (75%) - tripalmitin (25%)
`mixture, shaped into rods and adminiStered subcutaneous-
`ly (Battelle).
`These sustained release systems will be referred to by the nu-
`merical designation throughout the text. Additional data concern-
`ing these delivery systems has been provided by the developers
`(2,3). All are intended to be bio- degradable, with systems I, VI and
`Vll designed for subcutaneous implant and systems II, ill and IV
`designed for injection. System V was included as a non-sustained-
`release control.
`·
`
`Experiments in Monkeys
`Each delivery system was administered to 3 or 4 monkeys at a
`dose of approximately 10 mg/kg. With the exception of delivery
`system VIT, these were self-administrating monkeys and were on a
`rotating schedule of morphine, methamphetamine and saline self-
`injection. Effects of the naltrexone delivery system on morphine
`self-administration were measured as described previously ( 4) and
`will be reported separately. Blood samples were obtained, usually
`from a femoral vein, at periodic intervals up to 60 days after ad-
`ministration of the sustained re~ease system.
`At least several days were allowed to elapse after the delivery
`system either was removed or ceased releasing measurable
`amounts of naltrexone. Subsequently, a single intravenous bolus
`dose of naltrexone (3-5 mg/kg) was administered and periodic blood
`samples were obtained for a sufficient time so that the pertinent
`pharmacokinetic parameters of naltrexone could be determined
`from the plasma level-time profile.
`
`AMN1026
`IPR of Patent No. 7,919,499
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`

`

`175
`
`QUANTITATION OF NALTREXONE RELEASE
`DISCUSSION
`Injectable Systems
`The jn vivo release rate data for the injectable naltrexone deliv-
`ery systems are presented in fig. 1. Systems II, III and IV differ
`mainly in the vehicle used to suspend the microcapsules and in the
`route of injection. System V is a non-suStained-release control for-
`mulation ipcluded for comparative purposes. Comparison of the
`curve for sustained release system II (microcapsules suspended in
`the oily vehicle and administered intramuscularly) with the curve
`for the control formulation, system V (micronized naltrexone pa-
`moate suspended in the oily vehicle and administered intramuscu-
`larly), permits the conclusion that the microcapsule coating is re-
`sponsible for the pronounced sustained release effect with system
`II.
`Assay for Naltrexone
`A sensitive and specific assay for naltrexone concentrations in
`plasma has been described previously (5,o,7). The pharmacokinetic
`calculation of in vivo release rates is dependent on an assay that is
`specific for unchanged n!iltrexone and this specificity has been
`demonstrated with respect to the known metabolites of naltrexone
`(7).
`Calculation of Release Rates
`Release rates were calculated according to the Loo-Riegelman
`method (8). Either a two- or a three-compartment, open pharmaco-
`kinetic model was used to fit the plasma level-time data for the in-
`travenous bolus dose of naltrexone in each monkey (9). The three-
`compartment model was utilized when needed to obtain a good
`overall fit to the data. The pharmacokinetic parameters for nal-
`trexone, obtained from the intravenous bolus dose, were then uti-
`lized to calculate naltrexone release rates from the plasma naltrex-
`one level-time data obtained in the delivery system study (8). The
`total amount released over the entire time period was subsequently
`determined according to an equation presented previously (10).
`RESULTS
`The data for naltrexone concentration in plasma ~ a function of
`time after administration are summarized in table 1 for each of the
`seven delivery systems tested. Levels of about 0.25-p.5 ng/ml are
`n~ed to block morphine self-administration in these monkeys
`(11). Since this range is also the approximate sensitivity limit of
`
`AMN1026
`IPR of Patent No. 7,919,499
`
`

`

`r:n
`z
`1.38(0.38) g
`~
`~
`~
`"a
`t-j
`~
`f;;j
`~
`5.07(2.50) ;
`c::
`r:n
`5.19(0.41) ~
`5.55(1.31) ~
`~
`z
`
`2.06(0.43)
`
`2.55(0.65)
`3.19(1.03)
`
`-
`-
`-
`-
`
`-
`-
`
`VIJb
`
`0)
`-.:]
`.......
`
`1.46(0.36)
`
`2.25(1.98)
`
`-
`
`-
`-
`-
`-
`
`-
`-
`
`2.41 (0.77)
`
`4.57(2.54)
`
`-
`-
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`-
`-
`
`-
`
`2.31 (0.78)
`
`-
`
`3.57(2.31)
`
`-
`
`3.84(1.64)
`3.71 (1.45)
`
`-
`-
`
`5.80(4.0)
`
`4.66(1.58)
`
`
`
`--
`
`-
`
`-
`
`--
`
`-
`-
`
`g
`
`-
`
`g
`
`0.70(0.84)
`1.70(1.32)
`3.12(2.46)
`10.63(7.97)
`44.55(13.66)
`
`0.11(0.23)
`
`-
`
`-
`
`99. 7(41.4)b
`
`-
`-
`-
`
`0.35(0.40)
`
`0.56(0.38)
`
`-
`
`0.66(0.21)
`
`-
`
`0.57(0.04)C
`
`-
`-
`-
`
`1.19(0.30)
`1.26(0.63)
`
`-
`
`2.60(1.07)
`
`7.90(~.65)
`
`-
`-
`
`14.04(6.02)
`
`23.95(6.31)
`
`-
`-
`-
`-
`
`VI
`
`v
`
`IV
`
`13.87(5.39)
`
`4.40(2.03)
`
`1.52(0.70)
`
`-
`-
`
`1.23(0.50)
`
`1.47(0.72)
`
`-
`
`1.17(0.32)
`
`-
`-
`-
`
`0.92(0.26)
`0.55(0.18)
`
`-
`
`0.65(0.25)
`
`-
`
`1.12(0.21)
`
`-
`
`-
`
`
`--
`-
`
`2.16(0.61)
`1.58(0.56)
`2.13(0.75)
`2.45(0.69)b,e
`0.99(0.19)
`0.44(0.07)
`0.58(0.12)
`
`1.93(0.46)
`
`2.24(0.71)
`
`-
`
`-
`-
`
`-
`-
`
`2.87(0.51)
`
`-
`-
`
`3.02(0.68)
`
`-
`
`-
`
`0.79(0.10)
`
`-
`-
`-
`
`1.96(0.10)
`
`
`-
`
`--
`
`-
`-
`-
`
`2.16(0.19)
`
`-
`
`2.07(0.24)
`
`-
`
`2.50(0.37)
`2.14(0.43)
`
`2.64(0.42)
`
`8.08(5.36)
`
`4.11(0.87)
`
`-
`-
`
`-
`-
`
`4.69(4.90)
`
`-
`
`-
`
`-
`
`Mean Concentration of Naltrexone ln Plasma (ng/ml)•
`
`IJJb
`
`II
`
`I
`
`22
`21
`20
`19
`18
`16
`15
`14
`13
`12
`11
`9
`7
`6
`5
`4
`3
`2
`1
`0.5
`0.33
`0.29
`0.25
`0.125
`
`(day)
`Time
`
`TABLE1. Naltrexone Concentration in Plasma During the Time Period in Which the Monkey was Administered a
`
`Naltrexone Sustained Release Delivery System
`
`AMN1026
`IPR of Patent No. 7,919,499
`
`

`

`-:J
`-:J
`.......
`
`~ s ~ I
`i ~
`
`z
`~
`~
`
`0.08(0.14)
`
`0.79(0.45)
`
`,. 0.80(0.18)
`
`0.21(0.24)
`
`0.06(0.1)b
`
`0.36(0.30)
`
`other animals.
`omitted samples were at least 5-fold greater than corresponding values in
`1Sample(s) omitted due to apparent assay Interference. Values of the
`•sample(s) lost due to breakage.
`dQnly one value available.
`cMean of 2 animals.
`bMean of 3 animals.
`
`•Mean of 4 animals unless indicated otherwise. Standard deviation in
`
`parenthesis. Delivery systems are identified in the text and in Table 3.
`
`oselow detectable limits.
`
`g
`
`g
`g
`g
`
`g
`
`0.11 (0.18)
`0.36(0.35)
`0.20(0.18)
`0.23(0.23)
`
`0.56(0.38)
`
`0.13(0.27)
`
`0.65(0.46)
`
`0.14(0.28)
`
`0.84(0.68)
`
`0.13(0.27)
`
`0.83(0.28)
`
`0.28(0.33)
`
`1.01 (0.27)
`
`0.64(0.39)
`
`-
`
`0.60(0.21 )b.l
`
`0.58(0.21 )e.l
`
`-
`-
`-
`
`1.39(0.028)c.l
`
`g
`
`-
`-
`
`-
`
`0.82(0.2Q)b.l
`
`-
`
`-
`
`1.37(0.26)
`
`-
`
`
`
`--
`
`-
`-
`
`Q.48GI
`
`1.40(0.45)
`
`-
`
`1.72(0.56)
`
`-
`
`1.33(0.085)
`
`--
`
`1.88(0.096)
`
`-
`
`
`64
`57
`56
`54
`50
`47
`43
`42
`41
`40
`37
`36
`35
`33
`32
`30
`29
`28
`26
`25
`23
`
`AMN1026
`IPR of Patent No. 7,919,499
`
`

`

`178
`
`NALTREXONE SUSTAINED-RELEASE PREPARATIONS
`
`the assay, "measurable" levels can be considered to be "effective"
`levels in these monkeys. The corresponding average naltrexone re-
`lease rates for the seven systems are shown in table 2 and in fig-
`ures 1 and 2. Table 3 contains data summarizing the results of a
`comparison of the dose administered with the calculated amount of
`naltrexone released and, when. available, the amount of naltrexone
`the delivery system after removal from the
`recovered from
`monkey.
`
`->.
`
`0
`~
`(I)
`rJ)
`0
`"'0
`.._
`0
`~ .._..
`w
`1-
`<(
`0:::::
`
`t • II
`Ill
`[J II
`0 •
`IV
`.... v
`
`to 1
`
`10
`
`20
`
`30
`
`40
`
`60
`
`70
`
`w en <( w
`__) w
`0:::::
`w
`z
`0
`X w
`0:::::
`1-_J
`<t z
`0
`>
`>
`Zj
`0 w
`1-<t _J
`:::>
`(.)
`__)
`<t (.)
`
`Tl ME (day)
`FIGURE 1. Semilog plot of naltrexone in vivo release rate as a function of time fbr
`injectable sustained release delivery systems II, III, IV and V. Delivery systems are
`identified in the text and in table 3. Closed symbols represent an oil vehicle and
`open symbols an aqueous vehicle.
`
`AMN1026
`IPR of Patent No. 7,919,499
`
`

`

`QUANTITATION OF NALTREXONE RELEASE
`
`179
`The influence of the vehicle used to suspend the microcapsules
`on release of naltrexone can also be observed in fig. 1. A compari-
`son of system III (microcapsules suspended in an aqueous vehicle
`and administered intramuscularly) with system II suggests that the
`ipfluen'Ce of the vehicle occurs mainly over 'the first 15 days after
`administration. Subsequently, the release rate declines in approxi-
`mately parallel exponential fashion for the two systems. During
`the first 4-6 days after administration, system III has a release
`rate-time profile that parallels the exponential decline of releas.e
`rate for the non-sustained-release control. This rapid and extensive
`decline in release rate (note the logarithmic y-axis in fig. 1) sug-
`gests that a very significant fraction of the naltrexone in delivery
`system III was available for rapid release. A similar early rapid re-
`lease can also be observed for system IV (microcapsules suspended
`in an aqueous v~hicle and administered subcutaneously). A com-
`parison of aqueous microcapsule suspension systems ill and IV (fig.
`1) suggests that the intramuscular route (ill) yielded much higher
`release rates than the subcutaneous (IV) from 10-50 days after ad-
`ministration. Delivery system IV provides the smallest degree of
`sustained release of any of these microencapsulated naltrexone pa-
`moate systems. On the other hand, system II provides a significant
`release rate for a period of 60 days. Although the release was not
`zero order, the rates were within a fairly narrow range (fig. 1). In
`addition, it appears that the oil vehicle "protects" the naltrexone
`pamoate microcapsules from whatever causes the rapid initial
`burst of release with the aqueous vehicle.
`The calculated total extent of naltrexone release from each deliv-
`ery system is compared with the dose administered in table 3. Sys-
`tems III and IV yielded an incomplete recovery of the administered
`dose whereas the average recovery for system II was 89% of the
`dose. The microcapsule delivery systems UI, ill and IV) were char-
`acterized by a high degree of variability in the extent of recovery of
`the administered dose (table 3). Part of the reason for the greater
`variability observed for the microcapsule systems, compared to the
`other delivery systems, may be the difficulty in administering an
`accurate dose of the microcapsule suspension (especially for the
`aqueous systems). Alternatively, the release of naltrexone may be
`more variable with these delivery systems. Unfortunately, the
`nature of these microcapsule delivery systems precluded the possi-
`bility of removing the microcapsules remaining at the end of the
`sustained release study. Therefore, the unabsorbed naltrexone
`could not be assayed directly.
`
`AMN1026
`IPR of Patent No. 7,919,499
`
`

`

`an erroneously high recovery value.
`sample had an unusually high naltrexone concentration that resulted in
`•One monkey was omitted from the data analysis because one early
`dQnly one value available.
`
`•Mean of 4 animals unless indicated otherwise. Standard deviation In
`
`parenthesis. Delivery systems are identified in text and in Table 3.
`
`cMean of 2 animals.
`bMean of 3 animals.
`
`2.28(0.25) I
`
`~
`~
`~
`;g
`gj
`t%J >
`t"C
`
`38.5 0.09(0.16)
`31.5 0.78(0.29)
`24.5
`1.11 (0.26)
`1.41 (0.29)
`17.5
`10.5
`1.69(0.32)
`4.5
`1.5 2.82(0.95) g
`en
`0.75 3.92(1.44)
`t..::2
`0.37 5.13(1.97)
`~
`0.19 5.54(0. 72)
`:><
`0.06 5.17(1.11)
`
`33.5 0.08(0.14 )b
`26.5 0.13(0.15)
`21.5 0.92(0.90)
`18.0 2.78(1.39)
`14.5 4.36(2.28)
`11.0 4.06(1.60)
`8.0 3.04(1.07)
`6.0 2.91 (1.26)
`4.0
`2.3~(1.06)
`2.0 1.93(0.54)
`0.64 2.77(1.12)
`0.15 2.51 (1.31)
`
`6.0
`0.22(0.38
`4.5
`1.14(0.99)
`3.5
`2.50(1.63)
`2.5
`6.86(5.70)
`21.2(10.6)
`1.5
`0.66 54.5(3.16)
`0.16 51.9(14.8)
`
`34.5
`0.17(0.34)
`31.0
`0.17(0.34)
`27.5
`0.18(0.36)
`24.0
`0.38(0.45)
`0.46(0.53)
`2.1.0
`17.5
`0.59(0.41)
`13.5
`0. 70(0.11 )t
`12.0
`0.96(0,08)C
`10.5
`0.88(0.02)c
`8.0
`1.31 (0.27)
`6.0
`2.01(0.45)
`4.0
`5.68(2.13)
`2.0 12.4(4.06)
`0.64 21.5(9.19)
`0.15 19.6(7.82)
`
`52.0 0.11 (0.19)
`48.5 0.11(0.20)
`45.0 0.21 (0.19)
`41.5 0.34(0.32)
`38.0 0.58(0.38)
`34.5 0.72(0.52)
`31.0 0.81 (0.47)
`27.5 0.90(0.32)
`24.0 1.09(0.37)
`20.5 1.34(0.55)
`17.0 1.47(0.65)
`13.5 1.31(0.48)
`10.5 1.03(0.13)
`8.0 0.68(0.13)
`6.0 0.46(0.22)
`4.0 0.64{0.23)
`2.0 2.58(1.02)
`0.66 9.70(4.44)
`0.16 9.84(4.64)
`
`60.0 0.48(0.15)b
`51.5 0.46(0.11 )t
`48.0 1.18(0.39)t
`44.0 0.52(0.08)t
`36.5 1.01(0.27)
`30.0 1.35(0.43)
`26.5 1.51 (0.52)
`23.0 1.91 (0.64)
`19.5 2.04(0.69)
`16.0 2.33(0.65)
`12.5 2.89(0.89)
`9.0
`2.56(0.83)
`1.84(0.58)
`6.5
`5.5
`1.74(0.43)
`4.5
`2.24(0.39)b
`3.5
`1.68(0.46)b
`2.5 0.75(0.26)
`1.5 0.51 (0.19)
`0.66 0.68(0.21)
`0.16 0.50(0.17)
`
`36.0 1.24d
`32.5 1.09d
`26.0 1.58(0.22)
`21.0 1.89(0.21)
`16.5 2.07(0.39)
`13.0 2.16(0.48)
`10.5 2.24(0.50)
`2.22(0.64)
`8.0
`6.0 2.25(0.40)
`4.0 5.24(2.36)
`2.0
`7.14(1.03)
`0.64 5.28(4.43)
`0.15 2. 71 (0.90)
`
`0/olday
`
`(day)
`Time
`
`%/day
`
`(day)
`Time
`
`%/day
`
`(day)
`Time
`
`o/olday
`
`(day)
`Time
`
`%/day
`
`(day)
`Time
`
`%/day
`
`(day)
`Time
`
`%/day
`
`(day)
`Time
`
`VII"
`
`VI
`
`Vb··
`
`IV
`
`llfb
`
`II
`
`(b
`
`0
`00
`~
`
`TABLE 2. Mean Calculated Release Rates as a Function of Time After Administration for the Various Naltrexone
`
`Delivery Systemsa
`
`~
`
`~
`
`AMN1026
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`
`

`

`QUANTITATION OF NALTREXONE RELEASE
`
`181
`
`·TABLE 3. Comparison of the Naltrexone Dose Administered in
`Sustained Release Form with the Amount of Naltrexone Accounted for
`Experimentally in the Monkey
`
`Mean amount
`naltrexone
`administered
`(mg)
`
`Mean
`calculated
`amount
`naltrexone
`released (mg)
`
`Mean assayed
`amount
`remaining
`in delivery
`system (mg)
`
`42,1C
`35.3
`36.3
`26.2
`37.8
`44.0
`30.7
`
`38.9"
`31.6
`18.3
`19.5
`32.4
`30.0
`16.4
`
`0.0023C
`
`16.4'
`
`Percent of
`administered
`dose
`accounted fort>
`
`92(91-94)c
`89(58-116)
`53(30-74)d
`76(48-91)
`86(78-100)•
`68(56-87)
`1 07(92-120)d
`
`Delivery
`sys~em•
`
`I
`II
`Ill
`IV
`v
`VI
`VII
`
`•Delivery system identification: I = naltrexone in a physical blend with 90% (L 1:) lactic
`acid-1 0% glycolic acid copolymer, spherical beads 1.5 mm in diameter, subcutaneous,
`Dynatech #24086; II = naltrexone pamaate-poly(lactic acid) microcapsules suspended In
`2% aluminum monostearate-peanut oil and injected intramuscularly, Thies #GL-1-6-76-1;
`Ill = naJtrexone pamoate-poly(lactic acid) microcapsules suspended in a medium con-
`sisting of water, 2% Tween 20, 0.02% anti-foam silicone and 1 :10,000 phemerol and
`injected intramuscularly (Thies #GL-1-6-75-1); IV = naltrexone pamoate-poly(lactic acid)
`microcapsules suspended in an aqueous medium of 0.1% Tween 80 in Macrodex
`(6%
`dextran 70 in 5% dextrose/water for injection) and injected subcutaneously (Thies #GL-3-
`9-n-3); V = micronized naltrexone pamoate (batch #2M-1869-866-16) suspended in 2%
`aluminum monostearate-peanut oil and injected intramuscularly; VI = rods containing
`naltrexone supplied by Alza and administered subcutaneously; VII = naltrexone 33% in
`a dipalmitln (75%)-tripalmitin (25%) mixture shaped in rods and administered subcutane-
`ously (Battelle).
`bMean of 4 animals, unless stated otherwise. Range In parenthesis.
`cMean of 2 values. One animal became ill during the study and another had a sufficient
`number of piCJ,sma samples with assay interference that a quantitation of total amount
`released could not be made.
`dMean of 3 animals.
`•Mean of 3 animals. One animal omitted because of a 163% recovery due to one high
`data point and an insufficient number of other data points to obtain an accurate estimate
`of the amount released.
`'The rods removed from each monkey were weighed, dissolved in chloroform, and as-
`sayed spectrophotometrically for naltrexone at 282 nm.
`
`Subcutaneous Implants
`The release rate-time profiles for the subcutaneous implant deliv-
`ery systems are shown in fig. 2. System I (Dynatech) is character-
`ized by a more rapid release over the first 6 days followed by a
`very constant rate of naltrexone release throughout the remainder
`of the study. System VI (Alza) yielded a release rate-time profile
`
`AMN1026
`IPR of Patent No. 7,919,499
`
`

`

`182
`
`NALTREXONE SUSTAINED-RELEASE PREPARATIONS
`
`that was closer to being constant over the entire release period
`than any of the other systems. However, this system also was the
`shortest of the three in terms· of duration. Delivery system VTI
`(Battelle) is characterized by a rapid initial rate of release followed
`by a slowly declining rate from day 2 to about day 38. Overall,
`system I provides the longest duration of meaningful release rates
`of naltrexone. The "initial burst',. of release with this delivery
`system is larger than that observed with the other two implantable
`systems (fig. 2) but much smaller than that for the aqueous injecta-
`ble systems (compare fig. 2 with fig. 1, noting the logarithmic ordi-
`nate in fig. 1).
`The possibility of removal of the implanted delivery systems at
`termination of the sustained release study permits a more rigorous
`"mass balance" comparison of naltrexone dose with the sum of the
`calculated amount released plus the amount remaining in the de-
`livery system. Such a comparison was carried out with systems I
`and Vll (table 3). Assay of the removed delivery system for naltr~x­
`one content yielded negligible 8!DOUnts in system I. However, about
`
`8
`
`7
`
`6
`
`5
`
`• = I
`0 = VI
`A = VII
`
`~4
`"0
`........
`(1)
`~ 3
`
`"0 -0
`
`0 2
`~
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`w
`1-
`<(
`0::
`w
`(/)
`<( w
`_J w
`0::
`w z
`0
`X w
`0::
`1-
`...J
`<( z
`~~
`Zj
`Cl w
`1-
`<(
`_J
`
`::J <..> _J s
`
`TIME (day)
`FIGURE 2. Linear plot of naltrexone in vivo release rate as a function of time for
`implantable sustained release delivery systems I, VI and VII. Delivery systems are
`identified in the text and in table 3.
`
`AMN1026
`IPR of Patent No. 7,919,499
`
`

`

`183
`QUANTITATION OF NALTREXONE RELEASE
`half the dose remained in system VII at termination of the study.
`Data from both of these delivery systems provided an essentially
`complete accounting of the fate of the administered dose, as sum-
`marized in table 3. In system VI the device could not be removed at
`the e:rid of the study and the lower recovery with this system may
`be due to unreJeased drug. The variability in recovery between rep-
`licate monkeys was less with the three implantable naltrexone de-
`livery systems than with the injectable microcapsule systems (table
`3). This may be due to more accurate administration of the intend-
`ed dose as well as to the ability to remove the system and assay for
`unreleased naltrexone.
`
`REFERENCES
`
`1. R.E. Willette. In R.E. Willette (ed.), Narcotic Antagonists: The Search for Long-
`. Acting Preparations, National Institute on Drug Abuse Research Monograph 4.
`DHEW Pub. No. (ADM)76-296. Supt. of Docs., U.S. Govt. Print. Off., Washing-
`ton, D.C., 1-5 (1976).
`2. R.E. Willette. The development of sustained action preparations of narcotic an-
`tagonists. In R.C. Petersen (ed.), The International Challenge of Drug Abuse, Na-
`tional Institute on Drug Abuse Research Monograph 19. DHEW Pub. No.
`(ADM)78-654. Supt. of Docs., U.S. Govt. Print. Off., Washington, D.C., 333-339
`(1978).
`3. R.E. Willette (ed.), Narcotic Antagonists: The Search for Long-Acting Preparations,
`National Institute on Drug Abuse Research Monograph 4. DHEW pub. No.
`(ADM)76-296. Supt. of Docs., U.S. Govt. Print. Off., Washington, D.C., 13-42
`(1976).
`4. S.E. Harrigan and D.A. Downs. Continuous intravenous naltrexone effects on
`morphine self-administration in rhesus monkeys. J. Pharmacal. Exp. Ther., 2()4,
`481-486 (1978).
`5. R.A. Sams and L. Malspeis. Determination of naloxone and naltrexone as per-
`fluorohlkyl ester derivatives by electron-capture gas-liquid chromatography. J.
`Chromatogr., 125, 409-420 (1976).
`6. R.H. Rewrlng, V.K. Batra, T.M. Ludden, M.Y. Jao, B.E. Morrison, D.A. McCarthy,
`S.E. Harrigan, S.B. Ashcraft, R.A. · Sams, M.S. Bathala, A.E. Staubus and L.
`Malspeis. Plasma naltrexone kinetics after intravenous bolus administration in
`dogs and monkeys. J. Pharm. Sci., 68, 411-416 (1979).
`7. R.H. Reuning, S.B. Ashcraft and B.E. Morrison. An electron-capture gas chroma-
`tographic assay for naltrexone in biological fluids. This volume.
`8. J.C.K. Loo and S. Riegelman. New method for calculating the intrinsic absorption
`rate of drugs. J. Pharm. Sci., 5'!, 918-928 (1968).
`.
`9. W.G. Kramer. R.P. Lewis, T.C. Cobb, W.F. Forester Jr., J.A. Visconti, L.A. Wanke,
`H.G. Boxenbaum and R.H. Reuning. Pharmacokinetics of digoxin: Comparison
`o( a two- and a three-compartment model in man. J. Pharmacokin. Biopharm.,
`2, 299-312 (1974).
`10. M. Gibaldi and D. Perrier. Pharmacokinetics, Marcel Dekker, Inc., New York, p.
`137 (1975).
`11. S. Harrigan, personal communication.
`
`AMN1026
`IPR of Patent No. 7,919,499
`
`

`

`184
`NALTREXONE SUSTAINED-RELEASE PREPARATIONS
`ACKNOWLEDGMENTS
`
`The authors wish to acknowledge the contributions of Mr. James
`N. Wiley and Mr. Stephen E. Harrigan, Warner-Lambert/Parke-
`Davis, in carrying out all the experimental work with the monkeys.
`The developers of the various delivery systems are also acknowl-
`edged, among them Dr. C. Thies, (Washington University), Dr. D. L.
`Wise (Dynatech R/D Company), Dr. R. Capozza (Alza) and Dr. M.
`Sullivan (Battelle). Assays were carried out by S. B. Ashcraft and
`B. E. Morrison. Sgpported in part by Contract HSM-42-73-182 from
`The National Institute on Drug Abuse.
`
`AUTHORS
`R. H. Reuning, S. H. T. Liao, • and A. E. Staubus
`College of Pharmacy
`Ohio State University
`Columbus, OH 43210
`•current address:
`Burroughs Wellcome Company
`Research Triangle Park, NC 27709
`
`AMN1026
`IPR of Patent No. 7,919,499
`
`