PHARMACYLisrary’ 4
`SCHOOL OF PHARMAcy |
`
`Narcotic Antagonists:
`Naltrexone Pharmacochemistry and
`Sustained-Release 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 institute on Drug Abuse
`Division of Research
`5600 Fishers Lane
`Rockville, Maryland 20857
`
`For sale by the Superintendent of Documents, U.S. Government Printing Office
`Washington, D.C. 20402
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`IPR2025-00514
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`

`

`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 amountreleased 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,
`ytelding 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
`
`

`

`QUANTITATION OF NALTREXONE RELEASE
`
`173
`
`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
`idinitial renee rate of3-8%ul
`the dose per day over the>first 3-5 days followed by a rather
`conse 1-2%per dayto about day 36; and 4) essentiall
`mplete recovery of the dose was obtained for the Battel
`a Dnatech systems.
`
`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 monkeysis 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
`monkeyswill be included in subsequent manuscripts.
`
`EXPERIMENTAL
`
`Delivery Systems
`
`Thefollowing 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 mm in di-
`ameter, subcutaneous, Dynatech #24086;
`II. Naltrexone pamoate-poly(lactic acid) microcapsules sus-
`pended in 2% aluminum monostearate-peanutoil and in-
`jected intramuscularly, Thies #GL-1-6-76-1;
`
`

`

`174
`
`NALTREXONE SUSTAINED-RELEASE PREPARATIONS
`
`II. Naltrexone pamoate-poly(lactic 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-poly(lactic acid) microcapsules sus-
`pended in an aqueous medium of 0.1% Tween 80 in Macro-
`dex (6% dextran 70 in 5% dextrose/water for injection)
`and injected subcutaneously, Thies #GL-38-9-77-3;
`V. Micronized naltrexone pamoate (batch #2M?1869-866-16)
`suspended in 2% aluminum monostearate-peanut oil and
`injected intramuscularly;
`VI. Rods-naltrexone and hydrophobic polymer, Chronomer,
`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 providedby the developers
`(2,3). All are intended to be bio- degradable, with systems I, VI and
`VII designed for subcutaneous implant and systems II, III 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 VII, these were self-administrating monkeys and were on a
`rotating schedule of morphine, methamphetamine andsaline 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 release 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 plasmalevel-time profile.
`
`

`

`QUANTITATION OF NALTREXONE RELEASE
`
`175
`
`DISCUSSION
`
`Injectable Systems
`The.in vivo release rate data for the injectable naltrexone deliv-
`ery systems are presented in fig. 1. Systems II, If 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 included 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 (5,6,7). The pharmacokinetic
`calculation of in vivo release rates is dependent on an assay thatis
`specific for unchanged naltrexone 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 naltrexoneconcentration in plasma ag a function of
`time after administration are summarized in table 1 for each of the
`seven delivery systems tested. Levels of about 0.25-0.5 ng/ml are
`needed to block morphine self-administration in these monkeys
`(11). Since this range is also the approximate sensitivity limit of
`
`

`

`NALTREXONE SUSTAINED-RELEASE PREPARATIONS
`
`176
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`QUANTITATION OF NALTREXONE RELEASE
`
`177
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`

`

`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
`recovered from the delivery system after
`removal
`from the
`monkey.
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`TIME (day)
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`FIGURE1. Semilog plot of naltrexone in vivo release rate as a function of time for
`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.
`
`

`

`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
`influente 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 release
`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 ITI was available for rapid release. A similar early rapid re-
`lease can also be observed for system IV (microcapsules suspended
`in an aqueous vehicle and administered subcutaneously). A com-
`parison of aqueous microcapsule suspension systems III and IV (fig.
`1) suggests that the intramuscular route (III) 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(I, III 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 thepossi-
`bility of removing the microcapsules remaining at the end of the
`sustained release study. Therefore,
`the unabsorbed naltrexone
`could not be assayed directly.
`
`

`

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`180
`
`NALTREXONE SUSTAINED-RELEASE PREPARATIONS
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`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 assayed
`Mean
`Percentof
`amount
`calculated
`Mean amount
`administered
`remaining
`amount
`naltrexone
`dose
`in delivery
`naltrexone
`administered
`Delivery
`system*
`(mg)
`released (mg)
`system (mg)
`accounted for’
`
`
`|
`Il
`Ul
`IV
`V
`Vi
`Vil
`
`42.1°
`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
`
`0.0023¢
`—
`—
`_
`_
`_
`16.4!
`
`92(91-94)¢
`89(58—1 16)
`53(30-74)°
`76(48-91)
`86(78—100)¢
`68(56-87)
`107(92-120)¢
`
`*Delivery system identification: | = naltrexone in a physical blend with 90%(L+) lactic
`acid-10% glycolic acid copolymer, spherical beads 1.5 mm in diameter, subcutaneous,
`Dynatech #24086;Ii = naltrexone pamoate-poly(lactic acid) microcapsules suspended in
`2% aluminum monostearate-peanut oil and injected intramuscularly, Thies #GL-1-6-76-1;
`lil = naltrexone 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); 1V = naltrexone pamoate-poly(lactic acid)
`microcapsules suspended in an aqueous medium of 0.1% Tween 80 in Macrodex (6%
`dextran 70 in 5% dextrose/waterfor injection) and injected subcutaneously (Thies #GL-3-
`9-77-3); 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 dipalmitin (75%)-tripalmitin (25%) mixture shaped in rods and administered subcutane-
`ously (Battelle).
`‘Mean of 4 animals, unless stated otherwise. Rangein parenthesis.
`‘Mean of 2 values. One animal becameill during the study and another had a sufficient
`number of plasma samples with assay interference that a quantitation of total amount
`released could not be made.
`‘Meanof 3 animals.
`*Mean of 3 animals. One animal omitted because of a 163% recovery due to one high
`data point and an insufficient numberof 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
`
`

`

`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 VII
`(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 (comparefig. 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 VII (table 3). Assay of the removed delivery system for naltrex-
`one content yielded negligible amounts in system I. However, about
`
`
`
`(%ofdose/day)
`
`
`
`————— CALCULATEDINVIVONALTREXONERELEASERATE
`
`
`
`TIME (day)
`
`FIGURE 2.Linear plot of naltrexonein vivo release rate as a function of time for
`implantable sustained release delivery systems I, VI and VII. Delivery systemsare
`identified in the text and in table 3.
`
`

`

`QUANTITATION OF NALTREXONE RELEASE
`
`183
`
`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 end of the study and the lower recovery with this system may
`be due to unreleased 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 Monograph4.
`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
`morphineself-administration in rhesus monkeys. J. Pharmacol. Exp. Ther., 204,
`481-486 (1978).
`5. R.A. Sams and L. Malspeis. Determination of naloxone and naltrexone as per-
`fluoroalkyl ester derivatives by electron-capture gas-liquid chromatography. J.
`Chromatogr., 125, 409-420 (1976).
`.
`6. R.H. Reuning, 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., 57, 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
`of a two- and a three-compartment model in man. J. Pharmacokin. Biopharm.,
`9, 299-812 (1974).
`10. M. Gibaldi and D. Perrier. Pharmacokinetics, Marcel Dekker, Inc., New York, p.
`187 (1975).
`11. S. Harrigan, personal communication.
`
`

`

`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. Supported 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
`
`