Journal of Controlled Release 183 (2014) 154–166
`
`Contents lists available at ScienceDirect
`
`Journal of Controlled Release
`
`j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / j c o n r e l
`
`Review
`Naltrexone: A review of existing sustained drug delivery systems and
`emerging nano-based systems
`Nowsheen Goonoo a, Archana Bhaw-Luximon a, Reetesh Ujoodha a, Anil Jhugroo b,
`Gary K. Hulse c, Dhanjay Jhurry a,⁎
`a ANDI Centre of Excellence for Biomedical and Biomaterials Research, MSIRI Building, University of Mauritius, Réduit, Mauritius
`b Dept. of Medicine, University of Mauritius, Réduit, Mauritius
`c School of Psychiatry and Clinical Neurosciences, The University of Western Australia, M521, D Block, QEII Medical Centre, Nedlands, WA 6009, Australia
`
`a r t i c l e
`
`i n f o
`
`a b s t r a c t
`
`Article history:
`Received 10 February 2014
`Accepted 24 March 2014
`Available online 2 April 2014
`
`Keywords:
`Naltrexone
`Naltrexone sustained release formulations and
`safety
`Naltrexone-loaded nanocarriers and nanogels
`
`Narcotic antagonists such as naltrexone (NTX) have shown some efficiency in the treatment of both opiate addic-
`tion and alcohol dependence. A few review articles have focused on clinical findings and pharmacogenetics of
`NTX, advantages and limitations of sustained release systems as well as pharmacological studies of NTX depot
`formulations for the treatment of alcohol and opioid dependency. To date, three NTX implant systems have
`been developed and tested in humans. In this review, we summarize the latest clinical data on commercially
`available injectable and implantable NTX-sustained release systems and discuss their safety and tolerability
`aspects. Emphasis is also laid on recent developments in the area of nanodrug delivery such as NTX-loaded
`micelles and nanogels as well as related research avenues. Due to their ability to increase the therapeutic
`index and to improve the selectivity of drugs (targeted delivery), nanodrug delivery systems are considered as
`promising sustainable drug carriers for NTX in addressing opiate and alcohol dependence.
`© 2014 Elsevier B.V. All rights reserved.
`
`Contents
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`1.
`2.
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`3.
`4.
`5.
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`Introduction .
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`Current treatment against opiates and alcohol dependency .
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`2.1.
`Agonist therapy: methadone and associated problems .
`2.2.
`Partial agonist therapy: buprenorphine and associated problems .
`2.3.
`Antagonist therapy: naltrexone and its mechanism of action .
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`Limitations of oral NTX .
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`Drug delivery: basic principles .
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`Sustained-release NTX formulations
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`5.1.
`Sub-cutaneous formulations
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`5.2.
`Injectable formulations .
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`5.3.
`Novel implants and depot injections .
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`Sustained-release systems for NTX delivery .
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`6.
`Sustained-release NTX implants
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`7.
`Sustained-release NTX injections .
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`8.
`Safety and tolerability of extended-release formulations
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`9.
`10. Micelles and microspheres for sustained-release of NTX .
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`11.
`Nanogels
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`References .
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`⁎ Corresponding author. Tel.: +230 4651347.
`E-mail address: djhurry@uom.ac.mu (D. Jhurry).
`
`http://dx.doi.org/10.1016/j.jconrel.2014.03.046
`0168-3659/© 2014 Elsevier B.V. All rights reserved.
`
`AMN1081
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`

`

`1. Introduction
`
`2.1. Agonist therapy: methadone and associated problems
`
`N. Goonoo et al. / Journal of Controlled Release 183 (2014) 154–166
`
`155
`
`Treatment options for heroin addiction has long been dependent
`on three main alternatives namely detoxification, opioid agonist
`(i.e. methadone) and partial agonists (i.e. buprenorphine) mainte-
`nance treatment, and oral NTX. Detoxification followed by long-
`term residential treatment was found to cause some reduction in
`drug use but suffered from problems such as lack of retention in
`treatment and risk of overdose upon discharge [1]. Opioid maintenance
`treatment (OMT) involves the administration of opioid agonist medica-
`tions such as methadone, buprenorphine and medically dispensed
`heroin under supervision [2]. OMT has been effective in decreasing
`mortality rates, morbidity and drug-related criminal activity. How-
`ever, dropout rates remain quite high during the initial months of
`treatment.
`As regards alcohol abuse, detoxification, non-pharmacological
`(psychosocial) treatment methods and pharmacotherapy have not
`been very effective. Disulfiram (Antabuse®), Naltrexone (Revia®),
`and calcium acetylhomotaurinate (Acamprosate®) are the three
`major oral pharmacotherapies used in the treatment of alcoholism.
`Disulfiram is a deterrent medication and makes its ingestion un-
`pleasant. Acamprosate®, a glutamate antagonist has been found
`promising in the treatment of alcoholics [3,4] but present limita-
`tions. For some patients, combination therapy with NTX or disulfi-
`ram have proved to be effective [5].
`The development of long-acting depot formulations of NTX has
`led to improved results such as increased bioavailability and efficacy
`of treatment and is considered as a solution to the problem of non-
`compliance and extensive first pass metabolism associated with
`oral NTX. This has been summarized in two excellent review papers
`[6,7]. In their review, Lobmaier et al. [6] emphasized on NTX depot
`formulations for opioid and alcohol dependence, discussing the
`mode of administration, the pharmacokinetic properties, safety and
`tolerability of the systems. The authors concluded on the need for
`further research on NTX to effectively block clinically relevant
`doses of heroin. Krupitsky et al. [7] summarized the effectiveness
`and safety of long-acting sustained release injectable and implant-
`able formulations of NTX for heroin dependence. The authors con-
`cluded on improved tolerability and effectiveness of long-acting
`sustained-release NTX systems compared to oral NTX. They also
`mention that studies comparing the injectable formulation with
`oral NTX are required. In both reviews, the delivery systems are lim-
`ited to NTX-loaded polymer-based microspheres.
`This article reviews existing naltrexone delivery systems and their
`limitations and presents benefits of emerging nano-based delivery sys-
`tems. In the first part of the review, we present the mechanism of action
`of NTX and its interest as a substitute for methadone followed by an in-
`depth analysis of commercially available NTX formulations with more
`recent references based on clinical trials through 2011 to 2013. We
`have summarized safety and tolerability aspects of extended-release
`formulations to ease access to information. We also stress on new
`nano-based NTX developments such as block copolymer micelles and
`cross-linked nanogels that attract a lot of interest and opens up new
`perspectives for research.
`
`2. Current treatment against opiates and alcohol dependency
`
`Opiates generally refer to any of the narcotic opioid alkaloids found
`as natural products in the opium poppy plant, Papaversomniferum [8].
`Few examples of opiates include heroin and codeine. Opiate drugs
`act both in the central and peripheral nervous systems and opiate-
`dependent patients show impairment in brain functioning [9,10].
`Agonists and partial agonists such as methadone and buprenorphine
`respectively, and antagonists such as NTX have been used in the
`management of opioid dependence.
`
`Methadone was first developed in Germany in 1937. However, its
`use as a substitute for heroin in the management of heroin depen-
`dence was not until 1964 [11]. Methadone has cross tolerance with
`other opioid compounds such as heroin, morphine and codeine and
`can therefore be used as a chemical replacement for the illicit opioid.
`The treatment of opioid addicts with methadone involves an initial
`methadone maintenance program (MMT). MMT is the most widely
`used opioid substitution program for the management of heroin
`dependence and its clinical efficacy has been repeatedly shown by
`several studies [12]. Being long acting, methadone should be admin-
`istered only once daily as opposed to heroin which requires twice or
`thrice daily dose administration. Its oral route of administration sub-
`stantially reduces the potential risks of spreading Hepatitis C or HIV.
`However, methadone therapy has few limitations.
`Methadone therapy is associated with a number of problems. Due to
`its full μ opiate receptor agonist action, there is no limit to the level of re-
`spiratory depression or sedation that methadone can induce. As a result,
`methadone overdose can be lethal, with risk being particularly high
`during the induction period [13]. The combination of methadone with
`other opioid drugs, benzodiazepines or alcohol increases the risks of
`sudden cardiac death [14] and death by anoxic brain injury with pulmo-
`nary edema secondary to respiratory depression [15]. Methadone may
`increase the likelihood of QT interval prolongation [16] and may be as-
`sociated with torsades de pointes [17] that can be fatal.
`As methadone has a long half-life, coming off methadone is asso-
`ciated with a longer period of opioid withdrawal symptoms than
`when coming off heroin. This results in a significant degree of dis-
`comfort in patients who attempt to stop methadone. Methadone is a
`corrective but not a curative treatment for opioid addiction. Newer
`treatments with opioid antagonists like long acting NTX formulations
`need to be explored further as the initial results look promising.
`
`2.2. Partial agonist therapy: buprenorphine and associated problems
`
`Buprenorphine is a partial μ agonist and κ opiate receptor antagonist.
`It is also used in the treatment of opioid dependence and has several po-
`tential benefits over MMT. It is less sedating than methadone due to the
`fact that it is a partial μ receptor agonist. Also, it is associated with lower
`overdose risk since it rarely causes respiratory depression when used
`alone [18]. One way of reducing the abuse liability of buprenorphine
`[19] without affecting its bioavailability has been via the addition of nal-
`oxone hydrochloride to buprenorphine in a ratio of 1:4 (Suboxone,
`Reckitt Benckiser) [20]. Suboxone® was approved in April 2006 by the
`Therapeutics Goods Administration (TGA), and is now largely replacing
`buprenorphine hydrochloride (Subutex®) as the principal formulation
`for ambulatory clinical treatment of opioid dependence. Buprenorphine
`is available in different forms as summarized in Table 1.
`New dosage forms of buprenorphine include transdermal patches
`[22], orodispersible or mucoadhesive buccal films [23]. The transdermal
`buprenorphine patch, Transtec®, first launched in 2001 uses a matrix
`technology whereby buprenorphine is homogeneously incorporated
`in a solid polymer matrix patch [22]. Transdermal buprenorphine
`patches are available in three different dosages with total loading
`doses of 20 mg, 30 mg, and 40 mg which release the drug at a controlled
`rate of 35 μg/h, 52.5 μg/h and 70 μg/h respectively [22]. BUNAVAIL™ is
`the first and only buccal formulation of buprenorphine and naloxone
`[24]. A New Drug Application (NDA) was submitted to the Food and
`Drug Administration (FDA) in 2013 and is currently under review.
`A consensus on the relative superiority of buprenorphine over MMT
`remains elusive. Many studies reveal no significant differences between
`the treatments [25]. Others report significantly higher rates of retention
`in treatment, and abstinence from, or reduction in illicit opiate con-
`sumption among buprenorphine patients than among MMT patients
`[26]. A few studies described more favorable outcomes for MMT than
`
`AMN1081
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`

`

`156
`
`N. Goonoo et al. / Journal of Controlled Release 183 (2014) 154–166
`
`Table 1
`Different forms of buprenorphine.
`
`Trade name
`
`Dosage form
`
`Subutex® (buprenorphine)
`Suboxone® (buprenorphine/naloxone)
`Zubsolv® (buprenorphine/naloxone)
`Transtec®
`Butrans®
`Norspan ®
`
`Sublingual tablet (2 mg and 8 mg)
`Sublingual film (4 mg buprenorphine/1 mg naloxone and 12 mg buprenorphine/2.5 mg naloxone)
`Sublingual tablet (2 mg buprenorphine/0.5 mg naloxone and 8 mg buprenorphine/2 mg naloxone)
`Transdermal
`Transdermal (delivering 5, 10 or 20 g/h)
`Transdermal (delivering 5, 10 or 20 g/h)
`
`References
`
`[21]
`
`[22]
`[23]
`
`for buprenorphine in terms of retention, abstinence for at least three
`weeks, opioid-free urine [27], and cost-effectiveness [28]. Nevertheless,
`overall pharmacokinetic features suggest that buprenorphine is safer
`than MMT, with respect to its reduced risk of respiratory depression,
`withdrawal symptoms, and accidental opioid overdose deaths [29]
`and reduced potential for abuse [30].
`
`2.3. Antagonist therapy: naltrexone and its mechanism of action
`
`Narcotic antagonists such as NTX, have been found useful in the
`treatment of both opiate addiction and alcohol dependency [31,32].
`NTX has a chemical structure similar to opiates and can occupy the
`body's opiate receptors in preference to opiates. The ability of NTX
`to effectively antagonize heroin use is unequivocal [33,34]. Studies
`have reported serum NTX levels of 2.8 ng/ml as being effective in
`blocking 500 mg of snorted pure pharmaceutical diamorphine [35],
`serum naltrexone levels N2 ng/ml [34–38] as being effective in
`blocking the effects of 25 mg intravenously administered heroin,
`and others have reported plasma levels of less than 1 ng/ml as
`being capable of antagonizing the effects of 15 mg morphine [39].
`NTX is an opioid receptor antagonist that blocks the reinforcing
`effects of opioids and reduces alcohol consumption and craving.
`Historically, N-allylnorcodeine was the first opioid antagonist-like
`molecule developed in 1915. It acted by blocking the respiratory-
`depressant effects of morphine and heroin. In the 1940s, nalorphine
`was the first reported opioid antagonist but was found to cause dys-
`phoria, discouraging its use in the treatment of opioid intoxication
`and overdose. Naloxone was then developed in 1960 as a less toxic
`antagonist. It did not cause any dysphoria but suffered from short
`duration of action and poor oral bioavailability. To circumvent
`these disadvantages, NTX was developed in 1963 by Endo Laborato-
`ries, which was later acquired by DuPont. It is generally synthesized
`from thebaine (an opiate alkaloid) [40] and was found to have better
`oral bioavailability, a longer duration of action and twice as potent as
`naloxone. Naltrexone hydrochloride is freely soluble in water, slightly
`soluble in ethanol (approximately 96%), and practically insoluble in
`methylene chloride [41]. It is a BCS Class IV drug i.e. it has low solubility
`and low permeability.
`Table 2 gives a summary of the pharmacokinetic data of NTX. NTX
`is FDA-approved for the treatment of alcoholism or opioid addiction
`in the form of commercially available oral tablets e.g. Trexan®,
`Revia®, Depade® or the long-acting, high-dose depot form Vivitrol®
`for intramuscular injection.
`
`Table 2
`Pharmacokinetic data of NTX [37,42].
`
`Chemical formula
`Oral bioavailability
`Metabolism
`Peak concentration
`Half-life
`Duration of action
`Elimination
`Peak plasma level
`
`Naltrexone
`
`C20H23NO4
`Up to 40%
`Hepatic
`1–2 h
`Up to 14 h (oral)
`Up to 24+ h
`Hepatic metabolism and renal excretion
`1 to 2 ng/ml
`
`Studies have revealed that the mesolimbic dopamine system is
`the prime target of addictive drugs. This system originates in the ven-
`tral tegmental area (VTA) of the brain (Scheme 1). Most projection neu-
`rons of the VTA are dopamine-producing neurons. GABA interneurons
`suppress dopamine cell firing resulting in reduced dopamine release.
`Opioids block the inhibitory control exerted by these neurons over the
`VTA dopamine cell bodies resulting in increased VTA dopamine activity,
`thus enhancing brain-reward (reinforcement circuit in the human
`brain) and inducing drug-taking behavior and possibly drug-craving.
`Each addictive drug has a specific molecular target which engages a dis-
`tinct cellular mechanism. The main molecular receptors of opioids are
`μ-OR Gio protein-coupled receptors.
`NTX acts by blocking the μ-opiate receptors, thus reducing crav-
`ing. The precise mechanism for craving reduction has not been de-
`termined yet, but it is likely that NTX causes antagonism of opioid
`pathways to the nucleus accumbens, thereby reducing the total
`amount of dopamine released (Scheme 1). In addition, opioid antag-
`onists like NTX influences other biological systems such as G-
`receptor second messenger systems [43], immune system [44] and
`the HPA axis [45]. NTX is metabolized in the liver into a variety of
`metabolites, with 6-β-naltrexol being the metabolite useful in
`treating drug abuse (Scheme 2). 6-β-naltrexol is believed to act as
`a competitive antagonist at opioid receptors. Cytochrome P450 en-
`zymes, which are involved in the metabolism of methadone or
`buprenorphine do not play a role in NTX metabolism. NTX is largely
`metabolized by the aldo-ketoreductase family of enzymes (AKR1C1,
`1C2 and 1C4) [46] with AKR1C4 being the most efficient [47]. It is be-
`lieved that a polymorphism of the AKR1C4 enzyme is responsible for
`inter-individual variability in 6-β-naltrexol levels and could be used
`to explain the efficacy of and compliance with NTX treatment [46].
`Due to its higher potency compared to naloxone and cyclazocine,
`NTX is considered as the most promising narcotic antagonist used for
`the treatment of narcotic addiction [48,49]. A minimum plasma level
`of NTX of 1 ng/ml is required for blocking clinically relevant doses (e.g.
`25 mg) of intravenously administered heroin [50]. Evaluation of a pro-
`gram where cognitive behavioral therapy (CBT) and/or NTX were
`used over 12 weeks showed that addition of NTX significantly improved
`the abstinence rate (36.1% CBT against 62.6% CBT + NTX) [51].
`However, oral NTX (Revia® tablets) has been associated with
`high early dropout rates. It was shown that 37% of patients discontin-
`ue daily oral NTX by 12 weeks [52] and more than 80% discontinue
`use by 6 months [53]. As demonstrated by several studies, compli-
`ance is critical for the efficacy of NTX [54]. Moreover, orally adminis-
`tered NTX has poor bioavailability due to high hepatic metabolism
`(98%) and a wide fluctuation in drug plasma concentration occurs
`with orally administered NTX [55]. Indeed, a review of the effective-
`ness of oral naltrexone maintenance for the treatment of opioid de-
`pendence concluded that there was insufficient evidence to justify
`the use of NTX in maintenance treatment of opioid addicts [56].
`
`3. Limitations of oral NTX
`
`As mentioned earlier, NTX is available commercially as tablets
`for oral administration. However, they have several pharmaco-
`therapeutic limitations. First of all, more than 98% of the drug is me-
`tabolized in the liver and very small amount reaches the brain. Due
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`
`157
`
`VTA of brain consisting of
`GABAergic and dopaminergic
`neurons
`
`Alcohol stimulates the
`release of β-
`endorphins
`
`which bind to μ-
`opioid receptors
`
`thus
`releasing
`dopamine
`
`…
`
`…
`
`A
`
`B
`
`Alcohol stimulates the
`release of β-
`endorphins
`
`thereby
`preventing
`dopamine
`release
`
`…
`
`6- β-naltrexol blocks the
`binding of β-endorphins to
`μ-opioid receptors
`C
`
`β-endorphins
`
`6- β-naltrexol
`
`μ-opioid receptor
`
`dopamine
`
`Scheme 1. Schematic representation of interplay between GABAergic and dopaminergic
`neurons in (A) absence of drug of abuse and its antagonist, (B) presence of drug of
`abuse only and (C) presence of both drug of abuse and its antagonist.
`
`to extensive first pass metabolism, the concentration of naltrexone and
`the active metabolite, 6-β-naltrexol peaks within the first hour after
`oral dosing, followed by a steady decline each day during treatment
`[57]. This explains the need for the development of a system whereby
`NTX bypasses the liver i.e. an injectable long-acting drug delivery
`system. Such a system will enable the maintenance of a constant and
`predictable drug plasma concentration. According to a study conducted
`
`HO
`
`O
`
`O
`
`OH
`
`N
`
`HO
`
`O
`
`HO
`
`OH
`
`N
`
`Naltrexone (NTX)
`
`6-β-naltrexol
`
`Scheme 2. Metabolism of NTX to 6-β-naltrexol.
`
`by Verebey et al. [55] among alcoholics, drug plasma levels fluctuates
`much with orally administered NTX. In fact, a 100 mg naltrexone dose
`provided 96%, 86.5% and 46.6% blockade at 24 h, 48 h and 72 h respec-
`tively. Moreover, the use of oral NTX places the onus on the patients as
`to whether to take the medications or not and very often, they do not
`comply with the required frequency. Studies have also shown that a
`comparatively low proportion of patients choose to start NTX treatment
`[58]. Among those who do, many drop out early; one quarter after a few
`days [33] and as many as half in the first few weeks of treatment [59].
`This is a major problem given that several studies have demonstrated
`that missing even a few doses of NTX could lead to full relapse into opi-
`oid use and discontinuation of the treatment, despite intensive clinical
`interventions [54,60].
`
`4. Drug delivery: basic principles
`
`Drug delivery systems (DDS) may be differentiated according to the
`way the drug is administered or released. They may be administered
`through oral or parenteral (intravenous, intramuscular, subcutaneous,
`intradermal or intraperitoneal) routes [61].
`DDS can broadly be classified as immediate release and modified re-
`lease dosage forms. Modified-release systems can be further divided
`into delayed-, extended- and targeted-release systems. Furthermore,
`extended-release systems can be divided into sustained- and controlled
`release systems [61] (Fig. 1).
`Sustained release systems maintain the rate of drug release over a
`sustained period of time [61]. Sustained release systems may be either
`in the form of reservoir or matrix systems. Reservoir systems often
`follow a zero-order kinetics (linear release as a function of time) while
`matrix systems often follow a linear release as a function of the square
`root of time. Sustained release systems offer several advantages such
`as reduced fluctuations in drug concentrations, and reduced total
`dose. Also, the patient does not require taking the drug frequently and
`therefore resolves the issue of non-compliance.
`Controlled-release systems are different from sustained-release
`ones [61]. They are designed to maintain specific plasma concentrations,
`independent of the biological environment of the application site [61,
`62]. Another major difference is that sustained-release forms are often
`restricted to oral dosage forms. On the other hand, controlled-release
`systems are used in a variety of administration routes, including trans-
`dermal, oral and vaginal administration [61].
`Release from oral NTX tablets may be termed as a burst release,
`resulting in fluctuating plasma concentrations during the day (Fig. 2).
`NTX concentration peaks within the first hour of oral dosing followed
`by a fairly rapid decline in plasma levels to below the minimum thera-
`peutic levels (2 ng/ml) within 8 h of dosing [63]. The use of a sustained
`release NTX formulation will result in slow NTX release, avoiding the
`peaks and troughs associated with daily drug administration, while
`maintaining continuous therapeutic plasma levels for an extended
`time frame. This “smoothing out” of drug levels in the blood may de-
`crease the possibility of occurrence of adverse events associated with
`peaks, and improve efficacy by avoiding drug concentration troughs.
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`
`Minimum toxic concentration
`
`Table 3
`Kinetic models used for analysis of drug release data.
`
`Model Name
`
`Model
`
`Overall mean percent error
`
`158
`
`concentration
`
`Drug
`
`Zero order
`First order
`Higuchi
`Hixson–Crowwell
`Power law
`
`Mt = M0 + k0t
`log Ct = log C0 − Kt/2.303
`Mt = KHt1/2
`M01/3 − Mt
`
`1/3 = κ t
`ln F = ln Kp + p ln t
`
`18.28
`16.41
`10.65
`26.63
`7.66
`
`Mt: amount of drug dissolved in time t.
`M0: initial amount of drug in the solution.
`k0: zero-order release constant.
`Ct: concentration of drug dissolved in time t.
`C0: initial concentration of drug.
`K: first order rate constant.
`t: time.
`KH: Higuchi dissolution constant.
`κ: constant incorporating the surface-volume relation.
`F: fraction of drug released at time t.
`p, Kp : parameters of the model.
`
`are given in Table 4. The t50% value obtained for the more hydrophobic
`PEO–MMA copolymer (1:4) suggests a more sustained release com-
`pared to the PEO–MMA copolymer (1:1).
`
`ð6Þ
`
`−1 ¼ m
`tb
`
`1 F
`
`The use of kinetic models helps to elucidate release mechanisms, which
`can in turn be useful to control drug release. The mathematical models
`discussed above can help optimize existing systems and ultimately de-
`sign a polymer-based therapeutic system with the drug released at the
`required rate and concentration.
`
`5. Sustained-release NTX formulations
`
`An alternative NTX maintenance delivery against the problem of
`non-compliance involves injection or surgical insertion of a sustained
`release preparation of NTX, avoiding the gastro-intestinal route. This
`removes the need for daily oral NTX.
`
`5.1. Sub-cutaneous formulations
`
`The concept of sustained release preparations of NTX is not new.
`Beginning in the mid-1970s, a number of depot formulations of NTX
`were developed. While showing promising NTX release patterns,
`and being of ‘likely biodegradable materials’, most had unacceptable
`tissue compatibility. For example, Chiang et al. [67] conducted one of
`the early studies of sustained release NTX in normal, healthy volun-
`teers implanted subcutaneously with naltrexone-copolymer (90% L-
`lactic acid and 10% glycolic acid) beads. Following an initial burst of
`release, this formulation yielded relatively constant plasma levels
`of NTX (0.3–0.5 ng/ml) for up to 1 month. Data indicated that this
`NTX preparation had unacceptable levels of biocompatibility, with
`two of the three human subjects implanted with the naltrexone-
`copolymer (90% L-lactic acid and 10% glycolic acid) beads having
`
`Table 4
`Summary of parameters obtained for NTX release using the reciprocal powered method
`[66].
`
`Nanosystem
`
`PEO–MMA copolymer (1:1)
`PEO–MMA copolymer (1:4)
`
`Na
`
`6
`17
`
`R2
`
`0.895
`0.650
`
`E
`
`3.0
`10.5
`
`m
`
`1.967
`3.559
`
`b
`
`0.603
`0.431
`
`t50% (h)
`
`3.1
`19.0
`
`Controlled release
`Delayed release
`
`Immediate release
`Burst release
`
`Sustained release
`
`Minimum effective concentration
`
`Time/ hours
`
`Fig. 1. Drug release kinetics.
`
`Drug release may be modeled using different models as shown in
`Table 3 [64]. The R2 values are used to check which model best fits the
`release system.
`Polymer based drug delivery systems may be categorized as
`diffusion-controlled, solvent-activated (swelling or osmotically con-
`trolled), chemically controlled or externally-triggered (e.g. pH, tem-
`perature) [65].
`Immediate-release, modified-release, extended-release and delayed-
`release have been defined by the FDA. However, no definitions have
`been provided for targeted or controlled release [61].
`Barzegar-Jalali et al. reported on a general model applicable to
`multi-mechanistic release from nanoparticles (Eq. (6)) [66]. Parameters
`obtained from this model may be used to compare different delivery
`systems of a given drug as well as correlating with bioavailability data.
`Indeed, the release half life, t50% can be used to compare release rates
`of different systems. The values of the different parameters obtained
`for NTX-loaded hydrolyzable crosslinked nanoparticles (using Eq. (6))
`
`Fig. 2. (A) Typical profile of plasma NTX levels over 24 h following a 50 mg oral dose in
`humans. (B) Simulation of the daily fluctuations in plasma levels of NTX over the course
`of a month, assuming the patient adheres to the daily dosing of oral NTX.
`Reprinted with permission from [63].
`
`N: number of data in each set.
`E: percent error.
`F: fraction of drug released in time t.
`m, b: parameters of the model.
`
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`N. Goonoo et al. / Journal of Controlled Release 183 (2014) 154–166
`
`159
`
`them removed at approximately 3 to 4 weeks due to marked inflam-
`matory reactions or other local tissue irritation. Chiang concluded
`that this result “may preclude the clinical use of this particular prep-
`aration of beads” [67].
`
`noncompliance issue associated with oral NTX, and produce good
`treatment outcomes, the requirement that patients return for re-
`treatment every 30 days [74,85] is associated with high attrition
`rates post 60 days (25–36%) and limits clinical efficacy.
`
`5.2. Injectable formulations
`
`6. Sustained-release systems for NTX delivery
`
`Newer formulations of sustained-release NTX have provided
`more promising results. Injectable formulations of NTX, such as
`those produced by Biotek, Inc. (Depotrex®; [68]), Drug Abuse Sci-
`ences (Naltrel®; [69]) and Alkermes, Inc. (Vivitrex®; [70]) appear
`to produce both clinically relevant plasma concentrations of NTX
`(1–2 ng/ml) for approximately 3–6 weeks, with clinically acceptable
`incident level of tissue reactivity. For example, an injectable depot
`formulation of NTX (Depotrex®, 192 mg, 384 mg NTX base) antago-
`nized the effects of intravenously-administered heroin (0–25 mg)
`for 3–5 weeks, depending on NTX dose. This study demonstrated
`that Depotrex® was safe, effective, and well tolerated in opioid
`abusers who were not seeking treatment for their drug use. A subse-
`quent “proof-of-concept” clinical trial of Depotrex® in treatment-
`seeking heroin abusers showed a robust, dose-related increase in
`treatment retention, supporting the effectiveness of NTX in antago-
`nizing the objective and subjective effects of heroin [71].
`
`5.3. Novel implants and depot injections
`
`Recently, extended-release formulations that release NTX for
`1–7 months have become available for clinical use. Such systems
`consist of compressed NTX or NTX/polymer/copolymer administered
`sub-cutaneously or intra-muscularly [72]. Most studies have indicated
`the effectiveness of these systems which have acceptable adverse
`event profiles [50]. A 30 day injectable NTX, Vivitrol® was approved
`by the FDA for treatment of alcohol dependence or opioid dependence
`in 2006 and 2010, respectively. It was shown that patients who received
`400 mg treatment during 28 days had a blood NTX level of 1.23 ng/ml
`[73]. A larger 6-month trial of Vivitrol®: (205 received 380 mg injec-
`tions, 210 received 190 mg injections, 209 received placebo injec-
`tions, plus psychosocial intervention) also reported a reduction of
`25% (p = 0.03) in heavy drinking days in the 380 mg NTX, and 17%
`(p = 0.07) in the 190 mg dose compared to placebo recipients. How-
`ever 36% of patients failed to complete the 6-month course of
`