`
`Sustained-Release Injectable Drug Delivery
`A review on the current status of long-acting injectables, including commercially marketed products.
`This article is part of a special Drug Delivery issue.
`
`Nov 01, 2010
`
`By Yun-Seok Rhee [1], Chun-Woong Park [2], Patrick P. DeLuca [3], Heidi M. Mansour [4]
`
`
`
`Pharmaceutical Technology
`
`Volume 2010 Supplement, Issue 6
`
`This article is part of a special issue [5]on Drug Delivery
`
`Reproducible sustained delivery of a drug at a target
`site is one of the main themes in controlled drug-
`delivery systems. The most commonly used drug-
`delivery systems, which can release drugs longer
`than one week, are parenteral injections and
`implants. Certain implant systems can deliver drugs
`for more than one year, and the longest drug delivery
`can be achieved by biodegradable or
`nonbiodegradable implant systems. Some examples
`of US Food and Drug Administration approved long-
`acting products are listed in Table I.
`
`(GEORGE DIEBOLD, PHOTODISC, GETTY IMAGES)
`
`
`
`ALKERMES Exh. 2051
`Luye v. Alkermes
`IPR2016-1096
`
`
`
`
`Table I: Examples of US Food and Drug Admistration-approved long-acting formulations on the market.*
`
`Long-acting injectable formulations offer many advantages when compared with conventional
`formulations of the same compounds. These advantages include the following: a predictable drug-
`release profile during a defined period of time following each injection; better patient compliance; ease
`of application; improved systemic availability by avoidance of first-pass metabolism; reduced dosing
`frequency (i.e., fewer injections) without compromising the effectiveness of the treatment; decreased
`incidence of side effects; and overall cost reduction of medical care.
`
`This review focuses on the current status and explores long-acting injectables with special
`attention to marketed products. Injectable routes, types of long-acting injectables (i.e., oil-based
`injections, injectable drug suspensions, injectable microspheres, and injectable in situ systems),
`drugs and polymers for depot injections, commercially available depot injections, and future
`injectable sustained-release drug-delivery systems are also discussed.
`
`Types of injectable routes of administration
`
`It is well recognized that the advantages of parenteral injections are immediate systemic drug
`availability and rapid onset of action. Another significant and unique advantage of parenteral
`injection is a long-term drug delivery by the formation of a depot or reservoir at the injection site
`after drug administration. As depicted in Table I, intravenous (IV) injection can be used for
`certain prolonged acting drugs due to the drugs' long half-lives in the body after IV
`
`
`
`administration. The sustained release of drug from these preparations is a result of the long-
`acting property of drug and its residence in the bloodstream or the bone.
`
`In general, there are two routes by which long-acting parenteral injections are most frequently
`administered: intramuscular (IM) and subcutaneous (SC). To determine the injectable route of
`administration for long-term delivery formulations, many factors should be considered such as
`safety profile, ease of administration, patient's limited mobility, area for target injection sites,
`quality of life and cost of therapy (1). In many cases, SC is the preferred route for administering
`a drug by injection because of greater area for target injection sites, use of shorter needles, ease
`of self-administration, less discomfort and inconvenience for patients, and better safety profile
`(1). Various insulin products are given SC, and this route of administration presumably continues
`to represent the primary route of delivery for protein-based drugs. However, the volumes of SC
`injection are usually limited to no more than 1–2 mL, and only nonirritant substances can be
`injected by a SC route because irritants can cause pain, necrosis, and sloughing at the site of
`injection. On the other hand, greater injection volumes (2–5 mL) can be given by the IM route.
`Mild irritants, oils, and suspensions can be injected by IM route in the large skeletal muscles
`(i.e., deltoid, triceps, gluteus maximus, and rectus femoris) because these muscles are less richly
`supplied with sensory nerves and are more vascular. Therefore, a few SC injections for long-term
`release can be found on the market (i.e., Depo-SubQ Provera 104, Pfizer (New York); Nutropin
`Depot, Genentech (South San Francisco, CA), and Eligard, sanofi-aventis (Paris), and many
`long-acting IM injections are available on the market (oil-based injections, injectable drug
`suspensions, and injectable microspheres).
`
`Sustained-release properties of injectables
`
`Sustained-release parenteral injections can be divided into several types: oil-based injectable
`solutions, injectable-drug suspensions, polymer-based microspheres and polymer-based in-situ
`formings. Oil-based injectable solutions and injectable drug suspensions control the release for
`weeks while polymer-based microspheres and in-situ gels are claimed to last for months (1, 7).
`
`Oil-based injectable solutions and injectable drug suspensions. Conventional long-acting
`injections consist either of lipophilic drugs in aqueous solvents as suspensions or of lipophilic
`drugs dissolved in vegetable oils. The administration need for these long-acting formulations
`only takes place every few weeks or so. In the suspension formulations, the rate-limiting step of
`drug absorption is the dissolution of drug particles in the formulation or in the tissue fluid
`surrounding the drug formulation. Poorly water-soluble salt formations can be used to control the
`dissolution rate of drug particles to prolong the absorption, and olanzapine pamoate is an
`example of a poorly water-soluble salt form of olanzapine. Certain drugs for long-acting
`formulations are synthesized by esterification of the parent drug to a long-chain fatty acid. Based
`on its extremely low water solubility, a fatty acid ester of a drug dissolves slowly at the injection
`site after IM injection and is hydrolyzed to the parent drug. Once the ester is hydrolyzed
`intramuscularly, the parent drug becomes available in the systemic circulation. The release rate
`of paliperidone palmitate from long-acting injectable suspension is governed by this mechanism.
`In many formulations, a fatty acid ester of a drug is used to prepare an oil-based parenteral
`solution, and the drug-release rate from solution is controlled by the drug partitioning between
`the oil vehicle and the tissue fluid and by the drug bioconversion rate from drug esters to the
`
`
`
`parent drug. However, several other factors such as injection site, injection volume, the extent of
`spreading of the depot at the injection site, and the absorption and distribution of the oil vehicle
`per se might affect the overall pharmacokinetic profile of the drug. Decanoic acid esters of
`antipsychotic drugs are widely used for these oil-based IM injections.
`
`Polymer-based microspheres and in-situ formings. The development of polymer-based long-
`acting injectables is one of the most suitable strategies for macromolecules such as peptide and
`protein drugs. Advantages of polymer-based formulations for macromolecules include: in vitro
`and in vivo stabilization of macromolecules, improvement of systemic availability, extension of
`biological half life, enhancement of patient convenience and compliance, and reduction of dosing
`frequency.
`
`Among the various approaches to deliver macromolecules parenterally, biodegradable
`microsphere systems are the most commercially successful. The most crucial factor in the design
`of injectable microspheres is the choice of an appropriate biodegradable polymer. The release of
`the drug molecule from biodegradable microspheres is controlled by diffusion through the
`polymer matrix and polymer degradation. The nature of the polymer, such as composition of
`copolymer ratios, polymer crystallinities, glass-transition temperature, and hydrophilicities plays
`a critical role in the release process. Although the microspheres structure, intrinsic polymer
`properties, core solubility, polymer hydrophilicity, and polymer molecular weight influence the
`drug-release kinetics, the possible mechanisms of drug release from microsphere are as follows:
`initial release from the surface, release through the pores, diffusion through the intact polymer
`barrier, diffusion through a water-swollen barrier, polymer erosion, and bulk degradation. All
`these mechanisms together play a part in the release process (2).
`
`Another intensively studied polymeric injectable depot system is an in-situ-forming implant
`system. In situ-forming implant systems are made of biodegradable products, which can be
`injected via a syringe into the body, and once injected, congeal to form a solid biodegradable
`implant. This article will briefly summarize the types of in situ-forming implants because the
`topic has been intensively reviewed elsewhere (3–5). Biodegradable injectable in situ-forming
`implants are classified into five categories based on the mechanism of depot formation:
`thermoplastic pastes, in situ cross-linked polymer systems, in situ polymer precipitation,
`thermally induced gelling systems, and in situ solidifying organogels. The mechanism of depot
`formation of thermoplastic pastes is to form a semisolid upon cooling to body temperature after
`injection into the body in the molten form. Cross-linked polymer networks can be achieved in
`situ in various ways, forming solid polymer systems or gels. Methods for in situ cross-linked
`systems include free radical reactions, usually initiated by heat or absorption of photons, or ionic
`interactions between small cations and polymer anions. In situ formings can be produced by
`causing polymer precipitation from solution. A water-insoluble and biodegradable polymer are
`solubilized in a biocompatible organic solvent to which a drug is added which forms a solution
`or suspension after mixing. When this formulation is injected into the body, the water-miscible
`organic solvent dissipates and water penetrates into the organic phase. This leads to phase
`separation and precipitation of the polymer forming a depot at the site of injection. This method
`has been designed as Atrigel technology (QLT, Vancouver, Canada), which used as a drug-
`carrier system for Eligard. Thermally induced gelling systems show thermo-reversible sol/gel
`transitions and are characterized by a lower critical solution temperature. They are liquid at room
`
`
`
`temperature and produce a gel at and above the lower critical solution temperature. In situ
`solidifying organogels are composed of water-insoluble amphiphilic lipids, which swell in water
`and form various types of lyotropic liquid crystals.
`
`Drugs delivered as sustained-release injectables
`
`Various drugs are investigated for sustained-release injectable delivery systems for controlled
`drug delivery as recently described by these authors (6). These systems include small molecular
`drugs and protein/peptide drugs. Examples of drugs for sustained-release injectable delivery
`systems include: hormone therapy (i.e., human somatropin) (7, 8); protein therapeutics such as
`the analog of glucagon-like peptide-1 (9); recombinant human bone morphogenetic protein-2
`(10); superoxide dismutase (11); salmon calcitonin (12, 13); insulin (14–16); gene delivery such
`as plasmid DNA (17–19); cancer therapeutic agents such as bleomycin (20), paclitaxel (21),
`cisplatin (22), a peptide-like antineoplastic agent (23); postoperative pain therapeutic agents such
`as ketorolac tromethamine (24); schizophrenia drugs such as aripiprazole (25), olanzapine (26);
`contraceptive peptide vaccine (27); drugs to treat alcohol dependence such as naltrexone (28);
`and immunosuppressive drugs such as rapamycin (29).
`
`Despite a number of parenteral depot studies using a variety of drugs, only drugs in limited
`therapeutic areas are available on the market. Antipsychotic drugs and hormones have been used
`for more than five decades in the field of schizophrenia and hormone replacement therapy. Since
`the first launching of microsphere formulation, Lupron Depot (Abbott, Abbott Park, IL) for the
`palliative treatment of advanced prostate cancer in 1989, several microsphere formulations and
`in situ-forming implants have been released on the US market. The therapeutic indications and
`drugs of commercialized products include: the palliative treatment of advanced prostate cancer
`(leuprolide acetate and triptorelin pamoate); the treatment of acromegaly (octreotide acetate and
`lanreotide acetate); the long-term treatment of growth failure (somatropin-rDNA origin); the
`treatment of schizophrenia (risperidone); and the treatment of alcohol dependence (naltrexone).
`
`Polymers in injectable sustained release
`
`As recently described by these authors (6), a variety of biodegradable polymers for controlled
`drug delivery intensively studied over the past several decades include polylactides (PLA),
`polyglycolides (PGA), poly(lactide-co-glycolide) (PLGA), poly(ε-caprolactone) (PCL),
`polyglyconate, polyanhydrides, polyorthoesters, poly(dioxanone), and polyalkylcyanoacrylates.
`Among the various approaches to deliver macromolecules parenterally, injectable biodegradable
`microspheres are the most successful systems (30). Many microsphere research reports have
`demonstrated the usefulness of biodegradable polymers such as PLGA microspheres (31–38),
`PCL microspheres (39), polyanhydride microspheres (40), polyorthoesters microspheres (41),
`and polyalkylcyanoacrylate microspheres (42, 43).
`
`The Atrigel technology that is used in Eligard containing leuprolide acetate and PLGA is a once-
`monthly in situ-forming implant for the palliative treatment of advanced prostate cancer. Many
`reports have been published on novel biodegradable in situ-forming polymers such as multiblock
`poly(ether ester urethane)s consisting of poly-[(R)-3-hydroxybutyrate] (PHB), poly(ethylene
`glycol) (PEG), and poly(propylene glycol) (PPG) polymer (44), PEG-grafted chitosan polymer
`
`
`
`(Chitosan–PEG) (45), methoxy poly(ethylene glycol)–poly(sebacic acid–D,L–lactic acid)–
`methoxy poly(ethylene glycol) triblock copolymer (mPEG–poly(SA–LA)–mPEG) (46), PCL–
`PEG–PCL triblock copolymer (47), and PLGA–PEG–PLGA triblock copolymer (48).
`
`Commercialized polymer-based injectable depot systems have used polymers or copolymers
`composed of monomers of lactic and glycolic acid. These polymers have the advantages of being
`semipermeable, biocompatible, and biodegradable, which makes them universally acceptable as
`injectable materials for drug-depot systems (49).
`
`Commercially available injectable sustained-release drugs
`
`
`
`
`Table II. Commercially available injectable sustained-release drug-delivery systems.
`
`
`
`The list of commercially available injectable sustained-release drug delivery systems available on the
`market as pharmaceutical products is shown in Table II. Parenteral long-acting formulations (oil-based
`solutions and drug suspensions) have been in clinical use for many decades in the field of hormone
`replacement therapy. Sesame oil-based injection containing testosterone enanthate (i.e, Delatestryl,
`Endo Pharmaceuticals, Chadds Ford, PA) and castor oil-based injection containing estradiol valerate
`(Delestrogen, Monarch Pharmaceuticals, Bristol, TN) were approved by the US Food and Drug
`Administration in the 1950s, and drug suspension for injection containing medroxyprogesterone acetate
`(Depo-Provera, Pfizer) was approved by FDA in September 1960. The administration route of these
`products is IM injection, and all of these products are still available on the market. In 2004, long-acting
`SC injection of medroxyprogesterone acetate (Depo-SubQ Provera 104, Pfizer), which is equally effective
`despite an almost 30% reduction in the dose, was approved by FDA. The first long-acting injectable
`microspheres of recombinant growth hormone (Nutropin Depot, Genentech) received approval from
`FDA for pediatric growth hormone deficiency (GHD) in December 1999. Nutropin Depot is designed to
`be administered by SC injection once or twice monthly.
`
`In the 1960s, parenteral depot formulations of typical antipsychotic drugs were introduced for
`clinical use in Europe (50). Although long-acting typical antipsychotic formulations are widely
`used in Europe, clinicians in the United States have thus far been reluctant to use them despite
`their potential advantages because of several reasons such as concerns about increased adverse
`effects compared with oral therapy and the belief that patients do not accept or tolerate depot
`formulations as well as oral agents (51). Therefore, many oil-based depot formulations
`containing typical antipsychotic drugs (haloperidol decanoate, flupenthixol decanoate,
`fluphenazine decanoate, zuclopenthixol decanoate, and pipothiazine palmitate) are available on
`the market in Europe, Canada and Australia, but only haloperidol decanoate (Haldol Decanoate)
`and fluphenazine decanoate (Fluphenazine Decanoate injection) formulations are available in the
`US. In 2003, the long-acting formulation of risperidone (Rispedal Consta, Janssen, division of
`Ortho-McNeill Janssen Pharmaceutical, Titusville, NJ) became the first depot atypical
`antipsychotic drug to become available in the US (51). Rispedal Consta is formulated as an
`aqueous suspension of biodegradable microspheres. Water is added to the vial of microspheres,
`and the aqueous suspension is injected intramuscularly every 2 weeks (52). FDA approved
`paliperidone palmitate long-acting injectable suspension (Invega Sustenna, Janssen) for the acute
`and maintenance treatment of schizophrenia in July 2009 (53–56). Paliperidone palmitate, an
`atypical antipsychotic agent, is the palmitate ester of paliperidone and is the major active
`metabolite of risperidone (9-hydroxy-risperidone) (53). Paliperidone palmitate was formulated as
`an aqueous drug suspension with a specific particle-size distribution that has sustained-release
`properties and thus facilitates monthly dosing (53). In 2009, a long-acting depot formulation of
`olanzapine pamoate (Zyprexa Relprevv, Eli Lilly, Indianapolis, IN) was approved by FDA for
`the US market (57–59). Zyprexa Relprevv is an aqueous drug suspension containing a salt of
`pamoic acid and olanzapine (olanzapine pamoate monohydrate) for deep IM gluteal injection
`(60).
`
`Lupron Depot (leuprolide acetate) is the first marketed injectable PLGA microspheres in the US
`(approved in 1989) (61). Lupron Depot provides fairly constant release of the peptide during 1
`month or 3 months in humans after IM injection and show sufficiently reliable efficacy for the
`treatment of patients with hormone-dependent cancers such as advanced prostate cancer (61).
`
`
`
`Encouraged by success of Lupron depot, several PLGA microsphere formulations have been
`investigated, and Trelstar (triptorelin pamoate, Watson Pharmaceuticals, Corona, CA) received
`approval from FDA for the palliative treatment of advanced prostate cancer in June 2001.
`Trelstar is designed to be administered by a single IM injection in either the buttocks, and the
`dosing schedule (one-, three- or six-month) depends on the product strength selected. In January
`2002, the first parenteral in situ-forming formulation, Eligard was approved by FDA for the US
`market. Eligard uses the Atrigel technology, and Atrigel is a polymeric (nongelatin-containing)
`delivery system consisting of a biodegradable PLGA polymer formulation dissolved in a
`biocompatible solvent, N-methyl-2-pyrrolidone (NMP). Eligard is administered subcutaneously,
`where it forms a solid drug-delivery depot and is designed to deliver leuprolide acetate at a
`controlled rate during a one-, three-, four- or six-month therapeutic period.
`
`In April 2006, FDA approved naltrexone extended-release injectable suspension (Vivitrol,
`Alkermes, Waltham, MA) for the treatment of alcohol dependence. Vivitrol is supplied
`commercially as a microsphere formulation of naltrexone for suspension, to be administered by
`intramuscular injection every four weeks.
`
`Sandostatin LAR Depot (Novartis, Basel, Switzerland) received approval from FDA in
`November 1998 for the treatment of acromegaly, a chronically disfiguring and debilitating
`hormonal disorder. Sandostatin LAR Depot is a sterile PLGA microspheres formulation of
`octreotide acetate for IM injection at every four weeks. Although it is not available in the US, a
`prolonged release PLGA microsphere formulation of lanreotide acetate for injectable suspension
`(Somatuline LA, Ispen Pharmaceuticals, Kleve, Germany) is available as a commercially
`available pharmaceutical product on the market in Europe. The indication of Somatuline LA is
`the same as that of Sandostatin LAR Depot, and Somatuline LA is designed to be administered
`by IM injection every two weeks.
`
`FDA approved Somatuline Depot for the long-term treatment of acromegaly in August 2007.
`Somatuline Depot formulation consists of a unique supersaturated concentration of lanreotide
`acetate (24.6% w/w lanreotide base), and contains only water for injection as an excipient (62). It
`is thought to form a precipitated drug depot at the injection site due to the interaction of the
`formulation with physiological fluids because Somatuline Depot can produce a stable gel when
`mixed with water at a specific temperature and pressure. The most likely mechanism of drug
`release is a passive diffusion of the precipitated drug from the depot toward the surrounding
`tissues, followed by the absorption to the bloodstream for a month. The administration route of
`Somatuline Depot is deep SC injection.
`
`Injectable sustained-release drug-delivery systems in clinical trials
`
`
`
`
`Table III. Examples of injectable sustained-release drug delivery systems in clinical trials.
`
`Several clinical trials of injectable sustained-release drug delivery systems are currently conducted in the
`US. Some examples of injectable sustained-release drug delivery systems currently in clinical trials are
`listed in Table III.
`
`Phase I pharmacokinetic-pharmacodynamic studies are ongoing for microsphere formulation of
`progesterone to establish the minimum effective dose of progesterone microspheres suspension,
`for weekly intramuscular injection. Phase III clinical studies of aripiprazole for once monthly IM
`depot administration are ongoing to evaluate efficacy, safety, and tolerability. Phase I trials are in
`progress with once-monthly IM injection of octreotide pamoate to investigate safety and
`tolerability of an octreotide extended long-acting formulation after a single dose in humans.
`Phase III studies of pasireotide long-acting release formulation are underway to evaluate the
`efficacy and safety of pasireotide LAR.
`
`SABER is a potential parenteral in situ-forming system, and this system consists of sucrose
`acetate isobutyrate (SAIB), a pharmaceutically acceptable solvent, and one or more additives.
`One characteristic of the system is that a SAIB/solvent mixture has a low viscosity, but upon
`injection, the viscosity increases substantially as the solvent diffuses away from the SAIB (63).
`After dissolving or dispersing the drug in the SAIB/solvent solution, this solution is injected
`subcutaneously or intramuscularly. Upon injection, the solvent dissipates from the SAIB, and the
`increased viscosity controls the release of the drug from the gel. SABER-bupivacaine is designed
`to continuously deliver bupivacaine, a common local anesthetic, up to 72 hours to treat local
`post-surgical pain. This system injected at the surgical site prior to the wound closure and is
`currently in Phase III clinical studies in the US.
`
`ReGel (BTG, London) is a thermally reversible gelling system and is based on biodegradable
`triblock copolymer composed of PLGA–PEG–PLGA. Immediately upon injection and in
`response to body temperature, an insoluble gel depot is formed. OncoGel (BTG) is supplied as a
`frozen formulation of paclitaxel in ReGel and is entering Phase II trials. OncoGel is being
`injected directly into the tumor for oesophageal tumors, and the gel disappears in four to six
`weeks as it releases the paclitaxel.
`
`
`
`Conclusion
`
`As evident by the growing number of sustained-release injectable pharmaceutical products on the
`market, injectable depot systems are becoming one of the most effective systems for long-term
`drug delivery. Owing to the enhanced quality of life and cost of therapy supported by the
`advances in drug formulation and polymer science, more sophisticated injectable depot systems
`will be developed and commercialized in the near future. Moreover, the introduction of more
`potent drugs and protein/peptide drugs are particularly good candidates for formulation as long-
`acting parenteral depot systems. Polymer-based injectable depot systems for protein/peptide
`drugs have many advantages such as protection of sensitive proteins from degradation,
`prolonged or modified release, pulsatile release patterns, and enhancement of patient compliance.
`These important and unique advantages offer potential commercial success of future sustained-
`release injectable pharmaceutical products that have novel active pharmaceutical ingredients,
`including therapeutic proteins and peptides.
`
`Yun-Seok Rhee is research associate professor at Sungkyunkwan University, School of
`Pharmacy, Suwon, Gyeonggi-do, Republic of Korea. Chun-Woong Park is a postdoctoral
`fellow and visiting scholar, Patrick P. DeLuca is an emeritus professor, and Heidi M.
`Mansour* is an assistant professor of pharmaceutics and pharmaceutical technology, all at the
`University of Kentucky College of Pharmacy, Department of Pharmaceutical Sciences–Drug
`Development Division, 789 S. Limestone St., Lexington, KY 40536-0596, tel. 859.257.1571,
`heidi.mansour@uky.edu [6]
`. Heidi M. Mansour is also a member of Pharmaceutical Technology’s edtorial advisory board.
`
`*To whom all correspondence should be addressed.
`
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