Drug Deliv. and Transl. Res. DOI 10.1007/s13346-016-0305-z

REVIEW ARTICLE

Controlled release drug delivery systems to improve post-operative pharmacotherapy Prabhat Bhusal 1 & Jeff Harrison 1 & Manisha Sharma 1 & David S. Jones 2 & Andrew G. Hill 3 & Darren Svirskis 1

# Controlled Release Society 2016

Abstract Over 230 million surgical procedures are conducted worldwide each year with numbers increasing. Pain, undesirable inflammation and infection are common complications experienced by patients following surgery. Opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), local anaesthetics (LAs) and antibiotics are the commonly administered drugs peri-operatively to manage these complications. Postoperative pharmacotherapy is typically achieved using immediate-release dosage forms of drugs, which lead to issues around fluctuating plasma concentrations, systemic adverse effects and poor patient adherence. Controlled release (CR) systems for certain medicines including opioids, NSAIDs and antibiotics have demonstrably enhanced treatment efficacy in the post-surgical setting. However, challenges remain to ensure patient safety while achieving individual therapeutic needs. Newer CR systems in the research and development pipeline have a high level of control over medicine release, which can be initiated, tuned or stopped on-demand. Future systems will self-regulate drug release in response to biological markers providing precise individualized therapy. In this review, we cover currently adopted CR systems in postoperative pharmacotherapy, including drug eluting medical devices, and highlight a series of examples of novel CR tech-

* Darren Svirskis [email protected] 1

School of Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand

2

School of Pharmacy, Medical and Biological Centre, Queen’s University Belfast, Belfast, UK

3

Department of Surgery, South Auckland Clinical Campus, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 93311, Otahuhu, Auckland 1640, New Zealand

nologies that have the potential for translation into postsurgical settings to improve medication efficacy and enhance post-surgical recovery. Keywords Surgery . Post-operative management . Pharmacotherapy . Controlled release systems . Surgical recovery

Introduction Each year, more than 230 million surgical procedures are conducted worldwide, and this number is expected to increase in the future [1]. With operative mortality significantly decreasing over the last 50 years [2], the emphasis on peri-operative care has increasingly focused on decreasing surgical stress and the prevention and management of post-operative complications. Pain, undesirable inflammation and infection are common complications experienced by patients after surgery. These complications are managed with pharmacotherapy to varying degrees of success. The predominant approaches to achieve post-operative pharmacotherapy rely on immediaterelease dosage forms, which rapidly release their active payload following administration to the patient. This typically results in fluctuating levels of drugs risking toxicity during times of peak plasma concentrations and treatment failure during troughs. In addition, frequent administration is required resulting in poor adherence, which may have serious consequences [3]. Controlled release (CR) drug delivery systems rely on a combination of technologies to safely deliver doses of medicine to required locations over desirable periods of time. Various dosage forms of medicines including extended release (ER), sustained release (SR), delayed release (DR) and targeted release (TR) can be collectively termed CR delivery

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systems. SR and ER typically describe drug release over a prolonged period of time, whereas for DR systems, drug release does not start immediately following administration, but at a later preprogrammed time. TR describes systems which intentionally aim to achieve drug accumulation in specific locations such as an organ, tumour or even specific cell types [4]. This exciting research field has demonstrated positive outcomes for patients with increasing numbers of regulatory approvals and CR formulations being commercialized. CR drug delivery systems have benefited health care systems globally by improving pharmacotherapy and enhancing medication efficacy. Certain CR dosage forms of medicines are widely used in post-surgical settings including oral CR opioid tablets and capsules. They have obvious benefits by providing up to 24 h of continuous analgesic cover by releasing their payload slowly [5]. The ability of CR dosage forms to maintain drug levels within the therapeutic range for a prolonged period of time improves treatment efficacy and reduces adverse effects [5]. However, these oral CR systems release drug at an inflexible rate following administration and result in systemic exposure to the drug with associated side effects. The ideal CR system delivers drug to its site of action, at the required dose for the required period of time. CR delivery systems are not new; this has been a highly active research area since the 1970s with established translation pathways from the bench to the bedside [6]. Current research into ‘smart’ CR systems investigates the ability to increase or decrease drug release in situ in response to an external trigger or using a biological marker forming a closed-loop and self-regulating drug delivery system [7]. Application of these smart CR systems in post-surgical settings will have the advantage of tuning drug delivery in direct response to an individual’s changing needs. The aim of this review is to provide an overview of currently adopted CR systems in postsurgical settings and highlight some examples of novel CR technologies that have the potential to translate to improve post-operative pharmacotherapy in the future.

Post-operative complications and pharmacotherapy Surgeries typically have positive outcomes; however, unwanted post-surgical complications place a significant burden on patients and health care professionals while delaying recovery and hospital discharge. The controlled delivery of pharmacotherapy can improve the management of post-operative pain, inflammation and infection, promoting faster post-operative recovery. CR dosage forms of medicine have the ability to maintain drug levels within the therapeutic range for a prolonged period of time and thus improve treatment efficacy and reduce adverse effects [5]. Specifically, in post-operative pharmacotherapy, opioids, local anaesthetics (LAs), potent non-steroidal anti-inflammatory drugs (NSAIDs),

corticosteroids and antibiotics can and do benefit following formulation into CR dosage forms. A range of controlled delivery systems have been adopted and translated in post-surgical settings ranging from simple matrix systems and drug reservoirs with rate-controlling membranes to those relying on nanotechnology. Oral, transdermal and injectable dosage forms are often used to administer these CR systems to prolong the delivery of drugs for one or a few days. In addition to dedicated drug delivery systems, medical devices also have been used, which are augmented with CR drug delivery functionality; examples of this include surgical sutures [8, 9], wound dressing [10, 11], hernia repair mesh [12, 13], central lines and catheters [14, 15], bone cements [16] and orthopaedic implants [17]. Common post-operative complications are now discussed alongside current options for pharmacotherapy including CR systems. Pain Fifty to 70 % of patients experience moderate to severe pain following surgery, typically persisting for several days [18]. Opioids, non-steroidal anti-inflammatory drugs (NSAIDs) and local anaesthetics (LAs) are the common drugs used to manage pain post-operatively. Opioids are highly effective; however, their short elimination half-lives [19] mean that conventional dosage forms require regular administration to achieve prolonged pain relief resulting in fluctuations in plasma concentrations. Opioids are associated with systemic adverse effects, such as drowsiness, respiratory depression and gastrointestinal and bladder dysfunction, which, in addition to their potential for misuse and addiction, have led to alternate treatment options being actively sought [20]. NSAIDs are effective analgesics widely used on their own or in combination with other analgesics [21]. However, irritation to local tissues and gastric mucosa following both local and systemic administration of NSAIDs [22] is of concern alongside their effects on the renal system. LAs are widely used as nerveblocking agents to prevent the transmission of pain signals from disturbed tissue, but their short half-lives limit the period of effect. LAs are commonly administered by injection or infiltration at the surgical site to provide temporary analgesia. To prolong analgesic effects, elastomeric pumps have been used, but infection risks due to prolonged catheter placement and the potential to dislodge the catheter require frequent monitoring by trained staff, typically in an in-patient setting, which increases the total health care cost [23]. In addition, large bolus doses of LAs can be administered to local tissues to prolong analgesia; however, there are risks of systemic toxicity and local ischemia with this approach [24]. CR systems for post-operative pain are primarily formulated either to increase the duration of effect or to decrease adverse effects. Oral CR tablets and capsules containing opioids, and NSAIDs, are well known and frequently prescribed post-

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operatively. The first commercially available CR delivery system for opioid was MSContin® [19]. It is a tablet comprising a polymeric mix where morphine sulphate is blended in both hydrophilic (hydroxypropyl methylcellulose) and hydrophobic polymer (hydroxyl ethyl cellulose). The hydrophilic component allows rapid release of morphine sulphate, whereas the hydrophobic component achieves sustained release. Similarly, other examples of CR formulations for opioids that are commercially available include Oramorph® SR (morphine sulphate extended-release tablets), Avinza® (morphine sulphate extended-release capsules) and Kadian® (morphine sulphate extended-release capsules). Oramorph® SR is an extendedrelease tablet, where morphine sulphate is blended in hydroxyl propyl methyl cellulose (HPMC). This hydrophilic polymer forms like gel-like structure in the aqueous environment after ingestion, which retains its structure for some time to slow the release rate of morphine sulphate from the tablet [19]. Avinza® consists a mixture of immediate-release and extended-release components filled into a hard gelatin capsules. The immediate-release component consists of sugar/starch spheres that enable rapid release of morphine, whereas the extendedrelease component is the same sugar/starch spheres coated with an ammonium methacrylate copolymer. The penetration of fluids is slowed due to coating and is mediated by local pH modifier (fumaric acid), which achieves sustained release of morphine sulphate [19]. Kadian® is also an extended-release capsule consisting entirely of a polymeric blend of waterinsoluble ethyl cellulose and water-soluble polyethylene glycol and methacrylic acid copolymer [19]. The efficacy of these CR systems has been demonstrated in terms of maintaining plasma drug levels, reducing dosing frequency and improving treatment adherence [5]. However, oral CR systems containing opioids are less flexible when dosing adjustments are required compared to fast-acting dosage forms; safe and effective regimes are difficult to achieve with CR forms alone when pain levels are changing. In addition, there are concerns around incorrect use leading to toxicity; if the dosage form is broken, chewed or crushed, the full dose may be rapidly absorbed rather than absorbed slowly over an extended time resulting in concentrations in the body, reaching toxic levels. NSAIDs are formulated in oral CR systems not only for the sustained release achieved, but enteric-coated formulations are designed to reduce the cumulative exposure of NSAIDs on the upper GI tract epithelium. But, it is important to note that enteric-coated systems, which do not release drug into the stomach, are only partially successful in reducing NSAIDrelated GI complications due to the distal portion of the intestine being exposed to drug as it released locally and the entire GI tract being exposed to NSAIDs following systemic distribution [25]. An indomethacin-containing oral CR system (Osmosin®) based on osmotic platform was commercialized. But, it was withdrawn from the market after reports of

intestinal ulceration in elderly patients, possibly due to high local concentrations of indomethacin following lodging of the tablet into intestinal diverticula [26]. While the oral route is frequently preferred for both patients and health care professionals, it is not always a practical option in patients unable to swallow or where gastrointestinal function is compromised. Transdermal delivery systems (TDDS) for opioids such as Durogesic® (fentanyl matrix or reservoir systems) and Butrans® (buprenorphine matrix systems) can be beneficial to provide baseline cover for opioids. However, a prolonged lag time following the positioning of the TDDS on the skin can be an issue during their postoperative use. Lag time and absorption rates may differ according to the site of application and during activities of daily living as the rate of blood flow changes across various body parts [27], leading to interpatient and intrapatient variability. Meanwhile, removal of a patch in the event of side effects does not result in rapid resolution of the side effects as drug partitioned into the skin continues to be distributed systemically for some time. A patient-controlled transdermal delivery system (PCTDDS) has been designed to overcome the problem of conventional TDDS of opioids. IONSYS® (fentanyl HCl PCTDDS) is a FDA-approved TDDS, which can be applied to the upper arm or chest [28]. Electric current, triggered by the patient, is used to charge the drug molecule and drive it through the skin by iontophoresis [27]. Administering pain relief parenterally allows treatment to reach the site of action rapidly. While the invasive nature of parenteral administration is of concern, the development of injectables with CR properties can reduce the required frequency of administration and, therefore, the total number of injections. Parenteral CR systems such as microspheres and liposomes have been explored to prolong post-operative analgesia [29]. These micro- and nano-carriers can solubilize a wide range of drugs allowing them to be injected and achieving prolonged analgesic effects. A range of analgesics and anaesthetics, such as morphine, oroxymorphone, bupivacaine, lidocaine and ibuprofen, have been developed into liposomal formulations to alleviate post-operative pain. DepoDur® is an injectable liposomal formulation containing morphine sulphate, which was approved by the Food and Drug Administration (FDA) for epidural use in 2004 [30]. This formulation is based on the proprietary extended-release platform technology, DepoFoam®, that comprises multivesicular lipid particles having nonconcentric aqueous chambers to encapsulate morphine sulphate to render sustained release of drugs [31]. DepoDur® was developed with the aim to provide post-operative analgesia for up to 48 h [32] with efficacy demonstrated in a wide range of surgeries such as hip replacement surgery [33], lower abdominal surgery [34] and elective caesarean section delivery [35]. EXPAREL® is another liposomal formulation containing bupivacaine based on same DepoFoam® platform [36] and was approved by the FDA in

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October 2011. A bolus injection of EXPAREL® (266 mg of bupivacaine) is reported to provide analgesia up to 72 h following knee replacement surgery [37]. However, the benefits of EXPAREL® are unclear. Bagsby et al. conducted a retrospective cohort study to compare the efficacy of EXPAREL® against traditional peri-articular injections to control pain following total knee replacement surgery [38]. Inferior pain control with EXPAREL® was reported, and it is considerably more expensive than traditional injections. Injectable CR systems for pain relief must address concerns over local toxicity caused by the drug or CR system. McAlvin et al. reported inflammation with nerve and tissue injury following the injection of lidocaine- and bupivacaine-loaded microspheres into rats for sciatic nerve blockade [39]. In addition to local toxicity, there are safety concerns following inevitable systemic distribution. Recovery of these injectable CR systems is extremely difficult and practically often impossible. This inability for recovery is of concern in the event of toxicity or adverse drug reaction. In a randomized controlled trial, following DepoDur ® administration to manage postoperative pain after caesarean surgery, around 12.5 % of patients required an opioid antagonist due to the adverse effects caused by systemic distribution of opioids [40]. Combinations of drug and medical device such as surgical sutures [41, 42], wound dressings [10] and hernia repair mesh [43] have been investigated to provide sustained pain relief. Developing surgical sutures as CR systems is challenging as mechanical strength must be retained following drug incorporation. In a recent study, a sheet of biodegradable polymeric film comprising poly(lactic-co-glycolic acid) (PLGA) and ibuprofen was separately prepared and then later braided around commercially available VICRYL W9114® sutures (Fig. 1a) [41]. A burst of 75 to 85 % release was observed over the first day followed by sustained release over a further 6 days (Fig. 1b). Near-zero-order release of bupivacaine and mepivacaine over a period of 7 days was achieved from a

After surgery, there are alterations in the neuroendocrine, metabolic and immune systems that stimulate the systematic release of inflammatory modulators including cortisol, catecholamines, acute phase reactants and cytokines [44]. An appropriate balance is essential between pro-inflammatory and antiinflammatory modulators to promote wound healing and tissue repair. Exaggerated pro-inflammatory or antiinflammatory responses can prolong surgical recovery and if extreme can be fatal [45]. NSAIDs, LAs and corticosteroids are all effective to downregulate inflammation [46]. CR formulations to deliver NSAIDs and LAs are used for a combination of analgesic and anti-inflammatory effects and have been discussed in the BPain^ section. Corticosteroids are highly effective medicines to reduce inflammation and are used following ophthalmic, oral and dental surgery. Systemic administration of corticosteroids requires high doses to achieve the required concentrations at the intended site of action. This is exaggerated when the intended site of action has poor blood supply, such as ophthalmic tissues and bone. Exposure of systemic tissues to steroids results in well-recognized adverse events including delayed wound healing, metabolic disturbances, hypertension and osteoporosis. CR systems are used to deliver corticosteroids locally and over a prolonged period following surgery to tissues with a limited blood supply. Surodex ® is a dexamethasonecontaining biodegradable implant developed to control post-

Fig. 1 Schematic diagram showing preparation of drug-loaded sutures. a An ibuprofen-loaded polymeric sheet is separately prepared and physically braided around the suture. Suture coated with single-layered sheet of PLGA loaded with 10 % w/w ibuprofen (PLGA_IB_S) and suture coated

with multi-layered sheets of PLGA loaded with 15 % w/w ibuprofen and sandwiched between the sheets of PLGA (M-PLGA_IB_S). b In vitro drug release from PLGA_IB_S and M_PLGA_IB_S sutures. Reprinted with permission from Elsevier [41]

wound dressing prepared from silicon oxide (xerogel) microparticles embedded in co-polymer matrices [10]. However, with all these CR systems, drug release occurs at a predetermined rate, which cannot match the changing analgesic needs of individual patients. Future CR systems for postoperative pain should be engineered in such a way that release rates can be tuned according to an individual patient’s needs. Inflammation

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operative inflammation following cataract surgery [47]. It contains 60 μg of dexamethasone incorporated into a poly(lactic-glycolic)-acid (PLGA) matrix, which controls the release of dexamethasone over 7 days, achieving higher intraocular drug levels than with conventional dexamethasone drops [47]. Ozurdex®, Retiser and Iluvien® are all ocular implants which release corticosteroids over 6, 30 and 36 months, respectively, and are indicated for use in macular oedema and uveitis [7]. Ozurdex® is based on NOVADUR® CR platform, where dexamethasone is combined with the biodegradable PLGA to form a small rod-shaped implant. The implant slowly degrades following administration allowing for CR of dexamethasone as it diffuses through the polymer and as the polymer erodes [48]. Meanwhile, Retisert® and Iluvien® are fluocinolone acetonide (FA)-containing non-biodegradable implants, based on silicone elastomers and polyimide/ polyvinyl alcohol, respectively, which will allow the slow release of FA through diffusion. These CR systems deliver anti-inflammatory compounds locally to tissues hard to access from the blood supply while minimizing systemic exposure, therefore reducing systemic adverse events. There is potential for similar approaches to be used to module undesirable inflammation following joint and bone surgeries where blood supplies are poor or compromised.

Infection There is an increased risk of infection during and following surgery as the body’s natural defences are compromised. Approximately, 2 % of surgical patients are affected by surgical site infections (SSIs), although incidence rates vary by surgery type [49]. The overall cost of SSI treatment in the USA is estimated at $US10 billion annually [50]. Development of anti-microbial-resistant microbes is a serious concern as they significantly increase both mortality and morbidity. Infections caused by anti-microbial-resistant strains are often very difficult to treat, which ultimately increases the length of hospital stay and treatment costs [51]. Peri-operatively, frequent administration of high doses of antibiotics given orally and/or parenterally is required to achieve and maintain minimum inhibitory concentrations (MICs) in the target tissues. However, certain target tissues, such as within joints, have a poor blood supply with high systemic concentrations required to achieve the MIC at the target site. For some avascular sites such as bone, it is virtually impossible to achieve anti-infective treatment success through systemic drug delivery. Antibiotic concentrations below the MIC can result in the development of antibiotic-resistant strains [52]. Meanwhile, antibiotics such as aminoglycosides have narrow therapeutic indices (NTI) with conventional delivery methods associated with the risk of systemic toxicity including nephrotoxicity and ototoxicity [52].

CR systems can be used to achieve and maintain the MIC of anti-microbial agents at the site of infection for an extended period of time [52]. For infection sites with a good blood supply, oral sustained-release tablets are available to reduce the required dosing frequency and to minimize fluctuations in blood levels. Such systems include Moxatag® (amoxycilin), Augmentin® XR (amoxicillin/clavulanate potassium) and Cipro XR® (ciprofloxacin). Infection of prosthetic devices such as orthopaedic implants and hernia repair mesh following their implantation is a serious concern with systemic treatment challenging if the tissues have a poor supply of blood. Systemic treatment is also difficult as bacterial adhesion onto implanted devices results in biofilm formation at the device-tissue interface, through which drugs have limited penetration. In bone infections, it is often difficult to achieve microbicidal concentrations of an antibiotic at the target site without exceeding toxic systemic concentrations. The local delivery of antibiotics, such as following release from an implanted material, can achieve high local concentrations without raising serum concentrations. Interest in local delivery of an antibiotic to reduce the rate of post-operative infection rate is not a new concept; Jansen et al. reported the implantation of sulphanilamide crystals in compound fractures in 1939 [53]. More recently, local CR antibiotic delivery systems have been developed and refined. Antiinfective CR systems to control post-operative infections are available in the form of bone cements, bone implants, fillers, intra-vascular devices, various device coatings, wound dressing, surgical sutures and vascular grafts [54]. A range of antimicrobial agents such as gentamicin, tobramycin, vancomycin, amoxicillin and carbencillin have been incorporated into CR systems to control post-surgical infections [17, 55]. Various bone cements with antibiotic agents incorporated have been approved by the FDA such as Palacos® G (gentamicin), Cemex ® Genta (gentamicin), Simplex ® P (tobramycin), Combalt® G-HV (gentamicin), Samrtset® GHV (gentamicin) and Versabond® AB (gentamicin) [56]. The major limitation of these bone cements is the rapid burst of release following implantation over the first 24 to 48 h followed by much lower levels of sustained release associated with the inability to release the entire drug payload. When the local antibiotic concentration falls below MIC threshold, the cement becomes susceptible to microbial growth leading to secondary infections as a result of biofilm formation, with concerns around developing anti-microbial-resistant microbial strains due to the presence of sub-therapeutic concentrations of anti-microbial agents [57]. Furthermore, addition of antibiotic to the bone cement results in mechanical weakening, leading to rapid elution of antibiotic upon implantation and an increased risk of aseptic loosening of the implant. As a result, efforts have focused on designs to improve overall release of antibiotics without compromising the mechanical strength. Benoit et al. decreased the burst release by coating

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the material with a biodegradable polymer. The sustained release of vancomycin was achieved over 5 weeks when an antibiotic-loaded plaster of Paris was coated with polylactide-co-glycolide [16]. Similarly, options of adding additives to improve antibiotic release without compromising the mechanical strength of bone cement have been reported. Jackson et al. demonstrated that the addition of sodium chloride and dextran into bone cement improved drug release while maintaining mechanical strength [58]. Bacterial infection and biofilm formation can also be prevented either by coating the implantable devices by an anti-microbial-loaded matrix [12, 13, 17, 59] or by covalently bonding the anti-microbial agent directly to the surface of the device [60]. Importantly, the surface morphology and chemistry should not be altered significantly or integration with tissue will be effected. Recently, the CR of antibiotic from a perforated metallic implant was described without altering the surface [61]. Linezolid and cefazolin were packed into the hollow tubular reservoir, and the release occurred through the previously drilled pinholes (Fig. 2a). CR of antibiotic from this orthopaedic implant was demonstrated from set positions in vitro without altering mechanical integrity or surface morphology (Fig. 2b). However, the time course of release from this approach will need to be extended in the future and the desirable locations of release should be identified for successful in vivo translation. Wound dressings are designed to provide both a barrier to pathogens and a suitable environment to accelerate the healing process [62]. However, the dressing itself can act as an environment for microbial growth, particularly following the absorption of wound discharge. Wound dressings containing anti-microbial agents exist, which release antibiotics/anti-

microbial in a controlled fashion to the tissue they are in contact with. Current wound dressings available for this purpose include Contreet® Foam (silver), PolyMem Silver® (silver), Urgotul SSD® (silver sulphadiazine particles), Silvercel® (silver), Aquacel® (silver) and Acticoat® (silver) [63]. Recently, interest has increased around the CR of bioactives from surgical sutures to control post-operative infections [64]. The anti-microbial efficacy of triclosan-coated polyglactin 910 sutures (VICRYL® Plus) to decrease the incidence of surgical site infection (SSI) was demonstrated against conventional VICRYL® sutures in a retrospective controlled trial in patients undergoing abdominal surgeries [8]. But, the efficacy of surgical sutures coated with antibiotics to control SSI in wider post-surgical applications has been inconclusive. Recently, a recent systematic review and meta-analysis conducted by Chang et al. found that the triclosan-coated sutures did not significantly reduce SSI or wound breakdown following surgery [65]. In addition to sutures, antibiotic-impregnated catheters and central lines have also been developed and are recommended for use by the Centre of Disease Control and Prevention (CDC) [3]. A study conducted by Ramos et al. concluded that antibiotic-coated catheters significantly reduce the incidence of infections associated with central lines [66]. However, some studies have questioned the ability of these antibiotic-coated medical devices to control infection [14, 15]. SSI is multifactorial in origin, and the ability of CR systems to control infection depends upon a number of factors. A predetermined steady release of antibiotic release at the site of infection is not the ultimate solution to achieve maximum efficacy. The anti-microbial effect can be time dependent, requiring sustained release, or concentration dependent, requiring pulsatile release. The rationale of design of CR anti-

Fig. 2 Lateral image of the perforated orthopaedic implant (from right to left: one, two, three and four pin holes). b Percentage release of linezolid and cefazolin from orthopaedic implants [61]

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infective formulations will depend upon the antibiotic type and the ability of CR formulation to release its bioactive payload in accordance to the levels of microbes present. To some extent, CR systems have been successfully adopted into post-operative therapy with demonstrated improvement in treatment efficacy [36, 40, 67]. However, challenges remain to ensure patient safety while addressing individual therapeutic needs post-surgery. Many currently used CR systems cannot terminate medicine release when a target clinical goal has been achieved or in the event of medicine toxicity [68]. In addition, the incidence; intensity; and time course of pain, inflammation and possible infection differ between surgical procedures and among individual patients. CR systems, which release medicines at predetermined and inflexible rates, are not suitable for all patients nor for all procedures. Future systems will release bioactives at desirable locations when they are required promoting patient recovery, shortening hospital stay and reducing personal and societal costs.

Cutting edge technologies The limitations in current post-operative pharmacotherapy implicate the need for a new generation of CR systems to address the real and perceived problems of adverse effects and to individualize dosage regimen. Implantable CR systems with an ability to be recovered simply and rapidly from the body could stop drug release abruptly when it is no longer required or in the event of drug-related toxicity [69]. Biodegradable implants have the advantage of not requiring an additional procedure for removal. Non-biodegradable materials do not erode in the body and can be designed to retain their physical and mechanical properties and are well suited if recovery is required. Non-biodegrading polymers have niche roles, such as for the delivery of female contraceptive hormones (e.g. Norplant® and Implanon®), where they function as solid and recoverable CR implants [69]. Analgesics such as opioids and NSAIDs alongside LAs or antibiotics could all be formulated as slowly eluting implants and placed subcutaneously or at the surgical site. Implants can be prepared with large doses of medicine within a non-biodegradable matrix and can be designed to achieve predictable and desired release rates and may find use to manage pain, inflammation and infection. Most of the CR systems presented release drug at rates predetermined by the system itself and the physiology of the patient. To accurately address a patient’s therapeutic requirements, dosing needs to be individualized, which cannot be achieved with current CR systems. Recent research has demonstrated CR systems allowing drug release to be increased or decreased as required. These CR systems can alter the release rates of drug in response to a trigger, which can be in the form of heat, light, pH, magnetic field, ultrasound, mechanical force [70], electric current [71] or biochemical species [72].

As technologies mature and become more cost-effective, interest has increased around the micro-fabrication of devices, which can release discrete doses of medicine from microreservoirs [73]. Release can be tightly controlled ensuring the precise release of drug at the target site. Langer and co-workers reported a solid-state silicon microchip system, with the ability to deliver single or multiple medicines from microcompartments upon the application of a small electrical potential (Fig. 3) [74]. This device consists of hundreds of individually addressable drug reservoirs sealed with gold, which, when an electrical circuit is completed, functions as a dissolving anode. Drug release occurs upon the electrically driven dissolution of this metal membrane with the ability to deliver single or multiple drugs in a controlled fashion. These systems have been translated from the bench top into a first-in-human clinical trial of a wirelessly controlled microchip-based implant containing human parathyroid hormone (hPTH) for use in osteoporotic postmenopausal women [75]. The use of microfabrication to prepare CR devices holds exciting potential for use in the individualized treatment in post-operative pharmacotherapy. For example, opioids require precise dose titration to meet individual analgesic needs. Opioids could be loaded inside a number of individually addressable micro-reservoirs with accurate and timely release of doses achieved upon application of electrical stimuli. Perfectly timed release of opioids would provide adequate pain relief while decreasing the incidence of toxic side effects. The ability to produce devices with extremely small dimensions is another advantage, facilitating less invasive insertion and removal procedures [76]. Self-regulating CR systems can be developed to release their payload in the presence of biomarkers of pain, inflammation or infection [72, 77, 78]. Achieving an appropriate balance of inflammation is critical to the healing process. CR systems capable of releasing anti-inflammatory in accordance to local

Fig. 3 Pulsatile release of sodium fluorescein from a microchip on application of +1.04 V. Reprinted with permission from Macmillan Publishers [74]

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markers of undesirable inflammation would achieve therapeutic affect without hampering the healing process. A controlled drug delivery system capable or releasing bioactive in response to the human neutrophil elastase (HNE) enzyme was recently reported [79, 80]. This enzyme is primarily secreted by neutrophils at inflammatory sites. An enzyme-degradable poly(ethylene glycol) (PEG)-based hydrogel CR system was developed and loaded with a model peptide drug. HNE-sensitive linkers were initially photo-polymerized and anchored into a hydrogel system made up of poly-ethylene diacrylate (PEGDA). Drug release was triggered as HNE diffuses into the hydrogel system cleaving the HNE-sensitive linkers [80]. Drug release is localized and to scale with the level of HNE produced. Similarly, the concept of releasing drug in response to hydrogen peroxide, a compound produced during local inflammation, from an intrinsic conductive polymer (ICP) has been reported [81]. Future systems will utilize available and developing technologies to tune the release of antiinflammatory agents locally in response to biomarkers to modulate inflammation to desirable levels. pH changes can be used as a local marker of infection. Recently, a pH-responsive CR device loaded with gentamicin was reported for use following orthopaedic surgery [78]. Functionalized nanoparticle incorporating gentamycin sulphate was bonded to titanium surface of biomaterial. Triggered release of gentamicin in the event of infection was demonstrated due to bond cleavage in acidic environment. Approximately 50 to 70 % of gentamicin was released after 100 h at pH 4–5. The release rate of gentamicin decreased at elevated pH and the release were insignificant around physiological pH, confirming the ability of CR system to release GS only in the event of infection (Fig. 4). In an alternate approach, gentamicin has been bonded to a polyvinyl alcohol (PVA) carrier with release occurring only in the presence of Pseudomonas aeruginosa [77]. Proteinase from wounds infected with P. aeruginosa resulted in cleavage of this linker to the release of gentamicin. Such selfregulating CR systems would only release antibiotics locally

Fig. 4 Gentamicin release from a biomaterial surface as a function of pH. Infection is associated with a fall in pH resulting in release of antibiotic. Reprinted with permission from Elsevier [78]

when required reducing post-operative use of antibiotics and minimizing systemic side effects.

Challenges and promises of translating technologies into post-operative care While research into novel CR systems continues to grow, limited progress has been made to translate these systems from the lab bench to the bedside. Much research is driven by technology without the required focus on clinical applications [82]. The development of many novel CR formulations is halted before reaching the clinic due to technical limitations or their failure to demonstrate efficacy and safety. For example, ThermoDox®, a thermosensitive doxorubicin-containing liposomal formulation, was suspended after phase II and phase III clinical trials because, although well tolerated by patients, the life span increase did not reach required threshold. Cost-benefit must be demonstrated to ensure the drive for commercialization [83]. Technical challenges such as feasible and reproducible scale up and validation also limit the smooth translation of these CR technologies [84]. Despite these challenges, certain novel CR formulations do progress from the laboratory bench to patient bedside and offer exciting new benefits for patients. The successful clinical trial of a microchip-based implant containing hPTH in human was reported by Farra and co-workers in 2012 [75]. The release of hPTH was trailed remotely in a group of postmenopausal women to treat osteoporosis. The therapeutic effect was similar as that of the conventional injections of hPTH. This success has given the hope of advancing pharmacotherapy by addressing the issues of poor compliance with complex dosage regimens. Novel CR technologies promise exciting advances in postsurgical pharmacotherapy. Successful translation of these novel CR systems will lead to effective management of postoperative complications enhancing patient experiences and enabling faster surgical recovery. For the smooth translation of these CR technologies, there is a need for research to follow the identification of clinical needs and for collaborators from different fields to work together. Existing and developing technologies are being applied to CR systems to better address individual patient needs and promote safety. The ability to release medicines in response to biomarkers or other stimuli could benefit individuals as doses are matched to clinical need. Recent advances in CR delivery systems offer a range of clinical solutions to address the limitations in current postsurgical pharmacotherapy. There are opportunities for clinicians, pharmaceutical scientists, pharmacologist and chemical engineers to collaborate and match patient needs with existing or developing technologies to revolutionize post-operative pharmacotherapy.

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Conclusion This review has summarized the needs of post-operative pharmacotherapy and the benefits and limitations of the currently adopted CR systems. CR systems can release drugs where they are required, at an appropriate concentration for an extended period of time with the demonstrated ability to be translated from laboratory bench to patient bedside to improve treatment efficacy and adherence. Novel CR systems have exciting potential to address unmet needs in the growing surgical population in the near future. Future systems will deliver a wider range of medication as new technologies enable functionality and can alleviate safety concerns. Stimuli-responsive CR systems can tune drug release rates in response to patient need. In the future, these systems may utilize disease markers to self-regulate drug release such as a microbial infection triggering anti-microbial release. The use and continued translation of CR drug delivery systems will help alleviate patient suffering after surgery and enhance recovery with associated decreases in health and societal costs.

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14. Acknowledgments The authors would like to acknowledge Mr M. Naveed Yasin for his invaluable suggestions. We would like to thank the Faculty of Medical and Health Sciences, The University of Auckland, for providing Dean’s International Doctoral Scholarship to Prabhat Bhusal. We would also like to thank The Auckland Medical Research Foundation (AMRF) for supporting this research. All authors have reviewed and approved the submitted manuscript.

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Compliance with ethical standards Conflict of interest The authors declare that they have no conflicts of interest.

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