Elsevier

Journal of Controlled Release

Volume 327, 10 November 2020, Pages 834-856
Journal of Controlled Release

Review article
Zero-order drug delivery: State of the art and future prospects

https://doi.org/10.1016/j.jconrel.2020.09.020Get rights and content

Highlights

  • A critical review of translational zero-order drug delivery systems.

  • Summary of the current state of common drug delivery devices.

  • Discussion of the techniques being employed to advance towards zero-order release.

  • Insight on the future of zero-order drug release.

Abstract

Pharmaceutical drugs are an important part of the global healthcare system, with some estimates suggesting over 50% of the world's population takes at least one medication per day. Most drugs are delivered as immediate-release formulations that lead to a rapid increase in systemic drug concentration. Although these formulations have historically played an important role, they can be limited by poor patient compliance, adverse side effects, low bioavailability, or undesirable pharmacokinetics. Drug delivery systems featuring first-order release kinetics have been able to improve pharmacokinetics but are not ideal for drugs with short biological half-lives or small therapeutic windows. Zero-order drug delivery systems have the potential to overcome the issues facing immediate-release and first-order systems by releasing drug at a constant rate, thereby maintaining drug concentrations within the therapeutic window for an extended period of time. This release profile can be used to limit adverse side effects, reduce dosing frequency, and potentially improve patient compliance. This review covers strategies being employed to attain zero-order release or alter traditionally first-order release kinetics to achieve more consistent release before discussing opportunities for improving device performance based on emerging materials and fabrication methods.

Introduction

Drugs are an integral part of the global healthcare system and contribute to both preventing and treating disease. It is estimated that 50% of the global population consumes more than one dose of medication per day, a substantial increase from 33% in 2005 [1]. In the United States alone, 5.8 billion prescriptions were dispensed in 2018 and 85% of adults over the age of 60 are using prescription drugs [2,3]. The importance of prescription drugs and their capacity to improve health is underscored by the efficacy of blockbuster drugs, such as statins. One study found that statins taken preventatively by at-risk patients without prior cardiovascular events reduced the risk of all-cause mortality by 16% [4]. Another study found that for men with high levels of cholesterol, preventative statin use reduced 20-year all-cause mortality, risk of death by coronary heart disease, and risk of death by other cardiovascular diseases by 18%, 28%, and 25%, respectively [5].

Despite the demonstrable benefits of drugs, their impact is lessened by a number of factors including side effects, undesirable dosing regimens, and low patient compliance. It is estimated that patient adherence to drug regimens for chronic diseases is as low as 50% in western society and potentially even lower in developing countries, generally attributed to a combination of drug regimen complexity, socio-economic, and patient-related factors [6]. An estimated 33–50% of the U.S. population is non-adherent to treatment regimens [7], which negatively affects health outcomes and has important economic ramifications, with some estimates suggesting it costs the country $100–290 billion in added health care costs every year [[7], [8], [9]]. One study of diabetic patients over the age of 40 showed that poor adherence to drug regimens increased all-cause mortality by 45% [10].

Most clinically available drugs are administered as immediate release formulations, which include pills and capsules as well as intramuscular, intraperitoneal, and intravenous (IV) injections [11]. While these methods of delivery have important clinical applications, they are all generally limited by their pharmacokinetic profile, which is characterized by initial rapid drug distribution pushing systemic levels above the minimum effective concentration (MEC) but below the minimum toxic concentration (MTC) followed by a drop below the MEC over time as the drug is metabolized and cleared from the body (Fig. 1A) [12]. Remaining between the MEC and MTC is critical because it allows the patient to receive the benefit of the drug without experiencing severe adverse side effects [13]. This is easiest to achieve when the therapeutic window is large or when the biological half-life of the drug is long. A large therapeutic window allows systemic drug concentrations to remain safe and effective during both the initial peak and for several half-lives thereafter. Similarly, slow metabolism and clearance can extend the duration that drug levels remain within the MEC and MTC after administration. Unfortunately, not all drugs have a large therapeutic window or long half-life. In these instances, immediate release drug formulations only spend a small amount of time within the safe yet efficacious plasma concentration range before redosing. Compensating for this by increasing the administration frequency, while effective, is disadvantageous due to reduced patient compliance [14]. Fig. 1A demonstrates the difference in dosing frequency for a drug with a wide therapeutic window compared to a drug with a narrow therapeutic window.

Of these immediate release formulations, oral drugs are widely considered to be one of the most convenient modes of drug administration because they are non-invasive, cost effective, and allow for doses to be easily titrated [15]. These factors have made it the most common mode of administration, with some estimates suggesting that oral formulations comprise 90% of all drugs and about 50% of the drug delivery market [16]. Despite its advantages, oral delivery also presents several physiological and practical challenges that prevent it from being appropriate for all drugs. These limitations include the poor absorption of most macromolecular drugs as well as some small molecule drugs [17], first-pass metabolism [18], systemic dosing [19], variability of digestive residence time [20], and patient compliance issues when frequent administration is necessary due to a small therapeutic window and/or short half-life [7]. Bioavailability—the amount of drug that reaches circulation in an active form—is determined by a multitude of physiologic factors and intrinsic drug properties that affect its absorption through the gastrointestinal tract; factors that reduce bioavailability include alterations in gastrointestinal tract pH [21], the presence of the intestinal mucosa and healthy epithelium, which act as barriers decreasing drug transport into systemic circulation [11], and low drug solubility in water, which can lead to slow and inconsistent absorption [22]. In some cases, disease states can dramatically affect bioavailability, contributing to unpredictable plasma concentrations and shifts outside the therapeutic window [23]. Additionally, oral medications with narrow therapeutic windows are associated with more drug-related adverse events and subsequent increases in health cost [24], morbidity and mortality [25], and are an important cause of severe adverse events resulting in emergency hospital visits by older adults [26].

IV injections overcome several of the barriers facing oral delivery but are subject to other limitations that make them suitable for only a subset of use cases. IV administration allows for the rapid distribution of drugs, can achieve drug bioavailability at approximately 100% by bypassing first-pass metabolism by the liver prior to entering the systemic circulation, and is compatible with both small and large molecule delivery [11]. For drugs with narrow therapeutic windows, continuous IV drug infusion minimizes fluctuations outside the therapeutic window, thereby maintaining a steady plasma concentration [27]. However, this delivery system requires skilled placement by a healthcare professional and prolonged needle access, which exposes the patient to infection and limits mobility [28,29]. Like IV drug systems, other immediate release drugs, such as intramuscular and intraperitoneal injections, also avoid first-pass metabolism [30] but have generally not achieved clinical utility to the same degree as oral delivery, with some exceptions (e.g., insulin, vaccines) [31].

Controlled drug delivery systems seek to overcome the pharmacokinetic limitations of immediate release formulations by delivering drugs in a predetermined manner over a prolonged period of time, ranging from hours to months [32]. Most controlled drug delivery systems—including injectable FDA formulations—exhibit release kinetics characterized by an initial period of rapid release followed by first-order release in which the rate of drug release is proportional to the amount remaining in the device (Fig. 1B) [[33], [34], [35]]. These systems generally enhance drug delivery by delaying a fraction of the drug from entering circulation, thereby retarding metabolism and clearance [36,37]. The result is an extension of circulation time [38] and reduced peak drug concentrations, which can enable these devices to prolong the duration that drug remains safely within the therapeutic window [39]. This benefit can be especially pronounced for drugs with narrow therapeutic windows. Fig. 1B highlights the relative amount of time a device delivering drug with a large therapeutic window spends within the efficacious range compared to a device delivering drug with a narrow therapeutic window. As a result, devices exhibiting first-order release kinetics have been used clinically with drugs with large therapeutic windows and their clinical importance should not be overlooked; however, they have experienced far more limited success delivering drugs with narrow therapeutic windows.

Zero-order delivery systems are a form of controlled drug delivery that can potentially further expand and improve the performance of therapeutics beyond what is possible using current FDA-approved controlled-release systems, including drugs with small therapeutic windows or hepatic toxicity [40]. Zero-order drug delivery systems release drug at a constant rate throughout the lifetime of the device (Fig. 1C). At equilibrium, these devices release drug at the same rate that it is cleared from the body thus enabling stable drug plasma concentrations within the therapeutic window without the need for frequent redosing, thereby minimizing adverse effects and improving patient compliance [41,42]. Importantly, the overall cumulative dose within the body is also reduced compared to immediate-release and first-order release systems, ultimately reducing the risk of chronic toxicity (Fig. 1D). Unfortunately, decoupling the release rate from the amount of drug remaining in the device has often proved challenging, particularly for passive systems, which must be engineered to accommodate transport principles.

Several mathematical models exist to describe drug release kinetics. Of note are the Ritger-Peppas and Korsmeyer-Peppas models which describe drug release from polymeric systems and establish an exponential relationship between drug release and time [35]. Overall, this equation (Eq. (1)) serves to classify release profiles as either first-order or zero-order. For a thin film, when the exponent of release, n, is equal to 0.5, the system is classified as Fickian with diffusion driving first-order release. If n = 1, the model is non-Fickian and correlates with zero-order drug delivery, which is governed by forces like swelling and/or polymer chain relaxation. In the case of 0.5 < n < 1, drug release is determined by a combination of diffusion and swelling.MiM=Ktn

Ritger-Peppas and Korsmeyer-Peppas Mathematical Model. M represents the amount of drug at equilibrium, Mi represents the amount of drug released over time, K is the release velocity constant, and n is the exponent of release.

Importantly, the Ritger-Peppas and Korsemeyer-Peppas models are appropriate for MiMvalues less than 0.60, but cannot be validly applied to later-stage release conditions that fail to meet the underlying assumptions used to derive the equation [35,43]. Further, it should be noted that the value of n representing pure Fickian release varies as a function of device geometry with cylinders and spheres having values of 0.45 and 0.43, respectively [43].

This review will cover strategies and advances in temporally controlled drug delivery systems, with an emphasis on strategies that have either achieved zero-order delivery or pushed traditionally first-order delivery systems towards the goal of consistent release over time. These systems include degradable polymeric particles and implantable polymeric devices, diffusion-based devices such as passive microchips, hydrogels, osmotic pumps, intravaginal rings, and microneedles, and actuated devices including active microchips and macroscale implantable pumps. Each system has important advantages and limitations that dictate its potential clinical value, as shown in Table 1. This paper describes the key features of these systems, discusses recent efforts to attain zero-order release kinetics, and identifies opportunities for creating devices that achieve consistent release rates. This review will not discuss direction modification of drugs (e.g., PEGylation) because the release kinetics and therapeutic efficacy of modified drugs vary on a drug-to-drug basis.

Section snippets

Degradation-based delivery systems

Biodegradable delivery systems are typically composed of polymeric materials that are lysed by hydrolysis or enzymes into products that can be solubilized and cleared from the body [44]. Polymers undergo bulk degradation, surface erosion, or some combination of the two depending on their hydrophobicity and degradation rate [45]. Bulk-degrading polymers, such as poly(lactic-co-glycolic acid) (PLGA), absorb water leading to polymer chain lysis throughout the matrix and a drop in average molecular

Diffusion-based delivery systems

Diffusion-based drug delivery systems are driven by a concentration gradient between the device and the external environment [44]. In a polymeric device, diffusion can either occur on a molecular level in which drug passes between polymer chains, or on a macroscale level in which drug diffuses through pores in a polymer matrix [44]. Simple diffusion-based delivery systems experience decreasing rates of delivery over the lifetime of the device due to a decreasing concentration gradient, which

Perspectives & opportunities

Zero-order drug delivery devices offer the potential to precisely tune release kinetics to prolong drug concentrations within the therapeutic window. As a result, these systems can improve drug efficacy, reduce side effects, and reduce the frequency of administration, which can all contribute to improved patient compliance and disease management. However, the most appropriate drug delivery system for a particular indication depends on a number of factors including: (1) the drug half-life,

Clinical and commercial impact

Drugs have played a key role in improving quality of life and lifespan over the past century. Low patient compliance to drug therapies is a substantial global problem that contributes to poor health outcomes and unnecessary financial costs. The development of zero-order drug delivery systems has immense potential to improve drug efficacy, reduce side effects, and increase patient compliance by facilitating sustained delivery of therapeutics for extended periods of time without relying on

Funding

This material is based upon work supported by the National Science Foundation Graduate Research Fellowship under Grant No. 1842494. Any opinion, findings, and conclusions or recommendations expressed in this material are those of the authors(s) and do not necessarily reflect the views of the National Science Foundation.

Acknowledgement

We would like to acknowledge the use of BioRender to generate the diagrams shown in Figs. 6a, 7a, 8a, and 10.

References (312)

  • C.C. Lin et al.

    The biodegradation of biodegradable polymeric biomaterials

  • G. Adamo et al.

    Functionalization of nanoparticles in specific targeting and mechanism release

  • M.D. Blanco et al.

    Preparation of bupivacaine-loaded poly(ε-caprolactone) microspheres by spray drying: drug release studies and biocompatibility

    Eur. J. Pharm. Biopharm.

    (2003)
  • M. Ye et al.

    Issues in long-term protein delivery using biodegradable microparticles

    J. Control. Release

    (2010)
  • J. Wang et al.

    Characterization of the initial burst release of a model peptide from poly(D,L-lactide-co-glycolide) microspheres

    J. Control. Release

    (2002)
  • K. Park et al.

    Injectable, long-acting PLGA formulations: analyzing PLGA and understanding microparticle formation

    J. Control. Release

    (2019)
  • G. Acharya et al.

    A study of drug release from homogeneous PLGA microstructures

    J. Control. Release

    (2010)
  • C. Busatto et al.

    Effect of particle size, polydispersity and polymer degradation on progesterone release from PLGA microparticles: experimental and mathematical modeling

    Int. J. Pharm.

    (2018)
  • G. Mittal et al.

    Estradiol loaded PLGA nanoparticles for oral administration: effect of polymer molecular weight and copolymer composition on release behavior in vitro and in vivo

    J. Control. Release

    (2007)
  • D.T. O’Hagan et al.

    The preparation and characterization ofpoly(lactide-co-glycolide) microparticles: III. Microparticle/polymer degradation rates and the in vitro release of a model protein

    Int. J. Pharm.

    (1994)
  • D. Blanco et al.

    Protein encapsulation and release from poly(lactide-co-glycolide) microspheres: effect of the protein and polymer properties and of the co- encapsulation of surfactants

    Eur. J. Pharm. Biopharm.

    (1998)
  • M.J. Alonso et al.

    Biodegradable microspheres as controlled-release tetanus toxoid delivery systems

    Vaccine

    (1994)
  • D. Klose et al.

    How porosity and size affect the drug release mechanisms from PLGA-based microparticles

    Int. J. Pharm.

    (2006)
  • J. Rodríguez Villanueva et al.

    Optimising the controlled release of dexamethasone from a new generation of PLGA-based microspheres intended for intravitreal administration

    Eur. J. Pharm. Sci.

    (2016)
  • J. Kang et al.

    Comparison of the effects of Mg(OH)2 and sucrose on the stability of bovine serum albumin encapsulated in injectable poly(D,L-lactide-co-glycolide) implants

    Biomaterials

    (2002)
  • Z. Hu et al.

    Effect of bases with different solubility on the release behavior of risperidone loaded PLGA microspheres

    Colloids Surf. B: Biointerfaces

    (2011)
  • S. Fredenberg et al.

    The mechanisms of drug release in poly(lactic-co-glycolic acid)-based drug delivery systems – a review

    Int. J. Pharm.

    (2011)
  • H. Chen et al.

    Surface modification of PLGA nanoparticles with biotinylated chitosan for the sustained in vitro release and the enhanced cytotoxicity of epirubicin

    Colloids Surf. B Biointerfaces

    (2016)
  • J. Herrmann et al.

    The effect of particle microstructure on the somatostatin release from poly(lactide) microspheres prepared by a W/O/W solvent evaporation method

    J. Control. Release

    (1995)
  • D. Cun et al.

    High loading efficiency and sustained release of siRNA encapsulated in PLGA nanoparticles: quality by design optimization and characterization

    Eur. J. Pharm. Biopharm.

    (2011)
  • M.L. Hans et al.

    Biodegradable nanoparticles for drug delivery and targeting

    Curr. Opin. Solid State Mater. Sci.

    (2002)
  • F. Mohamed et al.

    Engineering biodegradable polyester particles with specific drug targeting and drug release properties INTRODUCTION AND SCOPE OF REVIEW

    Pharm. Assoc. J. Pharm. Sci.

    (2008)
  • J. Wu et al.

    Fabrication and characterization of monodisperse PLGA-alginate core-shell microspheres with monodisperse size and homogeneous shells for controlled drug release

    Acta Biomater.

    (2013)
  • S. D’Souza et al.

    Microsphere delivery of risperidone as an alternative to combination therapy

    Eur. J. Pharm. Biopharm.

    (2013)
  • C. Regnier-Delplace et al.

    PLGA microparticles with zero-order release of the labile anti-Parkinson drug apomorphine

    Int. J. Pharm.

    (2013)
  • Y.Y. Yang et al.

    Morphology, drug distribution, and in vitro release profiles of biodegradable polymeric microspheres containing protein fabricated by double-emulsion solvent extraction/evaporation method

    Biomaterials

    (2001)
  • H.B. Ravivarapu et al.

    Polymer and microsphere blending to alter the release of a peptide from PLGA microspheres

    Eur. J. Pharm. Biopharm.

    (2000)
  • M.D. Blanco et al.

    Development and characterization of protein-loaded poly(lactide-co-glycolide) nanospheres

    Eur. J. Pharm. Biopharm.

    (1997)
  • S. Nicoli et al.

    Design of triptorelin loaded nanospheres for transdermal iontophoretic administration

    Int. J. Pharm.

    (2001)
  • S. Rey-Vinolas et al.

    Polymers for bone repair

  • Global Medicines Use in 2020

  • Medicine Use and Spending in the U.S

  • C.B. Martin et al.

    Prescription Drug Use in the United States, 2015-2016 Key findings Data from the National Health and Nutrition Examination Survey

  • F. Taylor et al.

    Statins for the primary prevention of cardiovascular disease

  • A.J. Vallejo-Vaz et al.

    Low-density lipoprotein cholesterol lowering for the primary prevention of cardiovascular disease among men with primary elevations of low-density lipoprotein cholesterol levels of 190 mg/dL or above: analyses from the WOSCOPS (West of Scotland coronary prevention study) 5-year randomized trial and 20-year observational follow-up

    Circulation

    (2017)
  • Adherence to Long-Term Therapies: Evidence for Action

  • L. Osterberg et al.

    Adherence to medication

    N. Engl. J. Med.

    (2005)
  • M. Viswanathan et al.

    Interventions to improve adherence to self-administered medications for chronic diseases in the United States: a systematic review

    Ann. Intern. Med.

    (2012)
  • J.J. Mahoney et al.

    The unhidden cost of noncompliance

    J. Manag. Care Pharm.

    (2008)
  • Y.Y. Kim et al.

    Effect of medication adherence on long-term all-cause-mortality and hospitalization for cardiovascular disease in 65,067 newly diagnosed type 2 diabetes patients

    Sci. Rep.

    (2018)
  • Cited by (127)

    View all citing articles on Scopus
    View full text