Review articleZero-order drug delivery: State of the art and future prospects
Graphical abstract
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.
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 values 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.
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