Keynote (green)
Repurposing of parenterally administered active substances used to treat pain both systemically and locally

https://doi.org/10.1016/j.drudis.2022.07.006Get rights and content

Highlights

  • Micro- and nanosystems are exploited to repurpose old drugs.

  • Successful alternative approaches are available for pain treatment.

  • Abridged marketing authorization would shorten the path for official approval.

  • Complex formulations require high level assessment.

Abstract

Pain is a constant in our lives. The efficacy of drug therapy administered by the parenteral route is often limited either by the physicochemical characteristics of the drug itself or its adsorption–distribution–metabolism–excretion (ADME) mechanisms. One promising alternative is the design of innovative drug delivery systems that can improve the pharmacokinetics |(PK) and/or reduce the toxicity of traditionally used drugs. In this review, we discuss several products that have been approved by the main regulatory agencies (i.e., nano- and microsystems, implants, and oil-based solutions), highlighting the newest technologies that govern both locally and systemically the delivery of drugs. Finally, we also discuss the risk assessment of the scale-up process required, given the impact that this approach could have on drug manufacturing.

Teaser: The management of pain by way of the parenteral route can be improved using complex drug delivery systems (e.g., micro- and nanosystems) which require high-level assessment and shorten the regulatory pathway.

Introduction

Pain is present in our lives. It is comparable to an alarm that defends us from damage, but which is also a terrible enemy to fight, particularly when persistent. ‘Physiological’ pain has its origin in normal, functional nervous tissue, including the peripheral and central nervous systems, is of brief duration, and is generally described as acute. Evoked by noxious stimuli, it results from burns or cuts, bee stings, dental work, labor and childbirth, broken bones or surgery. By contrast, ‘pathological’ pain is a persistent condition arising from articular diseases, fibromyalgia, cancer, and neuropathic and visceral problems, among others. A repeated painful signal can induce a maladaptive response of the nervous system that alters pain perception as well as the efficacy of common analgesics.[1], [2] As a part of the chronic pain continuum, the term ‘nociplastic pain’ was recently proposed to describe the clinical and psychophysical findings related to altered nociceptive functions, in an attempt to join all the aforementioned conditions.3

Independently of the characteristics of pain, the Declaration of Montréal (2010) states that ‘the access to pain management is a fundamental human right’ and an integral component of Universal Health Coverage, a critical objective of the WHO.4

Painful and/or inflammatory conditions can be treated with numerous therapeutic agents belonging to different classes, including opioid analgesics, nonsteroidal anti-inflammatory drugs (NSAID), corticosteroids, and antiepileptics, or by using various techniques and administration protocols depending on the patient’s need. Indeed, infusions of pharmacological agents into the central neuraxis (e.g., opioid analgesics) can be required to provide good, long-term pain relief, whereas local injections of the drug (e.g., glucocorticoids) into the affected area is a valuable approach for targeting the specific inflamed tissues, thus improving the therapeutic activity and reducing adverse effects.5 However, the success of these different approaches is often limited either by the physicochemical characteristics of the drug substance itself or its ADME mechanisms.

To overcome these issues, the development of a medicinal product containing a substance never previously used in humans (‘first-in-human’) is an arduous process that requires a huge investment of money and time with no guarantee of returns. This is because 80% of approved drugs are reported to fail to yield profitable earnings for the companies that developed them.6 Most of the expenditure can be ascribed to the translation of a medicinal product from preclinical to clinical studies, necessary for demonstrating its efficacy and safety. Hence, approaches that make use of drug candidates with known safety profiles (drug repurposing) can effectively avoid time-consuming, laborious, high-risk, and costly processes. Typically, ‘old’ drug substances could be sourced from medicinal products (i) approved by regulatory agencies; (ii) undergoing clinical development for a different application; or (iii) that have been abandoned or have failed to demonstrate efficacy during clinical trials (Phase II or III).

To accomplish successful drug repositioning, both maximizing drug interaction at the target site and mitigating or eliminating adverse effects are mandatory. In this regard, the design of a drug delivery system offers unique potential for repurposing applications, by allowing researchers to overcome obstacles of solubility, ADME, and targeting, thus significantly expanding the range of potential novel indications. Benefits arise from the broad range of materials, structures, and physicochemical modifications, all of which can address patient’s needs. The development of a new drug product starting from an old active pharmaceutical ingredient (API) brings significant advantages from a regulatory point of view. In most cases, information regarding the efficacy and safety profiles of the drug substance is already available in literature or to the regulatory authorities. This means that the extent of the data to be provided by the applicant for the assessment process is reduced, and drug products can be authorized following an abridged application (Box 1). The nature and extent of such data can vary based on the type of the API (biological or nonbiological), the intrinsic complexity of the drug product, and its therapeutic indications.7

Based on these considerations, here we discuss how this idea has been successfully applied to design parenteral drug delivery systems for pain management in different settings (Fig. 1). We review cases of micro- and nanosystems (i.e., liposomes and nanoemulsions) available on the market to highlight the role of drug delivery systems in reducing adverse effects, optimizing PK, or improving patient compliance.

Section snippets

Lipid based-delivery systems

Lipid based-delivery systems offer the opportunity for optimizing a variety of therapeutics owing to their specific therapeutic benefits and versatility of application. Indeed, they are capable of encapsulating small drugs as well as macromolecules, protecting them from chemical degradation, increasing their in vivo half-life, enhancing the drug payload, and providing controlled release and targeted delivery, among other things. Two main classes are approved in pain management, namely

Long-acting injectable formulations

In the case of parenteral administration, long-acting implantable or injectable dosage forms (LAIs) extend drug release over a suitable period of time to guarantee a therapeutically relevant concentration either in the bloodstream or locally in a specific tissue/organ (e.g., eye or intra-articular cavity) for days, weeks, or months. Many technologies have been proposed for controlling drug release, including crystal suspensions, emulsions, or implantable or injectable dosage forms, which can be

High-level assessment of the scale-up and manufacturing processes

According to current pharmaceutical guidelines,81 any pharmaceutical process should be designed to be capable of reproducible performance. This means that, based on scientific data and experimental studies, each manufacturer should demonstrate that a medicinal product is routinely reproducible with the same level of quality, efficacy, and safety for the patient. This puts a strong focus on the understanding, control, and optimization of the critical manufacturing process parameters (CPPs)

Concluding remarks

A search through the available literature shows that drug delivery technology is a suitable tool for repurposing active substances currently in clinical use and administered by parenteral routes for treating pain, both systemic and local. The various cited examples that can be found on the market relate to different drug delivery systems, such as micro- and nanosystems (i.e., liposomes and nanoemulsions), together with long-acting formulations, such as biodegradable and nonbiodegradable polymer

Acknowledgments

The authors are grateful to Lynn Whitted for her language revision of this article.

Declaration of interest

None declared by authors.

Luigi Sebastiano Battaglia is Associate Professor at the Department of Drug Science and Technology, University of Turin, Italy, where he obtained a Degree in Pharmacy (2002) and a PhD in Drug Science (2009), and he performed all his academic career, including Research Associate (2006-2012) and Assistant Professor (2012-2020) positions. His main research interests concern drug delivery by means of solid lipid nanoparticles and nanoemulsions, aiming to overcome biological barriers (i.e. blood

References (83)

  • Y.D. Ji et al.

    The efficacy of liposomal bupivacaine for opioid and pain reduction: a systematic review of randomized clinical trials

    J Surg Res

    (2021)
  • S. Dutta et al.

    Propofol pharmacokinetics and pharmacodynamics assessed from a cremophor EL formulation

    J Pharm Sci

    (1997)
  • J.B. Glen et al.

    Pharmacology of an emulsion formulation of ICI 35 868

    Br J Anaesth

    (1984)
  • O. Von Dardel et al.

    Fat emulsion as a vechicle for diazepam. A study of 9492 patients

    Br J Anaesth

    (1983)
  • M.A.K. Mattila et al.

    Reduction of venous sequelae of i.v. diazepam with a fat emulsion as solvent

    Br J Anaesth

    (1981)
  • O. Ohmukai

    Lipo-NSAID preparation

    Adv Drug Deliv Rev

    (1996)
  • K. Yokoyama et al.

    Limethason as a lipid microsphere preparation: an overview

    Adv Drug Deliv Rev

    (1996)
  • L.D. Kumar et al.

    Advancement in contemporary diagnostic and therapeutic approaches for rheumatoid arthritis

    Biomed Pharmacother

    (2016)
  • F. Selmin et al.

    Regulatory aspects and quality controls of polymer-based parenteral long-acting drug products: the challenge of approving copies

    Drug Discov Today

    (2020)
  • J.F. Ferreira et al.

    Glucocorticoids and rheumatoid arthritis

    Rheum Dis Clin N A

    (2016)
  • A. Kumar et al.

    Efficacy of methylprednisolone acetate versus triamcinolone acetonide intra-articular knee injection in patients with chronic inflammatory arthritis: a 24-week randomized controlled trial

    Clin Ther

    (2017)
  • G. Spenlehauer et al.

    In vitro and In vivo degradation of poly(D, L lactide/glycolide) type microspheres made by solvent evaporation method

    Biomaterials

    (1989)
  • N. Gerwin et al.

    Intraarticular drug delivery in osteoarthritis

    Adv Drug Deliv Rev

    (2006)
  • G. Soubrane et al.

    Fluocinolone acetonide (ILUVIEN®) micro-implant for chronic diabetic macular edema

    J Français d’Ophtal

    (2015)
  • I.I. Salem et al.

    Pharmacokinetics of betamethasone after single-dose intramuscular administration of betamethasone phosphate and betamethasone acetate to healthy subjects

    Clin Ther

    (2012)
  • C.I. Nkanga et al.

    Clinically established biodegradable long acting injectables: an industry perspective

    Adv Drug Deliv Rev

    (2020)
  • A.H. Fong et al.

    Presumed sterile endophthalmitis afer intravitreal triamcinolone (Kenalog)-more common and less benign than we thought?

    Asia-Pacific J Ophthal

    (2017)
  • C.-J. Li et al.

    In vitro and in vivo release of dinalbuphine sebacate extended release formulation: effect of the oil ratio on drug release

    Int J Pharm

    (2017)
  • C.J. Woolf et al.

    Mechanism-based pain diagnosis: issues for analgesic drug development

    Anesthesiology

    (2001)
  • F. Brennan et al.

    Access to pain management as a human right

    Am J Public Health

    (2019)
  • J.A. DiMasi et al.

    Trends in risks associated with new drug development: success rates for investigational drugs

    Clin Pharmacol Ther

    (2010)
  • R. Araki et al.

    Development of a novel one-step production system for injectable liposomes under GMP

    Pharm Dev Technol

    (2018)
  • A. Wagner et al.

    Liposome technology for industrial purposes

    J Drug Deliv

    (2011)
  • K. Hippalgaonkar et al.

    Injectable lipid emulsions—advancements, opportunities and challenges

    AAPS PharmSciTech

    (2010)
  • C. Ghelardini et al.

    The pharmacological basis of opioids

    Clin Cases Miner Bone Metabol

    (2015)
  • N. Youssef et al.

    What epidural opioid results in the best analgesia outcomes and fewest side effects after surgery? A meta-analysis of randomized controlled trials

    Anesth Analg

    (2014)
  • M. Vercauteren et al.

    Cost-effectiveness of analgesia after Caesarean section. A comparison of intrathecal morphine and epidural PCA

    Acta Anaesthesiol Scand

    (2002)
  • D. Gambling et al.

    for the Single-Dose ESG. A comparison of Depodur™, a novel, single-dose extended-release epidural morphine, with standard epidural morphine for pain relief after lower abdominal surgery

    Anesth Analg

    (2005)
  • J. Portillo et al.

    Safety of liposome extended-release bupivacaine for postoperative pain control

    Front Pharmacol

    (2014)
  • B.M. Ilfeld et al.

    Clinical effectiveness of liposomal bupivacaine administered by infiltration or peripheral nerve block to treat postoperative pain: a narrative review

    Anesthesiology

    (2021)
  • A.D. Kaye et al.

    Exparel for postoperative pain management: a comprehensive review

    Curr Pain Headache Rep

    (2020)
  • Luigi Sebastiano Battaglia is Associate Professor at the Department of Drug Science and Technology, University of Turin, Italy, where he obtained a Degree in Pharmacy (2002) and a PhD in Drug Science (2009), and he performed all his academic career, including Research Associate (2006-2012) and Assistant Professor (2012-2020) positions. His main research interests concern drug delivery by means of solid lipid nanoparticles and nanoemulsions, aiming to overcome biological barriers (i.e. blood brain barrier) and to obtain targeted delivery, with a particular focus on protein drugs. He is Editorial Board Member of Pharmaceutics.

    Mirko Gabriele – Pharmaceutical Chemistry Degree and PhD in Biomolecular and pharmaceutical Science – is currently Sr Director Sterile Strategy Innovation and Technology in ThermoFisher, leader in the contract development and manufacturing (CDMO) space. With a strong history in R&D, Operations (technology transfer, production, maintenance and validation) and Quality (quality control and analytical method development). His main professional research interest is on sterile and non-sterile drugs manufacturing processes, focusing on their robustness and reproducibility, using state-of-art technology and innovative approaches.

    Francesca Selmin - Pharmaceutical Chemistry Degree and PhD in Medicinal Chemistry - is currently Associate Professor in Drug Delivery at the Department of Pharmaceutical Sciences, University of Milan (Italy). The research activities deal with the design and characterization of drug delivery systems intended for parenteral and oromucosal administration. Her research interests also include the study of European regulatory framework on the production, marketing and dispensing of medicinal products. To date, the research activity is documented by about 80 publications on international peer-review journals.

    View full text