Lipid-based carriers for the delivery of local anesthetics

ABSTRACT

Introduction: There is a clinical need for pharmaceutical dosage forms devised to prolong the acting time of local anesthetic (LA) agents or to reduce their toxicity. Encapsulation of LA in drug delivery systems (DDSs) can provide long-term anesthesia for inpatients (e.g. in immediate postsurgical pain control, avoiding the side effects from systemic analgesia) and diminished systemic toxicity for outpatients (in ambulatory/dentistry procedures). The lipid-based formulations described here, such as liposomes, microemulsions, and lipid nanoparticles, have provided several nanotechnological advances and therapeutic alternatives despite some inherent limitations associated with the fabrication processes, costs, and preclinical evaluation models.

Areas covered: A description of the currently promising lipid-based carriers, including liposomes, microemulsions, and nanostructured lipid carriers, followed by a systematic review of the existing lipid-based formulations proposed for LA. Trends in the research of these LA-in-DDS are then exposed, from the point of view of administration route and alternatives for non-traditionally administered LA molecules.

Expert opinion: Considering the current state and potential future developments in the field, we discuss the reasons for why dozens of formulations published every year fail to reach clinical trials; only one lipid-based formulation for the delivery of local anesthetic (Exparel®) has been approved so far.

KEYWORDS:

• Local anesthetics
• drug-delivery systems
• liposomes
• solid lipid nanoparticles
• nanostructured lipid carriers
• microemulsions
• routes of administration

Article highlights

• Long-term/low toxic anesthesia is most likely to be achieved with local anesthetics in nanotechnological products

• The route of administration determines the clinical efficacy and relative systemic toxicity of LA-in-nanocarrier formulations

• Liposomes are the most traditional lipid-based DDS; Ionic-gradient liposomes improve the upload capacity of liposomes for the charged LA form

• Microemulsions are effective systems for skin delivery of local anesthetics

• Lipid Nanoparticles (SLN, NLC) have proven advantages for encapsulating high amounts of base LA forms

• Dozens of pharmaceutical dosage formulations are published every year yet do not reach clinical trials, nor hit the market due to the fabrication process, costs, and preclinical assessment limitations

This box summarizes the key points contained in the article.

Declaration of interest

E de Paula and DR de Araújo are supported by FAPESP grant (#14/14457-5) and CNPq researcher fellowships. L Ribeiro is supported by a post-doc fellowship from FAPESP (#14/25372-0). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work has been sponsored in part by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP #14/14457-5; 14/25372-0). Conselho Nacional de Pesquinsa (CNPq #420869/2016-6).