Dexibuprofen Therapeutic Advances: Prodrugs and Nanotechnological Formulations

pharmaceutics Review Dexibuprofen Therapeutic Advances: Prodrugs and Nanotechnological Formulations Anna Gliszczy ńska 1,* and Elena Sánchez-López 2,3,* 1 Department of Chemistry, Wrocław University of Environmental and Life Sciences, Norwida 25, 50-375 Wrocław, Poland 2 Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, University of Barcelona, 08028 Barcelona, Spain 3 Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, 08028 Barcelona, Spain * Correspondence: [email protected] (A.G.); [email protected] (E.S.-L.) Abstract: S-(+) enantiomer of ibuprofen (IBU) dexibuprofen (DXI) is known to be more potent than its R-(−) form and exhibits many advantages over the racemic mixture of IBU such as lower toxicity, greater clinical efficacy, and lesser variability in therapeutic effects. Moreover, DXI potential has been recently advocated to reduce cancer development and prevent the development of neurode- generative diseases in addition to its anti-inflammatory properties. During the last decade, many attempts have been made to design novel formulations of DXI aimed at increasing its therapeutic benefits and minimizing the adverse effects. Therefore, this article summarizes pharmacological information about DXI, its pharmacokinetics, safety, and therapeutic outcomes. Moreover, modi- fied DXI drug delivery approaches are extensively discussed. Recent studies of DXI prodrugs and novel DXI nanoformulations are analyzed as well as reviewing their efficacy for ocular, skin, and oral applications. Citation: Gliszczyńska,A.; Sánchez-López, E. Dexibuprofen Keywords: dexibuprofen; NSAIDs; enantiomer; drug delivery; prodrugs Therapeutic Advances: Prodrugs and Nanotechnological Formulations. Pharmaceutics 2021, 13, 414. https://doi.org/10.3390/ 1. Introduction pharmaceutics13030414 Nonsteroidal anti-inflammatory drugs (NSAIDs) are members of a drug class that reduces pain, decreases fever, prevents blood clots, and decreases inflammation [1,2]. In Academic Editor: Armin Mooranian general, NSAIDs are characterized by a high degree of protein binding and small volumes of distribution [3]. However, in this family, differences in clearance and variability in Received: 8 February 2021 half-life are of special relevance. Among of all NSAIDs, ibuprofen (IBU) is one of the Accepted: 17 March 2021 most widely and frequently employed therapeutic agents with the lowest toxicity. IBU Published: 19 March 2021 was initially introduced in the UK in 1960s and afterwards during the 1970s worldwide as a prescription-only medication with recommendation dose 2400 mg/day (or higher in Publisher’s Note: MDPI stays neutral the USA) [4]. Nowadays, IBU is widely used in many countries and presents minimum with regard to jurisdictional claims in published maps and institutional affil- side effects involving gastric damage observed in many other NSAIDs. Over the last iations. three decades, the over-the-counter (OTC) IBU-containing preparations and the generic preparations sold by prescription and non-prescription are used as a NSAID with analgesic and antipyretic properties [5]. They are used for the treatment of osteoarthritis, rheumatoid arthritis and in a wide variety of other painful conditions [6]. These therapeutic effects come from activity of IBU to block prostaglandin synthesis by a non-selective, reversible Copyright: © 2021 by the authors. inhibition of the cyclooxygenase enzymes COX-1 and COX-2 [7]. IBU achieves high plasma Licensee MDPI, Basel, Switzerland. protein binding and low distribution volume, but it possesses the ability to be accumulated This article is an open access article in effective amounts in compartments where inflammation occurs. These compartments, distributed under the terms and conditions of the Creative Commons such as cerebrospinal fluid (CSF) where there is need for anti-inflammatory/analgesic Attribution (CC BY) license (https:// activity, are the target of IBU. creativecommons.org/licenses/by/ In most of the commercially available preparations, IBU occurs only as a diastereoiso- 4.0/). meric mixture which comprises equal quantities of R-(−)-ibuprofen and S-(+)-ibuprofen. Pharmaceutics 2021, 13, 414. https://doi.org/10.3390/pharmaceutics13030414 https://www.mdpi.com/journal/pharmaceutics Pharmaceutics 2021, 13, 414 2 of 19 Pharmaceutics 2021, 13, 414 2 of 18 In most of the commercially available preparations, IBU occurs only as a diastereoi- someric mixture which comprises equal quantities of R-(−)-ibuprofen and S-(+)-ibuprofen. DextrarotatoryDextrarotatory isomer of ibuprofen ibuprofen dexibuprofen dexibuprofen (DXI) is the the pharmacologically pharmacologically effective enantiomer,enantiomer, whichwhich waswas for for the the first first time time launched launched in Austriain Austria in 1994 in 1994 [8]. Racemic[8]. Racemic ibuprofen ibu- profenand DXI and differ DXI in differ their in physical, their physical, chemical, chemic and pharmacologicalal, and pharmacological properties properties as well as theirwell asmetabolic their metabolic profile [profile5,9]. In [5,9]. the last In the five last years, five 4836 years, patients 4836 patients have been have exposed been exposed to DXI to in DXIclinical in clinical trials and trials post and marketing post marketing surveillance surveillance (PMS) (PMS) trials. trials. Only inOnly 3.7% in of3.7% patients of patients have haveadverse adverse drug reactionsdrug reactions been reportedbeen reported and three and seriousthree serious adverse adverse drug reactions drug reactions (0.06%) (0.06%)occurred occurred [5]. It has [5]. been It has proven been inproven the in in vitro the modelin vitro that model dextrarotatory that dextrarotatory isomer exhibits isomer exhibitsabout 160-times about 160-times higher activity higher inactivity prostaglandins in prostaglandins inhibition inhibition in comparison in comparison to enantiomer to enantiomer(R). Other (R studies). Other of studies thromboxane of thromboxane generation generati in clottingon in clotting blood also blood confirmed also confirmed higher higheractivity activity of enantiomer of enantiomerS than S racemate than racemate [10]. Therefore, [10]. Therefore, it would it would be highly be highly advantageous advan- tageousto use DXI to use asa DXI pain as reliver. a pain Especially,reliver. Especially due to the, due fact to thatthe fact while that DXI while effectively DXI effectively inhibits inhibitsthe activity the activity of COX-1 of COX-1 and COX-2, and COX-2, the enantiomer the enantiomer (R) demonstrates (R) demonstrates the inhibition the inhibition only onlytowards towards COX-1 COX-1 and itand is worth it is worth noting noting that it that is responsible it is responsible increasing increasing the side the effects side effects in the ingastrointestinal the gastrointestinal tract [ 11tract]. [11]. rac-rac-IbuprofenIbuprofen undergoes an unusual metabolicmetabolic fatefate becausebecause inactiveinactive RR-(-(−−)-ibuprofen)-ibuprofen isis enzymatically enzymatically converted converted to to the therapeutically active enantiomer S-(+) [12]. [12]. This This may contributecontribute to to variability variability in in analgesia analgesia including including delayed delayed onset onset of activity and may explain thethe poorpoor relationshiprelationship observed observed between between plasma plasma concentrations concentrations of IBU of IBU and clinicaland clinical response re- sponsefor acute for pain acute and pain rheumatoid and rheumatoid arthritis arthritis [13]. According[13]. According to published to published data indata humans, in humans,average average 50% of 50% enantiomer of enantiomer (−) is ( metabolically−) is metabolically converted converted via catalytic via catalytic activity activity of fatty of fattyacyl acyl coenzyme coenzyme thioesterase thioesterase to more to more active active enantiomer enantiomer (+) (+) [14 [14,15],15] in in the the intestinalintestinal tract andand liver liver after after oral oral absorption absorption [16,17]. [16,17]. However, However, it it should should be be pointed out that the level of metabolicmetabolic inversion inversion of of IBU IBU may may vary between 35 and 85% depending on the formulation type,type, condition condition of of the the liver, liver, the the intake intake of of me medicines,dicines, and and the the state state of of the the disease disease [18,19]. [18,19]. DuringDuring this this process, the first first step is thethe activationactivation ofof RR-(-(−−)-ibuprofen)-ibuprofen in in the the presence of 2+ coenzymecoenzyme A A (CoA), (CoA), adenosine adenosine triphosphate triphosphate (ATP), and Mg2+ (Figure(Figure 1).1). OH O rac-ibuprofen H3C H H3C H carboxy-S-ibuprofen carboxy-R-ibuprofen OH OH hydroxy-S-ibuprofen hydroxy-R-ibuprofen S-ibuprofen glucuronide O O R-ibuprofen glucuronide S-(+)-ibuprofen R-(-)-ibuprofen acyl-CoA synthetase CoA ATP, Mg 2+ H C H H3C H 3 SCoA SCoA epimerase O O S-(+)-ibuprofenoyl-CoA R-(-)-ibuprofenoyl-CoA hybrid triglycerides incorporating ibuprofen FigureFigure 1.1. Metabolic conversion ofof RR-(-(−−)-ibuprofen)-ibuprofen to to SS-(+)-ibuprofen.-(+)-ibuprofen. Next, the AMP-derivative is esterified with coenzyme A (CoA) by the action of acyl-CoA synthetase. R-(−)-ibuprofen-CoA undergoes epimerization via the actions of the Pharmaceutics 2021, 13, 414 3 of 18 -methylacyl-coenzyme A racemase (encoded by gene AMACR) [20] to form S-(+)-ibuprofen- CoA, which is then hydrolyzed by a hydrolase to form S-(+)-ibuprofen [5]. The key step of this process is

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