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Co-crystals as a new approach to multimodal analgesia and the treatment of pain

Authors Almansa C, Frampton CS, Vela JM, Whitelock S, Plata-Salamán CR

Received 9 March 2019

Accepted for publication 22 July 2019

Published 4 September 2019 Volume 2019:12 Pages 2679—2689


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Erica Wegrzyn

Carmen Almansa,1 Christopher S Frampton,2 José Miguel Vela,1 Steve Whitelock,3 Carlos R Plata-Salamán4

1Esteve Pharmaceuticals, S.A., Parc Cientific Barcelona, Barcelona 08028, Spain; 2Rbar3 Ltd, Cambridge, UK; 3Mundipharma Research Ltd, Cambridge, UK; 4Esteve Pharmaceuticals, S.A., Torre Esteve, Barcelona 08038, Spain

Correspondence: Carmen Almansa
Esteve Pharmaceuticals, S.A., Parc Cientific Barcelona, C/Baldiri Reixac 4–8, Barcelona 08028, Spain
Tel +34 93 446 6148
Fax +34 93 446 6432

Abstract: Pain is highly prevalent, but frequently untreated or under-treated, and health care professionals are faced with a range of treatment challenges. Multimodal therapy is recommended and can be achieved using open combinations (ie, concomitant administration) of individual agents, fixed-dose combinations (FDCs), or multimodal agents (ie, single agents with multiple mechanisms of action). Co-crystallization of active pharmaceutical ingredients (APIs) offers another approach, with the potential to provide drugs with unique properties and advantages for therapeutic applications compared to combinations. API–API co-crystals are single-entity forms that offer a unique possibility of improving the physicochemical properties of both constituent APIs, as well as permitting their synchronous release. Consequently, this may positively impact on their pharmacokinetic (PK) properties and profiles, providing a potential advantage over FDCs and translating into improved clinical efficacy and safety profiles. We report here a revision of the literature concerning API–API co-crystals for the treatment of pain. It becomes apparent that identifying APIs with complementary mechanisms of action that can be adequately co-crystallized in an appropriate molecular ratio applicable for therapeutic use is challenging. In addition, API–API co-crystals normally result in a mere increased exposure of an API without defined clinical benefits (since, to maintain the benefit-risk, the dose needs to be proportionally reduced to adjust for the increased exposure). An exception to this is the co-crystal of tramadol-celecoxib (CTC), that represents a unique concept in co-crystal technology. In CTC neither of its three active components that have complementary mechanisms of action (ie, the two enantiomers of tramadol and celecoxib) show increased exposure levels versus commercially available single-entity reference products, but rather show a change in their PK profile with potential clinical advantages. CTC is in Phase III clinical development for the treatment of pain.

Keywords: co-crystal, efficacy, pain, multimodal, pharmacokinetics, physicochemical properties, safety

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