Copaiba oil enhances in vitro/in vivo cutaneous
permeability and in vivo anti-inﬂammatory effect of
Oliesia Gonzalez Qui
, Bryan Hudson Hossy
, Tatiana Almeida Padua
adia Campos de Oliveira Miguel
, Elaine Cruz Rosas
onica Freiman de Souza Ramos
Maria Bernadete Riemma Pierre
School of Pharmacy, Federal University of Rio de Janeiro,
Institute of Biomedical Sciences, Federal University of Rio de Janeiro and
Applied Pharmacology, Fiocruz, Rio de Janeiro, RJ, Brazil
anti-inﬂammatory activity; celecoxib;
copaiba oil; cutaneous permeability; topical
Maria Bernadete Riemma Pierre, School of
Pharmacy, Federal University of Rio de
Janeiro – Av. Carlos Chagas Filho 373,
21941-590, Rio de Janeiro, RJ, Brazil.
Received August 16, 2017
Accepted February 10, 2018
Objectives The aim of this article was to use copaiba oil (C.O) to improve skin
permeability and topical anti-inﬂammatory activity of celecoxib (Cxb).
Methods Formulations containing C.O (1–50%) were associated with Cxb (2%).
In vitro skin permeability studies were conducted using porcine ear skin. Histo-
logical analysis of the hairless mice skin samples after application of formulations
was achieved with the routine haematoxylin/eosin technique. The anti-inﬂamma-
tory activity was assessed using the AA-induced ear oedema mice model.
Key ﬁndings The formulation containing 25% C.O promoted the highest levels
of in vitro Cxb permeation through pig ear skin, retention in the stratum cor-
neum (SC) and epidermis/dermis of pig ear skin in vitro (~5-fold) and hairless
mice skin in vivo (~2.0-fold), as compared with the control formulation. At 25%,
C.O caused SC disorganization and increased cell inﬁltration and induced angio-
genesis without clear signs of skin irritation. The formulation added to 25% C.O
as adjuvant inhibited ear oedema and protein extravasation by 77.51 and 89.7%,
respectively, and that it was, respectively, 2.0- and 3.4-fold more efﬁcient than
the commercial diethylammonium diclofenac cream gel to suppress these inﬂam-
Conclusions 25% C.O is a potential penetration enhancer for lipophilic drugs
like Cxb that can improve cutaneous drug penetration and its anti-inﬂammatory
Celecoxib (Cxb), the ﬁrst selective cyclooxygenase-2
(COX-2) inhibitor marketed,
has been widely used in
the treatment of osteoarthritis, rheumatoid arthritis,
acute pain and relief of symptoms of primary dysmenor-
Currently, Cxb is commercialized only as cap-
sules for oral administration
and it causes less
gastrointestinal adverse effects than conventional non-
steroidal anti-inﬂammatory drugs
mainly due to selec-
tive inhibition of COX-2.
The prolonged oral admin-
istration of Cxb still causes systemic toxicity, increasing
the risk of severe gastrointestinal
effects, which are dose dependent.
Topical administration of Cxb represents a viable alter-
native for the treatment of cutaneous diseases, including
chemoprevention of skin cancer
because it inhibits
inﬂammation, which is closely associated with the develop-
ment of this cancer type.
However, the high Cxb
lipophilicity and the excellent barrier properties of the stra-
tum corneum (SC) have hindered the development of topi-
cal or transdermal formulations of this drug.
formulations containing adjuvant substances that change
the organization of SC can enhance penetration/retention
of Cxb in the skin.
Compounds that can reversibly change the SC barrier
have been widely described as penetra-
tion enhancers (P.Es). Terpenes are naturally occurring
© 2018 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 70 (2018), pp. 964–975