LINK PARA MINHA PAGINA NO RESEARCH GATE:

https://www.researchgate.net/profile/Maria_Bernadete_Pierre?ev=hdr_xprf 

In vitro Studies of Antitumor Effect, Toxicity/Cytotoxicity and Skin Permeation/Retention of a Green Fluorescence Pyrene‐based Dye for PDT Application. 

de França, B.M., Ghasemishahrestani, Z., de Souza, G.F., da Silva, R.N., Queiroz, D.D., Pierre, M.B.R., Pereira, M.D., Forero, J.S. and Corrêa, R.J. (2020), In vitro Studies of Antitumor Effect, Toxicity/Cytotoxicity and Skin Permeation/Retention of a Green Fluorescence Pyrene‐based Dye for PDT Application. Photochemistry and Photobiology. Accepted Author Manuscript. doi:10.1111/php.13335. Publicado online em 24 setembro de 2020.

ABSTRACT Photosensitizers (PS) are compounds that can generate reactive oxygen species under irradiation of appropriate light and are widely used in photodynamic therapy (PDT). Currently, topical PDT is an effective treatment for several skin diseases, including bacterial infections, fungal mycoses and psoriasis. In addition, PDT is also used to treat non‐melanoma skin cancer and can be a potential tool for melanoma, associated with other treatments. In this work, we evaluated the antitumor photoactivity of a new pyrene‐based PS (TPPy) by using the murine melanoma cell line (B16F10). The in vitro permeation/retention tests in porcine ear skin were also performed in order to evaluate the potential application of the PS for topical use in skin cancer. Moreover, to determine the toxicity in vivo, we used the Galleria mellonella as an alternative animal model of study. The results showed that TPPy is a promising PS for application in PDT, with potential antitumor photoactivity (IC50 6.5 μmol L‐1), absence of toxicity in the G. mellonella model at higher concentration (70.0 mmol L‐1) and the accumulation tendency in the Epidermis plus Dermis sites (165.20 ± 4.12 ng/cm2).

Caixa de texto

Polymeric nanoparticles favor the in vitro dermal accumulation of Protoporphyrin IX (PpIX) with optimal biocompatibility and cellular recovery in culture of healthy dermal fibroblasts after Photodynamic Therapy.

Journal of Photochemistry & Photobiology, A: Chemistry

Volume 386, 1 January 2020, 112109

https://doi.org/10.1016/j.jphotochem.2019.112109

artigo publicado:

https://reader.elsevier.com/reader/sd/pii/S1010603019311827?token=F3C75C4E263B92606CB2BD295A1A3E871634B71EC334886E1F4344E9139E25392757FA653B65DF7131CAB0071D8533F2

Abstract

The aim of this study was to investigate (i) the cutaneous accumulation of photosensitizer (PS) protoporphyrin IX (PpIX) encapsulated in nanoparticles (Np) by confocal laser scanning microscopy (CLSM) in animal model skin (ii) the in vitro dark cytotoxicity and phototoxicity of PpIX-Nps in dermal fibroblast cells (L929 fibroblast cells and (iii) the recovery of cell viability after PDT. The CLSM has shown higher PS concentration in the superficial skin; the stratum corneum (SC) for both encapsulated and free PpIX for all times evaluated (4 h, 8 h and 24 h). Although with lower PS accumulation in the deeper layers of the skin, ie; Epidermis + Dermis (EP + D) after 8 h the PS accumulation was significantly higher when encapsulated in Np. In brief, PpIX-Np was not cytotoxic to fibroblast cells in the dark (˜ 100% viable cells; excellent biocompatibility) and in the presence of light 8 h post incubation (phototoxicity) reached CC50 = 7.01 μg / ml (compared to free PpIX, CC50 = 0.84 μg / ml) meaning that PpIX in Nps were phototoxic to cells as expected; however at higher concentrations than free PpIX. Moreover, PpIX-Np has shown 100% of cell recovery 24 h post PDT in the fibroblast cells, indicating photoactivation protection of PpIX by the Nps in the healthy cells.

Caixa de texto

Controlling burst effect with PLA/PVA coaxial electrospun scaffolds loaded with BMP-2 for bone guided regeneration Talita Nascimentoda Silva, Raquel PiresGonçalves, Carol L.Rocha, Bráulio S.Archanjo, Carlos Augusto G.Barboza, Maria Bernadete R.Pierre, FrancelineReynaud, Paulo Henriquede Souza Picciani. Materials Science and Engineering: C, Volume 97, April 2019, Pages 602-612

Abstract

Biocompatible scaffolds have been used to promote cellular growth and proliferation in order to develop grafts, prostheses, artificial skins and cartilage. Electrospinning is widely studied as a method capable of producing nanofibers which enables cell attachment and proliferation, generating a functional scaffold that is suitable for many types of organs or tissues. In this study, electrospinning was used to obtain core-shell and monolithic fibers from the biocompatible poly (lactic acid) and poly (vinyl alcohol) polymers. The main purpose of this work is to produce core-shell nanofiber based scaffolds that works as a sustained delivery vehicle for BMP-2 protein, allowing those fibers to be used in the recovery of alveolar bone tissue without further bone surgery. Then, polymer nanofibers were manufactured by optimizing process parameters of coaxial electrospinning with emphasis on the most relevant ones: voltage, internal and external flows in an attempt to correlate fibers properties with protein releasing abilities. All nanofibers were characterized according to its morphology, thermal behaviour, crystallinity and release profile. For the release tests, bovine albumin was added into internal fiber for future periodontal restorage application. Obtained results demonstrate that fibers were formed with diameters up to 250 nm. According to electronic microscopy images, one could observe surface of nanofibers, thickness and core-shell morphology confirmed. X-ray diffraction analysis and contact angle tests showed fibers with low crystal degree and low hydrophobicity. Nanofibers structure affected in vitro release model tests and consequently the cellular assays.

https://www.sciencedirect.com/science/article/pii/S0928493118322938?via%3Dihu

Caixa de texto

Cutaneous Application of Celecoxib for Inflammatory and Cancer Diseases. 

Curr Cancer Drug Targets. 2018 Apr 30. doi: 10.2174/1568009618666180430125201. [Epub ahead of print]

Quinones OG1, Pierre MBR1. J Pharm Pharmacol. 2018 Jul;70(7):964-975. doi: 10.1111/jphp.12906. Epub 2018 Mar 29.

https://www.ncbi.nlm.nih.gov/pubmed/29714143

http://www.eurekaselect.com/161688/article

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) and particularly selective cyclooxygenase-2 (COX-2) inhibitors such as celecoxib (Cxb) are considered promising cancer chemopreventive for colon, breast, prostate, lung, and skin cancers. However, the clinical application to the prevention is limited by concerns about safety, potential to serious toxicity (mainly for healthy individuals), efficacy and optimal treatment regimen. Cxb exhibits advantages as potent antiinflammatory and gastrointestinal tolerance compared with conventional NSAID’s. Recent researches suggest that dermatological formulations of Cxb are more suitable than oral administration in the treatment of cutaneous disease, including skin cancer. To date, optimism has been growing regarding the exploration of the topical application of Cxb (in the prevention of skin cancers and treatment of cutaneous inflammation) or transdermal route reducing risks of systemic side effects.

Objective: This paper briefly summarizes our current knowledge of the development of the cutaneous formulations or delivery systems for Cxb as anti-inflammatory drug (for topical or transdermal application) as well its chemopreventive properties focused on skin cancer.

Conclusion: New perspectives emerge from the growing knowledge, bringing innovative techniques combining the action of Cxb with other substances or agents which act in a different way, but complementary, increasing the efficacy and minimizing toxicity.

Caixa de texto

Copaiba oil enhances in vitro/in vivo cutaneous permeability and in vivo anti-inflammatory effect of celecoxib.

Quiñones OG1, Hossy BH1, Padua TA2, Miguel NCO3, Rosas EC2, Ramos MFS1, Pierre MBR1

Abstract

The aim of this article was to use copaiba oil (C.O) to improve skin permeability and topical anti-inflammatory activity of celecoxib (Cxb).

Formulations containing C.O (1-50%) were associated with Cxb (2%). In vitro skin permeability studies were conducted using porcine ear skin. Histological analysis of the hairless mice skin samples after application of formulations was achieved with the routine haematoxylin/eosin technique. The anti-inflammatory activity was assessed using the AA-induced ear oedema mice model.

The formulation containing 25% C.O promoted the highest levels of in vitro Cxb permeation through pig ear skin, retention in the stratum corneum (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 angiogenesis 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 inflammatory parameters.

25% C.O is a potential penetration enhancer for lipophilic drugs like Cxb that can improve cutaneous drug penetration and its anti-inflammatory activity.

https://www.ncbi.nlm.nih.gov/pubmed/29600536

Caixa de texto

Liquid Crystalline Systems Based on Glyceryl Monooleate and Penetration Enhancers for Skin Delivery of  Celecoxib: Characterization, In Vitro Drug Release, and In Vivo Studies

Mariane de Cássia LimaDante, Livia NevesBorgheti-Cardoso, Marcia Carvalho de AbreuFantini, Fabíola Silva GarciaPraça, Wanessa Silva GarciaMedina, Maria Bernadete RiemmaPierre, Marilisa GuimarãesLara

• Journal of Pharmaceutical Sciences, In press, corrected proof, Available online 4 November 2017

ABSTRACT

Celecoxib (CXB) is a widely used anti-inflammatory drug that also acts as a chemopreventive agent against several types of cancer, including skin cancer. As the long-term oral administration of CXB has been associated with severe side effects, the skin delivery of this drug represents a promising alternative for the treatment of skin inflammatory conditions and chemoprevention of skin cancer. We prepared and characterized liquid crystalline systems based on glyceryl monooleate and water containing penetration enhancers which were primarily designed to promote skin delivery of CXB. Analysis of their phase behavior revealed the formation of cubic and hexagonal phases depending on the systems' composition. The systems' structure and composition markedly affected the in vitro CXB release profile. Oleic acid reduced CXB release rate, but association oleic acid/propylene glycol increased the drug release rate. The developed systems significantly reduced inflammation in an aerosil-induced rat paw edema model. The systems' composition and liquid crystalline structure influenced their anti-inflammatory potency. Cubic phase systems containing oleic acid/propylene glycol association reduced edema in a sustained manner, indicating that they modulate CXB release and permeation. Our findings demonstrate that the developed liquid crystalline systems are potential carriers for the skin delivery of CXB.

https://www.sciencedirect.com/science/article/pii/S0022354917307785

Copaiba oil: chemical composition and influence on in vitro cutaneous permeability of Celecoxib

Article Details

VOLUME: 14 

Year: 2017 (E-pub Abstract Ahead of Print)

DOI: 10.2174/1567201814666170825154453 

http://www.eurekaselect.com/155178/article?utm_source=TrendMD&utm_medium=cpc&utm_campaign=Curr_Drug_Deliv_TrendMD_

Abstract:

Background: Use of topical or transdermal administration of Celecoxib (Cxb) is an interesting strategy in cutaneous treatments since it reduces or avoids side effects of the oral route. However, Cxb´s high lipophilicity and the stratum corneum (SC) barrier impair cutaneous penetration. Objective: evaluate copaiba oil (C.O) as a potential skin penetration enhancer (P.E) for Cxb. Methods: The chemical composition of C.O was evaluated by GC-MS. Both in vitro release and permeability assay of Cxb in Polyethylene glycol 400/ propylene glycol (PEG 400/PG) vehicle associated to C.O (1-50% w/w) were determined in a modified diffusion cell fitted with a synthetic hydrophobic membrane and pig ear skin as model, respectively. Results: GC-MS analysis of C.O showed that it is composed of sesquiterpenes (68.65%) and diterpenes (22.26%). Formulations containing 25% C.O (F4) and 50% C.O (F5) have shown in vitro burst release in the first 2 h, but only F4 released 100% of drug after 24 h. The highest Cxb permeation across skin was obtained from F4 and the highest skin retentions for F4 and F5 in the stratum corneum and epidermis plus dermis. Conclusion: The increased Cxb permeability through skin and its retention for an extended time (24h) at 25% C.O suggest that it could be a promising adjuvant for the development of transdermal formulations of Cxb.

Keywords: copaiba oil, chemical composition, GC-MS methodology, in vitro cutaneous permeability, celecoxib, topical route, transdermal route.

http://benthamscience.com/journals/current-drug-delivery/volume/14/

Caixa de texto

J Photochem Photobiol B. 2017 Aug 8;174:298-305. doi: 10.1016/j.jphotobiol.2017.08.013. [Epub ahead of print]

α-Bisabolol improves 5-aminolevulinic acid retention in buccal tissues: Potential application in the photodynamic therapy of oral cancer.

Quintanilha NP1, Dos Santos Miranda Costa I1, Freiman de Souza Ramos M1, Campos de Oliveira Miguel N2, Riemma Pierre MB3.

Author information

Abstract

5-Aminolevulinic acid (5-ALA) is a prodrug used in photodynamic therapy (PDT) of tumors, including cancer of the oral mucosa. 5-ALA poorly penetrates oral tissues due to its high hydrophilicity, which impairs its local effects in PDT.

To examine whether α-bisabolol (α-Bis) influences the 5-ALA permeability in the porcine buccal mucosa, to an extent that improves its application in PDT (which requires low permeation and high retention in the buccal mucosa).

In vitro permeability studies with 5-ALA (1% and 10% w/w) associated with α-Bis (1% to 20% w/w) in propylene glycol were carried out at 4h and 24h using porcine buccal mucosa in a modified Franz cell system. The in vitro release profiles (0.5 to 48h) of the selected formulation and its respective control were determined using artificial membranes. Samples of buccal mucosa treated with the formulation were submitted to histopathological analysis, using a routine optical microscopy technique.

The association of 1% 5-ALA and 5% α-Bis provided the best results; after 4h of treatment with this formulation, the 5-ALA permeation was low and its retention in the mucosa was six-fold higher than that promoted by the control formulation (5-ALA alone). Histological analysis of the porcine buccal mucosa evidenced that 5% α-Bis altered the tissue morphology, which probably promoted 5-ALA retention. We concluded that 5% α-Bis is a potential adjuvant in formulations containing 5-ALA that could improve its retention after topical oral administration for the PDT treatment of cancer.

Copyright © 2017. Published by Elsevier B.V.

5-ALA; Histopathological analysis; Oral cancer; Photodynamic therapy; α-Bisabolol

PMID: 28818775 DOI: 10.1016/j.jphotobiol.2017.08.013

http://www.sciencedirect.com/science/article/pii/S1011134417303585

Caixa de texto

Curr Drug Deliv. 2017 Jan 25. [Epub ahead of print] Volume 14 , Issue 7 , 2017

In vitro and in vivo Evaluation of DMSO and Azone as Penetration Enhancers for Cutaneous Application of Celecoxib.

Senna TD, Santos HA, Kibwila DM, Leitão AC, Pyrrho AD, Pádula M, Rosas EC, Pádua TA, Lara MG, Pierre MB1.

Abstract

Celecoxib (CXB) has been explored as an anti-inflammatory or chemopreventive drug for topical treatment of skin diseases and cancer.

The main aim of this work was to investigate the potential of dimethylsufoxide (DMSO) and Azone (AZ) as penetration enhancers (P.Es) for topical delivery of CXB.

The in vitro studies, drug release, skin permeability and potential cytotoxicity/genotoxicity were carried out with formulations containing or not DMSO or AZ (5% and 10%). Skin irritation in rabbits and topical anti-inflammatory activity in mice were assayed in vivo.

Skin permeation was minimal while higher retention in SC and epidermis plus dermis was found (28.0 and 3 -fold respectively) from 10.0% AZ compared to the control indicating a localized CXB effect. CXB associated to 5% or 10% DMSO has shown high drug permeation through skin with low retention. Associations of CXB with both enhancers were not cytotoxic or genotoxic, suggesting safety for cutaneous application. In vivo skin irritation assays of all formulations indicated mild irritation effects and, thus, possible use for longer periods. In vivo anti-inflammatory tests showed that ear edema could be inhibited by CXB associated with 5.0% DMSO (53.0%) or 10.0% AZ (40.0%).These inhibition values were almost 2-fold higher when compared to a commercial formula.

Although DMSO- associated CXB is an efficient edema inhibitor its high skin permeation suggests risks of systemic effects, whereas association to 10%AZ may improve topical delivery of the drug with good anti-inflammatory activity and no cytotoxic/genotoxic or significant skin irritation effects.

https://www.ncbi.nlm.nih.gov/pubmed/28124617

http://www.eurekaselect.com/149496/article

Caixa de texto

EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES (2016)

Optimization of protoporphyrin IX skin delivery for topical photodynamic therapy: Nanodispersions of liquid-crystalline phase as nanocarriers

Fabia Cristina Rossetti, Lıvia Vieira Depieri, Fab´ıola Garcia Praca, Jose

Orestes Del Ciampo, Marcia C.A. Fantini, Maria Bernadete Riemma Pierre,

Antonio Claudio Tedesco, Maria Vitoria Lopes Badra Bentley

DOI: doi: 10.1016/j.ejps.2015.12.003

http://www.sciencedirect.com/science/article/pii/S0928098715300774

ABSTRACT

Nanodispersions of liquid-crystalline phases (NLPs) composed of monoolein and oleic acid were chosen as nanocarriers to improve the topical retention of the photosensitizer protoporphyrin IX (PpIX) and thereby optimize photodynamic therapy (PDT) using this photosensitizer. The nanodispersions were characterized by polarized light microscopy, small-angle X-ray diffraction and dynamic light scattering. The

stability and encapsulation efficiency (EE%) of the nanodispersions were also evaluated. In vitro and in vivo skin penetration studies were performed to determine the potential of the nanodispersions for cutaneous application. In addition, skin penetration and skin irritancy (in an animal model) after in vivo application were visualized by fluorescence light microscopy. The nanodispersion obtained was characterized as a monodisperse system (~150.0 nm) of hexagonal liquid-crystalline phase, which provided a high encapsulation efficiency of PpIX (~88 %) that remained stable over 90 days of investigation. Skin penetration studies demonstrated that the nanodispersion enhanced PpIX skin uptake 11.8- and 3.3-fold (in vitro) and 23.6- and 20.8-fold (in vivo) compared to the PpIX skin uptake of control formulations, respectively. In addition, the hexagonal phase nanodispersion did not cause skin irritation after application for two consecutive days. Overall, the results show that the nanocarrier developed is suitable for use in topical PDT with PpIX.

Keywords: Photodynamic therapy, Protoporphyrin IX, Skin penetration, Hexagonal phase nanodispersion, Monoolein.

Caixa de texto

Photodiagnosis and Photodynamic Therapy (2015)

2015 Mar;12(1):98-107. doi: 10.1016/j.pdpdt.2014.11.003. Epub 2014 Nov 25       

Using chitosan gels as a toluidine blue delivery system for photodynamic therapy of buccal cancer: In vitro and in vivo studies

Thierllen Barroso Gracianoa, Tatielle Soares Coutinhoa,Camila Beatriz Cressonia, Cristhiane de Paula Freitasa,Maria Bernadete Riemma Pierreb,Sanívia Aparecida de Lima Pereirac, Marcos Massao Shimanod,Renata Cristina da Cunha Frangea,Maria Teresa Junqueira Garcia

Summary

Background: Photodynamic therapy (PDT) is an emerging treatment that has demonstratedpotential for the clinical treatment of buccal cancer. It is based on the photoactivation of aphotosensitizer (PS) when irradiated by light at a specific wavelength. The light-excited PSgenerates reactive oxygen species that cause the destruction of tumor cells by apoptosis ornecrosis. Toluidine Blue O (TBO) is a PS that has shown potential for PDT in cancer treatment.However, saliva and mechanical activities quickly remove the PS from the surface of the buccalmucosa. Therefore, the bioavailability of PS at the surface of target tissues is reduced. The aimof this study was to evaluate the potential of chitosan (CH) gels in TBO delivery to buccal tissue.Methods: CH gels were obtained at different concentrations and their physico-chemical prop-erties (pH and rheology), mucoadhesion, in vitro release profile, in vivo retention and in vivoefficacy by the ability to induce cell apoptosis were evaluated.

Caixa de texto

APS PharmSciTech, Vol. 15, No. 6, December 2014    

DOI: 10.1208/s12249-014-0171-2

Liquid Crystalline Systems for Transdermal Delivery of Celecoxib: In Vitro Drug Release and Skin Permeation Studies

Éder André Estracanholli, Fabíola Silva Garcia Praça, Ana Beatriz Cintra,

Maria Bernadete Riemma Pierre, and Marilisa Guimarães Lara

Abstract. Liquid crystalline systems of monoolein/water could be a promising approach for the delivery of celecoxib (CXB) to the skin because these systems can sustain drug release, improve drug penetration into the skin layers and minimize side effects. This study evaluated the potential of these systems for the delivery of CXB into the skin based on in vitro drug release and skin permeation studies. The amount of CXB that permeated into and/or was retained in the skin was assayed using an HPLC method. Polarizing light microscopy studies showed that liquid crystalline systems of monoolein/water were formed in the

presence of CXB, without any changes in the mesophases. The liquid crystalline systems decreased drug release when compared to control solution. Drug release was independent of the initial water content of the systems and CXB was released from cubic phase systems, irrespective of the initial water content. The systems released the CXB following zero-order release kinetics. In vitro drug that cubic phase systems allowed drug permeation and retention in the skin layers. Cubic phase systems of monoolein/water may be promising vehicles for the delivery of CXB in/through the skin because it improved CXB skin permeation compared with the control solution

Caixa de texto

Chitosan-based mucoadhesive films containing 5- aminolevulinic acid for buccal cancer’s treatment. 

Irina dos Santos Miranda Costa, Renata Pereira Abranches, Maria Teresa Junqueira Garcia, Maria Bernadete Riemma Pierre. Journal of Photochemistry and Photobiology B: Biology. Volume 140, November 2014, Pages 266–275. 

https://www.ncbi.nlm.nih.gov/pubmed/25190225

ABSTRACT

Photodynamic therapy (PDT) is a relatively new method to treat various kinds of tumors, including those of the oral cavity. The topical 5-ALA-PDT treatment for tumors of the oral mucosa is preferred, since when administered systemically, there is a general photosensitization drawback in the patient. However, 5-ALA is a hydrophilic molecule and its penetration and retention is limited by topical route, including oral

mucosa. We propose a topical delivery system of chitosan-based mucoadhesive film, aiming to promote greater retention of 5-ALA in tissue. The chitosan (CHT) films (4% w/w) were prepared using the solvent evaporation/casting technique. They were tested without 5-ALA resulting in permeability to water vapor (W.V.P = 2.15–8.54 g mm/(h cm2 Pa) swelling .300.0% (±10.5) at 4 h or 24 h and in vitro residence time >24 h for all tests. CHT films containing 10.0% (w/w) 5-ALA have resulted in average weight of 0.22 g and thickness of 0.608 mm as suitable characteristics for oral application. In the presence of CHT films both in vitro permeation and retention of 5-ALA (1.0% or 10.0%) were increased. However, 10.0% 5-ALA presented highest values of permeation and retention (.4 and 17 times respectively, compared to propylene glycol vehicle). On the other hand, in vitro mucoadhesion of CHT films was decreased (18.2-fold and 3.1- fold) by 5-ALA addition (1.0% or 10.0% respectively). However, CHT film containing 10.0% of 5-ALA can be a potential delivery system for topical use in the treatment of tumors of the oral cavity using PDT because it favored the retention of 5-ALA in this tissue and has shown convenient mucoadhesion.

Caixa de texto

J Nanosci Nanotechnol. 2013 Oct;13(10):6533-40.

PLGA nanoparticles as delivery systems for protoporphyrin IX in topical PDT: cutaneous penetration of photosensitizer observed by fluorescence microscopy.

da Silva CL, Del Ciampo JO, Rossetti FC, Bentley MV, Pierre MB.

Source

School of Pharmacy, Department of Medicine, Federal University of Rio de Janeiro, Av Carlos Chagas Filho 373, 21.941.902, Rio de Janeiro, RJ, Brazil.

Abstract

Poly(D,L lactic-co-glycolic acid) (PLGA) based nanoparticles (NPs) are proposed for topical delivery of Protoporphyrin IX (PpIX) in Photodynamic Therapy of skin cancers. PpIX loaded into PLGA NPs showed nanometric average diameter (-280 nm), spherical forms and pH - 5.7, conditions suitable for topical application. In vitro release of PpIX from NPs was sustained up to 24 hr with a burst release effect of about 37.0% at 2 hr. Penetration and distribution of PpIX in hairless mice skin was determined by fluorescence microscopy 8 or 24 hrs after application of PpIX-NPs in the animals. At 24 hours, areas located in deeper regions of the skin were found to have greater fluorescence intensity. The finding indicates a localized effect of PpIX-NPs in the epidermis plus dermis--a site of action for topical PDT--and suggests a potential use of PpIX-NPs in PDT associated to skin cancer treatments.

 http://www.ncbi.nlm.nih.gov/pubmed/24245111

Caixa de texto

Curr Drug Targets. 2013 Oct 22. [Epub ahead of print], v 15 (3), 2014.

Microneedle-Based Drug Delivery Systems for Transdermal Route.

Pierre MB, Rossetti FC.

Source

Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Av. Carlos Chagas Filho 373, 21.941.902, Rio de Janeiro, RJ, Brazil. bernadete@pharma.ufrj.br.

Abstract

Transdermal delivery offers an attractive, noninvasive administration route but it is limited by the skin's barrier to penetration. Minimally invasive techniques, such as the use of microneedles (MNs), bypass the stratum corneum (SC) barrier to permit the drug's direct access to the viable epidermis. These novel micro devices have been developed to puncture the skin for the transdermal delivery of hydrophilic drugs and macromolecules, including peptides, DNA and other molecules, that would otherwise have difficulty passing the outermost layer of the skin, the SC. Using the tools of the microelectronics industry, MNs have been fabricated with a range of sizes, shapes and materials. MNs have been shown to be robust enough to penetrate the skin and dramatically increase the skin permeability of several drugs. Moreover, MNs have reduced needle insertion pain and tissue trauma and provided controlled delivery across the skin. This review focuses on the current state of the art in the transdermal delivery of drugs using various types of MNs and developments in the field of microscale devices, as well as examples of their uses and clinical safety.

Caixa de texto

Drug Dev Ind Pharm. 2013 Jul 4. [Epub ahead of print]

In vitro and in vivo influence of penetration enhancers in the topical application of celecoxib.

Quiñones OG, Mata Dos Santos HA, Kibwila DM, Leitão A, Dos Santos Pyrrho A, Pádula MD, Rosas EC, Lara MG, Pierre MB.

Source

School of Pharmacy, Federal University of Rio de Janeiro , Rio de Janeiro, RJ , Brazil .

Abstract

Abstract Objective: We investigated the potential effects of oleic acid (OA) and glycerol monooleate (GMO) on the skin delivery of CXB. Methods: The influence of both OA and GMO (5.0% or 10.0%) on the in vitro skin permeability of CXB (2.0%) was evaluated using propylene glycol (PG) as a vehicle. Also the in vitro potential cytotoxicity and genotoxicity and in vivo assays (skin irritation in rabbits and topical anti-inflammatory activity by in mice) were conducted. Results: As expected, the amount of CXB that permeated through the skin was minimal, but drug retention on the viable skin (epidermis plus dermis) was higher in association with treatment with 5.0% OA or GMO compared to the control treatment, meaning that there was a localized effect of CXB in the skin. No formulation presented cytotoxic or genotoxic potential, suggesting safety for cutaneous application. In vivo skin irritation assays indicated that no formulation was irritating to the skin becomes its use possible for a prolonged time. In vivo anti-inflammatory experiments indicated that both edema and protein extravasation were inhibited with a maximum % inhibition of 53.5.0% and 61.0% for 5.0 % GMO, respectively, and 48.0% and 35.5% for 5.0% OA, respectively. Such formulations were able to inhibit around twofold the percentage of ear edema in mice compared to a commercial product reference diclofenac commercial formula. Conclusion: There is no topical formulation currently available that contains both CXB and 5.0% GMO or OA, suggesting them as potential adjuvants that improve the skin delivery of CXB.

Caixa de texto

Photochem Photobiol. 2013 Sep-Oct;89(5):1176-84. doi: 10.1111/php.12121. Epub 2013 Aug 28.

Improved in vitro and in vivo cutaneous delivery of protoporphyrin IX from PLGA-based nanoparticles.

da Silva CL, Del Ciampo JO, Rossetti FC, Bentley MV, Pierre MB.

Source

School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, SP, Brazil.

Abstract

We report the development of D, L lactic co-glycolic acid) (PLGA)-based nanoparticles (NPs) for topical delivery of protoporphyrin IX (PpIX), a photosensitizer (PS), in treatments like photodynamic therapy (PDT) of skin cancers. PpIX-NPs were obtained in ~75.0% yield, encapsulation efficiency of 67.7%, drug content of 50.3 μg mg(-1), average diameter of 290 nm maintained up to 30 days and a zeta potential of 32.3 mV. Sustained in vitro release of PpIX through artificial membranes following Higuchi kinetics was kept up to 10 days. In vitro retentions of PpIX both in stratum corneum (SC) and epidermis + dermis ([EP + D]) were higher from NPs (23.0 and 10.0 times, respectively) compared to control solutions at all times. Quantification of PpIX by extraction, after in vivo skin application of NPs-PpIX on hairless mice, showed higher retention of the PS both in SC and in [EP + D] (3.0 and 2.0 times, respectively) compared to control solutions. Taken together, the results indicate that NPs are suitable for PpIX encapsulation showing minimal permeation through the skin and a localized effect, characteristics of a potential and promising delivery system for PDT-associated treatments of skin cancers, photodiagnosis and their off-label uses.

Caixa de texto

 PIERRE, M. B. R; Rossetti, F.C

Chapter 7 - Microneedles Technology For Transdermal Drug Delivery”. In: Physical Methods of drug

absorption enhancement.1 ed.Kerala: Research Singpost, 2012, v.01, p. 123-144.

Caixa de texto

AAPS PharmSciTech. 2012 Mar;13(1):101-11. doi: 10.1208/s12249-011-9725-8. Epub 2011 Dec 9.

In vitro characterization of chitosan gels for buccal delivery of celecoxib: influence of a penetration enhancer. I

Cid YP, Pedrazzi V, de Sousa VP, Pierre MB.

Source

Faculdade de Farmácia, Laboratório de Pesquisa e Desenvolvimento Farmacotécnico, Departamento de Medicamentos, Universidade Federal do Rio de Janeiro, Brazil.

Abstract

Celecoxib (Cx) shows high efficacy in the treatment of osteoarthritis and rheumatoid arthritis as a result of its high specificity for COX-2, without gastrolesivity or interference with platelet function at therapeutic concentrations. Besides of anti-inflammatory effects, Cx also has a potential role for oral cancer chemoprevention. For these conditions, oral administration in long-term treatment is a concern due to its systemic side effects. However, local application at the site of injury (e.g., buccal inflammation conditions or chemoprevention of oral cancer) is a promising way to reduce its toxicity. In this study, the in vitro characterization of mucoadhesive chitosan (CHT) gels associated to Azone® was assessed to explore the potential buccal mucosal administration of Cx in this tissue. Rheological properties of gels were analyzed by a rheometer with cone-plate geometry. In vitro Cx release and permeability studies used artificial membranes and pig cheek mucosa, respectively. Mucoadhesion were measured with a universal test machine. CHT gels (3.0%) containing 2.0% or 3.0% Az showed more appropriate characteristics compared to the others: pH values, rheology, higher amount of Cx retained in the mucosa, and minimal permeation through mucosa, besides the highest mucoadhesion values, ideal for buccal application. Moreover, the flux (J) and amounts of drug released decreased with increased CHT and Az concentrations. CHT gels (3.0%) associated with 2.0% or 3.0% Az may be considered potential delivery systems for buccal administration of Cx.

Caixa de texto

Arch Dermatol Res. 2011 Nov;303(9):607-21. doi: 10.1007/s00403-011-1166-4. Epub 2011 Jul 30.

Liposomal systems as drug delivery vehicles for dermal and transdermal applications.

Pierre MB, Dos Santos Miranda Costa I.

Source

Universidade Federal do Rio de Janeiro, Laboratório de Pesquisa e Desenvolvimento Farmacotécnico, Rio de Janeiro, RJ, Brasil. bernadete.pierre@gmail.com

Abstract

Enhancement strategies are necessary to improve the dermal/transdermal bioavailability of drugs applied to the skin due to its amazing barrier, the stratum corneum. Strategies to overcome this barrier, thus improving drug release to the skin include the use of penetration enhancers, specific delivery systems, supersaturated solutions and physical methods (iontophoresis, electroporation and ultrasound). Delivery of active agents to the skin by liposomal carriers has improved topical therapy in the field of dermatology. The interest in these carriers is based on their potential to enclose various types of biological materials and to deliver them to diverse cell types. Particularly, in recent years liposomes have been shown to be a promising drug-delivery system to the skin. Their use may produce several-fold higher drug concentrations in the epidermis and dermis and lower systemic concentrations when compared to conventional dosage forms. On the other hand, special characteristic vesicles like ethosomes, transfersomes and niosomes may be potential transdermal delivery systems for ionic molecules and polypeptides.

Caixa de texto

Biomed Chromatogr. 2011 Feb 10. doi: 10.1002/bmc.1596. [Epub ahead of print]

Celecoxib determination in different layers of skin by a newly developed and validated HPLC-UV method.

Praça FS, Bentley MV, Lara MG, Pierre MB.

Source

Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do Café, s/n, Ribeirão Preto, SP, Brazil.

Abstract

A simple, rapid and sensitive analytical procedure for the measurement of celecoxib (CXB) levels in skin samples after in vitro penetration studies was developed and validated. In vitro permeability studies in porcine skin were performed for quantification of CXB at different layers of skin, the stratum corneum (SC) and epidermis plus dermis (EP + D) as well as in the acceptor solution (AS) to assess CXB permeation through skin. CXB was quantified by HPLC using a C(18) column and UV detection at 251 nm. The mobile phase was methanol-water 72:28 (v/v) and the flow-rate was 0.8 mL/min. The CXB retention time was 5 min. The assay was linear for CBX in the concentration range of 0.1-3.0 μg/mL in the AS (drug permeated through skin) and 5.0-50.0 μg/mL for drug retained in SC and [EP + D] in vitro. The linear correlation coefficients for the different calibration curves were equal or greater than 0.99. Intra- and inter-assay variabilities were below 8.0%. Extraction of CXB from skin samples showed recoveries higher than 95.0% after 15 min of ultrasonic sound and centrifugation at 2500 rpm for 3 min. The method was considered appropriate for the assay of CXB in skin samples, after in vitro cutaneous penetration studies. Copyright © 2011 John Wiley & Sons, Ltd.

Caixa de texto

Influence of oleic acid on the rheology and in vitro release of lumiracoxib from poloxamer gels.

Moreira TS, de Sousa VP, Pierre MB. J Pharm Pharm Sci. 2010;13(2):286-302.

Purpose: Transdermal delivery of anti-inflammatory lumiracoxib (LM) could be an interesting strategy to avoid the side effects associated with systemic delivery, but it is ineffective due to the drug poor skin penetration. We have investigated the effects of oleic acid (OA), a lipid penetration enhancer, on the in vitro release of LM from poloxamer-based delivery systems (PBDS). The rheological behavior (shear rate dependent viscosity) and gelation temperature through measurements of optimal sol-gel transition temperatures (Tsol-gel) were also carried out in these systems.

Methods: In vitro release studies of LM from PBDS were performed using cellulose acetate as artificial membrane mounted in a diffusion system. The amount of LM released was divided by exposition area (microg/cm2) and these values were plotted as function of the time (h). The flux of the drug across the membrane (J) was calculated from the slope of the linear portion of the plot and expressed as microg/cm2. h -1. The determination of viscosity was carried out at different shear rates (gamma) between 0.1- 1000 S-1 using a parallel plate rheometer. Oscillatory measurements using a cone-plate geometry rheometer surrounded by a double jacket with temperature varying 4-40 degrees C, was used in order to determine Tsol-gel.

Results: Increase of both polymer and OA concentrations increases the viscosity of the gels and consequently reduces the in vitro LM release from the PBDS, mainly for gels containing OA at 10.0% compared to other concentrations of the penetration enhancer. Tsol-gel transition temperature was decreased by increasing viscosity; in some cases the formulation was already a gel at room temperature. Rheological studies showed a pseudoplastic behavior, which facilitates the flow and improves the spreading characteristics of the formulations.

Conclusions: Taken together, the results showed that poloxamer gels are good potential delivery systems for LM, leading to a sustained release, and also have appropriate rheological characteristics. Novelty of the work: A transdermal delivery of non-steroidal antinflammatory drugs like lumiracoxib (LM) can be an interesting alternative to the oral route of this drug, since it was recently withdraw of the market due to the liver damage when systemically administered in tablets as dosage form. There are no transdermal formulations of LM and it could be an alternative to treat inflammation caused by arthritis or arthrosis. Then, an adequate delivery system to LM is necessary in order to release the drug properly from the PBDS as well as have good characteristics related to semi-solid preparations for transdermal application, which were evaluated through in vitro release studies and rheological behavior in this paper, respectively.

Extração e purificação de fármacos anti-inflamatórios não esteroidais ciclo-oxigenase-2 seletivos.  

Moreira, T. S. A., Cid, Y. P., Pierre, M. B. R., Sousa, V. P. D., Kummerle, A. E., & Fraga, C. A. M. (2009). Química Nova, 32, 1324-1328. 

Celecoxib (CB) and lumiracoxib (LM) are potent COX-2 inhibitors widely marketed for the treatment of rheumatoid arthritis and osteoarthritis. Nevertheless, it is difficult to obtain because it are protected under patents. The aim of this work was to develop an extraction method of drugs, CB and LM, in order to obtain the drug with a purity degree appropriated for use in research projects. The developed method showed to be effective of both drugs, becoming interesting due to its low cost, easy and speed of execution, application to different dosage forms (capsules and tablets) and drugs with different physicochemical properties. 

Influence of ceramide 2 on in vitro skin permeation and retention of 5-ALA and its ester derivatives, for Photodynamic Therapy.

Pierre, M. B. R., Lopez, R. F. V., & Bentley, M. V. L. B. (2009). Brazilian Journal of Pharmaceutical Sciences, 45, 109-116. 

Photodynamic therapy (PDT) based on topical 5-aminolevulinic acid (5-ALA), an endogenous precursor of protoporphyrin, is an interesting approach for the treatment of skin cancer. However, 5-ALA is a hydrophilic molecule and such a characteristic limits its appropriate cutaneous penetration and retention. In this way, more lipophilic molecules, such as esterified 5-ALA derivatives, have been under investigation in order to improve the skin penetration of this molecule. Drug formulation can also alter 5-ALA skin penetration. Therefore, the aim of this work was to study the influence of ceramide 2 - the main lipid of the SC- on the cutaneous delivery of 5-ALA and its ester derivatives in vitro, using Franz diffusion cell. The skin permeation of all studied drugs was decreased in the presence of ceramide, representing a desirable characteristic in order to avoid the risk of systemic side effects. Nevertheless, the SC and [epidermis + dermis] retention after 16 h has also been decreased in the presence of ceramide, as compared to control. In conclusion, ceramide was not a good adjuvant, meaning that research of other vehicles could be useful to improve cutaneous delivery of 5-ALA. 

 A

Caixa de texto

 A novel transdermal delivery system for the anti-inflammatory lumiracoxib: influence of oleic acid on in vitro percutaneous absorption and in vivo potential cutaneous irritation.

Moreira TS, de Sousa VP, Pierre MB.

AAPS PharmSciTech. 2010 Jun;11(2):621-9. doi: 10.1208/s12249-010-9420-1. Epub 2010 Apr 7. Erratum in: AAPS PharmSciTech. 2010 Jun;11(2):719.

Abstract

Transdermal delivery of non-steroidal anti-inflammatory drugs may be an interesting strategy for delivering these drugs to the diseased site, but it would be ineffective due to low skin permeability. We investigated whether oleic acid (OA), a lipid penetration enhancer in poloxamer gels named poloxamer-based delivery systems (PBDS), can improve lumiracoxib (LM) delivery to/through the skin. The LM partition coefficient (K) studies were carried out in order to evaluate the drug lipophilicity grade (K(octanol/buffer)), showing values >1 which demonstrated its high lipophilicity. Both in vitro percutaneous absorption and skin retention studies of LM were measured in the presence or absence of OA (in different concentrations) in PBDS using porcine ear skin. The flux of in vitro percutaneous absorption and in vitro retention of LM in viable epidermis increased in the presence of 10.0% (w/w) OA in 25.0% (w/w) poloxamer gel. In vivo cutaneous irritation potential was carried out in rabbits showing that this formulation did not provide primary or cumulative cutaneous irritability in animal model. The results showed that 25.0% poloxamer gel containing 10.0% OA is potential transdermal delivery system for LM.

Caixa de texto

 Oleic acid as optimizer of the skin delivery of 5-aminolevulinic acid in photodynamic therapy.

Pierre MB, Ricci E Jr, Tedesco AC, Bentley MV.

Pharm Res. 2006 Feb;23(2):360-6. Epub 2006 Jan 1.

 Abstract

Purpose: In photodynamic therapy (PDT), topically applied aminolevulinic acid (5-ALA) is converted to protoporphyrin IX (PpIX), which upon light excitation induces tumor destruction. To optimize 5-ALA-PDT via improving the highly hydrophilic 5-ALA limited penetration into the skin, we propose the use of the known skin penetration enhancer, oleic acid (OA).

Methods: In vitro skin penetration and retention of 5-ALA (1% w/w) were measured in the presence or absence of OA (2.5, 5.0, and 10.0% w/w) in propylene glycol (PG) using porcine ear skin as the membrane. In vivo accumulation of PpIX, 4 h after application, was determined fluorometrically in healthy mice skin by chemical extraction of skin samples. In vivo PpIX fluorescence kinetics was also investigated by noninvasive techniques using an optical fiber probe, for 30 min up to 24 h after topical application of 1.0% 5-ALA + 10.0% OA in PG on hairless mice skins.

Results: The flux and in vitro retention of 5-ALA in viable epidermis increased in the presence of 10.0% (w/w) OA. The amounts of PpIX, evaluated both by chemical tissue extractions and in vivo measurements by an optical fiber probe, increased after applying 5-ALA formulations containing 5.0 or 10.0% OA. Moreover, in vivo kinetic studies showed an increase in skin PpIX accumulation when formulations containing 10% OA were used; PpIX accumulation was also maintained longer compared to controls.

Conclusions: Both in vitro and in vivo results show the OA potential as an optimizer of 5-ALA skin delivery.

Caixa de texto

In vitro skin permeation and retention of 5-aminolevulinic acid ester derivatives for photodynamic therapy.

De Rosa FS, Tedesco AC, Lopez RF, Pierre MB, Lange N, Marchetti JM, Rotta JC, Bentley MV.

J Control Release. 2003 Apr 29;89(2):261-9.

Abstract

In photodynamic therapy (PDT), 5-aminiolevulinic acid (5-ALA) applied topically is converted, via the heme cycle, into protoporphyrin IX (PpIX), a photosensitizing agent, which upon excitation with light can induce tumor destruction. Due to its hydrophilic and zwitterionic characteristics, 5-ALA has limited penetration into the skin. More lipophilic 5-ALA ester derivatives are expected to cross stratum corneum more easily than 5-ALA. According to the determination of the partition coefficients of 5-ALA methyl, n-butyl, n-hexyl and n-octyl esters, these compounds showed an increased affinity to the SC, with 5-ALA hexyl ester and 5-ALA-octyl ester having the highest partition coefficients. Our in vitro skin permeation studies demonstrated an increased permeated amount for hexyl-ALA after 6 h of incubation, compared to other esters and 5-ALA. After 6 h, more 5-ALA-hexyl ester and -octyl ester were retained at viable epidermis and dermis than 5-ALA. According to these results, and considering that the conversion of 5-ALA into PpIX occurs preferentially in epidermis, it can be supposed that topical use of ester derivatives with longer chains (C(6) or C(8)) is an interesting proposal to optimize topical 5-ALA-PDT

Caixa de texto

Stratum corneum lipids liposomes for the topical delivery of 5-aminolevulinic acid in photodynamic therapy of skin cancer: preparation and in vitro permeation study.

Pierre MB, Tedesco AC, Marchetti JM, Bentley MV.

BMC Dermatol. 2001;1:5. Epub 2001 Aug 30. 

Abstract

Background: Photodynamic therapy (PDT) using 5-aminolevulinic acid (5-ALA) is a skin cancer therapy that still has limitations due to the low penetration of this drug into the skin. We have proposed in this work a delivery system for 5-ALA based on liposomes having lipid composition similar to the mammalian stratum corneum (SCLLs) in order to optimize its skin delivery in Photodynamic Therapy (PDT) of skin cancers.

Methods: SCLLs were obtained by reverse phase evaporation technique and size distribution of the vesicles was determinated by photon correlation spectroscopy. In vitro permeation profile was characterized using hairless mouse skin mounted in modified Franz diffusion cell.

Results: Size exclusion chromatography on gel filtration confirmed vesicle formation. SCLLs obtained by presented a degree of encapsulation of 5-ALA around 5.7%. A distribution of vesicle size centering at around 500 nm and 400 nm respectively for SCLLs and SCLLs containing 5-ALA was found. In vitro 5-ALA permeation study showed that SCLLs preparations presented higher skin retention significantly (p < 0.05) on the epidermis without SC + dermis, with a decreasing of skin permeation compared to aqueous solution.

Conclusions: The in vitro delivery performance provided by SCLLs lead to consider this systems adequate for the 5-ALA-PDT of skin cancer, since SCLLs have delivered 5-ALA to the target skin layers (viable epidermis + dermis) to be treated by topical PDT of skin cancer.