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.KEY WORDS: in vitro skin permeation; lumiracoxib; oleic acid; poloxamer-based delivery systems; skin delivery.

Recebido em 19/6/08; aceito em 13/1/09; publicado na web em 30/4/09 EXTRACTION AND PURIFICATION OF SELECTIVES CICLOOXIGENASE-2 NONSTEROIDAL ANTIINFLAMMATORY DRUGS. 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.Keywords: celecoxib; lumiracoxib; extraction. INTRODUÇÃOOs anti-inflamatórios não esteroidais (AINEs) são fármacos amplamente utilizados no tratamento da dor, inflamação e febre. O mecanismo de ação dos compostos desta classe terapêutica envolve a inibição da enzima araquidonato ciclo-oxigenase (COX), a enzimachave para a síntese dos prostanóides e tromboxanos. Os prostanóides são mediadores celulares que modulam uma enorme variedade de processos fisiológicos e patológicos através de receptores de membrana localizados na superfície das células alvo.1 Estas sustâncias têm importante função homeostática na proteção da mucosa gástrica, fisiologia renal, gestação e agregação plaquetária, além de terem sua produção induzida em condições como inflamação e câncer.2 Desta forma, através da inibição da COX, os AINEs produzem os efeitos terapêuticos, mas também, numa maior ou menor extensão, alguns efeitos adversos como ulcerações, sangramentos, perfurações e obstruções gastrintestinais. 3,4Atualmente, sabe-se que existem duas isoformas da enzima ciclooxigenase: COX-1 e COX-2. A primeira é uma enzima constitutiva, expressa na maioria dos tecidos do organismo, agindo na produção de prostaglandinas que controlam os processos fisiológicos normais. 5A segunda é não constitutiva e tem sua expressão aumentada, principalmente, nos processos inflamatórios. 6Os primeiros AINES desenvolvidos (indometacina, naproxeno, ibuprofeno, entre outros) eram inibidores não seletivos das isoformas de COX e, apesar de terem eficácia comprovada quanto ao efeito antiinflamatório evidenciado, têm uso contínuo limitado devido a efeitos adversos gastrintestinais como displasia e dor abdominal, além de perfuração ou sangramento gastroduodenal em menor proporção. Esses efeitos adversos apresentados são oriundos da inibição da isoforma 1 da COX. Desse modo, a descoberta da segunda isoforma permitiu o desenvolvimento de uma subclasse de AINEs, os inibidores COX-2 seletivos, que apresentam o efeito terapêutico com a mesma eficácia, sem provocar os efeitos adversos indesejáveis oriundos da inibição da COX-1. Entre esses novos AINEs pode-se incluir celecoxibe, lumiracoxibe e etoricoxibe, indicados principalmente no tratamento da osteoartrite, artrite reumatóide, dor aguda ...

Summary: Tamoxifen (TXF) is a drug used as a hormonal agent for treatment of breast cancer. Due to its low solubility/bioavailability, the effectiveness of TXF can be improved when the drug is combined with drug delivery systems (DDS). For this reason, the in situ incorporation of TXF in polymer particles produced through miniemulsion polymerizations is studied here. Reactions were performed through standard free radical (FR) and RAFT polymerizations, using methyl methacrylate (MMA) as monomer and 2,2'-azobisisobutironitrila (AIBN) as initiator. It is shown that TXF can be incorporated successfully into the final polymer particles through miniemulsion polymerizations and that the presence of TXF in the reaction medium does not affect significantly the reaction rates, the particle size distribution and the molar mass distribution of the final polymer, even when the monomer feed contains 10 wt% of drug. Therefore, it is shown that DDS containing TXF can be produced by in situ miniemulsion FR and RAFT MMA polymerizations.

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Tamoxifen (TXF) is currently the only hormonal agent used for treatment of breast cancer. Although very effective, TXF presents low solubility in water, which affects its absorption and bioavailability. A common strategy to overcome this barrier is the formulation of a drug delivery system (DDS) in order to increase the drug stability and improve the treatment effectiveness. Reversible addition-fragmentation chain transfer (RAFT) polymerization is the most versatile method of controlled/living radical polymerization (CLRP), allowing for synthesis of well-defined polymers and being adapted to a wide range of polymerization systems. Miniemulsion polymerization is a dispersed system that is commonly used to prepare nanoparticles (NP) with 50 to 500 nm of diameter. The aim of this work was to evaluate the effect of the in situ incorporation of TXF during miniemulsion conventional and RAFT polymerizations, using methyl methacrylate (MMA) as monomer. Although the in situ addition of TXF promoted a slight reduction of the reaction rate, it did not affect the final particle size distribution of the latex or the molecular weight control exerted by the RAFT agent. The obtained results suggest that in situ incorporation of TXF during the synthesis of polymer NP via RAFT polymerization allows for production of a polymer DDS for different uses, such as the breast cancer treatment.