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Ciprofibrate (CIP) is a highly lipophilic and poorly water-soluble drug, typically used for dyslipidemia treatment. Although it is already commercialized in capsules, no previous studies report its solid-state structure, thus, information about the correlation with its physicochemical properties lacking. In parallel, recent studies have led to the improvement of drug administration, including encapsulation in polymeric nanoparticles (NPs). Here, we present CIP’s crystal structure determined by PDRX data. We also propose an encapsulation method for CIP in micelles produced from Pluronic P123/F127 and PEO-b-PCL, aiming to improve its solubility, hydrophilicity, and delivery. We determined the NPs’ physicochemical properties by DLS, SLS, ELS, and SAXS and the loaded drug amount by UV-Vis spectroscopy. Micelles showed sizes around 10–20 nm for Pluronic and 35–45 nm for the PEO-b-PCL NPs with slightly negative surface charge and successful CIP loading, especially for the latter, a substantial reduction in ζ-potential may be evidenced. For Pluronic nanoparticles, we scanned different conditions for the CIP loading, and its encapsulation efficiency was reduced while the drug content increased in the nanoprecipitation protocol. We also performed in vitro release experiments, results demonstrate that probe release is driven by Fickian diffusion for the Pluronic NPs and a zero-order model for PEO-b-PCL NPs.

Made available in DSpace on 2020-12-10T19:59:33Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-02-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Castor oil is an environmentally friendly alternative to hydrocarbon-based feedstocks for the synthesis of polyurethanes due to its major constituent, ricinoleic acid. This work aimed to obtain and characterize castor oil-based polyurethane (coPU) systems containing domperidone and verapamil hydrochloride, separately, as model drugs. The drug-loaded coPU systems were obtained by solvent evaporation method and were characterized by differential scanning calorimetry, thermogravimetry, Fourier transform infrared spectroscopy and X-ray powder diffraction. Additionally, dissolution studies and scanning electron microscopy were performed. Verapamil hydrochloride was successfully incorporated in coPU, once it interacted through hydrogen bonds, and this system showed as a potential candidate for sustained drug release. Domperidone precipitated during solvent evaporation, resulting in a drug suspension into the polymer matrix. However, around 20% of domperidone interacted chemically with the polymer by the reaction of the active hydrogen of domperidone imidazole groups with the terminal isocyanate of the prepolymer. Finally, the drug release profile is guided by the drug-polymer physicochemical interaction, which will depend on the drug and polymer functional groups that are stereochemically available. Univ Sao Paulo, Fac Pharmaceut Sci, Dept Pharm, BR-05508000 Sao Paulo, Brazil Fed Univ ABC UFABC, Ctr Nat & Human Sci CCNH, BR-09210580 Santo Andre, SP, Brazil Sao Paulo State Univ, Chem Inst, Dept Phys Chem, BR-14800060 Araraquara, SP, Brazil Sao Paulo State Univ, Chem Inst, Dept Phys Chem, BR-14800060 Araraquara, SP, Brazil FAPESP: 2013/14744-1

For many years, the idea of analyzing atom-atom contacts in amorphous drug-polymer systems has been of major interest, because this method has always had the potential to differentiate between amorphous systems with domains and amorphous systems which are molecular mixtures. In this study, local structure of ionic and noninonic interactions were studied by High-Energy X-ray Diffraction and Pair Distribution Function (PDF) analysis in amorphous solid dispersions of lapatinib in hypromellose phthalate (HPMCP) and hypromellose (HPMC-E3). The strategy of extracting lapatinib intermolecular drug interactions from the total PDF x-ray pattern was successfully applied allowing the detection of distinct nearest neighbor contacts for the HPMC-E3 rich preparations showing that lapatinib molecules do not cluster in the same way as observed in HPMC-P, where ionic interactions are present. Orientational correlations up to nearest neighbor molecules at about 4.3 Å were observed for polymer rich samples; both observations showed strong correlation to the stability of the systems. Finally, the superior physical stability of 1:3 LP:HPMCP was consistent with the absence of significant intermolecular interactions in (∆"Equation missing") in the range of 3.0 to 6.0 Å, which are attributed to C-C, C-N and C-O nearest neighbor contacts present in drug-drug interactions.

Buparvaquone (BPQ), a veterinary drug, was formulated as nanostructured lipid carriers (NLC) for leishmaniases treatment. The formulation design addressed poor water solubility of BPQ and lack of human drug delivery system. The DSC/TG and microscopy methods were used for solid lipids screening. Softisan® 154 showed highest BPQ solubility in both methods. The BPQ solubility in liquid lipids using HPLC revealed Miglyol® 812 as the best option. Response surface methodology (RSM) was used to identify the optimal Softisan154 : Miglyol 812 ratios (7 : 10 to 2 : 1) and Kolliphor® P188 and Tween® 80 concentration (>3.0% w/w) aiming forz-average in the range of 100–300 nm for macrophage delivery. The NLC obtained by high-pressure homogenization showed lowz-averages (z-average. Therefore, these drug delivery systems have the potential to improve the availability of affordable medicines due to the low cost of raw materials, using well established, reliable, and feasible scale-up technology.

Submitted by Vitor Silverio Rodrigues (vitorsrodrigues@reitoria.unesp.br) on 2014-05-27T11:26:56Z No. of bitstreams: 0Bitstream added on 2014-05-27T14:47:45Z : No. of bitstreams: 1 2-s2.0-84864851294.pdf: 2055476 bytes, checksum: bfbc1d756505b93c0ecb4b68a9071efa (MD5) Made available in DSpace on 2014-05-27T11:26:56Z (GMT). No. of bitstreams: 0 Previous issue date: 2012-08-15 O polimorfismo pode ocasionar desvios de qualidade durante o processo produtivo e influenciar o desempenho dos medicamentos. Por isso, o entendimento do fenômeno e suas implicações abre um campo amplo de possibilidades a serem exploradas na área farmacêutica, incluindo o surgimento de novos paradigmas e ferramentas na garantia da qualidade de medicamentos. Este trabalho apresenta uma introdução aos aspectos básicos do fenômeno do polimorfismo e suas implicações na produção e controle de medicamentos, com ênfase no polimorfismo dos fármacos. Palavras-chave: Polimorfismo de fármacos. Caracterização no estado sólido. Cristalografia de policristais. ABSTRACT Polymorphism can cause quality deviations during the production of medicines and can influence their effectiveness. Therefore, an understanding of this phenomenon and its implications opens a wide field of possibilities to be explored in the pharmaceutical field, including the emergence of new paradigms and tools for the quality assurance of medicines. This paper presents an introduction to basic aspects of the polymorphism phenomenon and its implications for the production and control of medicines, with emphasis on drug polymorphs. Keywords: Polymorphism of drugs. Solid State Characterization. Crystallography of Polycrystals. Polymorphism can cause quality deviations during the production of medicines and can influence their effectiveness. Therefore, an understanding of this phenomenon and its implications opens a wide field of possibilities to be explored in the pharmaceutical field, including the emergence of new paradigms and tools for the quality assurance of medicines. This paper presents an introduction to basic aspects of the polymorphism phenomenon and its implications for the production and control of medicines, with emphasis on drug polymorphs. Departamento de Farmácia Faculdade de Ciências Farmacêuticas Universidade de São Paulo, São Paulo Farmanguinhos Fundação Oswaldo Cruz, Rio de Janeiro, RJ Instituto de Química UNESP, Araraquara, SP Instituto de Química Universidade de São Paulo, São Paulo, SP Instituto de Química UNESP, Araraquara, SP

The antiparasitic niclosamide has shown promising anticancer activity in preclinical studies against several types of cancer, such as colorectal and prostate. Thus, the objective of this work was to develop innovative formulations for the repositioning of niclosamide as an anticancer agent. In chapter I, a critical review of the literature on the physicochemical properties of the drug was carried out, in addition the results of clinical studies against colorectal and prostate cancer. Besides, a review was carried out on studies that developed formulations containing this drug, as well as hypotheses to improve the biopharmaceutical performance of this molecule. In chapter II, the development of solid amorphous dispersion containing niclosamide was carried out. Drug/polymer solutions were acoustic levitated and characterized by synchrotron X-ray light. This set allowed fast, high quality measurements, as well as the identification of niclosamide recrystallization. Plasdone® and Soluplus® demonstrated better properties to form amorphous dispersions, with the latter showing superior solubility enhancement. The study showed that the developed formulation increased the apparent saturation solubility of niclosamide in water by two times. In chapter III the objective was the development, physicochemical characterization and in vitro anticancer activity of a niclosamide nanoemulsion, having HCT-116 cells as a cellular model. Preliminary results indicated Capmul® MCM C8 as the best liquid lipid for the system, but the first nanoemulsions containing this lipid were not stable to justify its usage. On the other hand, Miglyol® 812 indicated to be a suitable liquid lipid for the system. The niclosamide nanoemulsion (~200 nm) with Miglyol® 812 and poloxamer 188 was stable for 56 days, with a monomodal particle size distribution. Cell viability assay against HCT-116 cells demonstrated that niclosamide cytotoxicity is time and concentration dependent. Results herein obtained encourage further research to understand and optimize niclosamide performance as an anticancer drug substance. O antiparasitário niclosamida tem apresentado promissora atividade anticâncer em estudos pré- clínicos contra diversos tipos de câncer, como coloretal e próstata. Assim, o objetivo deste trabalho foi desenvolver formulações inovadoras para o reposicionamento da niclosamida como agente anticâncer. No capítulo I foi realizada revisão crítica da literatura sobre as propriedades físico-químicas do fármaco, além de resultados de estudos clínicos da niclosamida contra câncer de coloretal e de próstata. Além disso, foi feita revisão sobre estudos que desenvolveram formulações contendo esse fármaco, bem como hipóteses para melhorar o desempenho biofarmacêutico dessa molécula. No capítulo II foi realizado o desenvolvimento de dispersão solida amorfa contendo niclosamida. Soluções de fármaco/polímero foram levitadas em levitador acústico e caracterizadas por raios-X de luz síncrotron. Este conjunto permitiu medições rápidas e de alta qualidade, bem como identificação de recristalização da niclosamida. Plasdone® e Soluplus® demonstraram melhores propriedades para formar as dispersões amorfas, com o último apresentando aumento de solubilidade superior. O estudo mostrou que a formulação desenvolvida aumentou em duas vezes a solubilidade aparente de saturação da niclosamida em água. No capítulo III o objetivo foi o desenvolvimento, a caracterização físicoquímica e atividade anticâncer in vitro de uma nanoemulsão de niclosamida, tendo células HCT-116 como modelo celular. Resultados preliminares indicaram o Capmul® MCM C8 como o melhor lipídio líquido para o sistema, mas as primeiras nanoemulsões contendo este lipídio não foram estáveis para justificar seu uso. Por outro lado, Miglyol® 812 indicou ser um lipídio líquido adequado para o sistema. A nanoemulsão de niclosamida (~200 nm) com Miglyol® 812 e poloxâmero 188 foi estável por 56 dias, com distribuição monomodal do tamanho de partícula. O ensaio de viabilidade celular contra células HCT-116 demonstrou que a citoxicidade da niclosamida é dependente do tempo e da concentração. Os resultados aqui obtidos encorajam mais pesquisas para entender e otimizar o desempenho da niclosamida como uma substância anticancerígena.