Search

The levitation of samples in an acoustic field has been of interest in the preparation and study of amorphous solid dispersions (ASD). Here, niclosamide-polymer solutions were levitated in a multi-emitter single-axis acoustic levitator and analyzed for 10 min at a High-resolution synchrotron X-ray powder diffraction beamline. This assembly enabled high-quality and fast time-resolved measurements with microliter sample size and measurement of solvent evaporation and recrystallization of niclosamide (NCL). Polymers HPMCP-55S, HPMCP-50, HPMCP-55, Klucel®, and poloxamers were not able to form amorphous dispersions with NCL. Plasdone® and Soluplus® demonstrated excellent properties to form NCL amorphous dispersions, with the last showing superior solubility enhancement. Furthermore, this fast levitation polymer screening showed good agreement with results obtained by conventional solvent evaporation screening evaluated for five days in a stability study, carried out at 40 °C/75% RH. The study showed that acoustic levitation and high-resolution synchrotron combination opens up a new horizon with great potential for accelerating ASD formulation screening and analysis.

We use X-ray pair distribution function (PDF) analysis applied to high-energy synchrotron X-ray powder diffraction data to evaluate the amorphous solid dispersions interactions and their aging stability. The obtained systems are based on hydroxypropyl methylcellulose (hypromellose) derivatives and flubendazole (FBZ) drug dispersions prepared using a spray-dryer technique. We carry out stability studies under aging parameters (40 °C/75% relative humidity) to tune the systems’ recrystallization. The results reveal that ion-base interactions between the drug-polymer matrix are responsible for reducing clustering processes yielding slower recrystallization and different ordering in the hypromellose phthalate (HPMCP/FBZ) and hypromellose acetate succinate (HPMC-AS/FBZ) systems and complete drug clustering in hypromellose (HPMC-E3/FBZ). The structural ordering was accessed using differential X-ray PDFs that revealed the region between 3.5 A and 5.0 A could be related to FBZ intermolecular interactions and is more ordered for the least stable system (HPMC-E3/FBZ) and less ordered for the most stable system (HPMCP/FBZ). These results show that the ion-base interactions between drug and matrix occur at these intermolecular distances.

This work describes an exploratory experimental and in silico study of the influence of polymorphism, particle size, and physiology on the pharmacokinetics of lercanidipine hydrochloride (LHC). Equilibrium and kinetic solubility studies were performed on LHC forms I and II, as a function of pH and buffer composition. GastroPlus® was used to evaluate the potential effect of solubility differences due to polymorphism, particle size, and physiological conditions, on the drug pharmacokinetics. The results indicated that solubilities of LHC polymorphs are strongly dependent on the composition and pH of the buffer media. The concentration ratio (CI/CII) is particularly large for chloride buffer (CI/CII = 3.3-3.9) and exhibits a slightly decreasing tendency with the pH increase for all other buffers. Based on solubility alone, a higher bioavailability of form I might be expected. However, exploratory PBPK simulations suggested that (i) under usual fasted (pH 1.3) and fed (pH 4.9) gastric conditions, the two polymorphs have similar bioavailability, regardless of the particle size; (ii) at high gastric pH in the fasted state (e.g., pH 3.0), the bioavailability of form II can be considerably lower than that of form I, unless the particle size is < 20 μm. This study demonstrates the importance of investigating the effect of the buffer nature when evaluating the solubility of ionizable polymorphic substances. It also showcases the benefits of using PBPK simulations, to assess the risk and pharmacokinetic relevance of different solubility and particle size between crystal forms, for diverse physiological conditions.

Olive oil has been extensively applied in the pharmaceutical and cosmetic industries due to its biological properties. These are attributed to monounsaturated fatty acids like oleic acid and other minor components, such as phenolics and triterpenic acids. Oil-in-water nanoemulsion may enhance the solubility of poorly water-soluble drugs, which comprise about 40% of the currently marketed ones. However, the development of vegetable oil nanoemulsions is challenging due to their complex composition. In this study, olive oil nanoemulsions were prepared using high-pressure homogenization (HPH) and d -phase emulsification (DPE), as high- and low-energy processes, respectively. DPE has the potential to overcome the drawbacks of conventional Phase Inversion Methods. Aiming to achieve a deeper understanding of HPH and DPE processes, a design of experiment approach was successfully applied. This approach allowed identifying and understanding the relationship between input factors and their associated output response, at the stage of the nanoemulsion development. Moreover, in a specific range of critical process parameters and compositions, within the design space, nanoemulsions with similar mean particle sizes of 275 nm were achieved with equal composition, regardless of the use of the HPH or DPE process.

An orally disintegrating tablet is a novel formulation that dissolves in the saliva within a few seconds and without requiring of drinking additional water. This dosage form is a powerful way to deliver active drugs ingredients because it has many advantages. Many studies have compared this form of tablet with the ordinary forms in vitro and in vivo and found that orally disintegrating tablets have superior patient compliance and drug solubility. However, there are some criteria for the active pharmaceutical ingredients to prepare tablets as fast dissolve forms. There are several ways to prepare this dosage form and each method has its pros and cons. Technologies of preparation and various examples of orally disintegrating tablet available in the market using different preparing procedures are presented in this review. Taste masking is required form some active pharmaceutical ingredients to be formed as orally disintegrating tablets. In vitro evaluation and quality control measures of orally disintegrating tablet is also discussed in this review.

Cancer related to lymphangiogenesis has gained a great deal of attention in recent decades ever since specific markers of this intriguing system were discovered. Unlike the blood system, the lymphatic system has unique features that can advance cancer in future metastasis, or, conversely, can provide an opportunity to prevent or treat this disease that affects people worldwide. The aim of this review is to show the recent research of cancer treatment associated with the lymphatic system, considered one of the main gateways for disseminating metastatic cells to distant organs. Nanostructured systems based on theranostics and immunotherapies can offer several options for this complex disease. Precision targeting and accumulation of nanomaterials into the tumor sites and their elimination, or targeting the specific immune defense cells to promote optimal regression of cancer cells are highlighted in this paper. Moreover, therapies based on nanostructured systems through lymphatic systems may reduce the side effects and toxicity, avoid first pass hepatic metabolism, and improve patient recovery. We emphasize the general understanding of the association between the immune and lymphatic systems, their interaction with tumor cells, the mechanisms involved and the recent developments in several nanotechnology treatments related to this disease.

Considering the increased incidence of sporotrichosis and other fungal infections in rural and urban areas, and the limitations and adverse effects of oral itraconazole therapy, we studied nanostructured lipid carriers (NLC) as topical delivery systems to increase itraconazole localization in skin lesions and associate efficacy with reduced systemic exposure. Unloaded and itraconazole-loaded NLC showed nanometric size (~216–340 nm), negative zeta potential (~ -17 mV), and high entrapment efficiency (~97%). NLC treatment decreased transepidermal water loss, an index of cutaneous barrier function, in intact skin and in tissues damaged with a linear incision (to mimic lesions) by 23–36%, and reduced drug transdermal delivery by ~2-fold, demonstrating its ability to localize itraconazole within the skin. The unloaded and itraconazole-loaded NLC were considered safe, as indicated by scores of 0.5 and 0.6 in HET-CAM models, respectively, and lack of toxicity (measured by survival and health index) on the Galleria mellonella larvae. The values obtained for minimum inhibitory concentration and minimum fungicidal concentration on Sporothrix brasiliensis yeasts were 0.25 and 32 μg/mL, respectively. The drug in solution displayed similar values, indicating that encapsulation does not hinder itraconazole antifungal effect. NLC treatment improved the survival rate and health index of G. mellonella larvae infected with S. brasiliensis yeasts and C. albicans, demonstrating antifungal efficacy. Taken together, itraconazole encapsulation in NLC represents a viable strategy to optimize cutaneous localization without compromising its efficacy against fungal infections.

Drug repositioning may be defined as a process when new biological effects for known drugs are identified, leading to recommendations for new therapeutic applications. Niclosamide, present in the Model List of Essential Medicines, from the World Health Organization, has been used since the 1960s for tapeworm infection. Several preclinical studies have been shown its impressive anticancer effects, which led to clinical trials for colon and prostate cancer. Despite high expectations, proof of efficacy and safety are still required, which are associated with diverse biopharmaceutical challenges, such as the physicochemical properties of the drug and its oral absorption, and their relationship with clinical outcomes. Nanostructured systems are innovative drug delivery strategies, which may provide interesting pharmaceutical advantages for this candidate. The aim of this review is to discuss challenges involving niclosamide repositioning for cancer diseases, and the opportunities of therapeutic benefits from nanosctrutured system formulations containing this compound.

Made available in DSpace on 2019-10-06T05:45:57Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-08-15 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) As a new strategy for treatment of ductal carcinoma in situ, biocompatible and bioadhesive nanoemulsions for intraductal administration of the cytotoxic agent piplartine (piperlongumine) were optimized in this study. To confer bioadhesive properties, the nanoemulsion was modified with chitosan or hyaluronic acid. Tricaprylin was selected as the nanoemulsion non-polar phase due to its ability to dissolve larger drug amounts compared to isopropyl myristate and monocaprylin. Use of phosphatidylcholine as sole surfactant did not result in a homogeneous nanoemulsion, while its association with polysorbate 80 and glycerol (in a surfactant blend) led to the formation of nanoemulsions with droplet size of 76.5 +/- 1.2 nm. Heating the aqueous phase to 50 degrees C enabled sonication time reduction from 20 to 10 min. Inclusion of either chitosan or hyaluronic acid resulted in nanoemulsions with similar in vitro bioadhesive potential, and comparable ability to prolong mammary tissue retention (to 120 h) in vivo without causing undesirable histological alterations. Piplartine was stable in both nanoemulsions for 60 days; however, the size of loaded NE-HA was maintained at a similar range for longer periods of time, suggesting that this nanoemulsion may be a stronger candidate for intraductal delivery. Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, Av Prof Lineu Presses 1524, Sao Paulo, SP, Brazil Sao Paulo State Univ, Sch Pharmaceut Sci Araraquara, Araraquara, SP, Brazil Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo, SP, Brazil Univ Sao Paulo, Sch Pharmaceut Sci, Sao Paulo, SP, Brazil Univ Fed Ceara, Dept Inorgan & Organ Chem, Fortaleza, Ceara, Brazil Sao Paulo State Univ, Sch Pharmaceut Sci Araraquara, Araraquara, SP, Brazil FAPESP: 2013/16617-7 FAPESP: 2018/03418-0 FAPESP: 2018/13877-1 CNPq: 443549/2014-1 CAPES: 001 FAPESP: 2017/04174-4 FAPESP: 2017/23213-0 FAPESP: 2017/19059-6 FAPESP: 2018/18813-1

Orotic acid (OA), a heterocyclic compound also known as vitamin B13, has shown potent antimalarial and cardiac protection activities; however, its limited water solubility has posed a barrier to its use in therapeutic approaches. Aiming to overcome this drawback, OA freeze-dried nanocrystal formulations (FA, FB, and FC) were developed by using the high-energy milling method. Polysorbate 80 (FA) and povacoat® (FC) were used alone and combined (FB) as stabilizers. Nanocrystals were fully characterized by dynamic light scattering, laser diffraction, transmission electron microscopy, thermal analysis (thermogravimetry and derivative thermogravimetry, and differential scanning calorimetry), and X-ray powder diffraction revealing an acceptable polydispersity index, changes in the crystalline state with hydrate formation and z-average of 100-200 nm, a remarkable 200-time reduction compared to the OA raw material (44.3 μm). Furthermore, saturation solubility study showed an improvement of 13 times higher than the micronized powder. In addition, cytotoxicity assay revealed mild toxicity for the FB and FC formulations prepared with povacoat®. OA nanocrystal platform can deliver innovative products allowing untapped the versatile potential of this drug substance candidate.

Recently, several approaches have been reported to improve the dissolution rate and bioavailability of furosemide, a class IV drug. However, to the best of our knowledge, none of them proposed nanocrystals. In the last decade, nanocrystals successfully addressed solubility issues by increasing surface area and saturation solubility, both leading to an increase in the dissolution rate of poor water soluble drugs. The preparation of furosemide nanocrystals was by a rotation revolution mixer method. Size distribution and morphology were performed using laser diffraction and scanning electron microscopy, respectively. In addition, differential scanning calorimetry, thermogravimetry, X-ray powder diffraction (XRD) and low frequency shift-Raman spectroscopy allowed investigating the thermal properties and crystalline state. Solubility saturation and intrinsic dissolution rate (IDR) studies were conducted. The thermal analysis revealed lower melting range for the nanocrystals comparing to furosemide. Moreover, a slight crystalline structure change to the amorphous state was observed by XRD and confirmed by low frequency shift Raman. The particle size was reduced to 231 nm with a polydispersity index of 0.232, a 30-fold reduction from the original powder. Finally, the saturation solubility and IDR showed a significant increase. Furosemide nanocrystals showed potential for development of innovative formulations as an alternative to the commercial products.

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.

Esculetin, a natural coumarin derived from herbs, has shown different potential pharmacological activities. However, the poor aqueous solubility of esculetin may limit its therapeutic efficacy. Nanocrystal is a promising dosage form to overcome this drawback by enhancing drug saturation solubility. Hence, a laboratory-scale wet-bead milling approach was employed to develop an esculetin nanocrystal formulation. Povacoat™ was selected as a stabilizer after screening different surfactants and polymers. Design of experiments was applied to identify and understand the relationship between process parameters and formulation compositions at the stage of formulation optimization. Furthermore, the optimized formulation was solidified using two different approaches (spray-drying and freeze-drying) and characterized by dynamic light scattering, laser diffraction, transmission electron microscopy, scanning electron microscopy, thermal analysis, and X-ray powder diffraction. An esculetin-Povacoat™ nanocrystal formulation that maintained a 200 nm particle size for 180 days was successfully obtained with specific critical process parameters and formulation composition within the design space.

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.