Development of Environmentally Responsive Self-Emulsifying System Containing Copaiba Oil-Resin for Leishmaniasis Oral Treatment.

Leishmaniasis is a disease caused by protozoa species of the Leishmania genus, and the current treatments face several difficulties and obstacles. Most anti-leishmanial drugs are administered intravenously, showing many side effects and drug resistance. The discovery of new anti-leishmanial compounds and the development of new pharmaceutical systems for more efficient and safer treatments are necessary. Copaiba oil-resin (CO) has been shown to be a promising natural compound against leishmaniasis. However, CO displays poor aqueous solubility and bioavailability. Self-emulsifying drug delivery systems (SEDDS) can provide platforms for release of hydrophobic compounds in the gastrointestinal tract, improving their aqueous solubilization, absorption and bioavailability. Therefore, the present work aimed to develop SEDDS containing CO and Soluplus® surfactant for the oral treatment of leishmaniasis. The design of the systems was accomplished using ternary phase diagrams. Emulsification and dispersion time tests were used to investigate the emulsification process in gastric and intestinal environments. The formulations were nanostructured and improved the CO solubilization. Their in vitro antiproliferative activity against promastigote forms of L. amazonensis and L. infantum, and low in vitro cytotoxicity against macrophages were also observed. More studies are necessary to determine effectiveness of SOL in these systems, which can be candidates for further pharmacokinetics and in vivo investigations.

Model-Informed drug development of gastroretentive release systems for sildenafil citrate.

Gastroretentive drug delivery systems (GRDDS) are modified-release dosage forms designed to prolong their residence time in the upper gastrointestinal tract, where some drugs are preferentially absorbed, and increase the drug bioavailability. This work aimed the development of a novel GRDDS containing 60 mg of sildenafil citrate, and the evaluation of the feasibility of the proposed formulation for use in the treatment of pulmonary arterial hypertension (PAH), for once a day administration, by using in silico pharmacokinetic (PK) modeling and simulations using GastroPlusTM. The Model-Informed Drug Development (MIDD) approach was used in formulation design and pharmacokinetic exposure prospecting. A 22 factorial design with a central point was used for optimization of the formulation, which was produced by direct compression and characterized by some tests, including buoyancy test, assay, impurities, and in vitro dissolution. A compartmental PK model was built using the GatroPlusTM software for virtual bioequivalence of the proposed formulations in comparison with the defined target release profile provided by an immediate release (IR) tablet formulation containing 20 mg of sildenafil administered three times a day (TID). The results of the factorial design showed a direct correlation between the dissolution rate and the amount of hydroxypropyl methyl cellulose (HPMC) in the formulations. By comparing the PK parameters predicted by the virtual bioequivalence, the formulations F1, F2, F3 and F5 failed on bioequivalence. The F4 showed bioequivalence to the reference and was considered the viable formulation to substitute the IR. Thus, GRDDS could be a promising alternative for controlling the release of drugs with a pH-dependent solubility and narrow absorption window, specifically in the gastric environment, and an interesting way to reduce dose frequency and increase the drug bioavailability. The MIDD approach increases the level of information about the pharmaceutical product and guide the drug development for more assertive ways.

Biopredictive tools for the development of injectable drug products.

INTRODUCTION: Biopredictive release tests are commonly used in the evaluation of oral medicines. They support decision-making in formulation development and allow predictions of the expected in-vivo performances. So far, there is limited experience in the application of these methodologies to injectable drug products. AREAS COVERED: Parenteral drug products cover a variety of dosage forms and administration sites, including subcutaneous, intramuscular, and intravenous injections. In this area, developing biopredictive and biorelevant methodologies often confronts us with unique challenges and knowledge gaps. Here, we provide a formulation-centric approach and explain the key considerations and workflow when designing biopredictive assays. Also, we outline the key role of computational methods in achieving clinical relevance and put all considerations into context using liposomal nanomedicines as an example. EXPERT OPINION: Biopredictive tools are the need of the hour to exploit the tremendous opportunities of injectable drug products. A growing number of biopharmaceuticals such as peptides, proteins, and nucleic acids require different strategies and a better understanding of the influences on drug absorption. Here, our design strategy must maintain the balance between robustness and complexity required for effective formulation development.

Nanomedicine Ex Machina: Between Model-Informed Development and Artificial Intelligence.

Today, a growing number of computational aids and simulations are shaping model-informed drug development. Artificial intelligence, a family of self-learning algorithms, is only the latest emerging trend applied by academic researchers and the pharmaceutical industry. Nanomedicine successfully conquered several niche markets and offers a wide variety of innovative drug delivery strategies. Still, only a small number of patients benefit from these advanced treatments, and the number of data sources is very limited. As a consequence, "big data" approaches are not always feasible and smart combinations of human and artificial intelligence define the research landscape. These methodologies will potentially transform the future of nanomedicine and define new challenges and limitations of machine learning in their development. In our review, we present an overview of modeling and artificial intelligence applications in the development and manufacture of nanomedicines. Also, we elucidate the role of each method as a facilitator of breakthroughs and highlight important limitations.

Design of Nanostructured Lipid Carriers Containing Cymbopogon martinii (Palmarosa) Essential Oil against Aspergillus nomius.

Palmarosa essential oil (PEO) is an alternative to synthetic fungicides to control the contamination by food-deteriorating fungi, such as Aspergillus nomius. Nonetheless, the low long-term stability and volatility hamper its utilization. Thus, this study aimed to develop nanostructured lipid carriers (NLCs) containing PEO to improve its stability and consequently prolong the activity against A. nomius. A mixture design was applied to find the best preparation conditions for antifungal activity. The characterization analyses included size measurements, zeta potential (ζ-potential), entrapment efficiency (EE), and antifungal activity (by inhibition of mycelial growth (IMG) and/or in situ test (pre-contaminated Brazil nuts) tests). The nanocarriers presented particle sizes smaller than 300 nm, homogeneous size distribution, ζ-potential of -25.19 to -41.81 mV, and EE between 73.6 and 100%. The formulations F5 and F10 showed the highest IMG value (98.75%). Based on the regression model, three optimized formulations (OFs) were tested for antifungal activity (IMG and in situ test), which showed 100% of inhibition and prevented the deterioration of Brazil nuts by A. nomius. The preliminary stability test showed the maintenance of antifungal activity and physicochemical characteristics for 90 days. These results suggest a promising system as a biofungicide against A. nomius.

Design of composite microparticle systems based on pectin and waste material of propolis for modified l-alanyl-l-glutamine release and with immunostimulant activity.

Catabolic conditions like acquired immunodeficiency syndrome, cancer, and burn can cause immunosuppression. Amino acids such as alanine and glutamine are essential for the activity of the immune system. Propolis is immunostimulant and the waste of propolis extraction has been reused with technological and therapeutic purposes. Therefore, this study describes the association of propolis byproduct extract (BPE) with pectin to prepare spray-dried microparticles containing the dipeptide l-alanyl-l-glutamine as stimulant systems of neutrophils. The use of a factorial design allowed selecting the best formulation, which was characterized by morphology, size, and entrapment efficiency analyses. In addition, the systems were characterized by thermal and X-ray diffraction analysis, Fourier-transform infrared spectroscopy, in vitro drug release, and in vitro cytotoxicity and stimulation test of neutrophils. Small well-structured microparticles with good entrapment efficiency values were achieved. Thermal stability of formulation was observed, and it was proved that pectin, BPE and l-alanyl-l-glutamine were dispersed throughout the matrix. The drug was released from the microparticles during 24 h governed by swelling and diffusion. The drug-loaded formulations showed a significant stimulating effect on neutrophils. These structures could increase the activity of immune cells, and other in vitro and in vivo studies should be performed in the future.

A review of recent developments on micro/nanostructured pharmaceutical systems for intravesical therapy of the bladder cancer.

Bladder cancer (BC) is the most common tumor type of genitourinary tract, which affects more men than women. The conventional treatment is through chemotherapy or immunotherapy, but the radiotherapy and surgery may be necessary in cases of invasive cancer. The search for less invasive, safe and effective therapies has attracted researchers to the development of new drug delivery systems to carry drugs to be administered by catheter into the bladder. The research on intravesical systems for the BC treatment continues at a rapid pace and a variety of micro or nanostructured systems have been used. Micro/nanoparticles, liposomes, micelles, carbon nanotubes, hydrogels and nanogels can contribute to reduce the number of intravesical administrations due to the extended drug release as well as to reduce the adverse effects and to increase the patient adherence to the treatment. Thus, this article reviews relevant studies regarding these systems, which have shown promising perspectives for the treatment of BC. It is hoped that in a near future they can prove to be safe and efficient to benefit patients with BC.

Nanocarriers for photodynamic therapy-rational formulation design and medium-scale manufacture.

The development and manufacture of novel nanocarriers for drug delivery has proved challenging with regards to scale-up and pharmaceutical quality. Polymeric nanocarriers composed of poly(lactic-co-glycolic acid)-b-poly(ethylene glycol) (PLGA-PEG) were prepared and the photosensitizer meso-tetrakis(3-hydroxyphenyl) chlorin (mTHPC) was effectively encapsulated. Furthermore, the interplay of various process and formulation parameters and their impact on the most important product specifications were investigated by using a factorial design and a central composite design in a microfluidic manufacturing process. These nanoparticles for intravenous administration with a size of 97 ± 0.13 nm, narrow size distribution, and an encapsulation efficiency of more than 80% were produced at high throughput. In vitro stability and in vitro drug release testing were applied for quality control purposes. Finally, the toxicity of the photosensitizer was tested in vitro. The cytotoxicity was successfully reduced while the efficacy of the formulation was maintained. First observations using in vivo imaging suggest effective distribution of the nanocarrier system after injection into rodents. Thus, further in vivo testing of the beneficial effects of nanoencapsulation into the matrix system and its formulation will be considered for the delivery of mTHPC to tumor tissues during photodynamic therapy.

Formulation and characterization of ethylcellulose microparticles containing .L-alanyl- L-glutamine peptide.

CONTEXT: The L-alanyl-L-glutamine peptide (AGP) has been effective to promote acute glycemia recovery during long-term insulin-induced hypoglycemia (IIH), and the oral administration of AGP is suggested to prevent prolonged hypoglycemia, such as nocturnal hypoglycemia. OBJECTIVE: Considering the ability of AGP on glycemia recovery and AGP's fast metabolism, the aim of current study was to obtain and characterize ethylcellulose microparticles to deliver the drug for a prolonged time. MATERIALS AND METHODS: Microparticles were prepared by simple and double emulsification/hardening method and characterized by scanning electron microscopy, thermogravimetry (TG), differential scanning calorimetry (DSC), Fourier transform infra-red (FTIR) and FT-Raman spectroscopy and in vitro release. RESULTS AND DISCUSSION: Spherical structures with a mean diameter between 9.30 µm and 13.19 µm were formed. TG analysis showed that the thermal stability of AGP was even more increased by encapsulation with ethylcellulose. In addition, TG, DSC, FTIR and FT-Raman analyses proved that AGP was encapsulated in a molecular way. Higher values of encapsulation efficiency were observed for the microparticles prepared by double emulsification (57.83-83.67%) than for those prepared by simple emulsification (18.37%). However, the last ones could release the peptide in a quicker and more extensive manner than those prepared by double emulsification. CONCLUSION: For the first time, microparticles containing AGP were developed and exhibited prolonged in vitro release as well as protection to the drug, and it could be considered as a dosage form for patients who suffer from insulin-induced hypoglycemia and/or nocturnal hypoglycemia.