Control of Drug-Excipient Particle Attributes with Droplet Microfluidic-based Extractive Solidification Enables Improved Powder Rheology.

PURPOSE: Industrial implementation of continuous oral solid dosage form manufacturing has been impeded by the poor powder flow properties of many active pharmaceutical ingredients (APIs). Microfluidic droplet-based particle synthesis is an emerging particle engineering technique that enables the production of neat or composite microparticles with precise control over key attributes that affect powder flowability, such as particle size distribution, particle morphology, composition, and the API's polymorphic form. However, the powder properties of these microparticles have not been well-studied due to the limited mass throughputs of available platforms. In this work, we produce spherical API and API-composite microparticles at high mass throughputs, enabling characterization and comparison of the bulk powder flow properties of these materials and greater understanding of how particle-scale attributes correlate with powder rheology. METHODS: A multi-channel emulsification device and an extractive droplet-based method are harnessed to synthesize spherical API and API-excipient particles of artemether. As-received API and API crystallized in the absence of droplet confinement are used as control cases. Particle attributes are characterized for each material and correlated with a comprehensive series of powder rheology tests. RESULTS: The droplet-based processed artemether particles are observed to be more flowable, less cohesive, and less compressible than conventionally synthesized artemether powder. Co-processing the API with polycaprolactone to produce composite microparticles reduces the friction of the powder on stainless steel, a common equipment material. CONCLUSIONS: Droplet-based extractive solidification is an attractive particle engineering technique for improving powder processing and may aid in the implementation of continuous solid dosage form manufacturing.

Preparation and characterization of artemether-loaded niosomes in Leishmania major-induced cutaneous leishmaniasis.

Cutaneous leishmaniasis is the most prevalent form of leishmaniasis worldwide. Although various anti-leishmanial regimens have been considered, due to the lack of efficacy or occurrence of adverse reactions, design and development of novel topical delivery systems would be essential. This study aimed to prepare artemether (ART)-loaded niosomes and evaluate their anti-leishmanial effects against Leishmania major. ART-loaded niosomes were prepared through the thin-film hydration technique and characterized in terms of particle size, zeta potential, morphology, differential scanning calorimetry, drug loading, and drug release. Furthermore, anti-leishmanial effect of the preparation was assessed in vitro and in vivo. The prepared ART-loaded niosomes were spherical with an average diameter of about 100 and 300 nm with high encapsulation efficiencies of > 99%. The results of in vitro cytotoxicity revealed that ART-loaded niosomes had significantly higher anti-leishmanial activity, lower general toxicity, and higher selectivity index (SI). Half-maximal inhibitory concentration (IC50) values of ART, ART-loaded niosomes, and liposomal amphotericin B were 39.09, 15.12, and 20 µg/mL, respectively. Also, according to the in vivo study results, ART-loaded niosomes with an average size of 300 nm showed the highest anti-leishmanial effects in animal studies. ART-loaded niosomes would be promising topical drug delivery system for the management of cutaneous leishmaniasis.

Synthesis of Nanostructured Lipid Carriers Loaded Chitosan/ Carbopol Hybrid Nanocomposite Gel for Oral Delivery of Artemether and Curcumin.

BACKGROUND: Antimalarial therapy remains the utmost effective means for the management of malarial parasites in the liver and red blood cells. The application of these therapeutic agents is hampered by their improper application, hepato-toxicity caused by their continuous use, and degradation by hepatic enzymes. METHODS: Recent advancements in drug delivery applications have shown potential in improving the pharmacological properties of artemether. Nanostructured lipid carriers (NLCs) loaded chitosan (CH)/Carbopol (CB) hybrid gel was prepared using glycerol monostearate (GMS) as solid lipid and clove oil as a liquid lipid for artemether (ART) and curcumin (CR) for its localized effect on the liver. RESULTS: The smaller particle size (~118 ± 1.0 nm) and high zeta potential (- 41.1 ± 6.46 mV) confirm the formulation and stability of NLCs. On the other hand, the shape and morphology of prepared NLCs and gel showed a spherical and wrinkled surface with a size range of 150-250 nm. The release studies of the NLC's showed a controlled release of artemether (~ 92%) and curcumin (~ 83%) for up to 30 h. Photostability data showed that, approximately, ~86.5 ± 0.3% and ~60 ± 0.9% of nanoencapsulated artemether and curcumin were still detected on exposure to sunlight, respectively. It has been found from the permeation study that 69.8% and 49.1% of the drug was permeated across the mucus membrane in 24 h with a significant increase (P < 0.05) in flux as well as permeability coefficients. CONCLUSION: The overall results showed that prepared CH/CB/NLCs hybrid gel could be a promising vehicle for the effective delivery of ART and CR for the management of malarial parasites. Lay Summary: Antimalarial therapy remains the utmost effective means for the management of malarial parasites in liver and red blood cells. Recent advancements in drug delivery applications have shown potential in improving the pharmacological properties of artemether. Application of these therapeutic agents hampered by their improper application, hepato-toxicity caused by their continuous use and degradation by hepatic enzymes. To manage the above issues, we synthesize nanostructured lipid carriers (NLC's) loaded chitosan (CH)/Carbopol (CB) hybrid gel using glycerol monostearate (GMS) as solid lipid and clove oil as liquid lipid for artemether (ATR) and curcumin (CR) for its local action in liver and the major criteria were to find a protective barrier with hepatoprotective nature of the curcumin.

Fabrication and in vivo evaluation of ligand appended paclitaxel and artemether loaded lipid nanoparticulate systems for the treatment of NSCLC: A nanoparticle assisted combination oncotherapy.

The aim of present study was to develop folate appended PEGylated solid lipid nanoparticles(SLNs) of paclitaxel(FPS) and artemether(FAS). The SLNs were prepared by employing high pressure homogenization technique. The results of MTT assays revealed better cytotoxicity of FPS when given in combination with FAS on human lung cancer cell line H-1299 as compared to pure drugs, unconjugated SLNs and FPS alone. The cellular uptake of FPS and FAS was confirmed by fluorescence imaging and flow cytometric analysis. In-vivo pharmacokinetic study revealed better absorption and long circulation of FPS and FAS, which further leads to increased relative bioavailability of drugs(13.81-folds and 7.07-folds for PTX and ART, respectively) as compared to their solutions counterpart. In-vivo pharmacodynamic study confirmed tumor regression of developed SLNs formulations, which was observed highest when used in combination of FPS and FAS. Serum creatinine, blood urea nitrogen(BUN), SGOT, albumin and total protein levels revealed that formulated FPS and FAS does not exhibit any renal and hepatic toxicity. It can be concluded that by administering ART-SLNs along with PTX-SLNs via oral route, anticancer potential of PTX was improved without any toxicity (both renal, hepatic), thus, indicating the potential of developed formulations in reducing dose related toxicity of PTX.