Improvement in Pharmacological Activity of Mahkota Dewa (Phaleria macrocarpa (Schef. Boerl)) Seed Extracts in Nanoemulsion Dosage Form: In Vitro and In Vivo Studies.

BACKGROUND: Mahkota Dewa (Phaleria macrocarpa) seed has various phytochemical compounds and low pharmacological activities, including antioxidant and anti-inflammatory activities. OBJECTIVE: This research aimed to study nanoemulsion preparations of Mahkota Dewa seed (NE-BMD) for their anti-oxidant and anti-inflammatory properties. METHOD: The nanoemulsion was prepared using an ultrasonication probe and followed by selecting two formulations, F7 and F8. The anti-oxidant activity test was carried out using the DPPH method, meanwhile, the anti-inflammatory activity test was conducted using the protein denaturation method with Bovine Serum Albumin (BSA) for in vitro studies. In addition, for in vivo studies, the plethysmometer method was used with 1% carrageenan as an inducer. RESULTS: The characterization of NE-BMD preparations showed that the particle size and polydispersity index were 26,83 ± 1,27 nm (PI: 0.36 ± 0.03) and 30.73 ± 1.50 nm (PI: 0.32 ± 0.06) for NE-BMD F7 and F8 formulation, respectively. In addition, the anti-oxidant activity test revealed that the IC50 values of NE_BMD F7 and F8 were 15.62 ± 1.40 µg/ml and 28.39 ± 4.69 µg/ml, respectively. The protein denaturation test showed that the IC50 values for NE-BMD F7 and F8 were 94.39 ± 1.24 µg/ml and 196.63 ± 1.61 µg/ml, respectively. Meanwhile, the study of anti-inflammatory in vivo for NE-BMD F7 with a 1 g/kg BW dose showed a significant improvement in anti-inflammatory activity compared to BMD extract. CONCLUSION: This research suggests that due to the smaller drug particle size, the nanoemulsion dosage form of Mahkota Dewa seed extract has anti-oxidant and anti-inflammatory activities, thus emerging as an adjunct alternative treatment for inflammation.

Effect of Banana (Musa sp.) Peels Extract in Nanoemulsion Dosage Forms for the Improvement of Memory: In Vitro & In Vivo Studies.

BACKGROUND: Banana (Musa sp.) is a plant rich in phytochemical compounds, especially antioxidants, which are hypothesized to inhibit the activity of acetylcholinesterase, an enzyme associated with Alzheimer's Disease. OBJECTIVE: This research aimed to study nanoemulsion preparations of Kepok banana (KEP-NE) and Tanduk banana (TAN-NE) peel extracts for their activities as antioxidants, acetylcholinesterase as well as tyrosinase inhibitors, and as agents to improve short-term memory. METHODS: Nanoemulsion was prepared using a combination of high shear homogenization and ultrasonication. The antioxidant activity test was carried out using DPPH and ABTS methods. Meanwhile, memory improvement was studied in a mouse model with memory impairment induced by alloxan (120 mg/kg b.w) using the Y-maze apparatus. ELISA performed determination of acetylcholinesterase and tyrosinase inhibition. RESULTS: Characterization of the nanoemulsion was performed to include particle size, antioxidant activity, acetylcholinesterase, and tyrosinase inhibition. The particle size and polydispersity index (PI) of KEP-NE and TAN-NE were 84.2 nm (PI: 0.280) and 94.1 nm (PI: 0.282), respectively. The antioxidant activity of DPPH showed that the respective IC50 values of KEP-NE and TAN-NE were 0.64 µg/mL and 1.97 µg/mL. At the same time, the values with the ABTS method were 1.10 µg/mL and 1.72 µg/mL, respectively. The IC50 of KEP-NE on acetylcholinesterase inhibition was 108.80 µg/mL, and that on tyrosinase inhibition was 251.47 µg/mL. The study of short-term memory in the Y-maze revealed that the groups Kepok peel extracts 100 and 300 mg/kg b.w and KEP-NE 100 and 300 mg/kg b.w significantly (P < 0.05) improved short-term memory. CONCLUSION: This study suggests that the nanoemulsion dosage form of Kepok banana peel extract has antioxidant and acetylcholinesterase inhibition and tyrosinase inhibition activities and could potentially be an adjunct alternative treatment for memory disorders. Modifying the smaller drug particle size contributes to the delivery system. The nanoemulsion can increase pharmacological activity.

A Novel Desloratadine-Benzoic Acid Co-Amorphous Solid: Preparation, Characterization, and Stability Evaluation.

Low physical stability is the limitation of the widespread use of amorphous drugs. The co-amorphous drug system is a new and emerging method for preparing a stable amorphous form. Co-amorphous is a single-phase amorphous multicomponent system consisting of two or more small molecules that are a combination of drugs or drugs and excipients. The co-amorphous system that uses benzoic acid (BA) as an excipient was studied to improve the physical stability, dissolution, and solubility of desloratadine (DES). In this study, the co-amorphous formation of DES and BA (DES⁻BA) was prepared by melt-quenching method and characterized by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction (PXRD), and polarized light microscopy (PLM). Dissolution, solubility, and physical stability profiles of DES⁻BA were determined. The DES crystals were converted into DES⁻BA co-amorphous form to reveal the molecular interactions between DES and BA. Solid-state analysis proved that the co-amorphous DES⁻BA system (1:1) is amorphous and homogeneous. The DSC experiment showed that the glass transition temperature (Tg) of tested DES⁻BA co-amorphous had a higher single Tg compared to the amorphous DES. FTIR revealed strong interactions, especially salt formation. The dissolution rate and solubility of co-amorphous DES⁻BA (1:1) obtained were larger than the DES in crystalline form. The PXRD technique was used to assess physical stability for three months at 40 °C with 75% RH. The DES⁻BA co-amorphous system demonstrated better physical stability than a single form of amorphous DES. Co-amorphous DES⁻BA has demonstrated the potential for improving solid-state stability, as the formation of DES⁻BA co-amorphous salt increased solubility and dissolution when compared to pure crystalline DES. This study also demonstrated the possibility for developing a DES⁻BA co-amorphous system toward oral formulations to improve DES solubility and bioavailability.

Synthesis, characterization, and stability study of desloratadine multicomponent crystal formation.

This study describes the formation of multicomponent crystal (MCC) of desloratadine (DES). The objective of this study was to discover the new pharmaceutical MCC of DES using several coformers. The MCC synthesis was performed between DES and 26 coformers using an equimolar ratio with a solvent evaporation technique. The selection of the appropriate solvent was carried out using 12 solvents. The preview of the MCC of DES was performed using polarized light microscopy (PLM). The formation of MCC was confirmed using powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), fourier transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM). The accelerated stability of MCC at 40 °C and relative humidity of 75% was investigated using PXRD and FTIR. Depending on the prior evaluation, DES and benzoic acid (BA) formed the MCC. PLM and SEM results showed that crystal habit of combination between DES and BA differed from the constituent components. Moreover, the diffractogram pattern of DES-BA was distinct from the constituent components. The DSC thermogram showed a new peak which was distinct from both constituent components. The FTIR study proved a new spectrum. All characterizations indicated that a new solid crystal was formed, ensuring the MCC formation. In addition, DES-BA MCC had both chemical and physical stabilities for a period of 4 months.

Improving mechanical properties of desloratadine via multicomponent crystal formation.

We report the first multicomponent crystal of desloratadine, an important anti-histamine drug, with a pharmaceutically acceptable coformer of benzoic acid. The single crystal structure analysis revealed that this novel multicomponent crystal is categorized as salt due to the proton transfer from benzoic acid to the desloratadine molecule. By forming the salt multicomponent crystal, we demonstrated that the tabletability and plasticity of the multicomponent crystal was improved from the parent drug. In addition, neither capping nor lamination tendency was observed in the desloratadine-benzoic acid multicomponent crystal. The existence of a layered structure and slip planes are proposed to be associated with this improvement. The desloratadine-benzoate in this case shows an improved solubility in water and HCl 0.1N media and a better dissolution profile in water. However, the dissolution rate in HCl 0.1N media was found to be essentially indifference.

Curcumin nanoemulsion for transdermal application: formulation and evaluation.

The aim of this work is to develop a curcumin nanoemulsion for transdermal delivery. The incorporation of curcumin inside a nanoglobul should improve curcumin stability and permeability. A nanoemulsion was prepared by the self-nanoemulsification method, using an oil phase of glyceryl monooleate, Cremophor RH40 and polyethylene glycol 400. Evaluation of the nanoemulsion included analysis of particle size, polydispersity index, zeta potential, physical stability, Raman spectrum and morphology. In addition, the physical performance of the nanoemulsion in Viscolam AT 100P gel was studied. A modified vertical diffusion cell and shed snake skin of Python reticulatus were used to study the in vitro permeation of curcumin. A spontaneously formed stable nanoemulsion has a loading capacity of 350 mg curcumin/10 g of oil phase. The mean droplet diameter, polydispersity index and zeta potential of optimized nanoemulsion were 85.0 ± 1.5 nm, 0.18 ± 0.0 and -5.9 ± 0.3 mV, respectively. Curcumin in a nanoemulsion was more stable than unencapsulated curcumin. Furthermore, nanoemulsification significantly improved the permeation flux of curcumin from the hydrophilic matrix gel; the release kinetic of curcumin changed from zero order to a Higuchi release profile. Overall, the developed nanoemulsion system not only improved curcumin permeability but also protected the curcumin from chemical degradation.

Molecular inclusion complex of curcumin-ß-cyclodextrin nanoparticle to enhance curcumin skin permeability from hydrophilic matrix gel.

Curcumin (CUR) has various pharmacological effects, but its extensive first-pass metabolism and short elimination half-life limit its bioavailability. Therefore, transdermal application has become a potential alternative to delivery CUR. To increase CUR solubility for the development of a transparent homogenous gel and also enhance the permeation rate of CUR into the skin, ß-cyclodextrin-curcumin nanoparticle complex (BCD-CUR-N) was developed. CUR encapsulation efficiency was increased by raising the percentage of CUR to BCD up to 20%. The mean particle size of the best CUR loading formula was 156 nm. All evaluation data using infrared spectroscopy, Raman spectroscopy, powder X-ray diffractometry, differential thermal analysis and scanning electron microscopy confirmed the successful formation of the inclusion complex. BCD-CUR-N increased the CUR dissolution rate of 10-fold (p < 0.01). In addition, the improvement of CUR permeability acrossed skin model tissue was observed in gel containing the BCD-CUR-N and was about 1.8-fold when compared with the free CUR gel (p < 0.01). Overall, CUR in the form of the BCD-CUR-N improved the solubility further on the penetration of CUR.

SDS-coated atovaquone nanosuspensions show improved therapeutic efficacy against experimental acquired and reactivated toxoplasmosis by improving passage of gastrointestinal and blood-brain barriers.

Toxoplasmic encephalitis (TE) is the most common clinical manifestation of reactivated infection with Toxoplasma gondii in immunocompromised patients that is lethal if untreated. The combination of pyrimethamine plus sulfadiazine or clindamycin is the standard therapy for the treatment of TE, but these combinations are associated with hematologic toxicity and/or life-threatening allergic reactions. Therefore, alternative treatment options are needed. Atovaquone is safe and highly effective against T. gondii in vitro, but the oral micronized solution shows poor bioavailability. We synthesized atovaquone nanosuspensions (ANSs) coated with poloxamer 188 (P188) and sodium dodecyl sulfate (SDS) to improve oral bioavailability and passage through the blood-brain barrier (BBB). Coating of ANSs with SDS resulted in enhanced oral bioavailability and enhanced brain uptake of atovaquone compared to Wellvone(®) in murine models of acute and reactivated toxoplasmosis as measured by high performance liquid chromatography (HPLC). Parasite loads and inflammatory changes in brains of mice treated with SDS-coated ANS were significantly reduced compared to untreated controls and to Wellvone(®)-treated mice. In conclusion, nanosuspensions coated with SDS may ultimately lead to improvements in the treatment of TE and other cerebral diseases.

The role of apolipoprotein E in uptake of atovaquone into the brain in murine acute and reactivated toxoplasmosis.

We investigated whether coating of atovaquone nanosuspensions (ANSs) with apolipoprotein E (apoE) peptides improves the uptake of atovaquone into the brain. The passage across the blood-brain barrier (BBB) of ANSs stabilized by polysorbate 80 (Tween 80), poloxamer 184 (P184), or poloxamer 338 (P338) and the same formulations coated with apoE peptides were analyzed in vitro and in vivo. Passage through a rat coculture model of the BBB did not differ between individual atovaquone formulations, and the addition of apoE peptides did not enhance the transport. Following the induction of toxoplasmic encephalitis (TE) in mice, treatment with all atovaquone formulations reduced the number of parasites and inflammatory foci compared with untreated mice. Uptake of atovaquone into the brain did not depend on coating with apoE. Finally, incubation of apoE peptide-coated ANSs with brain endothelial cells for 30 min did result in the accumulation of nanoparticles on the cell surface but not in their uptake into the cells. In conclusion, ANSs coated with Tween 80 or poloxamers showed therapeutic efficacy in murine toxoplasmosis. ApoE- and apoE-derived peptides do not induce the uptake of ANSs into the brain. Alternative mechanisms seem to be in operation, thereby mediating the passage of atovaquone across the BBB.

Kinetic solubility and dissolution velocity of rutin nanocrystals.

Lyophilized rutin nanocrystals were intensively evaluated regarding their physicochemical properties with respect to particle size analyses, crystallinity, kinetic solubility and dissolution behavior. The particle size was determined by photon correlation spectroscopy (PCS) and laser diffraction (LD). DSC and X-ray diffraction were used to study the crystalline state of rutin nanocrystals. In a period of 1 week, the kinetic solubility was determined using a shaker at 25 degrees C. DSC and X-ray diffraction analyses showed that lyophilized rutin nanocrystals prepared by high pressure homogenization remained in crystalline state. Lyophilized rutin nanocrystals could be re-dispersed completely in water and the kinetic solubility in water increased to 133 microg/ml.. Lyophilized rutin nanocrystals were almost completely dissolved within 15 min in water, buffer of pH 1.2 and buffer of pH 6.8. In contrast, only 70% of rutin raw material (rutin microcrystals) was dissolved within 15 min. The superior physicochemical properties of rutin nanocrystals should overcome the absorption problem in the gastrointestinal tract and increase the bioavailability.

Development of an oral rutin nanocrystal formulation.

Dried rutin nanocrystals have been prepared by lyophilization and investigated regarding their physicochemical properties with respect to re-dispersability, particle size, morphology and dissolution behavior. Photon correlation spectroscopy (PCS) and laser diffractometry (LD) were employed to determine the particle size. Morphology of the particles was analyzed by light microscopy. Lyophilized rutin nanocrystals were incorporated into tablets and the dissolution behavior of the tablets was evaluated. Very fine particles of lyophilized rutin could be completely re-dispersed in the water. The PCS size average and polydispersity index (PI) of lyophilized rutin were of 721nm and of 0.288 after re-dispersion. The rutin nanocrystal-loaded tablets were produced using direct compression. The dissolution velocity of the rutin nanocrystal-loaded tablet was superior compared to rutin microcrystal-loaded and a marketed tablet. After 30min rutin was released and dissolved completely from the nanocrystal tablets in water. In contrast, only 71% and 55% of the total amount of rutin were dissolved from the microcrystal tablets and the marketed tablet, respectively. The improving dissolution behavior of the rutin nanocrystal-loaded tablet should lead to a better bioavailability of the poorly soluble rutin in the body.