The anticancer/cytotoxic effect of a novel gallic acid derivative in non-small cell lung carcinoma A549 cells and peripheral blood mononuclear cells from healthy individuals and lung cancer patients.

Gallic acid (GA) is a naturally occurring polyphenol with a strong antioxidant capacity. GA stimulates the apoptosis of cancer cells, thereby suppressing cancer cell invasion. However, the low oral permeability of GA limits its therapeutic use. In order to enhance the antioxidant capacity and oral permeability of GA, a series of compounds analogous to GA were synthesized: 4-methoxybenzenesulfonamide (MBS), 3,4-dimethoxybenzenesulfonamide (DMBS) and 3,4,5-trimethoxybenzenesulfonamide (TMBS). In the new compounds, hydroxyl groups were replaced with various numbers of methoxy groups (stronger electron-donating groups), to increase hydrophobicity and oral permeability compared to GA. In addition, the carboxylic group was replaced with a sulfonyl group (a stronger electron-withdrawing group), to increase the molecular polarity and antioxidative activities of the compounds. The cell counting kit-8 (CCK-8) assay was used to detect the effect of GA, MBS, DMBS, and TMBS on cell proliferation and apoptosis in peripheral blood mononuclear cells (PBMCs) from healthy individuals and non-small cell lung carcinoma A549 cells. Additionally, the comet assay was used to assess the genotoxicity of these compounds in PBMCs from healthy individuals, lung cancer patients, and A549 cells. Compared to untreated cells, TMBS reduced DNA damage more effectively than GA in PBMCs from lung cancer patients and healthy donors. Furthermore, in comparison to GA, TMBS was more cytotoxic in A549 cells. Moreover, TMBS was not cytotoxic in healthy PBMCs, suggesting that TMBS demonstrates therapeutic potential in cancer.

Anticarcinogenic impact of extracellular vesicles (exosomes) from cord blood stem cells in malignant melanoma: A potential biological treatment.

Incidence of Malignant Melanoma has become the 5th in the UK. To date, the major anticancer therapeutics include cell therapy, immunotherapy, gene therapy and nanotechnology-based strategies. Recently, extracellular vesicles, especially exosomes, have been highlighted for their therapeutic benefits in numerous chronic diseases. Exosomes display multifunctional properties, including inhibition of cancer cell proliferation and initiation of apoptosis. In the present in vitro study, the antitumour effect of cord blood stem cell (CBSC)-derived exosomes was confirmed by the CCK-8 assay (p < 0.05) on CHL-1 melanoma cells and improve the repair mechanism on lymphocytes from melanoma patients. Importantly, no significant effect was observed in healthy lymphocytes when treated with the exosome concentrations at 24, 48 and 72 h. Comet assay results (OTM and %Tail DNA) demonstrated that the optimal exosome concentration showed a significant impact (p < 0.05) in lymphocytes from melanoma patients whilst causing no significant DNA damage in lymphocytes of healthy volunteers was 300 µg/ml. Similarly, the Comet assay results depicted significant DNA damage in a melanoma cell line (CHL-1 cells) treated with CBSC-derived exosomes, both the cytotoxicity of CHL-1 cells treated with CBSC-derived exosomes exhibited a significant time-dependent decrease in cell survival. Sequencing analysis of CBSC exosomes showed the presence of the let-7 family of miRNAs, including let-7a-5p, let-7b-5p, let-7c-5p, let-7d-3p, let-7d-5p and two novel miRNAs. The potency of CBSC exosomes in inhibiting cancer progression in lymphocytes from melanoma patients and CHL-1 cells whilst causing no harm to the healthy lymphocytes makes it a potential candidate as an anticancer therapy.

A Combined Rheological and Thermomechanical Analysis Approach for the Assessment of Pharmaceutical Polymer Blends.

The viscoelastic nature of polymeric formulations utilised in drug products imparts unique thermomechanical attributes during manufacturing and over the shelf life of the product. Nevertheless, it adds to the challenge of understanding the precise mechanistic behaviour of the product at the microscopic and macroscopic level during each step of the process. Current thermomechanical and rheological characterisation techniques are limited to assessing polymer performance to a single phase and are especially hindered when the polymers are undergoing thermomechanical transitions. Since pharmaceutical processing can occur at these transition conditions, this study successfully proposes a thermomechanical characterisation approach combining both mechanical and rheological data to construct a comprehensive profiling of polymeric materials spanning both glassy and rubbery phases. This approach has been used in this study to assess the mechanical and rheological behaviour of heterogenous polymer blends of hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC) over a shearing rate range of 0.1-100 s-1 and a temperature range of 30-200 °C. The results indicate that HPC and HPMC do not appear to interact when mixing and that their mixture exhibits the mechanistic properties of the two individual polymers in accordance with their ratio in the mixture. The ability to characterise the behaviour of the polymers and their mixtures before, throughout, and after the glassy to rubbery phase transition by application of the combined techniques provides a unique insight towards a quality-by-design approach to this and other polymer-based solid dosage forms, designed with the potential to accelerate their formulation process through obviating the need for multiple formulation trials.

Interferon-γ liposome: a new system to improve drug delivery in the treatment of lung cancer.

Lung cancer is one of the main causes of death worldwide. Published data show the use of interferons (IFNs) in treating lung tumours. IFNs also have potential for their antiproliferative, antiangiogenic, immunoregulatory and proapoptotic effects. IFN-γ functions as an anticancer agent against various forms of cancer. This study aimed to investigate the effect of IFN-γ liposome (nano) on peripheral lymphocytes from 20 individuals in each group: lung cancer patients compared to healthy individuals. The effectiveness of IFN-γ liposome against oxidative stress was also evaluated in this study. A concentration of 100 U·mL-1 of IFN-γ liposome was used to treat the lymphocytes in the Comet and micronucleus assays based on the preliminary test for the optimal dose. The lymphocytes from lung cancer patients presented with higher DNA damage levels than those of healthy individuals. In healthy individuals, IFN-γ liposome did not cause any DNA damage in the lymphocytes. Also, it caused a significant reduction in DNA damage in the lymphocytes from lung cancer patients in both the Comet and micronucleus assays. The 100 U·mL-1 of IFN-γ liposome significantly reduced the oxidative stress caused by H2O2 and appeared to be effective in both groups using the Comet and micronucleus assays. Results from both Comet and micronucleus assays were consistent. The data obtained indicated that IFN-γ in both forms (IFN-γ bulk and IFN-γ nanoliposome) may potentially be effective for the treatment of lung cancer and showed the ability of IFN-γ liposome to reduce DNA damage more than the bulk form.

Repurposing of Guanabenz acetate by encapsulation into long-circulating nanopolymersomes for treatment of triple-negative breast cancer.

Poor patient response and limited treatment modalities are the major challenges against combating triple-negative breast cancer (TNBC). The high related mortality urges for novel cancer therapeutics. Guanabenz acetate (GA) is an orphan antihypertensive drug with a short half-life. Re-purposing (GA) by developing a polymersome (PS)-based cancer nanomedicine is an innovative approach in treating TNBC. Formulation and optimization of GA-loaded PEGylated Polycaprolactone PS through different process variables (solvent selection, the order of addition, pH of the aqueous phase, and drug to polymer ratio) were achieved by the nanoprecipitation method. The in vitro cellular uptake, anti-cancer, and anti-metastatic activity of GA and GA-loaded PS were tested in MDA-MB 231(TNBC cell line) and MCF-7 cell line. Western blot analysis was performed to elucidate the molecular anti-cancer mechanism. The in vivo biodistribution study and antitumor activity were investigated in the TNBC-xenograft model implanted in mice. Under optimized formulation conditions, GA-loaded PS had a nanosize of 90.5 nm with PDI < 0.2, a zeta potential -9.11 mV, drug encapsulation efficiency of 92.11% and sustained drug release for 6-days. GA-loaded PS exhibited enhanced cellular uptake and achieved a significantly lower IC50 in both breast cancer cell lines compared to free GA. Treatment with GA-loaded PS (60 µM) showed a significant reduction of 60.5 and 78.1% in cancer migration and metastasis in the case of MDA-MB 231 and MCF-7, respectively. Besides, drug-loaded PS increased phosphorylation of translational regulator eIF2α and decreased expression of Rac1 which were essential for decreasing cancer cell survival and metastasis. In vivo biodistribution study of GA-loaded PS showed long-circulating PS with high passively targeted tumor accumulation. Treatment with GA-loaded PS resulted in a significant decrease in tumor size and weight compared to free GA. In conclusion, GA-loaded PS is a new promising cancer therapeutics for the treatment of TNBC.

Solvent-free temperature-facilitated direct extrusion 3D printing for pharmaceuticals.

In an era moving towards digital health, 3D printing has successfully proven its applicability in providing personalised medicine through a technology-based approach. Among the different 3D printing techniques, direct extrusion 3D printing has been demonstrated as a promising approach for on demand manufacturing of solid dosage forms. However, it usually requires the use of elevated temperatures and/or the incorporation of an evaporable solvent (usually water). This can implicate the addition of a drying step, which may compromise the integrity of moisture- or temperature-sensitive drugs, and open the door for additional quality control challenges. Here, we demonstrate a new approach that simplifies direct extrusion 3D printing process with the elimination of the post-printing drying step, by merely adding a fatty glyceride, glyceryl monostearate (GMS), to a model drug (theophylline) and permeable water insoluble methacrylate polymers (Eudragit RL and RS). Indeed, rheological studies indicated that the addition of a combination of a plasticiser, (triethyl citrate), and GMS to theophylline: methacrylate polymer blends significantly reduced the extensional viscosity (to <2.5 kPa·Sec) at 90 °C. Interestingly, GMS demonstrated a dual temperature-dependant behaviour by acting both as a plasticiser and a lubricant at printing temperature (90-110 °C), while aiding solidification at room temperature. X-ray powder diffraction indicated incomplete miscibility of GMS within the polymeric matrix at room temperature with the presence of a subtle diffraction peak, at 2(Θ) = 20°. The 3D printed tablets showed acceptable compendial weight and content uniformity as well as sufficient mechanical resistance. In vitro theophylline release from 3D printed tablets was dependant on Eudragit RL:RS ratio. All in all, this work contributes to the efforts of developing a simplified, facile and low-cost 3D printing for small batch manufacturing of bespoke tablets that circumvents the use of high temperature and post-manufacturing drying step.

Ex vivo/in vitro effects of aspirin and ibuprofen, bulk and nano forms, in peripheral lymphocytes of prostate cancer patients and healthy individuals.

Inhibiting inflammatory processes or eliminating inflammation represents a logical role in the suppression and treatment strategy of cancer. Several studies have shown that anti-inflammatory drugs (NSAIDs) act as anticancer agents while reducing metastases and mortality rate. NSAIDs are seriously limited by their side effects and toxicity, which can become cumulative with their long-term administration for chemoprevention. In the current ex vivo / in vitro study, the genotoxicity mechanisms of NSAIDS in bulk and nanoparticle forms allowed a strategy to prevent and minimise the damage in human lymphocytes. When compared to their bulk forms, acetylsalicylic acid (Aspirin) nano and ibuprofen nano (IBU N), both NSAIDs in 500 µg/mL concentration significantly decreased DNA damage measured by alkaline comet assay. Micronuclei (MNi) frequency also decreased after ASP N (500 µg/mL), ASP B (500 µg/mL) and IBU N (200 µg/mL) in prostate cancer patients and healthy individuals, however, the ibuprofen bulk (200 µg/mL) showed a significant increase in MNi formation in lymphocytes from healthy and prostate cancer patients when compared to the respective untreated lymphocytes. These findings suggest that a reduction in particle size had an impact on the reactivity of the drug, further emphasising the potential of nanoparticles to improve the current treatment options.

Anticancer potential of myricetin bulk and nano forms in vitro in lymphocytes from myeloma patients.

Evading apoptosis and chemo-resistance are considered as very important factors which help tumour progression and metastasis. Hence, to overcome chemo-resistance, there is an urgent requirement for emergence of more effective treatment options. Myricetin, a naturally occurring flavonoid, is present in various plant-derived foods and shows antitumour potential in different cancers. In the present in vitro study, results from the comet assay demonstrated that myricetin bulk (10 µM) and nano (20 µM) forms exhibited a non-significant level of genotoxicity in lymphocytes from multiple myeloma patients when compared to those from healthy individuals. Western blot results showed a decrease in Bcl-2/Bax ratio and an increase in P53 protein levels in lymphocytes from myeloma patients, but not in lymphocytes from healthy individuals. A significant increase in intracellular reactive oxygen species level was also observed, suggesting that regulation of apoptotic proteins triggered by myricetin exposure in lymphocytes from myeloma patients occurred through P53 and oxidative stress-dependent pathways. The potency of myricetin against lymphocytes from myeloma patients marks it a potential candidate to be considered as an alternative to overcome chemo-resistance in cancer therapies.

Smart nanocrystal of indomethacin: Nanonization and characterization through top down method of media milling.

Indomethacin is potent and effective drug belongs to NSAID group having low bioavailability. To address this issue the novel method is Nanosuspensions which can be achieved through bottom up and top down methods. The drug concentration, batch size and crystallinity retention are the problems associated with bottom up method consequently top down method was applied. In current project batch size of 350 ml was prepared by mixing 3.5% of Indomethacin with polymer solution. Then it was introduced into Dena⌖ having 0.2µm yttrium reinforced zirconium beads. The effect of milling time was observed for sixty minutes. Stable nanocrystals with particle size of 161nm ±1.90 with PDI of 0.229 ±0.06 were produced. The DSC and PXRD confirmed the crystallinity of created nanocrystals. The pattern of particle size reduction was initially abrupt and then gradual. The two months Stability studies at 4°C and at 25°C revealed that polymers combination (PVP-K30, HPMC-6cps, SDS) were effective in marinating the stability. The SEM and TEM studies unfastened that nanocrystals were homogenously distributed with discrete crystalline morphology. The fabricated nanocrystals demonstrated marked dissolution rate compared to the raw and marketed formulations. It is demonstrated that it is useful for industry due to high drug concentration, large batch size and retention of distinct characteristics.

Additive Manufacturing of a Point-of-Care "Polypill:" Fabrication of Concept Capsules of Complex Geometry with Bespoke Release against Cardiovascular Disease.

Polypharmacy is often needed for the management of cardiovascular diseases and is associated with poor adherence to treatment. Hence, highly flexible and adaptable systems are in high demand to accommodate complex therapeutic regimens. A novel design approach is employed to fabricate highly modular 3D printed "polypill" capsules with bespoke release patterns for multiple drugs. Complex structures are devised using combined fused deposition modeling 3D printing aligned with hot-filling syringes. Two unibody highly modular capsule skeletons with four separate compartments are devised: i) concentric format: two external compartments for early release while two inner compartments for delayed release, or ii) parallel format: where nondissolving capsule shells with free-pass corridors and dissolution rate-limiting pores are used to achieve immediate and extended drug releases, respectively. Controlling drug release is achieved through digital manipulation of shell thickness in the concentric format or the size of the rate limiting pores in the parallel format. Target drug release profiles are achieved with variable orders and configurations, hence confirming the modular nature with capacity to accommodate therapeutics of different properties. Projection of the pharmacokinetic profile of this digital system capsules reveal how the developed approach can be applied in dose individualization and achieving multiple desired pharmacokinetic profiles.

Ex vivo/in vitro protective effect of myricetin bulk and nano-forms on PhIP-induced DNA damage in lymphocytes from healthy individuals and pre-cancerous MGUS patients.

2-Amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) is a central dietary mutagen, produced when proteinaceous food is heated at very high temperatures potentially causing DNA strand breaks. This study investigates the protective potential of a well-researched flavonoid, myricetin in its bulk and nano-forms against oxidative stress induced ex vivo/in vitro by PhIP in lymphocytes from pre-cancerous monoclonal gammopathy of undetermined significance (MGUS) patients and those from healthy individuals. The results from the Comet assay revealed that in the presence of myricetin bulk (10 µM) and myricetin nano (20 µM), the DNA damage caused by a high dose of PhIP (100 µM) was significantly (P < 0.001) reduced in both groups. However, nano has shown better protection in lymphocytes from pre-cancerous patients. Consistent results were obtained from the micronucleus assay where micronuclei frequency in binucleated cells significantly decreased upon supplementing PhIP with myricetin bulk (P < 0.01) and myricetin nano (P < 0.001), compared to the PhIP treatment alone. To briefly determine the cellular pathways involved in the protective role of myricetin against PhIP, we studied gene expression of P53 and ATR kinase (ATM- and Rad3-related), using the real-time PCR technique.

An in vitro investigation into the protective and genotoxic effects of myricetin bulk and nano forms in lymphocytes of MGUS patients and healthy individuals.

The present study investigated the genoprotective and genotoxic effects of myricetin bulk (10 µM) and nano forms (20 µM) in the lymphocytes from pre-cancerous, monoclonal gammopathy of unknown significance (MGUS) patients and healthy individuals using the Comet and micronucleus assays. The study also evaluated the effect of myricetin on P53 expression levels, using the Western blot technique. Results showed that throughout the in-vitro treatment, lymphocytes from the patients group had higher levels of baseline DNA damage compared to the healthy group. Myricetin in both forms induced significant DNA damage, only at higher concentrations (>40 µM). The micronucleus assay showed a significant reduction (P < 0.01) in the frequency of micronuclei in mono-nucleated cells in the patient group treated with the nano form of myricetin at the non-toxic dose of 20 µM. There was a significant increase in both gene and protein P53 levels in lymphocytes isolated from healthy individuals and pre-cancerous patients. These results suggested a protective effect of myricetin and indicated its nutritional supplement potential for protection against cancer development among patients suffering from MGUS.

ROS-induced oxidative damage in lymphocytes ex vivo/in vitro from healthy individuals and MGUS patients: protection by myricetin bulk and nanoforms.

We investigated the protective role of myricetin bulk and nanoforms, against reactive oxygen species (ROS)-induced oxidative stress caused by hydrogen peroxide and tertiary-butyl hydro peroxide in lymphocytes in vitro from healthy individuals and those from pre-cancerous patients suffering with monoclonal gammopathy of undetermined significance (MGUS). The change in intracellular reactive oxygen species was measured once cells were treated with myricetin bulk forms and nanoforms with and without either hydrogen peroxide or tertiary-butyl hydro peroxide co-supplementation. The direct and indirect antioxidant activity of myricetin was spectrofluometrically measured using the fluorescent dye 2',7'-dichlorofluorescin diacetate and using the Comet assay, respectively. Hydrogen peroxide (50 µM) and tertiary-butyl hydro peroxide (300 µM) induced a higher level of reactive oxygen species-related DNA damage and strand breaks. Addition of myricetin nanoform (20 µM) and bulk (10 µM) form could, however, significantly prevent hydrogen peroxide- and tertiary-butyl hydro peroxide-induced oxidative imbalances and the nanoform was more effective. Glutathione levels were also quantified using a non-fluorescent dye. Results suggest that myricetin treatment had no significant effect on the cellular antioxidant enzyme, glutathione. The current study also investigates the effect of myricetin on the induction of double-strand breaks by staining the gamma-H2AX foci immunocytochemically. It was observed that myricetin does not induce double-strand breaks at basal levels rather demonstrated a protective effect.

Pluronic F127 thermosensitive injectable smart hydrogels for controlled drug delivery system development.

Understanding structure-property relationships is critical for the development of new drug delivery systems. This study investigates the properties of Pluronic smart hydrogel formulations for future use as injectable controlled drug carriers. The smart hydrogels promise to enhance patient compliance, decrease side effects and reduce dose and frequency. Pharmaceutically, these systems are attractive due to their unique sol-gel phase transition in the body, biocompatibility, safety and injectability as solutions before transforming into gel matrices at body temperature. We quantify the structural changes of F127 systems under controlled temperature after flow, as experienced during real bodily injection. Empirical formulae combining the coupled thermal and shear dependency are produced to aid future application of these systems. Induced structural transitions measured in-situ by small angle x-ray and neutron scattering reveal mixed oriented structures that can be exploited to tailor the drug release profile.

3D printed oral theophylline doses with innovative 'radiator-like' design: Impact of polyethylene oxide (PEO) molecular weight.

Despite the abundant use of polyethylene oxides (PEOs) and their integration as an excipient in numerous pharmaceutical products, there have been no previous reports of applying this important thermoplastic polymer species alone to fused deposition modelling (FDM) 3D printing. In this work, we have investigated the manufacture of oral doses via FDM 3D printing by employing PEOs as a backbone polymer in combination with polyethylene glycol (PEG). Blends of PEO (molecular weight 100 K, 200 K, 300 K, 600 K or 900 K) with PEG 6 K (plasticiser) and a model drug (theophylline) were hot-melt extruded. The resultant filaments were used as a feed for FDM 3D printer to fabricate oral dosage forms (ODFs) with innovative designs. ODFs were designed in a radiator-like geometry with connected paralleled plates and inter-plate spacing of either 0.5, 1, 1.5 or 2 mm. X-ray diffraction patterns of the filaments revealed the presence of two distinctive peaks at 2θ = 7° and 12°, which can be correlated to the diffraction pattern of theophylline crystals. Blends of PEO and PEG yielded filaments of variable mechanically resistance (maximum load at break of 357, 608, 649, 882, 781 N for filament produced with PEO 100 K, 200 K, 300 K, 600 K or 900 K, respectively). Filaments of PEO at a molecular weight of 200-600 K were compatible with FDM 3D printing process. Further increase in PEO molecular weight resulted in elevated shear viscosity (>104 Pa.S) at the printing temperature and hindered material flow during FDM 3D printing process. A minimal spacing (1 mm) between parallel plates of the radiator-like design deemed essential to boost drug release from the structure. This is the first report of utilising this widely used biodegradable polymer species (PEOs and PEG) in FDM 3D printing.

Novel Ran-RCC1 Inhibitory Peptide-Loaded Nanoparticles Have Anti-Cancer Efficacy In Vitro and In Vivo.

The delivery of anticancer agents to their subcellular sites of action is a significant challenge for effective cancer therapy. Peptides, which are integral to several oncogenic pathways, have significant potential to be utilised as cancer therapeutics due to their selectivity, high potency and lack of normal cell toxicity. Novel Ras protein-Regulator of chromosome condensation 1 (Ran-RCC1) inhibitory peptides designed to interact with Ran, a novel therapeutic target in breast cancer, were delivered by entrapment into polyethylene glycol-poly (lactic-co-glycolic acid) PEG-PLGA polymeric nanoparticles (NPs). A modified double emulsion solvent evaporation technique was used to optimise the physicochemical properties of these peptide-loaded biodegradable NPs. The anti-cancer activity of peptide-loaded NPs was studied in vitro using Ran-expressing metastatic breast (MDA-MB-231) and lung cancer (A549) cell lines, and in vivo using Solid Ehrlich Carcinoma-bearing mice. The anti-metastatic activity of peptide-loaded NPs was investigated using migration, invasion and colony formation assays in vitro. A PEG-PLGA-nanoparticle encapsulating N-terminal peptide showed a pronounced antitumor and anti-metastatic action in lung and breast cancer cells in vitro and caused a significant reduction of tumor volume and associated tumor growth inhibition of breast cancer model in vivo. These findings suggest that the novel inhibitory peptides encapsulated into PEGylated PLGA NPs are delivered effectively to interact and deactivate Ran. This novel Ran-targeting peptide construct shows significant potential for therapy of breast cancer and other cancers mediated by Ran overexpression.

Enhanced dissolution rate of Ketoprofen by fabricating into smart nanocrystals.

The low bioavailability of Ketoprofen is associated with its hydrophobic nature that can be solved by nanonization. For this purpose, a polymeric solution with drug concentration of 3.5% w/w was formulated. The produced solution was milled for 60 minutes in DENA® mill which contains 0.2µ m yttrium reinforced zirconium beads. The Physicochemical properties, characterization including stability studies of the prepared nanoparticles were carried out using pharmacopeial techniques of zeta potential, PXRD, DSC, SEM and TEM. Results suggest that stable crystalline nanocrystals with a size of 169±1.98nm with PDI of 0.194±0.04 and zeta potential of -22.0±2.25mV were produced. Moreover, enhances in-vitro release rate of 78.6% for the processed Ketoprofen was achieved in first 5 min as compared to raw form and marketed drug which released only 22.9% and 33.1% of drug respectively. The 60 days stability studies at 4oC & 25°C revealed that polymers PVP-K30-HPMC-6cps-SDS were effective in stabilizing the nanocrystals. Comparatively stable ketoprofen nanocrystals were successfully produced by DENA® mill with marked enhanced dissolution rate. It proved a useful for commercialization technique due to high drug concentration and retention of distinct characteristics at large scale.

Fabrication and characterization of dexibuprofen nanocrystals using microchannel fluidic rector.

PURPOSE: Dexibuprofen is an enantiomer of ibuprofen with low bioavailability which results from its hydrophobic nature. Nanosuspensions have developed a podium to solve the in vitro dissolution problem that frequently occurs in current research. MATERIALS AND METHODS: The drug and polymer solutions were mixed in a microchannel fluid reactor and the successive embryonic nanosuspension was decanted into a vial having the polymer solution. The impact of different process and formulation parameters including inlet angle, antisolvent and solvent flow rate(s), mixing time, drug concentration, polymer type and concentration was evaluated. RESULTS AND DISCUSSION: Stable dexibuprofen nanocrystals with a particle size of 45±3.0 nm and polydispersity index of 0.19±0.06 were obtained. Differential scanning calorimetry and powder X-ray diffraction confirmed the crystallinity. The key parameters observed were inlet angle 10°, antisolvent to solvent volume of 2.0/0.5 mL/min, 60 minutes mixing with 5 minutes sonication, Poloxamer-407 with a concentration of 0.5% w/v and drug concentration (5 mg/mm). The 60-day stability studies revealed that the nanocrystals were stable at 4°C and 25°C. The scanning electron microscopy and transmission electron microscopy images showed crystalline morphology with a homogeneous distribution. CONCLUSION: Stable dexibuprofen nanocrystals with retentive distinctive characteristics and having marked dissolution rate compared to raw and marketed formulations were efficiently fabricated. In future perspectives, these nanocrystals could be converted to solid dosage form and the process can be industrialized by chemical engineering approach.

From 'fixed dose combinations' to 'a dynamic dose combiner': 3D printed bi-layer antihypertensive tablets.

There is an increased evidence for treating hypertension by a combination of two or more drugs. Increasing the number of daily intake of tablets has been reported to negatively affect the compliance of patients. Therefore, numerous fixed dose combinations (FDCs) have been introduced to the market. However, the inherent rigid nature of FDCs does not allow the titration of the dose of each single component for an individual patient's needs. In this work, flexible dose combinations of two anti-hypertensive drugs in a single bilayer tablet with a range of doses were fabricated using dual fused deposition modelling (FDM) 3D printer. Enalapril maleate (EM) and hydrochlorothiazide (HCT) loaded filaments were produced via hot-melt extrusion (HME). Computer software was utilised to design sets of oval bi-layer tablets of individualised doses. Thermal analysis and x-ray diffractometer (XRD) indicated that HCT remained crystalline in the polymeric matrix whilst EM appeared to be in an amorphous form. The interaction between anionic EM and cationic methacrylate polymer may have contributed to a drop in the glass transition temperature (Tg) of the filament and obviated the need for a plasticiser. Across all tablet sets, the methacrylate polymeric matrix provided immediate drug release profiles. This dynamic dosing system maintained the advantages of FDCs while providing a superior flexibility of dosing range, hence offering an optimal clinical solution to hypertension therapy in a patient-centric healthcare service.

Tablet fragmentation without a disintegrant: A novel design approach for accelerating disintegration and drug release from 3D printed cellulosic tablets.

Fused deposition modelling (FDM) 3D printing has shown the most immediate potential for on-demand dose personalisation to suit particular patient's needs. However, FDM 3D printing often involves employing a relatively large molecular weight thermoplastic polymer and results in extended release pattern. It is therefore essential to fast-track drug release from the 3D printed objects. This work employed an innovative design approach of tablets with unique built-in gaps (Gaplets) with the aim of accelerating drug release. The novel tablet design is composed of 9 repeating units (blocks) connected with 3 bridges to allow the generation of 8 gaps. The impact of size of the block, the number of bridges and the spacing between different blocks was investigated. Increasing the inter-block space reduced mechanical resistance of the unit, however, tablets continued to meet pharmacopeial standards for friability. Upon introduction into gastric medium, the 1 mm spaces gaplet broke into mini-structures within 4 min and met the USP criteria of immediate release products (86.7% drug release at 30 min). Real-time ultraviolet (UV) imaging indicated that the cellulosic matrix expanded due to swelling of hydroxypropyl cellulose (HPC) upon introduction to the dissolution medium. This was followed by a steady erosion of the polymeric matrix at a rate of 8 µm/min. The design approach was more efficient than a comparison conventional formulation approach of adding disintegrants to accelerate tablet disintegration and drug release. This work provides a novel example where computer-aided design was instrumental at modifying the performance of solid dosage forms. Such an example may serve as the foundation for a new generation of dosage forms with complicated geometric structures to achieve functionality that is usually achieved by a sophisticated formulation approach.