Asiatic acid-entrapped transfersomes for the treatment of hypertrophic scars: In vitro appraisal, bioactivity evaluation, and clinical study.

Non-invasive treatment options for hypertrophic scars (HTS) are limited, and treating HTS remains challenging due to their unappealing appearance and associated social stigma. In this work, a novel transfersomal system named Asiatic acid-entrapped transfersomes (AATs) was prepared. AATs were evaluated for their skin permeability, anti-inflammatory activity, and other characteristic parameters to determine the most promising formulation. Asiatic acid-entrapped transfersomal gel (AATG), which was obtained by incorporating the lead AATs in a gel base, underwent testing in an 8-week, double-blind, placebo-controlled, split-skin clinical study. The net skin elasticity (R5), melanin index (MI), and skin surface hydration were analyzed employing Cutometer®, Mexameter®, and Corneometer®, respectively, in order to evaluate the effectiveness of the developed AATG. AATs exhibited vesicular sizes and zeta potential values within the range of (27.15 ± 0.95 to 63.54 ± 2.51 nm) and (-0.010 to -0.129 mV), respectively. TW80AAT gave the highest %EE (90.84 ± 2.99%), deformability index (101.70 ± 11.59 mgs-1), permeation flux at 8 h (0.146 ± 0.005 mg/cm2/h), and anti-inflammatory activity (71.65 ± 1.83%). The clinical study results of AATG indicated no adverse skin reactions. Furthermore, product efficacy tests demonstrated a significant reduction in MI and an increase in net skin elasticity at 2, 4, and 8 weeks. These pilot study outcomes support the effectiveness of the AATG.

Preparation, Characterization and Permeation Study of Topical Gel Loaded with Transfersomes Containing Asiatic Acid.

The objective of this study is to investigate the in vitro permeation of asiatic acid (AA) in the form of a topical gel after entrapment in transfersomes by Franz diffusion cells. Transfersomes composed of soybean lecithin and three different edge activators including Tween 80 (TW80), Span 80 (SP80) and sodium deoxycholate (SDC) at the ratio of 50:50, 90:10 and 90:10, respectively, together with 0.3% w/w of AA, were prepared by a high-pressure homogenization technique and further incorporated in gels (TW80AATG, SP80AATG and SDCAATG). All transfersomal gels were characterized for their AA contents, dynamic viscosity, pH and homogeneity. Results revealed that the AA content, dynamic viscosity and pH of the prepared transfersomal gels ranged from 0.272 ± 0.006 to 0.280 ± 0.005% w/w, 812.21 ± 20.22 to 1222.76 ± 131.99 Pa.s and 5.94 ± 0.03 to 7.53 ± 0.03, respectively. TW80AATG gave the highest percentage of AA penetration and flux into the Strat-M® membrane at 8 h (8.53 ± 1.42% and 0.024 ± 0.008 mg/cm2/h, respectively) compared to SP80AATG (8.00 ± 1.70% and 0.019 ± 0.010 mg/cm2/h, respectively), SDCAATG (4.80 ± 0.50% and 0.014 ± 0.004 mg/cm2/h, respectively), non-transfersomal gels (0.73 ± 0.44 to 3.13 ± 0.46% and 0.002 ± 0.001 to 0.010 ± 0.002 mg/cm2/h, respectively) and hydroethanolic AA solution in gel (1.18 ± 0.76% and 0.004 ± 0.003 mg/cm2/h, respectively). These findings indicate that the TW80AATG might serve as a lead formulation for further development toward scar prevention and many types of skin disorders.

Rheological Investigation of Hydroxypropyl Cellulose-Based Filaments for Material Extrusion 3D Printing.

The rheological properties of drug-polymer mixtures have a significant influence on their processability when using transformative techniques, such as hot-melt-extrusion and material-extrusion 3D printing; however, there has been limited data on printable systems. This study investigated the rheological properties of 17 formulations of successful printed tablets for both immediate and controlled release. Hydroxypropyl cellulose was used in various ratios to obtain printable filaments in combination with various drugs (indomethacin or theophylline), polymers and disintegrants. The complex viscosity, shear thinning behavior and viscoelastic properties were affected by the drug load, polymer composite, disintegrant type, temperature and shear rate applied. Larger windows of processing viscosity were revealed. The viscosity of the printable blends could be as low as the range 10-1000 Pa·s at 100 rad/s angular frequency. All formulations showed shear thinning behavior with a broad slope of complex viscosity from -0.28 to -0.74. The addition of 30-60% drug or disintegrant tended to have greater viscosity values. While microcrystalline cellulose was found to be an alternative additive to lower the storage and loss modulus among disintegrants. This rheological data could be useful for the preformulation and further development of material-extrusion 3D-printing medicines.

Four Novel Pharmaceutical Cocrystals of Oxyresveratrol, Including a 2 : 3 Cocrystal with Betaine.

Cocrystal engineering can alter the physicochemical properties of a drug and generate a superior drug candidate for formulation design. Oxyresveratrol (ORV) exhibits a poor solubility in aqueous environments, thereby resulting in a poor bioavailability. Extensive cocrystal screening of ORV with 67 cocrystal formers (coformers) bearing various functional groups was therefore conducted using grinding, liquid-assisted grinding, solvent evaporation, and slurry methods. Six cocrystals (ORV with betaine (BTN), L-proline (PRL), isonicotinamide, nicotinamide, urea, and ethyl maltol) were found, including four novel cocrystals. Powder X-ray diffraction, low frequency Raman spectroscopy, and thermal analysis revealed unique crystal forms in all obtained samples. Conventional Raman and infrared data differentiated the cocrystals by the presence or absence of a hydrogen bond interacting with the aromatic ring of ORV. The crystal structures were then elucidated by single-crystal X-ray diffraction. Two new cocrystals consisting of ORV : BTN (2 : 3) and ORV : PRL : H2O (1 : 2 : 1) were identified, and their crystal structures were solved. We report novel cocrystalline solids of ORV with improved aqueous solubilities and the unique cage-like crystal structures.

Tailoring immediate release FDM 3D printed tablets using a quality by design (QbD) approach.

The aims of this work were to produce immediate release printed tablets using fused deposition modelling (FDM) technique and to systematically explore the effects of different compositions on drug release by Quality by Design approach. Screening studies of various drug loadings and excipients were conducted by hot melt extrusion and FDM printing to set up the appropriate limit of each independent factor (critical material attribute, CMA) in Design of Experiment. This study demonstrated that the use of polymeric mixture containing different theophylline loadings (10, 30 and 60% w/w) in combination with multiple pharmaceutical polymers (hydroxy propyl cellulose (HPC), Eudragit® EPO, Kollidon® VA 64) and disintegrant (sodium starch glycolate) were successfully hot melt-extruded and FDM printed with no plasticizer. Rheological measurement was performed to understand the critical process parameters (CPP) while the mechanical property of extrudable and printable filaments was investigated by 3-point test for the formulation development. Surprisingly, HPC were found to be superior as a flexibility modifier in all printable filaments. A range of pharmaceutical characterizations were examined to ensure the critical quality attributes (CQA). Characteristic dissolution profiles were obtained. D-optimal mixture design of 17 formulations suggested that theophylline release was considerably affected by the combined action of different excipients and could predict the optimum formulation with the required quality target product profile (QTPP) in pharmacopoeia (85% release at 30 min). Therefore, this can be a useful platform to develop immediate release products for a specific group of patients commercially.

Efficacy and safety of inhaled nebulized sodium nitrite in asthmatic patients.

BACKGROUND: Nitrite is a physiologic nitric oxide (NO) derivative that can be bioactivated to NO. NO has been shown to attenuate airway inflammation and enhance the anti-inflammatory effect of corticosteroids in the animal model of asthma. Here, we aimed to investigate the efficacy and safety of inhaled sodium nitrite as add-on therapy with inhaled corticosteroid (ICS) in adult patients with persistent asthma. METHODS: In protocol 1, 10 asthmatic patients were administered a single dose of nebulized 15-mg sodium nitrite to assess safety, effect on lung function, and pharmacokinetics of nitrite within 120 min. In protocol 2, 20 patients were randomly assigned to a nitrite (15 mg twice daily) group or a placebo group to assess the efficacy over 12 weeks. The primary outcome was the forced expiratory volume in 1 s (FEV1). The secondary outcomes were other lung function parameters, unplanned asthma-related visits at the emergency department (ED) or outpatient department (OPD), admission days, asthma control test (ACT), and safety. RESULTS: Nebulized sodium nitrite had neither acute adverse effect nor effect on lung function test within 120 min. No blood pressure change was seen. At week 12, FEV1 increased in the nitrite group, whereas there was no change in the placebo group. There were 5 events of asthma exacerbation, 4 ED visits, and one unplanned OPD visit in the placebo group, but none of these was noted in the nitrite group. There was no change in ACT scores in both groups. No adverse event was reported during 12 weeks in the nitrite group. There was no change in methemoglobin levels and sputum inflammatory markers. CONCLUSION: From our pilot trial, nebulized sodium nitrite is safe in asthmatic patients, and shows the potential to reduce asthma exacerbation compared with placebo.

Transfersomes: A Promising Nanoencapsulation Technique for Transdermal Drug Delivery.

Transdermal delivery systems have gained much interest in recent years owing to their advantages compared to conventional oral and parenteral delivery systems. They are noninvasive and self-administered delivery systems that can improve patient compliance and provide a controlled release of the therapeutic agents. The greatest challenge of transdermal delivery systems is the barrier function of the skin's outermost layer. Molecules with molecular weights greater than 500 Da and ionized compounds generally do not pass through the skin. Therefore, only a limited number of drugs are capable of being administered by this route. Encapsulating the drugs in transfersomes are one of the potential approaches to overcome this problem. They have a bilayered structure that facilitates the encapsulation of lipophilic and hydrophilic, as well as amphiphilic, drug with higher permeation efficiencies compared to conventional liposomes. Transfersomes are elastic in nature, which can deform and squeeze themselves as an intact vesicle through narrow pores that are significantly smaller than its size. This review aims to describe the concept of transfersomes, the mechanism of action, different methods of preparation and characterization and factors affecting the properties of transfersomes, along with their recent applications in the transdermal administration of drugs.

In situ monitoring of the crystalline state of active pharmaceutical ingredients during high-shear wet granulation using a low-frequency Raman probe.

Optimization of manufacturing processes based on scientific evidence is important in the quality control of active pharmaceutical ingredients (APIs) and drug products, particularly when crystal forms change during production, which could affect subsequent drug performance. In this study, we verified crystalline states using various crystal faces and excipients during high-shear wet granulation based on non-contact low-frequency (LF) Raman probe monitoring. Four model drugs [indomethacin (IND), acetaminophen (APAP), theophylline (TP), and caffeine (CAF) polymorphs and cocrystals] were mixed with microcrystalline cellulose and hydroxypropyl cellulose with the addition of water over time. The LF Raman probe showed comparatively high sensitivity in monitoring 5-20% APAP and IND in a wet mass. Notably, as observed from the characteristic LF Raman peak shifts, form I TP and CAF and their cocrystals were more susceptible to transformation to the monohydrate form than form II. This method was also shown to be applicable in monitoring a commercial formulation of eight excipients and revealed crystalline transformations after 15 min of mixing. Therefore, probe-type LF Raman spectroscopy can be successfully employed to distinguish and monitor the crystalline state of APIs in real time during high-shear wet granulation, in which there is a risk of crystal transformation.

Measurement of the Water Content in Semi-solid Formulations Used to Treat Pressure Ulcers and Evaluation of Their Water Absorption Characteristics.

We investigated the water contents in commercial semi-solid preparations used for pressure ulcer (PU) treatment using near-IR spectroscopy (NIRS) and compared the results with those measured using the Karl Fischer (KF) method. The aim of this study was to determine a standard method and select the appropriate topical preparation with the optimal moisture for PU treatment. The water absorption properties of bases and formulations were evaluated with a time-dependent factor using Transwell as the model membrane. KF and NIRS were applicable as measurement methods of the water content in semi-solid formulations. NIRS was shown to be a useful, simple, nondestructive tool that is more advantageous than the KF method. The water absorption characteristics tested using Transwell revealed that the rate of and capacity for water absorption are determined not only by the absorption ability of the polymer base but also by other factors, such as the osmotic pressure exerted by additives. KF and NIR measurements can be used to choose external skin preparations to control the amount of water in PU treatment.

Exploring Novel Cocrystalline Forms of Oxyresveratrol to Enhance Aqueous Solubility and Permeability across a Cell Monolayer.

Oxyresveratrol (ORV) is a naturally extracted compound with many pharmacological activities. However, information about the crystalline form is not known when considering the development of a form for oral dosage. Cocrystal engineering offers drug molecular understanding and drug solubility improvements. Thus, we attempted cocrystallization of ORV using 10 carboxylic acids as a coformer at a 1:1 M ratio. Each combination was processed with liquid-assisted grinding, solvent evaporation and a slurry method, then characterized by powder X-ray powder diffraction (PXRD), conventional and low-frequency Raman spectroscopy and thermal analysis. The solubility, dissolution and permeation studies across Caco-2 cell monolayers were conducted to evaluate the ORV samples. A screening study revealed that an ORV and citric acid (CTA) cocrystal formed by ethyl acetate-assisted grinding had characteristic PXRD peaks (14.0 and 16.5°) compared to those of ORV dihydrate used as a starting material. Low-frequency Raman measurements, with peaks at 100 cm-1, distinguished potential cocrystals among three processing methods while conventional Raman could not. An endothermic melt (142.2°C) confirmed the formation of the novel crystalline complex. The solubility of the cocrystal in the dissolution media of pH 1.2 and 6.8 was approximately 1000 µg/mL, a 1.3-fold increase compared to ORV alone. In vitro cytotoxicity studies showed that the cocrystal and physical blend were not toxic at concentrations of 25 and 12.5 µM ORV, respectively. The ORV-CTA cocrystal enhanced the cellular transport of ORV across Caco-2 monolayers. Therefore, cocrystallization could be used to improve aqueous solubility and permeability, leading to better oral bioavailability of ORV.

Laser irradiation to produce amorphous pharmaceuticals.

Using a high-power CO2 laser to irradiate powder beds, it was possible to induce phase transformation to the amorphous state. Irradiation of a model drug, indometacin, resulted in formation of a glass. Varying the settings of the laser (power and raster speed) was shown to change the physicochemical properties of the glasses produced and all irradiated glasses were found to be more stable than a reference glass produced by melt-quenching. Irradiation of a powder blend of paracetamol and polyvinylpyrrolidone K30 was found to produce a solid amorphous dispersion. The results suggest that laser-irradiation might be a useful method for making amorphous pharmaceuticals.