Tranexamic acid loaded in a physically crosslinked trilaminate dressing for local hemorrhage control: Preparation, characterization, and in-vivo assessment using two different animal models.

This work aimed at formulating a trilaminate dressing loaded with tranexamic acid. It consisted of a layer of 3 % sodium hyaluronate to initiate hemostasis. It was followed by a mixed porous layer of 5 % polyvinyl alcohol and 2 % kappa-carrageenan. This layer acted as a drug reservoir that controlled its release. The third layer was 5 % ethyl cellulose backing layer for unidirectional release of tranexamic acid towards the wound. The 3 layers were physically crosslinked by hydrogen bonding as confirmed by Infrared spectroscopy. Swelling and release studies were performed, and results proposed that increasing number of layers decreased swelling properties and sustained release of tranexamic acid for 8 h. In vitro blood coagulation study was performed using human blood and showed that the dressing significantly decreased coagulation time by 70.5 % compared to the negative control. In vivo hemostatic activity was evaluated using tail amputation model in Wistar rats. Statistical analysis showed the dressing could stop bleeding in a punctured artery of the rat tail faster than the negative control by 59 %. Cranial bone defect model in New Zealand rabbits was performed to check for bone hemostasis and showed significant decrease in the hemostatic time by 80 % compared to the control.

Formulation of Saxagliptin Oral Films: Optimization, Physicochemical Characterization, In-Vivo Assessment, and In-Vitro Real-Time Release Monitoring via a Novel Polyaniline Nanoparticles-Based Solid-Contact Screen Printed Ion-Selective Electrode.

Oral dispersible films have received broad interest due to fast drug absorption and no first-path metabolism, leading to high bioavailability and better patient compliance. Saxagliptin (SXG) is an antidiabetic drug that undergoes first-path metabolism, resulting in a less active metabolite, so the development of SXG oral dispersible films (SXG-ODFs) improves SXG bioavailability. The formula optimisation included a response surface experimental design and the impact of three formulation factors, the type and concentration of polymer and plasticiser concentration on in-vitro disintegration time and folding endurance. Two optimised SXG-ODFs prepared using either polyvinyl alcohol (PVA) or hydroxypropyl methylcellulose were investigated. SXG-ODFs prepared with PVA demonstrated a superior rapid disintegration time, ranging from 17 to 890 s, with the fastest disintegration time recorded at 17 s. These short durations can be attributed to the hydrophilic nature of PVA, facilitating rapid hydration and disintegration upon contact with saliva. Additionally, PVA-based films displayed remarkable folding endurance, surpassing 200 folds without rupture, indicating flexibility and stability. The high tensile strength of PVA-based films further underscores their robust mechanical properties, with tensile strength values reaching up to 4.53 MPa. SXG exhibits a UV absorption wavelength of around 212 nm, posing challenges for traditional quantitative spectrophotometric analysis, so a polyaniline nanoparticles-based solid-contact screen-printed ion-selective electrode (SP-ISE) was employed for the determination of SXG release profile effectively in comparison to HPLC. SP-ISE showed a better real-time release profile of SXG-ODFs, and the optimised formula showed lower blood glucose levels than commercial tablets.

Optimized mucoadhesive niosomal carriers for intranasal delivery of carvedilol: A quality by design approach.

Carvedilol (CV), a ß-blocker essential for treating cardiovascular diseases, faces bioavailability challenges due to poor water solubility and first-pass metabolism. This study developed and optimized chitosan (CS)-coated niosomes loaded with CV (CS/CV-NS) for intranasal (IN) delivery, aiming to enhance systemic bioavailability. Utilizing a Quality-by-Design (QbD) approach, the study investigated the effects of formulation variables, such as surfactant type, surfactant-to-cholesterol (CHOL) ratio, and CS concentration, on CS/CV-NS properties. The focus was to optimize specific characteristics including particle size (PS), polydispersity index (PDI), zeta potential (ZP), entrapment efficiency (EE%), and mucin binding efficiency (MBE%). The optimal formulation (Opt CS/CV-NS), achieved with a surfactant: CHOL ratio of 0.918 and a CS concentration of 0.062 g/100 mL, using Span 60 as the surfactant, exhibited a PS of 305 nm, PDI of 0.36, ZP of + 33 mV, EE% of 63 %, and MBE% of 57 %. Opt CS/CV-NS was characterized for its morphological and physicochemical properties, evaluated for stability under different storage conditions, and assessed for in vitro drug release profile. Opt CS/CV-NS demonstrated a 1.7-fold and 4.8-fold increase in in vitro CV release after 24 h, compared to uncoated CV-loaded niosomes (Opt CV-NS) and free CV, respectively. In vivo pharmacokinetic (PK) study, using a rat model, demonstrated that Opt CS/CV-NS achieved faster Tmax and higher Cmax compared to free CV suspension indicating enhanced absorption rate. Additionally, Opt CV-NS showed a 1.68-fold higher bioavailability compared to the control. These results underscore the potential of niosomal formulations in enhancing IN delivery of CV, offering an effective strategy for improving drug bioavailability and therapeutic efficacy.

Hemostatic Alginate/Nano-Hydroxyapatite Composite Aerogel Loaded with Tranexamic Acid for the Potential Protection against Alveolar Osteitis.

Wound control in patients on anticoagulants is challenging and often leads to poor hemostasis. They have a higher tendency to develop alveolar osteitis after tooth extraction. The application of a hemostatic dressing that has a high absorbing capacity and is loaded with an antifibrinolytic drug could help in controlling the bleeding. Alginate/nano-hydroxyapatite (SA/Nano-HA) composite aerogels loaded with tranexamic acid (TXA) were prepared. Nano-HA served as a reinforcing material for the alginate matrix and a source of calcium ions that helps in blood clotting. It influenced the porosity and the water uptake capacity. TXA release from SA/Nano-HA aerogels showed a biphasic profile for up to 4 h. Blood coagulation studies were performed on human whole blood. The TXA-loaded aerogel significantly reduced the clotting time by 69% compared to the control (p < 0.0001). Recalcification time was significantly reduced by 80% (p < 0.0001). Scanning electron microscopy analysis revealed the porous nature of the aerogels and the ability of the optimum aerogel to activate and adhere platelets to its porous surface. The cell migration assay showed that there was a delay in wound healing caused by the TXA aerogel compared to the control sample after treating human fibroblasts. Results suggest that the developed aerogel is a promising dressing that will help in hemostasis after tooth extraction.

Colon targeting of celecoxib nanomixed micelles using pulsatile drug delivery systems for the prevention of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a debilitating condition characterized by chronic inflammation of the colon which can increase the risk of colon cancer. Celecoxib (CXB), a cyclooxygenase-2 inhibitor, showed potential for the prophylaxis against IBD. However, it suffers from poor aqueous solubility and cardiovascular toxicity on prolonged use. Here, CXB solubility was enhanced using nanomixed micelles (NMMs) and then colon targeted in a pulsatile system to minimize systemic side effects. Pluronic P123 NMMs with bile salts or hydrophilic Pluronics were prepared using the thin film hydration technique. NMMs were characterized for particle size, size distribution and zeta potential before and after freeze drying and for solubility enhancement. The freeze dried NMMs were then loaded in pulsatile systems with varying tablet plugs containing time-dependent polymers at different concentrations. The optimum NMM consisted of Pluronic P123 and sodium taurocholate (1:1) and CXB:surfactant mixture ratio of 1:30. The pulsatile capsules, containing a tablet plug made of 75% Carbopol®, achieved the target release profile with 88.35% of the dose released after an 8 hrs lag period. Finally, the optimum NMM/pulsatile system showed protective effect against experimentally-induced colitis compared to conventional capsules and pulsatile capsules filled with pure CXB.

Effects of ionic interactions on protein stability prediction using solid-state hydrogen deuterium exchange with mass spectrometry (ssHDX-MS).

Deuterium incorporation in solid-state hydrogen deuterium exchange with mass spectrometry (ssHDX-MS) has been correlated with protein aggregation on storage in sugar-based solid matrices. Here, the effects of sucrose, arginine and histidine buffer on the rate of aggregation of a lyophilized monoclonal antibody (mAb) were assessed using design of experiments (DoE) and response surface methodology. Lyophilized formulations were characterized using ssHDX-MS and Fourier transform infrared spectroscopy (ssFTIR) to assess potential correlation with stability in solid state. The samples were subjected to storage stability at 5 °C and stressed stability at 40 °C/75% RH for 6 months, and the aggregation rate was measured using size exclusion chromatography (SEC). Different levels of arginine had no significant effect on deuterium uptake in ssHDX-MS, although stability studies showed that aggregation rate decreased with increasing arginine concentration. Similarly, when histidine buffer was replaced with phosphate buffer at the same pH and molarity, ssHDX-MS showed no differences in deuterium uptake, but storage stability studies showed a significant increase in aggregation rate. The results suggest that proteins can be stabilized in amorphous solids by ionic interactions which ssHDX-MS does not detect, an important indication of the limitations of the method.

Zero-order release and bioavailability enhancement of poorly water soluble Vinpocetine from self-nanoemulsifying osmotic pump tablet.

Solid self-nanoemulsifying (S-SNEDDS) asymmetrically coated osmotic tablets of the poorly water-soluble drug Vinpocetine (VNP) were designed. The aim was to control the release of VNP by the osmotic technology taking advantage of the solubility and bioavailability-enhancing capacity of S-SNEDDS. Liquid SNEDDS loaded with 2.5 mg VNP composed of Maisine™ 35-1, Transcutol® HP, and Cremophor® EL was adsorbed on the solid carrier Aeroperl®. S-SNEDDS was mixed with the osmotic tablet excipients (sodium chloride, Avicel®, HPMC-K4M, PVP-K30, and Lubripharm®), then directly compressed to form the core tablet. The tablets were dip coated and mechanically drilled. A 32*21 full factorial design was adopted. The independent variables were: type of coating material (X1), concentration of coating solution (X2), and number of drills (X3). The dependent variables included % release at 2 h (Y1), at 4 h (Y2), and at 8 h (Y3). The in vivo performance of the optimum formula was assessed in rabbits. Zero-order VNP release was obtained by the single drilled 1.5% Opadry® CA coated osmotic tablets and twofold increase in VNP bioavailability was achieved. The combination of SNEDDS and osmotic pump tablet system was successful in enhancing the solubility and absorption of VNP as well as controlling its release.

The discovery and investigation of a crystalline solid solution of an active pharmaceutical ingredient.

Understanding the phase behavior of crystal forms is essential in drug formulation development, as physical stability of the active pharmaceutical ingredient (API) is critical to achieving the desired bioavailability. Solvents greatly impact the physical stability of crystalline solids, resulting in a variety of well-known phase transitions, such as hydrate/solvate formation. However, solvent incorporation may also result in the formation of a less-known crystalline solid solutions (CSSs). The identification and characterization of CSSs and their effect on API physicochemical properties have not been investigated. This is the first reported instance of a CSS for an API. An exhaustive study of the phase behavior of the enantiotropically related polymorphs, I and II, of Benzocaine in water and ethanol revealed that Form I formed a CSS with water below 294.5K. Construction of the phase diagrams of Forms I and II in water and ethanol revealed that CSS formation significantly decreased the phase transition temperature between Forms I and II in water. This change resulted from the increased disorder in the lattice of Form I due to the presence of water. This work demonstrates the importance of understanding the formation of CSSs on the thermodynamic behavior of crystalline pharmaceutical solids.

Comparative Study Between Different Ready-Made Orally Disintegrating Platforms for the Formulation of Sumatriptan Succinate Sublingual Tablets.

Sumatriptan succinate (SS) is a selective serotonin receptor agonist used for the treatment of migraine attacks, suffering from extensive first-pass metabolism and low oral bioavailability (∼14%). The aim of this work is to compare the performance of different ready-made co-processed platforms (Pharmaburst®, Prosolv ODT®, Starlac®, Pearlitol Flash®, or Ludiflash®) in the formulation of SS sublingual orodispersible tablets (ODTs) using direct compression technique. The prepared SS ODT formulae were evaluated regarding hardness, friability, simulated wetting time, and in vitro disintegration and dissolution tests. Different mucoadhesive polymers-HPMC K4M, Carbopol®, chitosan, or Polyox®-were tested aiming to increase the residence time in the sublingual area. A pharmacokinetic study on healthy human volunteers was performed, using LC/MS/MS assay, to compare the optimum sublingual formula (Ph25/HPMC) with the conventional oral tablet Imitrex®. Results showed that tablets prepared using Pharmaburst® had significantly (p < 0.05) the lowest simulated wetting and in vitro disintegration times of 17.17 and 23.50 s, respectively, with Q 5 min of 83.62%. HPMC showed a significant (p < 0.05) increase in the residence time from 48.44 to 183.76 s. The relative bioavailability was found to be equal to 132.34% relative to the oral tablet Imitrex®. In conclusion, Pharmaburst® was chosen as the optimum ready-made co-processed platform that can be successfully used in the preparation of SS sublingual tablets for the rapid relief of migraine attacks.

The effect of ionotropic gelation residence time on alginate cross-linking and properties.

The ability to engineer biocompatible polymers with controllable properties is highly desirable. One such approach is to cross-link carbohydrate polymers using ionotropic gelation (IG). Previous studies have investigated the effect of curing time on alginate cross-linking. Herein, we discuss a novel study detailing the effect of IG residence time (IGRT) on the cross-linking of alginate with calcium ions (Ca2+) along with water migration (syneresis) and their subsequent impact on the pharmaceutical properties of alginate particles. IGRT was shown to have a significant effect on particle size, porosity, density, mechanical strength and swelling of calcium alginate particles as well as drug release mechanism. Furthermore, we describe a novel application of electron dispersive spectroscopy (EDS), in conjunction with Fourier Transform- infra red (FT-IR) spectroscopy, to analyze and monitor the changes in Ca2+ concentration during cross-linking. A simple procedure to determine the concentration and distribution of the surface and internal Ca2+ involved in alginate cross-linking was successfully developed.

Combined mixture-process variable approach: a suitable statistical tool for nanovesicular systems optimization.

OBJECTIVES: This study aims to illustrate the applicability of combined mixture-process variable (MPV) design and modeling for optimization of nanovesicular systems. METHODS: The D-optimal experimental plan studied the influence of three mixture components (MCs) and two process variables (PVs) on lercanidipine transfersomes. The MCs were phosphatidylcholine (A), sodium glycocholate (B) and lercanidipine hydrochloride (C), while the PVs were glycerol amount in the hydration mixture (D) and sonication time (E). The studied responses were Y1: particle size, Y2: zeta potential and Y3: entrapment efficiency percent (EE%). Polynomial equations were used to study the influence of MCs and PVs on each response. Response surface methodology and multiple response optimization were applied to optimize the formulation with the goals of minimizing Y1 and maximizing Y2 and Y3. RESULTS: The obtained polynomial models had prediction R(2) values of 0.645, 0.947 and 0.795 for Y1, Y2 and Y3, respectively. Contour, Piepel's response trace, perturbation, and interaction plots were drawn for responses representation. The optimized formulation, A: 265 mg, B: 10 mg, C: 40 mg, D: zero g and E: 120 s, had desirability of 0.9526. The actual response values for the optimized formulation were within the two-sided 95% prediction intervals and were close to the predicted values with maximum percent deviation of 6.2%. CONCLUSIONS: This indicates the validity of combined MPV design and modeling for optimization of transfersomal formulations as an example of nanovesicular systems.

Design and optimization of topical methotrexate loaded niosomes for enhanced management of psoriasis: application of Box-Behnken design, in-vitro evaluation and in-vivo skin deposition study.

Psoriasis, a skin disorder characterized by impaired epidermal differentiation, is regularly treated by systemic methotrexate (MTX), an effective cytotoxic drug but with numerous side effects. The aim of this work was to design topical MTX loaded niosomes for management of psoriasis to avoid systemic toxicity. To achieve this goal, MTX niosomes were prepared by thin film hydration technique. A Box-Behnken (BB) design, using Design-Expert(®) software, was employed to statistically optimize formulation variables. Three independent variables were evaluated: MTX concentration in hydration medium (X1), total weight of niosomal components (X2) and surfactant: cholesterol ratio (X3). The encapsulation efficiency percent (Y1: EE%) and particle size (Y2: PS) were selected as dependent variables. The optimal formulation (F12) displayed spherical morphology under transmission electron microscopy (TEM), optimum particle size of 1375.00 nm and high EE% of 78.66%. In-vivo skin deposition study showed that the highest value of percentage drug deposited (22.45%) and AUC0-10 (1.15 mg.h/cm(2)) of MTX from niosomes were significantly greater than that of drug solution (13.87% and 0.49 mg.h/cm(2), respectively). Moreover, in-vivo histopathological studies confirmed safety of topically applied niosomes. Concisely, the results showed that targeted MTX delivery might be achieved using topically applied niosomes for enhanced treatment of psoriasis.