Search Results (27)

Background/Objectives: Chronic lung diseases are among the leading causes of death worldwide. In the treatment of these diseases, non-steroidal anti-inflammatory drugs can be effective. We have previously developed an excipient formulation alongside a modern manufacturing protocol, which we aim to further investigate. We have chosen two new model drugs, meloxicam (MX) and its water-soluble salt, meloxicam-potassium (MXP). The particles in dry powder inhaler (DPI) formulation were expected to have a spherical shape, fast drug release, and good aerodynamic properties. Methods: The excipients were poloxamer-188, mannitol, and leucine. The samples were prepared by spray drying, preceded by solution preparation and wet grinding. Particle size was determined by laser diffraction, shape by scanning electron microscopy (SEM), crystallinity by powder X-ray diffraction (PXRD), interactions by Fourier-transform infrared spectroscopy (FT-IR), in vitro drug dissolution by paddle apparatus, and in vitro aerodynamic properties by Andersen cascade impactor and Spraytec^® device. Results: We achieved the proper particle size (<5 μm) and spherical shape according to laser diffraction and SEM. The XRPD showed partial amorphization. FT-IR revealed no interaction between the materials. During the in vitro dissolution tests, more than 90% of MX and MXP were released within the first 5 min. The best products exhibited an aerodynamic diameter of around 4 µm, a fine particle fraction around 50%, and an emitted fraction over 95%. The analysis by Spraytec^® supported the suitability for lung targeting. Conclusions: The developed preparation process and excipient system can be applied in the development of different drugs containing DPIs. Full article

Background: Nanocrystals, a carrier-free nanotechnology, offer significant advantages for pulmonary drug delivery by enhancing the dissolution and solubility of poorly soluble drugs while maintaining favorable biological properties and low toxicity. This study aims to investigate the aerodynamic performance and stability of nanocrystal-based dry powders (NC-DPs). Methods: Nanocrystalline suspensions were produced via wet media milling and subjected to stability studies before undergoing nano spray drying. A factorial design was employed to optimize the process parameters. The influence of mannitol and leucine, individually and in combination, was evaluated in terms of aerodynamic properties (Aerodynamic Particle Sizer (APS), in silico modeling) and the physicochemical stability at room temperature (in a desiccator) and accelerated conditions (40 ± 2 °C, 75 ± 5% relative humidity). Results: APS analysis revealed that leucine-containing powders (K-NC-Ls) exhibited the smallest median (1.357 µm) and geometric mean (1.335 µm) particle sizes, enhancing dispersibility. However, in silico results indicated the highest exhaled fraction for K-NC-L, highlighting the need for optimized excipient selection. Although mannitol showed the lowest exhaled fraction, it was mainly deposited in the extra-thoracic region in silico. The mannitol/leucine combination (K-NC-ML) revealed a low exhaled fraction and high lung deposition in silico. Also, K-NC-ML demonstrated superior stability, with a 6% reduction in D[0.5] and a 5% decrease in span overtime. Furthermore, no significant changes in crystallinity, thermal behavior, drug release, or mass median aerodynamic diameter were observed under stress conditions. Conclusions: These findings confirm that combined incorporation of mannitol and leucine in NC-DP formulations enhances stability and aerodynamic performance, making it a promising approach for pulmonary drug delivery. Full article

Background and Objectives: This study aimed to develop an embolic agent with short-term embolic effects using cilastatin as the basic material. Materials and Methods: The particle size distribution of 25 mg cilastatin-based short-term embolic agents was evaluated microscopically under three different mixing conditions. A total of thirty-six healthy male Sprague Dawley rats were divided into four groups. Each group of six rats was injected once into the tail artery with 0.4 mL each of (A) Cilastatin + D-Mannitol Mixture, (B) Iohexol, (C) Prepenem, and (D) embolization promoter (EGgel). Results: A visual inspection of the tail appearance of rats in each group was performed at 0, 3, 7, 15, and 21 days. At weeks 1 and 3, three rats per group were euthanized, and histopathological analyses were performed on the specimens obtained from each group. No significant differences were observed on day 7, but mild inflammation was observed in Group (D) on day 15. Histopathological inflammation scoring of tail central artery embolization was performed using a six-point scale (from 0 = absent to 5 = marked inflammation). Three groups were formed consisting of six male New Zealand white rabbits each: control, positive control, and test groups. The control group received an Iohexol injection (rabbits: 0.8 mL). The positive control and experimental groups were injected with prepenem and cilastatin/D-mannitol compound, respectively (0.8 mL), and vascular angiography was performed. The order of occlusion progression after embolization was as follows: test group, positive control group, and control group. Conclusions: We developed a cilastatin/D-mannitol compound that exhibits characteristics of short-term embolization by utilizing the pharmacokinetic properties of cilastatin and the crystalline material D-mannitol. We evaluated its particle size distribution microscopically, conducted histopathological evaluation including inflammation via animal experiments, and assessed the embolization effect. Full article

Purpose: We report the successful surgical treatment of a case of spontaneous complete anterior crystalline lens luxation in a patient affected by retinitis pigmentosa (RP), associated with elevated intraocular pressure and pupillary block. Additionally, we review the current literature regarding the association between ectopia lentis and RP. Case description: A 44-year-old female RP patient presented to our emergency department reporting severe ocular pain in her left eye (LE) and sickness. She had no history of ocular trauma and did not report systemic disorders. The best corrected visual acuity at presentation was 1/20 in her LE, the intraocular pressure was 60 mmHg, and slit lamp examination showed in her LE a complete dislocation of the lens in the anterior chamber, with mydriasis, atalamia, and a pupillary block. The patient had been administered intravenous mannitol 18% solution and dorzolamide–timolol eye drops and was hospitalized for urgent lens extraction. Anterior segment optical coherence tomography and ultrasound biomicroscopy were performed before surgery. Decompressive 23-gauge pars plana vitrectomy and phacoemulsification were performed, and the capsular bag was removed due to marked zonular weakness, with deferred intraocular lens implant. Conclusions: Acute angle closure glaucoma in patients with RP may be rarely caused by spontaneous anterior lens dislocation. To our knowledge, this is the first report of spontaneous anterior lens dislocation in an RP patient, documented through photographs, anterior segment optical coherence tomography, and ultrasound biomicroscopy. Full article

Poor water solubility of drugs is a limiting factor for their bioavailability and pharmacological activity. Many approaches are known to improve drug solubility, and among them, the physical method, solid dispersions (SDs), is applied. SDs are physical mixtures of a drug and a carrier, sometimes with the addition of a surfactant, which can be obtained by milling, cryomilling, spray-drying, or lyophilization processes. In this study, solid dispersions with etodolac (ETD-SDs) were prepared by the milling method using different carriers, such as hypromellose, polyvinylpyrrolidone, copovidone, urea, and mannitol. Solubility studies, dissolution tests, morphological assessment, thermal analysis, and FTIR imaging were applied to evaluate the SD properties. It was shown that the ball-milling process can be applied to obtain SDs with ETD. All designed ETD-SDs were characterized by higher water solubility and a faster dissolution rate compared to unprocessed ETD. SDs with amorphous carriers (HPMC, PVP, and PVP/VA) provided greater ETD solubility than dispersions with crystalline features (urea and mannitol). FTIR spectra confirmed the compatibility of ETD with tested carriers. Full article

The present study compared vacuum drum drying (VDD) and conventional spray drying (SD) for solidifying crystalline ABT-199 nanosuspensions into redispersible oral drug products. The aim was to optimize formulation compositions and process conditions to maintain nanoparticle size after tablet redispersion. The impact of drug load (22%, 33%, 44%) and type of drying protectant (mannitol, mannitol/trehalose mix (1:1), trehalose) on redispersibility and material powder properties were investigated. Moreover, compression analysis was performed assessing the influence of compaction pressure on primary nanocrystal redispersibility and tablet disintegration. Higher drug loads and lower drying protectant levels resulted in particle growth, confirming a drug load dependence on redispersibility behavior. Notably, all drying protectants showed similar protection properties at properly chosen drying process parameters (T_g-dependent), except when VDD was used for mannitol formulations. Differences between the applied drying processes were observed in terms of downstream processing and tabletability: mannitol-containing formulations solidified via VDD showed an improved processability compared to formulations with trehalose. In conclusion, VDD is a promising drying technique that offers advantageous downstream processability compared to SD and represents an attractive novel processing technology for the pharmaceutical industry. As demonstrated in the present study, VDD combines higher yields with a leaner manufacturing process flow. The improved bulk properties provide enhanced tabletability and enable direct compression. Full article

Non-steroidal anti-inflammatory piroxicam (PRX) is a poorly water-soluble drug that provides relief in different arthritides. Reducing the particle size of PRX increases its bioavailability. For pediatric, geriatric, and dysphagic patients, oral dispersible systems ease administration. Moreover, fast disintegration followed by drug release and absorption through the oral mucosa can induce rapid systemic effects. We aimed to produce an orodispersible lyophilizate (OL) consisting of nanosized PRX. PRX was solved in ethyl acetate and then sonicated into a poloxamer-188 solution to perform spray-ultrasound-assisted solvent diffusion-based nanoprecipitation. The solid form was formulated via freeze drying in blister sockets. Mannitol and sodium alginate were applied as excipients. Dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA) were used to determine the particle size. The morphology was characterized by scanning electron microscopy (SEM). To establish the crystallinity, X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) were used. A disintegration and in vitro dissolution test were performed. DLS and NTA presented a nanosized PRX diameter. The SEM pictures showed a porous structure. PRX became amorphous according to the XRPD and DSC curves. The disintegration time was less than 1 min and the dissolution profile improved. The final product was an innovative anti-inflammatory drug delivery system. Full article

Designing spray-dried particles for inhalation aims at specific physicochemical properties including a respirable aerodynamic diameter and adequate powder dispersibility. Leucine, an amphiphilic amino acid, has been shown to aid in optimizing bulk powder properties. Mannitol, a model crystalline active and common bulking agent, was co-sprayed with leucine at several excipient ratios, ethanol/water ratios, and spray dryer outlet temperatures in order to experimentally probe the underlying particle formation mechanisms in this binary crystalline system. During the droplet drying of two crystallizing components, the material that nucleates first will preferentially enrich the surface. It is desired to have a completely crystalline leucine shell to improve powder properties, however, mannitol competes with leucine for the surface depending on excipient concentration and manufacturing parameters. The resulting particles were studied initially and at a two-month timepoint via solid state characterization, visual analysis, and particle size analysis in order to detect changes in bulk powder properties. It was determined that, similar to systems where only leucine can crystallize, initial leucine saturation in the formulation dictates powder characteristics. Full article

Over the past few decades, there has been a considerable rise in the incidence and prevalence of pulmonary fungal infections, creating a global health problem due to a lack of antifungal therapies specifically designed for pulmonary administration. Amphotericin B (AmB) and itraconazole (ITR) are two antifungal drugs with different mechanisms of action that have been widely employed in antimycotic therapy. In this work, microparticles containing a high dose of AmB and ITR (20, 30, and 40% total antifungal drug loading) were engineered for use in dry powder inhalers (DPIs) with an aim to improve the pharmacological effect, thereby enhancing the existing off-label choices for pulmonary administration. A Design of Experiment (DoE) approach was employed to prepare DPI formulations consisting of AmB-ITR encapsulated within γ-cyclodextrin (γ-CD) alongside functional excipients, such as mannitol and leucine. In vitro deposition indicated a favourable lung deposition pattern characterised by an upper ITR distribution (mass median aerodynamic diameter (MMAD) ~ 6 µm) along with a lower AmB deposition (MMAD ~ 3 µm). This offers significant advantages for treating fungal infections, not only in the lung parenchyma but also in the upper respiratory tract, considering that Aspergillus spp. can cause upper and lower airway disorders. The in vitro deposition profile of ITR and larger MMAD was related to the higher unencapsulated crystalline fraction of the drug, which may be altered using a higher concentration of γ-CD. Full article

Crystalline carriers such as dextrose, sucrose, galactose, mannitol, sorbitol, and isomalt have been reported to increase the solubility, and dissolution rates of poorly soluble drugs when employed as carriers in solid dispersions (SDs). However, synthetic polymers dominate the preparation of drugs: excipient SDs have been created in recent years, but these polymer-based SDs exhibit the major drawback of recrystallisation upon storage. Also, the use of high-molecular-weight polymers with increased chain lengths brings forth problems such as increased viscosity and unnecessary bulkiness in the resulting dosage form. An ideal SD carrier should be hydrophilic, non-hygroscopic, have high hydrogen-bonding propensity, have a high glass transition temperature (T_g), and be safe to use. This review discusses sugars and polyols as suitable carriers for SDs, as they possess several ideal characteristics. Recently, the use of low-molecular-weight excipients has gained much interest in developing SDs. However, there are limited options available for safe, low molecular excipients, which opens the door again for sugars and polyols. The major points of this review focus on the successes and failures of employing sugars and polyols in the preparation of SDs in the past, recent advances, and potential future applications for the solubility enhancement of poorly water-soluble drugs. Full article

Spray freeze-drying has emerged as a valid alternative to traditional spray drying to produce therapeutic dry microparticles. In particular, the spherical shape and high porosity of spray freeze-dried microparticles make them suitable for pulmonary drug delivery through dry powder inhalers. However, an appropriate particle size and fine particle fraction are required to guarantee lung deposition. This study used ultrasonic spray freeze-drying to generate dry microparticles composed of mannitol either alone or added with the bronchodilator salbutamol sulphate. The influence of the solid concentration and the feed flow rate on the particle size, morphology, surface area, porosity, and crystallinity was investigated. Growing particle size was observed, increasing the concentration and feed flow rate. Similarly, the addition of the drug led to a larger particle size and surface area. The in vitro simulation of drug deposition highlighted the dependence of the aerodynamic properties on the solid concentration and feed flow rate. Due to the lower density and particle geometric size, the highest fine particle fraction (26%) and smallest mass median aerodynamic diameter (4.4 μm) were reached at the lowest solid concentration and feed flow rate. Full article

Carrier-free spray-dried dispersions for pulmonary delivery, for which the demand is growing, frequently require the incorporation of dispersibility-enhancing excipients into the formulations to improve the efficacy of the dosage form. One of the most promising of such excipients, L-leucine, is expected to be approved for inhalation soon and has been studied exhaustively. However, during stability, small fibers protruding from the particles of leucine-containing powders have occasionally been observed. To clarify the origin of these fibers and assess their potential influence on the performance of the powders, three different classes of spray-dried leucine-containing formulation systems were studied over an 8-month accelerated stability program. These systems consisted of a large molecule biologic (bevacizumab) in conjunction with a glass former (trehalose), an amorphous small-molecular mass active (moxidectin), and a crystallizing active (mannitol). It was determined that the appearance of the fibers was due to the presence of small quantities of leucine in higher energy states, either because these were amorphous or present as a less stable crystalline polymorph. It was further shown that the growth of these leucine fibers caused no significant physicochemical instability in the powders. Nor, more importantly, did it decrease their aerosol performance in a dry powder inhaler or reduce the concentration of their active pharmaceutical ingredients. Full article

Olaparib (OLA) is an anticancer agent that acts by inhibiting the poly (ADP-ribose)-polymerase-I (PARP-I). Due to its low solubility and low permeability, it has been placed as a BCS Class-IV drug and hence its clinical use is limited. In this study, we develop the nanocrystals of OLA as a way to improve its solubility and other performances. The OLA-NCs were prepared by antisolvent precipitation method through homogenization and probe sonication technique using a novel amphiphilic polymeric stabilizer (Soluplus^®). Particle characterization resulted approximately 103.13 nm, polydispersity-index was 0.104 with positive zeta-potential of +8.67 mV. The crystal morphology by SEM of OLA-NCs (with and without mannitol) exhibited nano-crystalline prism-like structures as compared to the elongated OLA-pure. The DSC, XRD and FTIR were performed to check the interaction of Soluplus, mannitol and OLA did not exhibit any physical interaction among the OLA, Soluplus^® and mannitol that is indicated by the presence of parent wave number peak. Two-fold increased solubility of OLA was found in PBS with Soluplus^® from the NCs (69.3 ± 6.2 µgmL⁻¹) as compared to pure drug (35.6 ± 7.2 µgmL⁻¹). In vitro release of drug from OLA-NCs was higher (78.2%) at 12 h at pH 6.8 and relatively lower (53.1%) at pH 1.2. In vitro cellular cytotoxicity and anticancer effects were examined on MCF-7 cells. OLA-NCs were found effectively potent to MCF-7 cells compared with OLA-pure with approximately less than half IC50 value during MTT assay. Estimation of p53, Caspase-3 and Caspase-9 in MCF-7 cells indicated that OLA-NCs have significantly (p < 0.05) increased their expressions. After single oral dose in rats, 12 h plasma drug concentration-time profile indicated approximately 2.06-, 2.29-, 2–25- and 2.62-folds increased Cmax, AUC0-12 h, AUC0-∞ and AUMC0-∞, respectively, from the NCs as compared to OLA-pure. Storage stability indicated that the OLA-NCs was physically and chemically stable at 4 °C, 25 °C and 40 °C up to 6-months. Overall, OLA-NCs were deliberated; its potential feasibility to overwhelm the formulation challenges related to poorly soluble drugs and its future clinical applications. Full article

We offer a report on the synthesis of low-molecular weight biobased poly(mannitol sebacate) (PMS) and its functionalization with acrylate groups (PMSAc). These synthesized polyesters were blended at a low level (10 wt%) with poly (lactic acid) PLA to prepare aligned fibers by electrospinning, coupled with a rotatory collector. The obtained fibers were extensively studied by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and wide-angle X-ray diffraction (WAXS), employing synchrotron radiation. The incorporation of the PMSs on the PLA fibers did not significantly affect the fiber diameters, whereas the alignment was almost maintained. The crystallinity and thermal properties were also slightly modified with the addition of PMSs, and an increase in the degree of crystallinity and in the glass transition temperature of the blend compared to PLA was observed. Remarkably, the PLA/PMSs fibers were more ductile due to the elastomeric character of PMS, with higher values of elongation at break and tensile strengths, and a smaller Young modulus in comparison with the PLA fibers. These modifications of the properties were more noticeable in the case of the acrylated PMS, which also provided readily available functional groups at the surface for further chemical reactions, such as the Michael addition or crosslinking processes. Full article

Positively charged NCs of TZP (0.1%, w/v) for ocular use were prepared by the antisolvent precipitation method. TZP is a novel 5-Hydroxymethyl-Oxazolidinone class of antibiotic and is effective against many drug-resistant bacterial infections. Even the phosphate salt of this drug is poorly soluble, therefore the NCs were prepared for its better solubility and ocular availability. P188 was found better stabilizer than PVA for TZP-NCs. Characterization of the NCs including the particle-size, PDI, and ZP by Zeta-sizer, while morphology by SEM indicated that the preparation technique was successful to get the optimal sized (151.6 nm) TZP-NCs with good crystalline morphology. Mannitol (1%, w/v) prevented the crystal growth and provided good stabilization to NC₁ during freeze-drying. FTIR spectroscopy confirmed the nano-crystallization did not alter the basic molecular structure of TZP. DSC and XRD studies indicated the reduced crystallinity of TZP-NC₁, which potentiated its solubility. An increased solubility of TZP-NC₁ (25.9 µgmL⁻¹) as compared to pure TZP (18.4 µgmL⁻¹) in STF with SLS. Addition of stearylamine (0.2%, w/v) and BKC (0.01%, w/v) have provided cationic (+29.4 mV) TZP-NCs. Redispersion of freeze-dried NCs in dextrose (5%, w/v) resulted in a clear transparent aqueous suspension of NC₁ with osmolarity (298 mOsm·L⁻¹) and viscosity (21.1 cps at 35 °C). Mannitol (cryoprotectant) during freeze-drying could also provide isotonicity to the nano-suspension at redispersion in dextrose solution. In vitro release in STF with SLS has shown relatively higher (78.8%) release of TZP from NC₁ as compared to the conventional TZP-AqS (43.4%) at 12 h. TZP-NC₁ was physically and chemically stable at three temperatures for 180 days. The above findings suggested that TZP-NC₁ would be a promising alternative for ocular delivery of TZP with relatively improved performance. Full article