Extended Release Profile Research Articles

Disulfiram-containing polymeric nanocapsules with anticancer activity for cancer treatment.

Disulfiram, a medication traditionally used to treat alcohol addiction, has gained attention as a potential cancer treatment in recent years. Disulfiram works by inhibiting the enzyme aldehyde dehydrogenase, involved in the breakdown of acetaldehyde, a by-product of alcohol metabolism. This results in the build up of acetaldehyde in the body leading to unpleasant side effects such as nausea and vomiting when alcohol is consumed while taking the drug. With cancer treatment, disulfiram has been found to have several mechanisms of action. It has been shown to inhibit cancer cell growth and metastasis and to induce apoptosis in cancer cells. Additionally, disulfiram has been found to sensitize cancer cells to other treatments, including chemotherapy and radiation therapy, by increasing their susceptibility to these treatments. Disulfiram treatment is effective against a variety of cancers, including breast cancer, prostate cancer, and glioblastoma. Overall, disulfiram holds promise as a potentially effective and inexpensive cancer treatment. Thus, researchers are exploring various delivery systems for disulfiram in cancer treatment to improve its effectiveness and reduce its side effects. Among delivery systems nanoparticles and liposomes have been used to deliver disulfiram. Our study demonstrates the efficacy of polycaprolactone-based nanocapsules for encapsulating DSF, maintaining stable size distribution (∼250nm) and long-term stability. These nanocapsules exhibit sustained, controlled DSF release, effectively addressing the drug's instability in the bloodstream and showing promising therapeutic potential. Notably, DSF-loaded nanocapsules exhibited a twofold increase in cytotoxicity against certain tumors compared to free DSF, attributed to their extended-release profile. These findings highlight the potential of nanocapsules to improve therapeutic efficacy while reducing side effects.

3D printed extended-release hydrochlorothiazide tablets.

In this study 3D printed tablets (printlets) with extended release of hydrochlorothiazide (HHT) as model active ingredient were designed and developed. Four formulations, F0.1SSE, F1SSE, F0.1DLP and F1DLP, have been manufactured and characterized, using non-typical semi-solid extrusion (SSE) with UV light solidification and digital light processing (DLP) techniques. Obtained rheological studies pointed out to F1SSE and F1DLP as more suitable for SSE and DLP printing, respectively. Photopolymerization process between photopolymer (PEGDA) and photoinitiator (DPPO; 0.1% and 1%) was investigated using FTIR, with PCA modeling utilized to analyze spectral variations over time and estimate crosslinking kinetics. SSE printlets averaged ∼6.5 mm in diameter, ∼3 mm in height and ∼110 mg in mass, while DLP printlets averaged ∼8.5 mm in diameter, ∼2.5 mm in height, with masses of ∼170 mg (F0.1DLP) and ∼220 mg (F1DLP). All four formulations complied to the requirements of European pharmacopeia for uniformity of dosage units of single dose preparations. In vitro release studies indicated extended-release profiles in both 0.1M Hydrochloric acid (HCl) and phosphate buffer pH 6.8 for SSE and DLP printlets. The release kinetics of HHT from the printlets were modeled to fit First order, Higuchi, Korsmeyer-Peppas and Hixson-Crowell equations and the most probable ones were determined based on the R2 values and Akaike information criterion. FTIR and Raman spectroscopic analyses of printlets confirmed the presence of characteristic peaks from both, HHT and excipients, as well as modifications in bonds due to the photopolymeric reaction.

Tailoring moxifloxacin hydrochloride loaded oleic acid liposomes for the topical management of Methicillin-Resistant Staphylococcus aureus (MRSA)- Induced skin infection: In-vitro characterization and in-vivo assessment.

Oleic acid liposomes (OALs) are novel vesicular carriers ofunsaturated fatty acids and their corresponding ionized species, arranged within an enclosed lipid bilayer. This study aimed to encapsulate moxifloxacin HCl (MOX), a broad-spectrum antibacterial drug into OALs for effective treatment of Methicillin-resistant Staphylococcus aureus (MRSA) infection through topical application. Various OALs were formulatedby combining varied quantities of phosphatidylcholine (PC), oleic acid (OA), and cholesterol (CH) with 50 mg of MOX. The OALs were produced utilizing varying sonication durations. MOX-loaded OALs were formulated using the thin film hydration method by applying (24) a full factorial design utilizing the Design-Expert® software. The formula for MOX-loaded OALs was OAL13, which consisted of 200 mg of PC and 20 mg of OA. The mixture was sonicated for 5 min. The OAL13 exhibited spherical vesicles with a small diameter and a smooth outer surface. Additionally, the entrapment efficiency was measured to be 75.00 ± 1.41 %, the particle size was 234.65 ± 4.74 nm, the polydispersity index was 0.53 ± 0.01, and the zeta potential was -38.50 ± 0.42 mV. The OAL13 formula exhibited an extended release profile. Moreover, the antibiofilm activity of OAL13 gel and MOX-loaded liposomes gel against MRSA infection demonstrates greater activity than the MOX gel at the maximum concentration used (MIC/2). Furthermore, the in-vivo study showed that OAL13 improved MOX's antimicrobial and immunomodulatory effects against MRSA infection by increasing TLR-2 and IL-1β, as well as their downstream molecules NF-κB and TNF-α. Moreover, the histopathological examination conducted by a skin irritation test has verified the safety of OAL13. Overall, the results demonstrated the significant efficacy of MOX-loaded OALs in the treatment of MRSA infected wounds when applied topically.

Formulation, Development, and Characterization of AMB-Based Subcutaneous Implants using PCL and PLGA via Hot-Melt Extrusion

The hot-melt extrusion process is currently considered a prominent manufacturing technique in the pharmaceutical industry. The present study is intended to develop amlodipine besylate (AMB)-loaded subcutaneous implants to reduce the frequency of administration, thus improving patient compliance during hypertension management. AMB subcutaneous implants were prepared using continuous hot-melt extrusion technology using poly(caprolactone) and poly(lactic-co-glycolic acid) with dimensions of 3.70 cm (length) by 2.00 mm (diameter). The implants were characterized for thermal characteristics, drug-excipient incompatibilities, surface morphology, fracturability, in vitro drug release, and stability studies. Differential scanning calorimetry study confirmed the drug's crystalline state within the fabricated implants, while textural analysis demonstrated good fracturability in the lead formulation. Scanning electron microscopy revealed the smooth surface morphology of the lead subcutaneous implant. The lead formulation showed an extended drug release profile over 30 days (~ 2.25 mg per day) and followed zero-order release kinetics (R2 value to 0.9999) with a mean dissolution time of 14.96 days. The lead formulation remained stable for 30 days at accelerated stability conditions of 40°C and 75% relative humidity. In conclusion, developing hot-melt extruded implants could be an alternative to the conventional amlodipine besylate (AMB) formulation.Graphical

Enhanced Stability and In Vitro Biocompatibility of Chitosan-Coated Lipid Vesicles for Indomethacin Delivery.

Lipid vesicles, especially those utilizing biocompatible materials like chitosan (CHIT), hold significant promise for enhancing the stability and release characteristics of drugs such as indomethacin (IND), effectively overcoming the drawbacks associated with conventional drug formulations. This study seeks to develop and characterize novel lipid vesicles composed of phosphatidylcholine and CHIT that encapsulate indomethacin (IND-ves), as well as to evaluate their in vitro hemocompatibility. The systems encapsulating IND were prepared using a molecular droplet self-assembly technique, involving the dissolution of lipids, cholesterol, and indomethacin in ethanol, followed by sonication and the gradual incorporation of a CHIT solution to form stable vesicular structures. The vesicles were characterized in terms of size, morphology, Zeta potential, and encapsulation efficiency and the profile release of drug was assessd. In vitro hemocompatibility was evaluated by measuring erythrocyte lysis and quantifying hemolysis rates. The IND-ves exhibited an entrapment efficiency of 85%, with vesicles averaging 317.6 nm in size, and a Zeta potential of 24 mV, indicating good stability in suspension. In vitro release kinetics demonstrated an extended release profile of IND from the vesicles over 8 h, contrasting with the immediate release observed from plain drug solutions. The hemocompatibility assessment revealed that IND-ves exhibited minimal hemolysis, comparable to control groups, indicating good compatibility with erythrocytes. IND-ves provide a promising approach for modified indomethacin delivery, enhancing stability and hemocompatibility. These findings suggest their potential for effective NSAID delivery, with further in vivo studies required to explore clinical applications.

Quality by Design (QbD)-Driven Development and Optimization of Tacrolimus-Loaded Microemulsion for the Treatment of Skin Inflammation.

Background: Skin inflammation represents a hallmark of many skin conditions, from psoriasis to eczema. Here, we present a novel microemulsion formulation for delivering a low dose of potent immunosuppressant, tacrolimus, to the skin for local inflammation control. The efficacy of topically delivered tacrolimus in controlling skin inflammation can be enhanced by packaging it into microemulsions. Microemulsions are small-size, thermodynamically stable, and surfactant-rich emulsions that can enhance tissue penetration and local tissue retention of poorly soluble drugs, which can reduce dosing frequency and potentially improve patient compliance. Methods: We present a novel approach for microemulsion manufacturing that uses a combination of both low and high-energy methods. The microemulsion composition and manufacturing parameters were optimized by adopting Quality by Design methodologies. The FMECA (Failure, Mode, Effects, Criticality Analysis)-based risk assessment, D-optimal Design of Experiment (DoE), and statistical analysis of parameters impacting responses through the multiple linear regression (MLR) was implemented for identifying critical formulation and process parameters. Results: Through QbD strategy, a stable microemulsion with optimized drug loading that met all critical quality attributes (CQAs) was identified. The optimal microemulsion candidate was successfully scaled up three-fold with retained CQAs. The presented microemulsion showed a slow and extended drug release profile in vitro. Conclusions: Presented findings suggest that microemulsions are a promising novel approach for tacrolimus delivery to the skin. Further, we also demonstrated that a combination of low-energy emulsification and microfluidization processes can produce stable and robust microemulsions with small droplet size that can be implemented in drug delivery of poorly soluble anti-inflammatory drugs. To the best of our knowledge, this is the first report of QbD-driven optimization of microemulsion manufacturing by microfluidization.

Fabrication of pyrroloquinoline quinone-loaded small unilamellar vesicles through various downsizing techniques for biomedical applications

Treatment of injuries to bone structure represents a significant economic burden for health care institutions and systems worldwide. The development of tissue engineering scaffolds has expanded to include the incorporation of nanotechnology platforms such as liposomes for the efficient delivery of chemotherapeutic agents. Pyrroloquinoline quinone (PQQ) is a naturally occurring quinone with antioxidant and tissue regenerative properties. In this study, the liposome-based encapsulation of PQQ was achieved by studying the effect of different downsizing methods and lipid compositions. Liposomal sonication produced stable vesicles of sizes <200 nm. The incorporation of PQQ into the liposomes and its interactions with the lipids enhanced their stability for up to four weeks and allowed sustained release for seven weeks. The results demonstrate the ability of these systems to encapsulate PQQ with high stability, efficient entrapment, and extended release profiles for their potential use in biomedicine as a delivery system for bone tissue engineering.

Novel nanoformulation for enhanced amphotericin B efficacy and sustained release using vetiver root cellulose nanofibers against Candida albicans

The formidable antifungal agent, Amphotericin B, is well-known for its potency; however, its clinical application has been significantly limited due to toxicity and poor solubility. This study aims to address these challenges by developing and evaluating a novel nano-cellulose-based formulation of Amphotericin B to enhance its efficacy. Amphotericin B was encapsulated within cellulose nanofibers at varying ratios to optimize formulation parameters, including drug concentration, particle size, zeta potential, and entrapment efficiency. Notably, a composition ratio of 10:1 of cellulose nanofibers to Amphotericin B achieved an impressive encapsulation efficiency of 96.64%. Subsequent physicochemical characterizations employing techniques such as FTIR, DLS, XRD, and SEM provided insights into structural attributes and interactions within formulation. Controlled and extended-release profiles were observed at various physiological pH levels, with the Korsmeyer-Peppas model showing the highest correlation, indicating predominant drug diffusion. Importantly, nanoformulation demonstrated non-toxicity to A431 cells and human erythrocytes up to a maximum concentration of 20 μg/ml, as corroborated by MTT and hemolysis assays. Furthermore, antimicrobial susceptibility and efficacy assessments, conducted using agar disc diffusion and broth micro-dilution methods, revealed enhanced inhibition of Candida albicans growth. The nanoformulation produced a larger diameter of the inhibition zone (DIZ) of 19.66 mm compared to a DIZ of 16.33 mm for Amphotericin B alone. Impressively, the nanoformulation exhibited a minimum inhibitory concentration (MIC) of 25 μg/ml against Candida albicans, underscoring its heightened efficacy. Additionally, the formulation's ability to improve the targetability and bioavailability of Amphotericin B holds promise for enhancing its antifungal effectiveness while reducing associated toxicity.

HPMC Extended-Release Multi-Composite Matrix for Co-delivery of Oxcarbamazepine and Vitamin D.

Background: Carbamazepine (CBZ) is considered as first-line treatment for epilepsy. The literature has signified a history of non-uniform drug performance and clinical failures. However, many studies suggested that Oxcarbazepine (OXC), a structural analog of CBZ, may have an equivalent antiepileptic effect. OXC follows a different metabolic pathway other than CBZ. However, both share the same mechanism of action by blocking voltage-gated sodium channels. Objectives: This study aimed to form hydroxypropyl methylcellulose (HPMC) extended-release tablets containing OXC combined with vitamin D. Methods: These formulated tablets were tested for their dissolution rate, tablet hardness, friability, thickness and pharmacokinetic parameters (Cmax and Cmin). Blood sodium levels were additionally investigated to ensure the absence of hyponatremia; the main side effect of long-term use of CBZ and some of its derivatives. Results: The use of HPMC inhibited the formation of dihydrate OXC form thus offering a significant extended-release profile. OXC also showed a highlighted capability to attain high bioavailability. Microcrystalline cellulose (MCC) was also added to tablets formed to inhibit polymorphic transformation. Tablets containing OXC co-delivered with vitamin D ensured significantly decreased susceptibility to hyponatremia, and an extended-release profile was evident. Lower amounts of OXC were loaded in formed tablets containing vitamin D owing to the synergistic effect between vitamin D and antiepileptic drugs. Conclusion: Conclusively, employing these newly HPMC-constructed tablets of OXC co-delivered with vitamin D appeared to be a promising option for the effective management of epilepsy with least side effects.

Fabrication and optimization of extended-release beads of diclofenac sodium based on Ca++ cross-linked Taro (Colocasia esculenta) stolon polysaccharide and pectin by quality-by-design approach

The present investigation was aimed to fabricate and optimize extended-release beads of diclofenac sodium based on an ion-cross-linked matrix of pectin (PTN) and taro (Colocasia esculenta) stolon polysaccharide (TSP) with 23 full factorial design. Total polysaccharide concentration (TPC), polysaccharide ratio (PR), and cross-linker concentration ([CaCl2]) were taken as independent factors with two levels of each. Initially, TSP was extracted, purified, and characterized. Fourier-transform infrared spectroscopy (FTIR) and Differential Scanning Calorimetry (DSC) showed drug-polymer compatibility. The study also revealed the significant positive effect of TSP on drug entrapment efficiency (DEE) and sustaining drug release. The response variables (DEE, cumulative % drug-release at 1, 2, 4, 6, and 10 h, release-constant, time for 50 % and 90 % drug release (T50%, T90%), release-similarity factor (f2), and difference factor (f1) were analyzed, and subsequently, independent fabrication variables were numerically optimized by Design-Expert software (Version-13; Stat-Ease Inc., Minneapolis). The optimized batch exhibited appreciable DEE of 88.5 % (± 2.2) and an extended-release profile with significantly higher T50%, T90%, and release-similarity factor (f2) of 4.7 h, 11.4 h, and 71.6, respectively. Therefore, the study exhibited successful incorporation of the novel TSP as a potential alternative adjunct polysaccharide in the pectin-based ion-cross-linked inter-penetrating polymeric network for extended drug release.

Quality by design approach for fabrication of extended-release buccal films for xerostomia employing hot-melt extrusion technology

The study endeavors the fabrication of extended-release adipic acid (APA) buccal films employing a quality by design (QbD) approach. The films intended for the treatment of xerostomia were developed utilizing hot-melt extrusion technology. The patient-centered quality target product profile was created, and the critical quality attributes were identified accordingly. Three early-stage formulation development trials, complemented by risk assessment aligned the formulation and process parameters with the product quality standards. Employing a D-optimal mixture design, the formulations were systematically optimized by evaluating three formulation variables: amount of the release-controlling polymer Eudragit® (E RSPO), bioadhesive agent Carbopol® (CBP 971P), and pore forming agent polyethylene glycol (PEG 1500) as independent variables, and % APA release in 1, 4 and 8 h as responses. Using design of experiment software (Design-Expert®), a total of 16 experimental runs were computed and extruded using a Thermofisher ScientificTM twin screw extruder. All films exhibited acceptable content uniformity and extended-release profiles with the potential for releasing APA for at least 8 h. Films containing 30% E RSPO, 10% CBP 971P, and 20% PEG 1500 released 88.6% APA in 8 h. Increasing the CBP concentration enhanced adhesiveness and swelling capacities while decreasing E RSPO concentration yielded films with higher mechanical strength. The release kinetics fitted well into Higuchi and Krosmeyer-Peppas models indicating a Fickian diffusion release mechanism.

Novel Dry Hyaluronic Acid-Vancomycin Complex Powder for Inhalation, Useful in Pulmonary Infections Associated with Cystic Fibrosis.

Polyelectrolyte-drug complexes are interesting alternatives to improve unfavorable drug properties. Vancomycin (VAN) is an antimicrobial used in the treatment of methicillin-resistant Staphylococcus aureus pulmonary infections in patients with cystic fibrosis. It is generally administered intravenously with a high incidence of adverse side effects, which could be reduced by intrapulmonary administration. Currently, there are no commercially available inhalable formulations containing VAN. Thus, the present work focuses on the preparation and characterization of an ionic complex between hyaluronic acid (HA) and VAN with potential use in inhalable formulations. A particulate-solid HA-VAN25 complex was obtained by spray drying from an aqueous dispersion. FTIR spectroscopy and thermal analysis confirmed the ionic interaction between HA and VAN, while an amorphous diffraction pattern was observed by X-ray. The powder density, geometric size and morphology showed the suitable aerosolization and aerodynamic performance of the powder, indicating its capability of reaching the deep lung. An in vitro extended-release profile of VAN from the complex was obtained, exceeding 24 h. Microbiological assays against methicillin-resistant and -sensitive reference strains of Staphylococcus aureus showed that VAN preserves its antibacterial efficacy. In conclusion, HA-VAN25 exhibited interesting properties for the development of inhalable formulations with potential efficacy and safety advantages over conventional treatment.

Formulation Development of Solid Self-Nanoemulsifying Drug Delivery Systems of Quetiapine Fumarate via Hot-Melt Extrusion Technology: Optimization Using Central Composite Design.

Quetiapine fumarate (QTF) was approved for the treatment of schizophrenia and acute manic episodes. QTF can also be used as an adjunctive treatment for major depressive disorders. QTF oral bioavailability is limited due to its poor aqueous solubility and pre-systemic metabolism. The objective of the current investigation was the formulation development and manufacturing of solid self-nanoemulsifying drug delivery system (S-SNEDDS) formulation through a single-step continuous hot-melt extrusion (HME) process to address these drawbacks. In this study, Capmul® MCM, Gelucire® 48/16, and propylene glycol were selected as oil, surfactant, and co-surfactant, respectively, for the preparation of S-SNEDDS. Soluplus® and Klucel™ EF (1:1) were selected as the solid carrier. Response surface methodology in the form of central composite design (CCD) was utilized in the current experimental design to develop the S-SNEDDS formulations via a continuous HME technology. The developed formulations were evaluated for self-emulsifying properties, particle size distribution, thermal behavior, crystallinity, morphology, physicochemical incompatibility, accelerated stability, and in vitro drug release studies. The globule size and emulsification time of the optimized SNEDDS formulation was 92.27 ± 3.4 nm and 3.4 ± 3.38 min. The differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) studies revealed the amorphous nature of the drug within the formulation. There were no drug-excipient incompatibilities observed following the Fourier transform infrared (FTIR) spectroscopy. The optimized formulation showed an extended-release profile for 24 h. The optimized formulation was stable for three months (last time-point tested) at 40 °C/75% RH. Therefore, the developed S-SNEDDS formulation could be an effective oral delivery platform for QTF and could lead to better therapeutic outcomes.

Designing an effective dissolution test for bilayer tablets tailored for optimal melatonin release in sleep disorder management.

This project aims to investigate the release performance of bilayer tablet (BL-Tablet) designed with both fast and slow-release technology, targeting sleep disorders. The tablet incorporates Melatonin, extracts of Eschscholzia californica and Melissa officinalis. In order to validate the effectiveness of the extended-release profile, an advanced dissolution test was herein proposed. This new method utilizes biorelevant intestinal fluid media and incorporates a stomach-to-intestine fluid changing (SIFC) system. To demonstrate the advantages of employing this method for assessing the controlled release profile of active ingredients, the dissolution results were compared with those obtained using the conventional EU Pharmacopoeia approach. Furthermore, the comparative analysis was extended to include a monolayer tablet version (ML-Tablet) lacking the slow-release technology. Technological characterization and bioaccessibility studies, including intestinal permeability test, were conducted as well to assess the pharmacological performance and bioavailability of active ingredients. The dissolution data recovered revealed that the two dissolution methods did not exhibit any significant differences in the release of ML-Tablet's. However, the dissolution profile of the BL-Tablet exhibited notable differences between the two methods particularly when assessing the behavior of the slow-release layer. In this scenario, both methods initially exhibited a similar release pattern within the first approximately 0.5 h, driven by the fast-release layer of the tablet. Following this, distinct gradual and sustained releases were observed, spanning 2.5 h for the EU Pharmacopoeia method and 8 h for the new SIFC-biorelevant dissolution method, respectively. Overall, the novel method demonstrated a substantial improvement compared to conventional EU Pharmacopoeia test in evaluating the performance of a controlled slow-release technology. Remarkably, the prolonged release technology did not have an adverse impact on melatonin intestinal absorption, and, consequently, maintaining its potential bioavailability of around 78%. Concluding, this research provides valuable insights into how the innovative dissolution test can assist formulators in developing controlled release formulations.

Long-Term Insect Repellent Electrospun Microfibers from Recycled Poly(ethylene terephthalate).

In recent years, there has been an increase in the incidence of insect-borne diseases. Topically applied insect repellents are used to prevent these infectious diseases, but concerns of skin permeability and rapid evaporation rates have made way for alternative preventative methods. Encapsulation of insect repellents in polymeric materials allows for nonskin contact methods of repellent delivery with extended-release profiles without the need for reapplication. Poly(ethylene terephthalate) (PET) is widely used in textiles as well as food packaging and other single-use applications. This short product lifespan makes PET a major environmental pollutant; thus, recycling of PET is of great interest and utility. We report on the fabrication and evaluation of recycled PET microfibers containing N,N-diethyl-meta-toluamide (DEET) and picaridin and the first evaluation of dual repellent loading (DEET/picaridin) via electrospinning. The electrospun microfibers displayed a repellent retention up to 97% within the polymer network upon processing. Release profiles were characterized by isothermal thermogravimetric analysis (TGA). Hansen solubility parameters correlated release profiles with the chemical affinity between PET and the repellent substrate. Insect repellency was assessed against live mosquitoes using a novel bioassay method. Repellency was observed to be as high as 100% for over 1 week and 80% for over 3 weeks. Our method allows for long-lasting repellency with the potential for large-scale textile manufacturing.

Development and In Vitro-In Vivo Correlation Evaluation of IMM-H014 Extended-Release Tablets for the Treatment of Fatty Liver Disease.

This study aimed to develop extended-release tablets containing 25 mg IMM-H014, an original drug formulated by a direct powder pressing method based on pharmaceutical-grade hydrophilic matrix polymers such as hydroxypropyl methylcellulose, to establish an in vitro-in vivo correlation (IVIVC) to predict bioavailability. The tablets' mechanical properties and in vitro and in vivo performance were studied. The formulation was optimized using a single-factor experiment and the reproducibility was confirmed. The in vitro dissolution profiles of the tablet were determined in five dissolution media, in which the drug released from the hydrophilic tablets followed the Ritger-Peppas model kinetics in 0.01 N HCl medium for the first 2 h, and in phosphate-buffered saline medium (pH 7.5) for a further 24 h. Accelerated stability studies (40 °C, 75% relative humidity) proved that the optimal formulation was stable for 6 months. The in vivo pharmacokinetics study in beagle dogs showed that compared to the IMM-H014 immediate release preparation, the maximum plasma concentration of the extended-release (ER) preparation was significantly decreased, while the maximum time to peak and mean residence time were significantly prolonged. The relative bioavailability was 97.9% based on the area under curve, indicating that the optimal formulation has an obvious ER profile, and a good IVIVC was established, which could be used to predict in vivo pharmacokinetics based on the formulation composition.

An Intragastric Delivery Device Employing FDM Technology: 3D-Printed Tablet Containing Green Developed Mosapride-Saccharin Co-crystals

Mosapride citrate (MC) is a poorly soluble short half-life drug with more pronounced absorption in the stomach. The present study aimed to incorporate MC co-crystals with enhanced solubility into 3D-printed floating tablets. MC co-crystals were prepared via the green method using Saccharin sod. as a co-former at a (1:1) molar ratio. The prepared co-crystals were assessed for solubility, FTIR, thermal behavior, and SEM. Then, it was incorporated into zero % infill 3D-printed tablets of different configurations at two thickness levels by the FDM printing technique. Printed tablets were evaluated for dimensions, weight deviation, friability, and in vitro floating behavior. Drug release and kinetic of the MC release were also assessed. Solubility study of the co-crystals showed a significant (p value < 0.05) increased solubility over pure MC. FTIR and thermal behavior confirmed hydrogen bonding formation during co-crystallization. The obstructed particles had an erratic protrusion form, similar to a nodule, as illustrated by SEM. The printed tablets showed acceptable physicochemical properties. Tablets floated for about ≥ 12 h without floating lag time. In vitro drug release exhibited variable extended release profiles with different lag times depending on the configuration indicating that the tablet’s wall thickness and surface area were the factors manipulated to control drug release. Kinetic analysis of the release data displayed intermediate kinetics between zero-order and diffusional kinetics. The intragastric extended release profile for MC co-crystals of improved solubility could be successfully, economically, and quickly developed utilizing the 3D printing technique.Graphical

Preparation of chitosan nanoparticles for simultaneous drug delivery of dacarbazine and enoxaparin in melanoma

The aim of this study was to investigate the anti-melanoma and anti-angiogenic effects of enoxaparin surface-coated dacarbazine-loaded chitosan nanoparticles (Enox-Dac-Chi NPs). The prepared Enox-Dac-Chi NPs had a particle size of 367.95 ± 1.84 nm, zeta potential of −7.12 ± 0.25 mV, efficiency of drug loading (DL%) of 73.90 ± 3.84 %, and attached enoxaparin percentage of 98.53 ± 0.96 %. Both drugs had extended-release profiles and approximately 96 % of enoxaparin and 67 % dacarbazine were released within 8 h. The Enox-Dac-Chi NPs with IC50 of 59.60 ± 1.25 μg/ml were the most cytotoxic against melanoma cancer cells compared with chitosan nanoparticles containing only dacarbazine (Dac-Chi NPs) and free dacarbazine. There was no significant difference between the cellular uptake of Chi NPs and enoxaparin coated Chi NPs (Enox-Chi NPs) in B16F10 cells. Enox-Chi NPs with an average anti-angiogenic score of 1.75 ± 0.125 had more anti-angiogenic effect than enoxaparin. The results showed that simultaneous delivery of dacarbazine and enoxaparin by chitosan nanoparticles can enhance the anti-melanoma effect of dacarbazine. Additionally, enoxaparin can prevent the melanoma metastasis by its anti-angiogenic activity. Thus, the designed nanoparticles can be introduced as effective drug delivery vehicles for the treatment and prevention of metastatic melanoma.

Design and optimization of ciprofloxacin hydrochloride biodegradable 3D printed ocular inserts: Full factorial design and in-vitro and ex-vivo evaluations: Part II

Coupling hot-melt extrusion (HME) with fused deposition modeling three-dimensional printing (FDM-3DP) can facilitate the fabrication of tailored, patient-centered, and complex-shaped ocular dosage forms. We fabricated ciprofloxacin HCl ocular inserts by coupling high-throughput, solvent-free, and continuous HME with FDM-3DP. Insert fabrication utilized biocompatible, biodegradable, bioadhesive Klucel™ hydroxypropyl cellulose polymer, subjected to distinct FDM-3DP processing parameters, utilizing a design of experiment approach to achieve a tailored release profile. We determined the drug content, thermal properties, drug-excipient compatibility, surface morphology, in vitro release, antibacterial activity, ex-vivo transcorneal permeation, and stability of inserts. An inverse relationship was noted between insert thickness, infill density, and drug release rate. The optimized design demonstrated an amorphous solid dispersion with an extended-release profile over 24 h, no physical or chemical incompatibility, excellent mucoadhesive strength, smooth surface, lack of bacterial growth (Pseudomonas aeruginosa) in all release samples, and prolonged transcorneal drug flux compared with commercial eye drops and immediate-release inserts. The designed inserts were stable at room temperature considering drug content, thermal behavior, and release profile over three months. Overall, the fabricated insert could reduce administration frequency to once-daily dosing, affording a promising topical delivery platform with prolonged antibacterial activity and superior therapeutic outcomes for managing ocular bacterial infections.

Chitosan-Based Ciprofloxacin Extended Release Systems: Combined Synthetic and Pharmacological (In Vitro and In Vivo) Studies.

Ciprofloxacin is one of the most effective antibiotics, but it is characterized by a range of side effects. Elaboration of drug-releasing systems which allow to diminish toxicity of ciprofloxacin is a challenging task in medicinal chemistry. The current study is focused on development of new ciprofloxacin releasing systems (CRS). We found that ultrasound efficiently promotes N,N'-dicyclohexyl carbodiimide-mediated coupling between COOH and NH2 functionalities in water. This was used for conjugation of ciprofloxacin to chitosan. The obtained ciprofloxacin/chitosan conjugates are capable of forming their self-assembled nanoparticles (SANPs) in aqueous medium. The SANPs can be additionally loaded by ciprofloxacin to form new CRS. The CRS demonstrated high loading and encapsulation efficiency and they are characterized by extended release profile (20 h). The elaborated CRS were tested in vivo in rats. The in vivo antibacterial effect of the CRS exceeded that of the starting ciprofloxacin. Moreover, the in vivo acute and subacute toxicity of the nanoparticles was almost identical to that of the chitosan, which is considered as the non-toxic biopolymer.