In vitro Modified Release Studies on Melatoninergic Fluorinated Phenylalkylamides: Circumventing their Lipophilicity for Oral Administration.

INTRODUCTION: In an attempt to circumvent the lipophilicity burden for the oral administration of new potent synthetic melatoninergic fluorine-substituted methoxyphenylalkyl amides, we conducted in vitro modified release studies using carefully selected matrix tablets' biopolymeric materials in different ratios. METHOD: In particular, we sought to attain release profiles of these analogues similar to that of the parent compound, the chronobiotic hormone Melatonin (MLT), and also of the commercially available drug, Circadin®. RESULT: It was found that some of these systems, albeit being more lipophilic than MLT, mimic the in vitro release patterns of melatonin and Circadin®. CONCLUSION: Moreover, a number of these derivatives were proven suitable for dealing with sleep onset problems, whilst others for dealing with combined sleep onset/sleep maintenance dysfunctions.

In Vitro Profile of Hydrocortisone Release from Three-Dimensionally Printed Paediatric Mini-Tablets.

Three-dimensional (3D) printing is quickly being adopted in pharmaceutics due to the many advantages it offers, including treatment, adaptability, the reduction in waste and the accelerated development of new formulations. In this study, micro-extrusion printing was implemented for the production of modified-release hydrocortisone (HCT) mini-tablets for paediatric patients. For the developed formulations, Gelucire® 44/14 and Precirol® ATO 5 were used as the main inks at three different ratios: 70%/30%, 60%/40% and 50%/50%, respectively. The printing parameters (temperature and pressure) were altered accordingly for each ratio to achieve printability. The printed mini-tablets exhibited excellent printing quality, featuring consistent layer thicknesses and smooth surfaces. Dissolution tests were performed, and the results indicated a successful modified release of HCT from the mini-tablets. In summary, micro-extrusion exhibited favourable processing abilities for powder blends, facilitating quick printing and the fabrication of potential personalized dosages.

Design and Development of Low- and Medium-Viscosity Alginate Beads Loaded with Pluronic® F-127 Nanomicelles.

The anionic polymer sodium alginate, a linear copolymer of guluronic and mannuronic acids, is primarily present in brown algae. Copolymers are used in the sodium alginate preparation process to confer on the material strength and flexibility. Micelles and other polymeric nanoparticles are frequently made using the triblock copolymer Pluronic® F-127. The purpose of the present study is to determine the effect of sodium alginate's viscosity (low and medium) and the presence of Pluronic® F-127 micelles on the swelling behavior of the prepared pure beads and those loaded with Pluronic® F-127 micelles. The Pluronic® F-127 nanomicelles have a size of 120 nm. The swelling studies were carried out at pH = 1.2 (simulated gastric fluid-SGF) for two hours and at pH = 6.8 (simulated intestinal fluid-SIF) for four more hours. The swelling of both low- and medium-viscosity alginate beads was minor at pH = 1.2, irrespective of the use of Pluronic® F-127 nanomicelles. At pH = 6.8, without Pluronic® F-127, the beads showed an enhanced swelling ratio for the first four hours, which was even higher in the medium-viscosity alginate beads. With the addition of Pluronic® F-127, the beads were dissolved in the first and second hour, in the case of the low- and medium-alginate's viscosity, respectively. In other words, the behavior of the mixed hydrogels was the same during the swelling experiments. Therefore, the presence of Pluronic® F-127 nanomicelles and medium-viscosity sodium alginate leads to a higher swelling ratio. A model drug, acetyl salicylic acid (ASA), was also encapsulated in the mixed beads and ASA's release studies were performed. In conclusion, the prepared systems, which are well characterized, show potential as delivery platforms for the oral delivery of active pharmaceutical ingredients and biopharmaceuticals.

Potent Lipophilic Melatoninergic x-fluoro-y-methoxy Substituted Phenylalkylamides: Molecular Dynamics Calculations and in vitro Modified Release in Aqueous Media from Tablet Formulations.

INTRODUCTION: We report herein on the design and development of matrix tablets containing potent synthetic melatonin (MLT) receptor analogues, the x-fluoro-y-methoxy substitiuted phenylalkylamides (compounds I-IV), the preparation and melatoninergic potency of which was recently communicated. > Methods: The presence of the fluorine atom in compounds I-IV, besides not affecting their binding affinity, compared to the pineal hormone melatonin, it also slows down their metabolism, which is a major drawback of MLT. However, as fluorine increases the lipophilicity, solid pharmaceutical formulations of I-IV, involving the appropriate biopolymers for their modified release in aqueous media, were developed in the context of the present work. > Results: The release profile of analogues I-IV was found to be similar to that of MLT and also of the commercially available drug, Circadin®. Some of these systems are suitable for dealing with sleep onset problems, whilst others for dealing with combined sleep onset/sleep maintenance problems. > Conclusion: Apart from the nature and relevant content of the formulants used, this bimodal release profile of the new analogues depends, to a large extent, on the diverse structural arrangement of their side chains in space, as nicely demonstrated by the molecular dynamics calculations, conducted in the context of this study. >.

Dissolution Assay of Bupropion/Naltrexone Hydrochloride Salts of Bilayer Composition Tablets Following the Development and Validation of a Novel HPLC Method.

Compounded medicinal products containing bupropion hydrochloride (BUP·HCl) and naltrexone hydrochloride (NTX·HCl) are available as adjunct therapy for the management of weight in obese/overweight adults. The present work describes the development and validation of a novel RP-HPLC method for a simultaneous quantitation during the dissolution of both drugs from compounded bilayer composition tablets. The method involves a Nucleosil 100-3 C-18 column (4.6 × 150 mm) and a mobile phase of a 70%/30% v/v ACN/KH2PO4·H2O aqueous solution of a 5 mM concentration. The flow rate was set at 1.35 mL/min and the detection was conducted using UV spectrophotometry (λmax 214 nm). The method was validated according to the ICH guidelines and fulfilled the specifications for the specificity, linearity, accuracy, precision and stability for both the sample and standard solutions. Furthermore, the robustness of the method was evaluated by applying a fractional factorial experimental design and by utilizing both graphical and statistical approaches to identify the HPLC factors that should be strictly controlled during the analysis. The method proved to be suitable for the analysis of the dissolution samples and, consequently, the release of BUP·HCl and NTX·HCl from the formulations.

Excipients Used for Modified Nasal Drug Delivery: A Mini-Review of the Recent Advances.

The ongoing challenging task in the field of nasal drug delivery is the maintenance of an efficient concentration of the active substance in the target area for an adequate period of time. Thus, there is an urgent need to develop effective new strategies for drug delivery to the nose, using cutting edge technology and materials for this particular type of drug delivery. This review gives an account of the critical components of nasal drug delivery and the parameters influencing drug absorption in the nose, including the excipients required for modified drug administration.

Environmental impacts due to the use of sunscreen products: a mini-review.

Sunscreen use has increased in recent years, as sunscreen products minimize the damaging effects of solar radiation. Active ingredients called ultraviolet (UV) filters or UV agents, either organic or inorganic, responsible for defending skin tissue against harmful UV rays, are incorporated in sunscreen formulations. UV agents have a serious impact on many members of bio communities, and they are transferred to the environment either directly or indirectly. Many organic UV filters are found to be accumulated in marine environments because of high values of the octanol/water partition coefficient. However, due to the fact that UV agents are not stable in water, unwanted by-products may be formed. Experimental studies or field observations have shown that organic UV filters tend to bioaccumulate in various aquatic animals, such as corals, algae, arthropods, mollusks, echinoderms, marine vertebrates. This review was conducted in order to understand the effects of UV agents on both the environment and marine biota. In vivo and in vitro studies of UV filters show a wide range of adverse effects on the environment and exposed organisms. Coral bleaching receives considerable attention, but the scientific data identify potential toxicities of endocrine, neurologic, neoplastic and developmental pathways. However, more controlled environmental studies and long-term human use data are limited. Several jurisdictions have prohibited specific UV filters, but this does not adequately address the dichotomy of the benefits of photoprotection vs lack of eco-friendly, safe, and approved alternatives.

Modified Release of the Pineal Hormone Melatonin from Matrix Tablets Containing Poly(L-lactic Acid) and Its PLA-co-PEAd and PLA-co-PBAd Copolymers.

In terms of drug delivery, the attractive properties of poly(L-lactic acid) (PLA) and its aliphatic polyesters, poly(ethylene adipate) (PEAd) and poly(butylene adipate) (PBAd), render them ideal co-formulants for the preparation of modified-release pharmaceutical formulations. Furthermore, we have previously demonstrated that by adding a "softer" aliphatic polyester onto the macromolecular chain of PLA, i.e., PEAd or PBAd, resulting in the formation of the PLA's copolymers (PLA-co-PEAd and PLA-co-PBAd, in 95/5, 90/10, 75/25 and 50/50 weight ratios), the hydrolysis rate is also severely affected, leading to improved dissolution rates of the active pharmaceutical ingredients (API). In the present report, we communicate our findings on the in vitro modified release of the chronobiotic hormone melatonin (MLT), in aqueous media (pH 1.2 and 6.8), from poly(L-lactic acid) and the aforementioned copolymer matrix tablets, enriched with commonly used biopolymers, such as hydroxypropylmethylcellulose (HPMC K15), lactose monohydrate, and sodium alginate. It was found that, depending on the composition and the relevant content of these excipients in the matrix tablets, the release of MLT satisfied the sought targets for fast sleep onset and sleep maintenance. These findings constitute a useful background for pursuing relevant in vivo studies on melatonin in the future.

Melatonin/Cyclodextrin Inclusion Complexes: A Review.

Melatonin (MLT) is involved in many functions of the human body, mainly in sleeping-related disorders. It also has anti-oxidant potential and has been proven very effective in the treatment of seasonal affective disorders (SAD), which afflict some people during short winter days. Melatonin has been implicated in a range of other conditions, including Parkinson's disease, Alzheimer's and other neurological conditions, and in certain cancers. Its poor solubility in water leads to an insufficient absorption that led scientists to investigate MLT inclusion in cyclodextrins (CDs), as inclusion of drugs in CDs is a way of increasing the solubility of many lipophilic moieties with poor water solubility. The aim of this review is to gather all the key findings on MLT/CD complexes. The literature appraisal concluded that MLT inclusion leads to a 1:1 complex with the majority of CDs and increases the solubility of the hormone. The interactions of MLT with CDs can be studied by a variety of techniques, such as NMR, FT-IR, XRD and DCS. More importantly, the in vivo experiments showed an increase in the uptake of MLT when included in a CD.

Recent Advances in the Excipients Used in Modified Release Vaginal Formulations.

The formulation of an ideal vaginal drug delivery system (DDS), with the requisite properties, with respect to safety, efficacy, patient compliance, aesthetics, harmonization with the regulatory requirements, and cost, requires a meticulous selection of the active ingredients and the excipients used. Novel excipients defined by diversity and multifunctionality are used in order to ameliorate drug delivery attributes. Synthetic and natural polymers are broadly used in pharmaceutical vaginal formulations (solid, semi-solid dosage forms, implantable devices, and nanomedicines) with a promising perspective in improving stability and compatibility issues when administered topically or systemically. Moreover, the use of biopolymers is aiming towards formulating novel bioactive, biocompatible, and biodegradable DDSs with a controllable drug release rate. Overviewing vaginal microenvironment, which is described by variable and perplexed features, a perceptive choice of excipients is essential. This review summarizes the recent advances on the excipients used in modified vaginal drug delivery formulations, in an attempt to aid the formulation scientist in selecting the optimal excipients for the preparation of vaginal products.

3D-Printed Oral Dosage Forms: Mechanical Properties, Computational Approaches and Applications.

The aim of this review is to present the factors influencing the mechanical properties of 3D-printed oral dosage forms. It also explores how it is possible to use specific excipients and printing parameters to maintain the structural integrity of printed drug products while meeting the needs of patients. Three-dimensional (3D) printing is an emerging manufacturing technology that is gaining acceptance in the pharmaceutical industry to overcome traditional mass production and move toward personalized pharmacotherapy. After continuous research over the last thirty years, 3D printing now offers numerous opportunities to personalize oral dosage forms in terms of size, shape, release profile, or dose modification. However, there is still a long way to go before 3D printing is integrated into clinical practice. 3D printing techniques follow a different process than traditional oral dosage from manufacturing methods. Currently, there are no specific guidelines for the hardness and friability of 3D printed solid oral dosage forms. Therefore, new regulatory frameworks for 3D-printed oral dosage forms should be established to ensure that they meet all appropriate quality standards. The evaluation of mechanical properties of solid dosage forms is an integral part of quality control, as tablets must withstand mechanical stresses during manufacturing processes, transportation, and drug distribution as well as rough handling by the end user. Until now, this has been achieved through extensive pre- and post-processing testing, which is often time-consuming. However, computational methods combined with 3D printing technology can open up a new avenue for the design and construction of 3D tablets, enabling the fabrication of structures with complex microstructures and desired mechanical properties. In this context, the emerging role of computational methods and artificial intelligence techniques is highlighted.

Recent Advances in the Excipients Used for Modified Ocular Drug Delivery.

In ocular drug delivery, maintaining an efficient concentration of the drug in the target area for a sufficient period of time is a challenging task. There is a pressing need for the development of effective strategies for drug delivery to the eye using recent advances in material sciences and novel approaches to drug delivery. This review summarizes the important aspects of ocular drug delivery and the factors affecting drug absorption in the eye including encapsulating excipients (chitosan, hyaluronic acid, poloxamer, PLGA, PVCL-PVA-PEG, cetalkonium chloride, and gelatin) for modified drug delivery.

Probing the Release of Bupropion and Naltrexone Hydrochloride Salts from Biopolymeric Matrices of Diverse Chemical Structures.

In the last decades, the notion of including excipients in the formulations, as inert substances aiding production processes, has changed and they are recently viewed as multifunctional discrete entities. It is now well documented that excipients serve several roles, spreading from the stabilization and modified release, to providing biocompatible properties and targeting moieties. The aim of this study was to develop matrix-based oral drug delivery systems of bupropion hydrochloride (BUP·HCl) and naltrexone hydrochloride (NTX·HCl), suitable for releasing these active substances in a modified manner, providing a stable level of drug release, which is simultaneously therapeutically effective and non-toxic, thus reducing side effects, after a single dose administration, throughout the gastrointestinal tract. The new formulations, employing hydroxypropylmethycellulose (HPMC K15M) (a cellulosic polymer, which, generally hydrates to form a gelatinous layer that is critical to prevent wetting and rapid drug release from the matrices), poly(methacylic acid-co-ethyl acrylate) 1:1 (Eudragit® L100-55: effective for site specific drug delivery in intestine), poly(ethylene oxide) (PEO) (7 × 106: a high molecular weight polymer, water-soluble, in micro-granular powder form), as the rate controlling polymers, were chosen to lead to a "soothing out" release pattern of these drugs, at 0 ≤ t ≤ 120 min. Moreover, the release of the two drugs from the ulvan-based tablets, was found to follow the desired profile, throughout the entire course of the dissolution experiments.

Pineal hormone melatonin as an adjuvant treatment for COVID­19 (Review).

The beneficial properties of the pineal hormone, melatonin, as a neuroprotective and cardioprotective agent, have been previously identified. Furthermore, melatonin plays essential roles in biological rhythms resynchronization, sleep initiation/maintenance and metabolic, ocular, rheumatological diseases. In addition to these functions, melatonin is known to exert immunomodulation, anti­inflammatory and anti­oxidative effects. Due to these properties, coupled with its non­toxic nature, melatonin has been suggested to limit viral infections; however, melatonin cannot be classified as a viricidal drug. In addition, the recent increase in the number of clinical trials on melatonin's role, as an adjuvant treatment for COVID­19, has resurged the interest of the scientific community in this hormone. The present short review aimed to improve the understanding of the antiviral/anti­COVID­19 profile of melatonin and the clinical trials that have recently been conducted, with respect to its co­administration in treating individuals with COVID­19.

Biophysical Evaluation and In Vitro Controlled Release of Two Isomeric Adamantane Phenylalkylamines with Antiproliferative/Anticancer and Analgesic Activity.

The aqueous dissolution profile of the isomeric synthetic adamantane phenylalkylamine hydrochlorides I and II was probed. These adducts have shown significant antiproliferative/anticancer activity associated with an analgesic profile against neuropathic pain. They are both devoid of toxic effects and show appreciable enzymatic human plasma stability. The structures of these two compounds have been elucidated using 2D NMR experiments, which were used to study their predominant conformations. Compound II's scaffold appeared more flexible, as shown by the NOE spatial interactions between the alkyl bridge chain, the aromatic rings, and the adamantane nucleus. Conversely, compound I appeared very rigid, as it did not share significant NOEs between the aforementioned structural segments. MD simulations confirmed the NOE results. The aqueous dissolution profile of both molecules fits well with their minimum energy conformers' features, which stem from the NOE data; this was nicely demonstrated, especially in the case of compound II.

UV Filters and Their Distribution on the Skin through Safe, Non-Penetrating Vehicles.

The effects of ultraviolet (UV) radiation trigger human skin reaction, which can result in erythema, photoaging, and/or skin cancer. Sunscreens play an important role against the negative effects of UV radiation on the human skin. However, they should satisfy certain criteria, with the main one being photostability, to avoid the formation of health-threatening reactive intermediates. It has to be kept in mind, however, that photo-stable UV filters have the undesirable propensity to transfer energy to molecular oxygen and generate the very reactive singlet oxygen. They should also be well tolerated, while at the same time, they should not permeate into the skin and cause toxic effects. Thus, there is an ongoing need to develop effective and safe non-penetrating sunscreen formulations. The search for innovative active substances, efficacious combinations, and the design of vehicles or carriers has led to the implementation of advanced delivery systems. This study intended to review the commonly used UV radiation thwarting agents (organic and inorganic UV filters), compile the relevant toxicity studies, evaluate their margin of safety, and assess the current situation on innovative sunscreen formulations.

Probing the release of the chronobiotic hormone melatonin from hybrid calcium alginate hydrogel beads.

A variety of commonly used hydrogels were utilized in the preparation of calcium alginate beads, which incorporate the chronobiotic hormone melatonin (MLT). The in vitro release of the hormone in aqueous media at pH 1.2 and 6.8 was probed in the conjunction with the swelling of the beads and their thermal degradation properties. It has been found that the release of MLT from the beads was reversibly proportional to the extent of their expansion, which depends on the molecular mass/viscosity of the biopolymers present in the beads; the higher the molecular mass/viscosity of the hydrogels the greater the beads swelling and the less the MLT's release. Thermogravimetric analysis (TGA) data support the presence of the components in the hybrid hydrogel beads and elucidate their effects on the thermal stability of the systems. Thus, the physicochemical properties of the biopolymers used, along with their stereoelectronic features modulate the release of MLT from the beads, providing formulations able to treat sleep onset related problems or dysfunctions arising from poor sleep maintenance.

Modified release of furosemide from Eudragits® and poly(ethylene oxide)-based matrices and dry-coated tablets.

Modified release of furosemide from tablet formulations is preferred by patients, because of physiological problems, acute diuresis being the most serious, compared to the forms designed for immediate release. With this in view, we aimed at achieving furosemide's longer gastric retention and waste minimization by preparing matrix and compression coated tablets incorporating different grades of Eudragit® and poly(ethylene oxide) (PEO), polyvinylpyrrolidone (PVP) and lactose monohydrate. Dissolution profiles of the new formulations were compared with that of the main stream drug Lasix®, 40 mg tablets. The results indicate that the use of Eudragit® in conjunction with either PVP or lactose monohydrate led to a slower release rate in the intestinal fluids compared to Lasix®. Moreover, furosemide release in the intestinal pH from matrix tablets and compression coated tablets was not noticeably different. Formulations incorporating PEO led to sustained release, in intestinal fluids, which depended on the molecular weight of PEO.

Utilization of a Single Experimental Design for the Optimization of Furosemide Modified-Release Tablet Formulations.

BACKGROUND: The loop diuretic drug furosemide is widely used for the treatment of edema in various conditions, such as pulmonary, cardiac and hepatic edema, as well as cardiac infarction. Furosemide, due to its poor water solubility and low bioavailability after oral administration of conventional dosage form, is categorized as class IV in the biopharmaceutical classification system. OBJECTIVE: In the case of furosemide, this release profile is responsible for various physiological problems, acute diuresis being the most serious. This adverse effect can be circumvented by the modified release of furosemide from tablet formulations compared to those forms designed for immediate release. METHODS: In this report, a D-optimal combined experimental design was applied for the development of furosemide containing bilayer and compression coated tablets, aiming at lowering the drug's burst release in the acidic environment of the stomach. A D-optimal combined design was selected in order to include all requirements in one design with many levels for the factors examined. The following responses were selected as the ones reflecting better criteria for the desired drug release: dissolution at 120 min (30-40%), 300 min (60-70%) and 480 min >95%. The new formulations, suggested by the Doptimal combined design, incorporated different grades of Eudragit ® polymers (Eudragit® E100 and Eudragit® L100-55), lactose monohydrate and HPMC K15M. The dissolution profile of furosemide from these systems was probed via in vitro dissolution experiments in buffer solutions simulating the pH of the gastrointestinal tract. RESULTS: The results indicate that the use of Eudragit® E100 in conjunction with lactose monohydrate led to 21.32-40.85 % drug release, in the gastric medium, in both compression-coated and bilayer tablets. This is lower than the release of the mainstream drug Lasix® (t=120 min, 44.5% drug release), implying longer gastric retention and drug waste minimization. CONCLUSION: Furosemide's release in the intestinal environment, from compression coated tablets incorporating Eudragit® L100-55 and HPMC K15M in the inner core or one of the two layers of the bilayer tablets, was delayed, compared to Lasix®.

Development and Characterization of Eudragit®-Based Electrospun Nanofibrous Mats and Their Formulation into Nanofiber Tablets for the Modified Release of Furosemide.

Furosemide, a chloride channel blocker ordinarily used as a high-ceiling or loop diuretic, is practically insoluble in water and dilute acids. Due to its acidic nature, furosemide is mostly absorbed in the stomach and in the upper small intestine. Efforts have focused on the development of sustained release systems of furosemide in order to improve the effectiveness of the drug, which exhibits poor aqueous solubility and poor permeability. Recently, electrospun nanofibrous drug delivery systems have emerged as promising alternative solid-dosage forms due to their advantages of high porosity, high surface to volume ratio, and high drug-loading efficacy. Herein, a number of nanofibrous mats composed of different types of Eudragit® polymers in various concentrations and combinations loaded with furosemide were designed, successfully electrospun, and characterized using SEM, FTIR, DSC, and TGA analyses. The nanofibrous nonwovens were formulated in nanofiber tablets and the release profile of furosemide from them was evaluated at pH 1.2 and 6.8 and compared to that of physical mixture matrix tablets of analogous composition as well as to that of a commercial formulation. It was found that the release of furosemide was compatible with the gastroretentive and slower intestinal release requirements with a well-defined absorption window, while some nanofiber formulations could act as furosemide carriers in emergency situations where a relatively fast onset of its action is required, as in the case of critically ill post-traumatic patients.