Although homeostasis is a commonly accepted concept, there is incontrovertible evidence that biological processes and functions are variable and that variability occurs in cycles. In order to explain and understand dysregulation, which has not been embraced by homeostatic principles, the allostatic model has emerged as the first serious challenge to homeostasis, going beyond its homeostatic roots. Circadian rhythm is the predominant variation in the body, and it is a pattern according to which many physiological and pathological events occur. As there is strong experimental and clinical evidence that blood pressure fluctuations undergo circadian rhythm, there is equally strong evidence that targeted time therapy for hypertension provides a better outcome of the disease. The research has gone even further throughout the development and approval process for the use of pulsatile drug release systems, which can be considered as an option for an even more convenient dosage regimen of the medicines needed.

Since glaucoma is a serious health problem, numerous therapeutics are being developed to reduce Intraocular Pressure (IOP) as the only modifiable factor of all glaucoma symptoms. IOP-lowering agents are divided into six groups, each of which has a specific mechanism of action and side effects, which are the focus of this article and are explained in detail. All the mentioned agents are formulated as eye drops. However, as conventional topical eye drops have significant disadvantages, of which poor bioavailability and patient noncompliance are the main, novel approaches to designing their drug delivery systems were used and briefly presented in this review. Review Article Rahić et al.; OR, 14(2): 17-33, 2021; Article no.OR.66197 18 Graphical Abstract

Glaucoma is considered to be one of the biggest health problems in the world. It is the main cause of preventable blindness due to its asymptomatic nature in the early stages on the one hand and patients’ non-adherence on the other. There are several approaches in glaucoma treatment, whereby this has to be individually designed for each patient. The first-line treatment is medication therapy. However, taking into account numerous disadvantages of conventional ophthalmic dosage forms, intensive work has been carried out on the development of novel drug delivery systems for glaucoma. This review aims to provide an overview of formulation solutions and strategies in the development of in situ gel systems, nanosystems, ocular inserts, contact lenses, collagen corneal shields, ocular implants, microneedles, and iontophoretic devices. The results of studies confirming the effectiveness of the aforementioned drug delivery systems were also briefly presented.

The kinetics of passive transport of ketoprofen and metformin, as model substances for high and low permeability, respectively, across the artificial membrane under the influence of the pH of donor solution was investigated. There was an upward trend in the apparent permeation coefficient (Papp) of ketoprofen with the decrease in pH to a value close to pKa. At the pH value below pKa the permeation coefficient had lower value, due to the higher retention of ketoprofen in the artificial membrane. Metformin is a low permeable compound, and the highest permeation values were recorded at pH 7.4. Two dissociation constants determine that metformin at physiological pH exists as a hydrophilic cationic molecule, i.e. predominantly in ionized form. At pH values below 2.8, metformin mainly exists in diprotonated form, and it was, thus, very poorly permeable. The highest retention, i.e. affinity of both ketoprofen and metformin to the membrane, was at the lowest pH values, which is explained by different mechanisms. At higher pH values of donor compartment the substances showed significantly less affinity to the membrane. The obtained values of apparent permeation coefficients at studied pH values showed good correlation with the obtained experimental values by other in vitro methods.

MicroRNAs (miRNAs) represent endogenous small RNAs that post-transcriptionally regulate gene expression and, thus they are involved in the onset and progression of various diseases and conditions (Bader et al., 2010) such as for overweight and obesity. Antiadipogenic miRNA-27a is a negative regulator in fat metabolism, which inhibits adipocyte differentiation through downregulation of adipogenic marker genes (e.g. PPARγ) (Kim et al., 2010). Reduced miRNA-27a levels are often associated with the development of obesity and, therefore, this miRNA might represent a promising candidate for miRNA mimic replacement therapy (Lin et al., 2009). However, the application of naked RNAs has shown low membrane permeability, cellular uptake, and rapid degradation in the circulation. The present study aimed to develop a cationic, lipid-based nanoparticle system for targeting adipose tissue and delivering miRNA-27a. These systems are composed of positively charged nanostructured lipid carriers (cNLCs) and negatively charged miRNAs, which results in complex formation based on electrostatic interactions between these components. Materials and methods

Omeprazole is a proton pump inhibitor commonly used in pediatric patients (Wensel, 2009). Pediatric patients are usually unable to swallow solid dosage forms and they need dose adjustment. Therefore, the dosage form of choice for this population is compounded liquid preparation. Since pharmacies don't usually dispose of pure active substances, compounded liquid preparations are most commonly prepared from commercially available solid dosage forms, in a way that tablets are simply pulverized or capsule contents emptied, adding water or one of the commercially available vehicles (Haywood and Glass, 2013). Considering the risks associated with the preparation and use of compounded preparations, the Chapter <795> of the US Pharmacopoeia states that the beyond-use date is 14 days for non-preserved aqueous oral formulations, if stored in the refrigerator. Preserved aqueous preparations can be stored for 35 days at controlled room temperature or in the refrigerator (USP, 2015).

Many different and innovative approaches have been investigated to reduce the barrier effects of the stratum corneum (SC) and one of those are microneedles. Microneedles (MNs) are micron-sized needles which assist drug delivery through skin by creating microchannels (micron-scale pores) in SC that are large enough to enable drugs, including macromolecules, to enter the skin while being small enough to avoid pain, irritation and needle phobia. They have the capacity to play a role in modern healthcare as they reduce pain, tissue damage and transmission of infection and have potential for selfadministration in comparison to traditional needles. MNs have been fabricated by a variety of methods, from a range of materials (including silicon, glass, metal, carbohydrates and polymers) and in varying geometries (Quinn et al., 2014). Additive manufacturing (AM), more commonly known as three-dimensional (3D) printing represents a new, cutting-edge technology of 3D objects fabricated from a digital model generated using computer-aided design (CAD) software by fusing or depositing proper material (e.g., ceramics, liquids, metal, plastic, powders or even living cells) in layers. Suitable thermoplastic material in the form of a filament is fed into the printer by rollers, where it is heated to just above its softening point (glass transition temperature, Tg) by heating elements into a molten state. The melted or softened material guided by gears is moved towards heat end where it is extruded from the printer’s head, through a nozzle and subsequently deposited layer-by-layer on a build plate, cooling and solidifying in under a second. The printer’s head moves within the xand y-axes, whereas the platform can move within the z-axis, thus creating 3D structures (Alhnan et al., 2016; Goole and Amighi, 2016; Jamróz, 2018; Prased and Smyth, 2016). The aim of this work was to fabricate biodegradable PLA microneedles using innovative FDM 3D-printing technology on two different 3D printers and then chemically etch their arrays to obtain ideally sized and shaped needles.

Approximately 70-90% of the new active pharmaceutical ingredients/drugs are poorly soluble in water/biological fluids. Improvement of solubility, dissolution rate, bioavailability are the main characteristics of drug nanocrystals that are important for oral drug administration. High bioadhesive activity, depending on the type of stabilizer, is considered to be an essential feature of drug nanocrystals for oral, dermal, ocular dosage forms (Chang et al., 2015; Sheokand et al., 2018; Tuomela et al., 2016). Drug nanocrystals are solid nanosized particles of pharmacologically active substances, mainly BCS class IIa and IIb, 200 to 600 nm in diameter, homogeneously coated with 10-50% stabilizer/surfactants and/or polymers, forming ultrafine dispersion (Malamatari et al., 2018). Drug nanocrystals are usually in the crystalline state, but depending on the manufacturing method and process parameters, they may be in the amorphous state (Shete et al., 2014). Drug nanocrystals can be obtained by increasing their particle size by controlled precipitation/agglomeration from solution or by reducing drug particle size by milling to the desirable size. The two basic methods for obtaining drug nanocrystals are bottom up (e.g., precipitation) and top down (e.g., milling) methods, or drug nanocrystals can be made by a combination of these processes. By combining these two methods the desired particle size of drugs can be achieved and disadvantages of the individual methods are overcomed. These methods are intended for the preparation of liquid pharmaceutical nanosuspensions whose internal phase consists of drug nanocrystals particles, which can be converted into solid drug nanocrystals by post-production processes (spray drying, freeze drying or other process) in order to improve chemical, physical stability of drug during storage, when the selected stabilizer of drug nanocrystal could not provide long-term stability of the liquid nanosuspension (Sheokand et al., 2018).

Although transdermal drug delivery systems (DDS) offer numerous benefits for patients, including the avoidance of both gastric irritation and first-pass metabolism effect, as well as improved patient compliance, only a limited number of active pharmaceutical ingredients (APIs) can be delivered accordingly. Microneedles (MNs) represent one of the most promising concepts for effective transdermal drug delivery that penetrate the protective skin barrier in a minimally invasive and painless manner. The first MNs were produced in the 90s, and since then, this field has been continually evolving. Therefore, different manufacturing methods, not only for MNs but also MN molds, are introduced, which allows for the cost-effective production of MNs for drug and vaccine delivery and even diagnostic/monitoring purposes. The focus of this review is to give a brief overview of MN characteristics, material composition, as well as the production and commercial development of MN-based systems.

: Medicinal nail lacquers are the most effective topical treatment of nail diseases. These formulations generally are organic solutions of the active substance as well as film-forming polymer and plasticizer, which affects the characteristics of the film formed after application and solvent evaporation. The aim of this work was to test the effects of plasticizer present in nail lacquer formulations on permeation kinetics of fluconazole through the bovine hoof membrane in a novel in vitro test. The formulations contained Eudragit RS100 dis- solved in acetone, and dibutyl-phthalate, PEG 400 or propylene glycol as plasticizers present in two different concentrations. Permeation studies were carried out during the 7-day period, and the obtained permeability pro- files analyzed using similarity and difference factors, and by model-dependent permeation kinetics. When analyzed within the same strength, the highest extent of fluconazole permeation was obtained from the formula- tion with a lower concentration of propylene glycol at 0.9% fluconazole concentration, while for formulations with 1.8% and 2.7% of fluconazole, the highest permeation was achieved from the formulation with the high- er content of PEG400. The permeation profiles showed a greater difference within one formulation of different fluconazole content than with the same plasticizer present in different concentrations, when using dibutyl- phthalate and PEG400. The permeation profiles were similar when using propylene glycol. When comparing formulations with the same concentrations of plasticizers, there were differences in formulations with the high- er fluconazole concentrations. Permeation kinetics depended on fluconazole concentration as well as the path length the active substance had to pass to reach the receptor solution.

In this work, we compared the pharmaceutical-technological characteristics of ranitidine hydrochloride film coated tablets (tablets R1, tablets R2) of different manufacturers as well as the influence of excipients of the core tablet and/or film-coating. The results of assay (R1=97.55% ± 1.81%; R2=95.03% ± 0.82%), uniformity of dosage units (R1=267.55 mg ± 4.96 mg; R2=308.75 mg ± 2.67 mg), friability testing (R1=0.037%; R2=0.009%) and disintegration time (R1=239 sec; R2=317 sec) of tablets for both generic drugs meet pharmacopoeial requirements. Significant variations were observed in hardness testing for tablets R1 (RSD=26.69%) compared to hardness testing for tablets R2 (RSD=5.64%). Tested pharmaceutical equivalents may be considered bioequivalent because of the results of in vitro dissolution testing of ranitidine tablets (R1=97.17% ± 1.39%; R2=96.99% ± 3.76%). Tested tablets, containing various excipients, and having different pharmaceutical-technological characteristics, have met all requirements of the European and American pharmacopoeias. Tablets R2 were harder and had lower disintegration time, which resulted in the dissolution of more than 80% of ranitidine within 45 minutes. Patients with lactose intolerance have to be cautious when taking tablets R2, since these tablets contain lactose.