Current Pharmaceutical Design - Volume 24, Issue 13, 2018

Background: In this contribution an overview is given on own work concerning drug loaded Polyelectrolyte Complex (PEC) Nanoparticles (NP) used to functionalize Bone Substitute Materials (BSM) for the therapy of bone defects associated with systemic bone diseases. In this context, drug loaded PEC NP have certain advantages, which are exemplarily summarized herein. Methods: Concerning preparative methods PEC NP were fabricated by controlled mixing of polycation and polyanion solutions and integration of charged drugs during and after mixing. Control was taken on the stoichiometric ratio related to cationic and anionic repeating units, which was chosen close to zero for the final applied PEC NP. Concerning analytical methods a couple of physical-chemical methods were applied like colloid titration, Dynamic Light Scattering (DLS), Scanning Force Microscopy (SFM), Fourier Transform infrared (FTIR) spectroscopy, Ultraviolet-Visible (UV-VIS) and Circular Dichroism (CD) spectroscopy to characterize colloid stability, adhesiveness, drug loading and release of PEC NP. Moreover, standard biochemical and microbiological assays were applied. Conclusion: Drug loaded PEC NP consist of oppositely charged biorelated Polyelectrolytes (PEL) like ionic polysaccharides or ionic polypeptides and also synthetic PEL, which are mixed and processed in aqueous media. At first, freshly prepared drug/PEC NP exhibit time dependent colloidal stability in the range of weeks and months, which enables and simplifies storage, transport and application in the medical field. Secondly, after deposition and drying of drug/PEC NP a local wet adhesive PEC matrix at the BSM remains in contact to relevant aqueous media (e.g. buffer, cell culture medium), which minimizes asepsis, systemic toxicity, immune or inflammatory reaction. Thirdly, cell compatible PEC NP coatings were identified, which showed only minimal effects on various relevant bone related cells due to biorelateness, complexation, local confinement and low surface area. Fourthly, PEC NP elute drugs for bone healing like bisphosphonates, antibiotics and growth factors (e.g. bone morphogenetic proteins) in delayed and sustained manner. Moreover, the onset of elution could be triggered by thermoresponsive PEL via temperature increase giving clinicians a tool into hand allowing spatiotemporal drug release on demand. Finally, drug/PEC NP could be integrated into commercial or still developed allotropic stabilizing or defect filling BSM systems.

Background: The Oral Liquid Drug Delivery System (OLDDS) remains the primary choice of dosage form, though challenging, for the pharmaceutical scientists. In the last two decades, Oral Liquid Controlled Release (OLCR) formulation has gained a lot of attention because of its advantages over the conventional dosage forms. Method: The world of nanotechnology has paved multiple ways to administer the drug through oral cavity in liquid dosage form with an additional advantage of control over the release. In the current study, the various approaches towards the same have been discussed comprehensively to understand the different mechanisms of OLCR. Conclusion: This review also emphasizes on the existing techniques and the developments that have been made to improve on its efficacy including various formulation related factors. It also provides valuable insights into the role of polymers in the development of OLCR formulation that can be used in the management of Gastroesophageal Reflux Disease (GERD).

The properties of many drugs which have been available on the pharmaceutical market for a long time still need to be improved. Cocrystals are the solid state drug modification which can improve properties such as low solubility, stability and mechanical properties (e.g. compressibility). In this paper, examples of how to use cocrystals to modify properties of API (Active Pharmaceutical Ingredient) will be reported. Additionally, in this review, the way from an idea of the new cocrystal to drug dosage form registration will be shortly described.

The brain is a complex, regulated organ with a highly controlled access mechanism: The Blood-Brain Barrier (BBB). The selectivity of this barrier is a double-edged sword, being both its greatest strength and weakness. This weakness is evident when trying to target therapeutics against diseases within the brain. Diseases such as metastatic brain cancer have extremely poor prognosis due to the poor permeability of many therapeutics across the BBB. Peptides can be designed to target BBB receptors and gain access to the brain by transcytosis. These peptides (known as BBB-shuttles) can carry compounds, usually excluded from the brain, across the BBB. BBB-shuttles are limited by poor loading of therapeutics and degradation of the peptide and cargo. Likewise, nano- submicro- and microparticles can be fine-tuned to limit their degradation and with high loading of therapeutics. However, most nano- and microparticles' core materials completely lack efficient targeting, with a few selected materials able to cross the BBB passively. Combining the selectivity of peptides with the high loading potential of nano-, microparticles offers an exciting strategy to develop novel, targeted therapeutics towards many brain disorders and diseases. Nevertheless, at present the field is diverse, in both scope and nomenclature, often with competing or contradictory names. In this review, we will try to address some of these issues and evaluate the current state of peptide mediated nano,-microparticle transport to the brain, analyzing delivery vehicle type and peptide design, the two key components that must act synergistically for optimal therapeutic impact.

Polymeric nanoparticles are promising drug delivery systems due to their physicochemical properties, which may be explored to improve the treatment and prevention of several diseases, including oral conditions. Moreover, the pharmacological effects of polymers may be improved by nanostructuration. Therefore, this article provides a detailed review of the studies published between 2010 and 2017 covering the use of polymeric nanoparticles in the treatment and/or prevention of oral diseases. A brief description about the dental biofilm and oral diseases is presented in first part of the article. The following section includes an important discussion about the strategies studied to improve the treatment and prevention of these diseases using polymeric nanoparticles: (i) a better drug antibacterial effect, (ii) the release of the drug in a time-controlled way, (iii) the increase of drug uptake by cells, (iv) the cytotoxicity in tumor cells and solubility in water, and (v) mucoadhesive drug delivery systems. Furthermore, the composition and size of the polymeric nanoparticles explored by these strategies were described. Finally, in the last part of this review, the in vitro and in vivo results which demonstrate the effect of these systems in the treatment and/or prevention of the most prevalent oral disorders were highlighted: dental carious lesions, oral cancer, and periodontal and endodontic diseases.

Quinazoline is an aromatic bicyclic compound exhibiting several pharmaceutical and biological activities. This study was conducted to investigate the potential wound healing properties of Synthetic Quinazoline Compound (SQC) on experimental rats. The toxicity of SQC was determined by MTT cell proliferation assay. The healing effect of SQC was assessed by in vitro wound healing scratch assay on the skin fibroblast cells (BJ-5ta) and in vivo wound healing experiment of low and high dose of SQC on adult Sprague-Dawley rats compared with negative (gum acacia) and positive control (Intrasite-gel). Hematoxylin and Eosin (H), Masson's Trichrome (MT) staining and immunohistochemistry analysis were performed to evaluate the histopathological alterations and proteins expression of Bax and Hsp70 on the wound tissue after 10 days. In addition, levels of antioxidant enzymes (catalase, glutathione peroxidase and superoxide dismutase), and malondialdehyde (MDA) were measured in wound tissue homogenates. The SQC significantly enhanced BJ-5ta cell proliferation and accelerated the percentage of wound closure, with less scarring, increased fibroblast and collagen fibers and less inflammatory cells compared with the negative control. The compound also increases endogenous enzymes and decline lipid peroxidation in wound homogenate.

Background: Cyclodextrins (CDs) are versatile excipients with an essential role in drug delivery, as they can form non-covalently bonded inclusion complexes (host-guest complexes) with several drugs either in solution or in the solid state. Methods: The main purpose of this publication was to carry out a state of the art of CDs as complexing agents in drug carrier systems. In this way, the history, properties and pharmaceutical applications of the CDs were highlighted with typical examples. The methods to enhance the Complexation Efficiency (CE) and the CDs applications in solid dosage forms were emphasized in more detail. Results: The main advantages of using these cyclic oligosaccharides are as follows: (1) to enhance solubility/ dissolution/ bioavailability of poorly soluble drugs; (2) to enhance drug stability; (3) to modify the drug release site and/or time profile; and (4) to reduce drug side effects (for example, gastric or ocular irritation). These compounds present favorable toxicological profile for human use and therefore there are various medicines containing CDs approved by regulatory authorities worldwide. On the other hand, the major drawback of CDs is the increase in formulation bulk, once the CE is, in general, very low. This aspect is particularly relevant in solid dosage forms and limits the use of CDs to potent drugs. Conclusion: CDs have great potential as drug carriers in Pharmaceutical Technology and can be used by the formulator in order to improve the drug properties such as solubility, bioavailability and stability. Additionally, recent studies have shown that these compounds can be applied as active pharmaceutical ingredients.

Background: The objective of this study was to apply Quality by Design (QbD) principles on process parameter optimization for the development of hybrid delivery system (combination of (SLNs) and In-situ gelling system) for hydrophilic drug Moxifloxacin Hydrochloride (MOX) to achieve its controlled delivery, which otherwise may not be possible through single type of technology. Methods: Risk assessment studies were carried out to identify probable risks influencing CQAs on the product. In design of experiments (DoE), the process parameters (independent variables) i.e., chiller temperature X1, High Pressure Homogenization (HPH) pressure X2, and HPH cycles X3 were optimized using a three-factor two level face-centered central composite design to streamline the influence on three responses, namely encapsulation efficiency Y1, particle size Y2 and outlet temperature Y3. Independent and dependent variables were analyzed to establish a full-model second-order polynomial equation. F value is used to confirm the omission of insignificant parameters/interactions to derive a reduced-model polynomial equation to predict the Y1, Y2 and Y3 for optimized moxifloxacin in situ gelled nanosuspension. Results: Desirability plots showed the effects of X1, X2, and X3 on Y1, Y2 and Y3, respectively. The design space is generated to obtain optimized process parameters viz. chiller temperature (-5°C), HPH pressure 800 – 900 bar and 8 cycles that resulted in nanosuspension with ≈ 500 nm size, encapsulation efficiency >65% and final formulation temperature <23°C that were necessary to maintain the formulation in a liquid state. Conclusion: Quality by Design (QbD) approach is recently been encouraged by regulatory bodies to improve the quality of the finished product. This approach proved to be a useful tool in the development of robust nanosuspension of highly hydrophilic drugs with improved efficiency. Results indicate that such hybrid gel systems can be used to control the release of SLNs from application site and prolong their action in a sustained manner.