Current Drug Delivery - Volume 10, Issue 1, 2013

Oral dosage forms have always been considered the preferred route of delivery, due to lower unit dose cost and improved patient compliance. The great increase in the duration and quality of human life was made possible by the availability of effective and well tolerated drugs, able to deal adequately with serious and widespread diseases. Now, the pharmaceutical challenge is shifted to drugs and preparations more specifically and focused on the needs of patient or groups of patients. Personalization of medicines or formulations can occur on the basis of dose adjustment, drug combination or different delivery kinetics. Innovative drug delivery systems have the potential to make treatments safer and more effective, or more convenient or acceptable to patients. Drug delivery systems are complex formulations in which the elements can concur to determine the delivery rate and kinetics. This paper is focused on the description of two technologies, such as powder agglomeration and module assembling, as approaches to obtain personalized dosage forms, dosing flexibility and/or combination products, as a function of patient’s needs and his therapeutic treatment.

Dose limitations in therapy induced by adverse effects due to unselective drug availability are a common problem. One prominent example for this dilemma are inflammatory diseases of the gastrointestinal tract. The challenge for drug delivery systems in the therapy of these diseases is the delivery of the active ingredient to the site of inflammation. Colloidal carriers allow to improve delivery of drugs to the site of action and appear promising to overcome this general therapeutic drawback. Here we focus on nanocarrier-based drug delivery strategies for the treatment of common inflammatory disorders like inflammatory bowel disease and gastric ulcer.

There are still so-called unmet needs in the treatment of epithelial and cutaneous lesions. Mucositis, ocular lesions, chronic skin wounds represent typical examples. These pathologies do not yet afford a satisfactory treatment. In particular chronic wounds represent a major health care burden, likely to increase as the population ages. Healing of epithelial and cutaneous lesions progresses through a complex cascade of events starting with the secretion in the local environment of a pool of growth factors, cytokines and proteins from the serum and degranulating platelets. Recently platelet lysate (PL), a hemoderivative obtained by platelet destruction by freeze-thawing of a platelet rich plasma (PRP) sample in the presence of an anticoagulant agent, has proved capable of promoting the healing of buccal and corneal lesions. Since the efficacy of growth factors (GFs) critically depends on the way they are made available to the injured tissue, the development of suitable therapeutic vehicles is of paramount importance to release GFs according to the repairing requirements. The present work focuses on the development and testing of few such formulations, in particular a mucoadhesive gel and an in situ gelling buccal spray for the treatment of oral mucositis, and a thermosensitive eye drop solution for corneal lesions. Besides technological characterization, the formulations have been preliminarily screened with an ELISA assay, a cell proliferation test and an in vitro wound healing test. Some formulations have been used in early clinical trials.

Recently ZnO quantum dots are reported to be very promising for drug delivery. It has also been reported that adsorptive material can deliver drug molecules by simple adsorption and they release the drug at site of action by subsequent desorption. This has been shown for carbon nanotubes and some other hydrophobic molecules for transdermal applications in the literature. Therefore it was aimed to find the effect of ZnO quantum dots on transdermal penetrations of selected model drug molecules (ketoprofen and dexketoperofen). Drug coated ZnO quantum dots were found to increase transdermal penetration of ketoprofen and dexketoprofen through rat skin.

Identification of the most relevant epitopes is the initial challenge of peptide-based vaccine design. Chimeric conserved epitopes of the Group A Streptococcus (GAS) M-protein were used in the development of an anti-GAS vaccine candidate. Previously, these epitopes have incorporated a GCN4 peptide from yeast to maintain their native helical structure. Here, we designed a new peptide epitope based on the minimal B-cell epitope from GAS M-protein. This new epitope was able to adopt the desired helical conformation without the need for the foreign GCN4 flanking sequence. The selected epitope induced significant immune responses upon administration with external adjuvant, and when incorporated into the Lipid Core Peptide (LCP) system. Moreover, the antibodies produced against this epitope were able to recognize the native p145 sequence from M-protein.

In psychiatry, around 130 drugs are available which have been detected and developed during the last 60 years. These drugs are effective and essential for the treatment of many psychiatric disorders and symptoms. Therapeutic outcomes, however, are still far from satisfactory for many patients. One major reason underlying insufficient response or problems of tolerability or toxicity is considerable interindividual variability in the pharmacokinetic properties of the patients. At the exact same dose, a more than 20-fold interindividual variation in steady state concentrations of the drugs in the body may result. Patients differ in their ability to absorb, distribute, metabolize and excrete drugs due to concurrent disease, age, concomitant medication or genetic peculiarities. A valuable tool for tailoring the dosage of the prescribed medication(s) to the individual characteristics of a patient is therapeutic drug monitoring (TDM). For a considerable number of psychopharmacologic compounds, TDM has become a clinical routine for dose adjustment. The benefits of TDM regarding optimization of psychopharmacotherapy can be further enhanced by genotyping of cytochrome P450 enzymes (CYP). These enzymes are highly polymorphic and involved in the metabolism of most psychotherapeutic drugs. Genotyping related information may be supportive especially for drugs that are predominantly metabolized by CYP2C19 or CYP2D6. The in vivo activity of CYP isoenzymes can be determined using probe drug assays. When used appropriately, phenotyping and genotyping methods are most helpful for problem solving and improvement of the outcomes of psychopharmacotherapy for many patients.

Midkine (MK) is a member of midkine family which is composed of MK and pleotrophin (PTN). MK behaves like a cytokine and growth factor, promotes the proliferation, differentiation, survival, adhesion, migration of cells. MK expression usually increases during ischemia, inflammation, tissue repair, neoplastic transformation and in different toxic conditions. Immune cells and most of organs have MK secretion function in fetal and adult life. MK could be a promising prognostic/diagnostic marker and a potential target in many of diseases including malignancy, toxic and inflammatory diseases. This review focuses on both cell protective and immune-modulatory roles of MK in different in vitro and in vivo disease models and human reports. MK is still a novel molecule in the regulation of organ development and the etiology of many diseases.

Histidine (His)-phosphorylation is labile at low pH and has therefore not been in the focus of proteomic analysis in the past although a few single-case studies have been performed. The systematic investigation of model substances generates confidence in experimental procedures and allows determining their limits. In order to extend earlier peptide studies to His-phosphoproteins and elucidate their behavior and recovery in proteomic procedures, potassium phosphoramidate (PPA) was used to generate model proteins, which were subsequently exposed to gel electrophoresis, enzymatic digest and mass spectrometry based protein analysis. Myoglobin having eleven His-residues was highly phosphorylated by PPA showing a distribution of modified protein forms with four phosphate-carrying His-residues in the most abundant species. Since myoglobin is a heme-binding protein it was additionally indicated that synthetic phosphorylation may retain protein folding targeting only structurally accessible His-residues. Insulin, β-casein and cytochrome C were phosphorylated on their His-residues and the corresponding peptides were detected in protein digest mixtures and in background of tryptically digested Escherichia coli lysate. In gel electrophoresis protocols, lengthy procedures at low pH such as staining reduced recovery. Synthetic phosphorylation of proteins and peptides with PPA allows the generation of suitable standard compounds for the systematic optimization of analytical protocols. All tested proteins responded to PPA treatment, partially even preserving tertiary structure. A distribution of modified protein forms was generated which could be subjected to further separation to isolate the fully phosphorylated species.

Beta3-adrenoreceptors (B3AR) are traditionally known as metabolic receptors in adipose tissue, but came into focus in the cardiovascular field after our demonstration of their expression in human cardiac myocytes and endothelial cells, where they mediate endothelium-dependent relaxation of coronary resistance vessels through production of both nitric oxide and endothelium-dependent hyperpolarization factor(s) (EDHF). B3AR are also expressed at the plasma membrane of rodent and human cardiac myocytes. Notably, their expression is increased in several forms of human cardiomyopathies, which raises questions about their adaptive or maladaptive role in myocardial remodelling. To test the hypothesis that they may counteract the adverse effect of B1-B2-AR overactivation, we set out to study the cardiac phenotype of transgenic mice expressing human recombinant B3AR under the cardiac-specific alpha-MHC promoter. While exhibiting no apparent phenotype at basal state, these mice seem protected from hypertrophic remodeling under a variety of stresses, without developing left ventricular dysfunction. Notably, this protection seems to depend on a functional nitric oxide synthase (NOS), as it is abrogated under NOS inhibition. These features can all be recapitulated in homotypic cardiac myocytes cultures in vitro. B3AR transgenic mice may also be protected from fibrosis through a paracrine cross-talk to cardiac fibroblasts. These data suggest a beneficial role of B3AR in myocardial remodeling through attenuation of fibrosis and of excessive cardiac myocyte hypertrophy, while at the same time optimizing perfusion. As B3AR are resistant to homologous desensitization, they are attractive targets for therapeutic interventions in the setting of chronic sympathetic stimulation, as it is prevalent in heart failure and several cardiomyopathies.

Pharmacy profession also involves identifying, solving and preventing drug-related problems, as well as encouraging proper use of medications, thus improving clinical outcome of the treatment. Pharmacotherapy is usually thaught as lectures in pharmacy schools and many students have a difficulty in implementing the theoretical knowledge into practice. Therefore courses on “rational drug use or rational pharmacotherapy” should be given by problem based teaching methods. Since 2009, “Rational Drug Use” courses are given in Marmara University School of Pharmacy by such a method (based on simulated patients and dispensing score) developed by the ‘Turkish Pharmacological Society’. The method enables problem based learning and it is also used in some of the pharmacy schools in Turkey and in Near East University in Northern Cyprus. This kind of learning will provide ability for critical thinking, improve problemsolving skills and decision making during pharmacotherapy.

Recent studies suggest that overproduction of reactive oxygen and nitrogen species (ROS/RNS), lowered antioxidant defense of the body. Oxidative stress is damaging to DNA, lipids, proteins and many more vital macromolecules. Consequences of oxidative stress thought to contribute to the development of a wide range of diseases including Alzheimer's disease, Parkinson's disease, diabetes, rheumatoid arthritis, neurodegeneration in motor neuron diseases and many cancer types. Melatonin (MLT) is a powerful antioxidant with a particular role in the protection of nuclear and mitochondrial DNA. To find an improved antioxidant activity, developments of novel synthetic analogues are under investigation. These studies may offer a new progress and approach in antioxidant drug development as well as antioxidant chemistry. Therefore, we have been synthesizing novel MLT derivatives and investigating their antioxidant capacities. This review gives a brief knowledge about the MLT based analogue indole derivatives as potential antioxidants.

A number of Polycyclic Aromatic Hydrocarbons (PAHs) have been shown to be toxicants, and induce carcinogenic and immunotoxic effects. Since PAHs are often present in low concentrations and it may be difficult to determine them in complex matrices, it is therefore essential to use powerful analytical tools to separate and identify the analyses in the samples. In this paper, initially, a short description of the principles, instrumentation, and use of common extraction and analytical techniques for PAH pollutants and their metabolites will be made in light of the previously reported works and major reviews. Special attention will be given to the use of modern polarographic and voltammetric techniques on the mercury and different types of solid electrodes, together with their some practical applications. The main drawbacks and limitations of these methods will also be discussed.

Plants have become a unique source for the mankind either as food or medicine. No doubt this relationship initiated instinctively to satisfy the inner man, while later they noticed the healing potential of plants. This had been the beginning point of traditional medicines worldwide. Among the ca. 300.000 plant species have been identified on the earth so far, only a fraction (ca.120.000) has been reported to be used as food or remedy. The remaining part has still waited for discovery of their beneficial effects on human health. The metabolite composition of the plants has attracted the scientific community rather than plants itself. However, random screening of plants for potential health benefits without any evidence is a tedious task. Investigation planning based on the traditional use of plants has become one of the solutions to overcome this problem. Thenceforth 1985 increasing numbers of scientific field surveys have been conducted throughout Turkey for the documentation of folkloric utilization of plants against disease symptoms. However, due to the impact of modernization in society accessibility of reliable information has become problematic day-by-day. Moreover, increasing number of migrations from rural areas to urban to improve the living conditions makes difficult to find informants in countryside. In order to rescue this valuable information before complete vanishing, several alternative survey techniques have been attempted. In this study, reports on Turkish folk medicine which have been conducted so far will be evaluated. Based on the data obtained, past and present situations will be discussed.

Fast-dissolving drug-delivery systems were first developed in the late 1970s as an alternative to tablets, capsules, and syrups for pediatric and geriatric patients who experience difficulties swallowing traditional oral solid dosage forms. In response to this need, a variety of orally disintegrating tablet (ODT) formats were commercialized, which disintegrate within 1 min when placed in the mouth without drinking water or chewing. Oral drug delivery technology has improved from conventional dosage forms to modified release dosage forms to ODT to the recent oral disintegrating films (ODF). Oral disintegrating film or strip that employs a water dissolving polymer which allows the dosage form to quickly hydrate by saliva, adhere to mucosa, and disintegrate within a few seconds, dissolve and releases medication for oromucosal absorption when placed on the tongue or oral cavity. Oral strip technology provides an alternate route for drugs with first pass metabolism. This review give details of materials used in ODF, manufacturing aspects, technologies, evaluation tests and marketed products.

As the main intent of delivering maximum concentration of drug available from the dosage form, an oral compression coated tablet (CCT) was intended to develop with a predetermined lag time of 6 hrs before immediate release of drug to target circadian rhythms of rheumatoid arthritis. Solid dispersions are promising approach to enhance drug release, which later will be developed as core tablet formulation and compression coated with polyethylene oxide (PEO WSR 303). Solid dispersions were formulated with different ratio of drug and carrier (sucrose fatty acid esters 1811) using solvent evaporation and melt granulation technique, optimized solid dispersion was formulated as core tablet with different diluents. Optimized core tablet was compression coated with PEO WSR 303 along with a channeling agent (DCL 21, mannitol, HPMC 5 cps and starch 1500). Lag time before immediate release of drug was markedly dependent on weight ratios of polymer and channeling agent used, which ranged from 4 to 12 hrs. Optimized solid dispersion (S9) was used for formulating optimized core tablet formulation (C8). CCT (T8) prepared with core tablet (C8) along with mannitol provided a lag time of 6 hrs with minimum concentration of channeling agent used, which was also supported from the permeability study results. Incompatibility and characterization was confirmed from DSC, XRD, FTIR and SEM studies. Unaltered Cmax and AUC0-t but delayed Tmax following oral ingestion of optimized formulation (T8) to human volunteers indicated clear lag time before immediate release of drug, which is suitable for treating rheumatoid arthritis following circadian rhythm.

The successful delivery of nucleic acids into cells and their availability at the intracellular sites of action remain a major challenge in gene therapy, because cells are resistant to the uptake of genetic materials and contain a variety of mechanisms that degrade nucleic acids. To develop a nonviral carrier, we have recently designed a series of metal complexes with polybenzimidazole (pbzim) that serve as DNA-condensing agents. In this study, we prepared a group of Co(II)-pbzim complexes that bear variable numbers of both positive charges and benzimidazole (bzim) groups. First, the formation of condensates at varied molar ratios of complex to DNA was examined by multiple biophysical measurements at pH 7.4. The results showed that the size, morphology, and surface charge of the condensates formed via a Co(II) complex dose-dependent process can be controlled by utilization of different complexes. Then, the imaging examination performed with both confocal and fluorescence microscope indicated that the DNA condensates can be internalized into cells. Luciferase activity assay showed that the DNA condensates formed at 1:1 of molar ratio are in favor of cell transfection because of their appropriate size, profile, and positive surface charges. The addition of the helper lipid DOPE can enhance both cellular uptake of the condensates and expression of the transferred genes. The MTT data indicated that cytotoxicity of both Co(II) complexes and condensates is enhanced with increasing positive charges and bzim groups. All the results revealed that the physical properties, cell transfection, and cytotoxicity of the condensates are regulated by the positive charges and bzim groups on the metal complexes.

Earlier described dextran-based contrast agents for magnetic resonance imaging (MRI) comprising the gadolinium chelate diethylenetriamine pentaacetic acid (GdDTPA, 1) have shown significantly shorter in vivo contrast duration in rat than what would be expected from the initial average molecular weight (Mw) of the dextran fraction (71.4 kD). To investigate this further, four dextran fractions with given initial average molecular weight (Mw) of 10.4, 41.0, 71.4 and 580 kD were used as starting material to prepare products 2-5 where one of the carboxylic acid functionalities in GdDTPA was used as a direct covalent ester linker to hydroxyl groups in dextrans. A fifth derivative (6) was an amide-ester bound β-alanine-DTPAGd conjugate with dextran having Mw 71.4 kD. The reference compound GdDTPA (1) and gadoliniumlabelled dextran derivatives 2-6 were injected intravenously in rabbits. Pharmacokinetic parameters showed that when GdDTPA is ester-bound directly to dextran hydroxyls, the cleavage rates of 2-5 were only moderately dependent on the molecular weights of the dextrans, having blood pool half-lives comparable to the low-molecular reference compound (t 1/2,β 0.3 – 0.5 hrs.). Presence of a β-alanine spacer in 6 prolonged the plasma half-life t 1/2,β to 6.9 hours, rendering a blood residence time suitable for blood pool slow release of GdDTPA. Biological cleavage regenerates the clinically acceptable carrier dextran and the β-alanine derivative of GdDTPA, pointing at a clinically acceptable product class for blood-pool contrast in MRI.

In this study we developed and evaluated a prototype of an effective occlusive mucoadhesive system for prophylaxis and/or treatment of oral mucositis based on chitosan and gelatine models together with nystatin as a prophylactic agent incorporated into the formulation and investigated drug release in-vitro. Results of in vitro studies showed that chitosan and gelatine based gels posses properties that makes them excellent candidates for treatment of oral mucositis. These properties include not only the palliative effects of an occlusive dressing but also the potential for delivering therapeutic compounds with chitosan gels providing drug concentrations above their minimum inhibition concentration and extending the retention time in the oral cavity due to their bioadhesive properties. Chitosan also offers an advantage over suspensions because of its inherent antimicrobial properties. The performance of gelatin-based gels highlights the novel, non-toxic, in situ forming gelatine based hydrogel. The results of in vitro drug release experiments demonstrated that all the hydrogel showed sustained release properties.