Three-dimensional printed dosage forms based on disease-focussed perspectives.

OBJECTIVES: Three-dimensional printing (3DP) has gained importance worldwide recently as a novel drug manufacturing technology. 3DP technologies are suitable in the pharmaceutical field because of having the potential in personalized medicine. The aim of this review is to present an overview of the use of 3DP technologies in pharmaceutical area, their working principles and critical process parameters. In addition, this review presents an innovative approach that evaluates the use of 3DP technologies on disease to disease. KEY FINDINGS: This review covers the potential use of 3DP technologies in different diseases by evaluating them on a research basis. These diseases can be summarized as cardiovascular, neurological, respiratory, oncological, inflammatory, vaginal, dermatological and other diseases. It has been focussed on manuscripts that published after 2015. Studies on the use of 3DP in each disease group have been systematically reviewed by considering the methods, types of printers used and the prepared dosage forms. Oral formulations (tablets and films), implants, topical systems and vaccines are some of the examples of the mentioned dosage forms. SUMMARY: This review presented a systematic and novel overview of the use of 3DP in the treatment of different clinical disorders.

Effects of electrospun fiber curcumin on bisphenol A exposed Caco-2 cells.

Curcumin; the major polyphenolic compound, isolated from Curcuma longa L.; loaded polyvinylpyrrolidone K90 fibers were prepared using electrospinning method. Effectiveness was tested on human colorectal adenocarcinoma cells with the presence of the endocrine disrupter Bisphenol A. Curcumin-loaded fibers were shown to have good physicochemical properties where excellent morphology of the electrospin fibers were formed. With the presence of 8 nM Bisphenol A, 17.37 mM fibers were found to inhibit proliferation in the cells in a dose-dependent manner. Fibers induced a significant increase in malondialdehyde by Thiobarbituric Acid Reactive Substances Assay compared to the control and this effect was supported by the presence of Bisphenol A. Western blot results indicate Super Oxide Dismutase-1 levels were increased by fiber, while Bisphenol A coincubated group resulted in a decrease. Fibers increased the expression of Estrogen Receptor 2, while Estrogen Receptor 1 expression did not change. Estrogen Receptor 2 expression was increased by coincubation with Bisphenol A; indicating a possible role of Estrogen Receptor 2 in the protective effects of fiber. This study presents that fiber had enhanced bioavailability and solubility with increased anticancer effect in human colon adenocarcinoma cells in presence of Bisphenol A; where involved mechanisms are antioxidant system and estrogen receptor expression.

Peptide-protein based nanofibers in pharmaceutical and biomedical applications.

In recent years, electrospun fibers have found wide use, especially in pharmaceutical area and biomedical applications, related to the various advantages such as high surface-volume ratio, high solubility and having wide usage areas they have provided. Biocompatible and biodegradable fibers can be obtained by using peptide-protein structures of plant and animal derived along with synthetic polymers. Plant-derived proteins used in nanofiber production can be listed as, zein, soy protein, and gluten and animal derived proteins can be listed as casein, silk fibroin, hemoglobine, bovine serum albumin, elastin, collagen, gelatin, and keratin. Plant and animal proteins and synthetic peptides used in electrospun fiber production were reviewed in detail. In addition, the important physical properties of these materials for the electrospinning process and their use in pharmaceutical and biomedical areas were discussed.

The effect of a new wound dressing on wound healing: Biochemical and histopathological evaluation.

Electrospinning process has gained importance in the production of wound dressings in recent years. The wound dressings prepared by electrospinning method provide many advantages over conventional wound dressings. The aim of this study was to assess the histological, biochemical, and immunohistochemical evaluation of collagen/doxycycline loaded nanofiber wound dressing in both acute and chronic wound healing. Full-thickness wound model was created on rats and rats were divided in two main groups: normoglycemic (acute) and hyperglycemic (chronic) groups. Each group was divided into three sub groups: not treated (control) group, treated with nanofiber wound dressing group and treated with commercial product group. Wound closure rates were measured. Oxidative events were investigated by biochemical analyses. In addition to histological studies, matrix metalloproteinase, tissue inhibitor of metalloproteinase, vascular endothelial growth factor, basic-fibroblast growth factor, and von Willebrand factor levels were investigated with immunohistochemical studies. According to the biochemical analyses, it was concluded that the nanofiber wound dressing helps to increase antioxidant capacity and decrease lipid peroxidation. Immunohistochemical studies showed that nanofiber wound dressing enhanced angiogenesis and shortened the inflammatory phase. It was concluded that an effective and safe prototype nanofiber wound dressing, which has similar wound healing effect to the commercial product, has been developed to be used in acute or chronic wound treatment.

Development and characterization of rapid dissolving ornidazole loaded PVP electrospun fibers.

Gingivitis is a common and mild form of periodontal disease and can be described as a limited inflammation of the gingiva. This study aims to develop and characterize rapid releasing mucoadhesive fibers containing ornidazole with electrospinning process for the treatment of gingivitis. Polyvinylpyrrolidone (PVP) was chosen as a polymer and used at different concentrations of 10%, 12.5%, and 15%. Scanning electron microscopy images showed that fiber diameters increased with increasing polymer concentrations. Tensile strength and elongation at break values of fibers increased with increasing PVP amount, whereas the loading of ornidazole into the fibers decreased these parameters. The contact angle values of all fibers were found to be 0° due to the hydrophilic nature of PVP. Ornidazole was released within 5 min and diffused from all of the fibers faster than that of gel and solution formulations. Electrospun ornidazole fibers were found efficient against Porphyromonas gingivalis in antimicrobial activity studies. The results demonstrated that ornidazole loaded fibers could be a potential drug delivery system for the treatment of gingivitis.

Fabrication of doxycycline-loaded electrospun PCL/PEO membranes for a potential drug delivery system.

Potential usage of biodegradable and biocompatible polymeric nanofibers is the most attention grabbing topic for the drug delivery system. In order to fabricate ultrafine fibers, electrospinning, one of the well-known techniques, has been extensively studied in the literature. In the present study, the objective is to achieve the optimum blend of hydrophobic and hydrophilic polymers to be used as a drug delivery vehicle and also to obtain the optimum amount of doxycycline (DOXH) to reach the optimum release. In this case, the biodegradable and biocompatible synthetic polymers, poly(ε-caprolactone) (PCL) and poly(ethylene oxide) (PEO), were blended with different ratios for the production of DOXH-loaded electrospun PCL/PEO membranes using electrospinning technique, which is a novel attempt. The fabricated membranes were subsequently characterized to optimize the blending ratio of polymers by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction analysis (XRD) and water contact angle analysis. After the characterization studies, different amounts of DOXH were loaded to the optimized blend of PCL and PEO to investigate the release of DOXH from the membrane used as a drug delivery vehicle. In vitro drug release studies were performed, and in vitro drug release kinetics were assessed to confirm the usage of these nanofiber materials as efficient drug delivery vehicles. The results indicated that 3.5% DOXH-loaded (75:25 w/w) PCL/PEO is the most acceptable membrane to provide prolonged release rather than immediate release of DOXH.

Preparation and characterization of electrospun nanofibers containing glutamine.

Oral mucositis is a painful inflammation of mucous membranes commonly after chemotherapy or radiotherapy. The aim of this study was to develop mucoadhesive nanofibers containing glutamine via electrospinning and to characterize them for the treatment of oral mucositis. Different mucoadhesive polymers were tried for preparing nanofibers and sodium alginate nanofibers were chosen after the characterization studies. Glutamine-loaded nanofibers were produced and characterized. Glutamine loaded onto nanofibers was confirmed by differantial scanning calorimetry and fourier transform infrared spectroscopy analyses. As a result, scanning electron microscopy observations showed that the glutamine loaded nanofibers had average diameter of 160nm. Glutamine amount was found to be 0.452mg/cm(2). Work of mucoadhesion, tensile strength and elongation at break values of the glutamine loaded nanofibers were found to be 0.165mJ/cm(2), 2.61mPa and 6.62% respectively. In vitro dissolution tests showed that more than 85% of the drug was diffused from the nanofibers at the end of 4h. Stability studies showed that there was no significant changes at 4 and 25°C/65% relative humidity storage conditions. Therefore, these results demonstrate that glutamine loaded nanofibers could have potential as an oromucosal drug delivery system for the treatment oral mucositis.

Investigation of the effect of intracolonic melatonin gel formulation on acetic acid-induced colitis.

The aims of the present study were to develop a colon-specific gel formulation of melatonin with sodium alginate and to evaluate its in vitro characteristics and intracolonic performance on oxidative stress parameters, such as nitric oxide (NOx), malondialdehyde (MDA) and glutathione (GSH) levels in rats with acetic acid-induced colitis. The melatonin-alginate gel formulations were prepared and their physico-pharmaceutical properties were determined. Formulation M5, which contained 3% of sodium alginate and 20% polyethylene glycol, was used for in vivo studies. The in vivo studies were conducted in rats with acetic acid-induced colitis. NOx, MDA and GSH levels were determined and histological investigations were performed. It was found that formulation M5 was the most suitable formulation for the colon-specific melatonin gel, in terms of pH, viscosity, drug release and mucoadhesion properties. The MDA levels in the tissues of Group 2 (treated with an intracolonic gel formulation without melatonin) were found to be significantly higher than in Group 1 (the untreated group). NOx levels decreased with the intracolonic and systemic melatonin treatment in the colitis-induced rats. Neither intracolonic nor intra-peritoneal (IP) melatonin treatment affected GSH levels. The epitelization of the colon tissues in groups administered with intracolonic melatonin, IP melatonin, and the intracolonic gel formulation without melatonin was much better than that found in the untreated group. It was concluded that melatonin participated in various defense mechanisms against the colonic inflammatory process, and that the dose, route and formulation type were the most important parameters in the effectiveness of melatonin.

Investigation of the effects of local glutathione and chitosan administration on incisional oral mucosal wound healing in rabbits.

The aim of the present study was to investigate the effects of local glutathione (GSH) and chitosan applications on the oxidant events and histological changes that occur, during healing processes in rabbits with incisional intraoral mucosal wounds. For this purpose, discs containing glutathione and chitosan (1:1) were prepared and their physicochemical characteristics were evaluated. New Zealand white rabbits were used in in vivo studies. A standard incision was applied to the oral mucosa of rabbits. The rabbits were divided into four groups, being: an untreated incisional group (n=6), a group treated with discs containing GSH+chitosan (n=6), a group treated with discs containing solely chitosan (n=5) and a group treated with discs containing solely GSH (n=5). The levels of malondialdehyde (MDA), glutathione and nitric oxide (NOx) in the oral wound tissues were measured on the fifth day after the injury. Histological changes in the wound tissues were also investigated. The tissue MDA levels in the group treated with the disc containing GSH+chitosan were found to be lower than those in the other groups. There were no statistically significant differences in terms of tissue GSH and NOx levels between the group treated with the disc comprising GSH+chitosan and the control group that had untreated incision wounds. According to the histological findings, wound healing in the group treated with the disc containing solely chitosan was found to be better than in the other groups. The results of the experiments showed that the local application to the intraoral incision wounds of chitosan+GSH, and chitosan alone, can be effective in the wound healing processes of soft tissues and dental implants.

Effects of epidermal growth factor on lipid peroxidation and nitric oxide levels in oral mucosal ulcer healing: a time-course study.

PURPOSE: Epidermal growth factor (EGF) has been used as a vulnerary agent. Epidermal growth factor accelerates wound healing. Nitric oxide (NO) is considered to be an important factor which is involved in wound healing. The objective of this study was to examine the effects of interactions between exogenous EGF and NOx which may have either similar or quite opposed properties in the process of oral wound repair on different days. In addition, lipid peroxidation was found to be an indicator of free radical damage. METHODS: Five-month-old New Zealand albino male rabbits were used for this study. A surgical incision was made in the right mandibula diestema region of the rabbits, which were then divided into controls and EGF implanted groups. All parameters were analyzed by spectrophotometry. RESULTS: In the EGF-implanted groups, both the NOx and lipid peroxidation indicator levels significantly decreased in comparison to those of the control groups on the first day after wounding. However, on the 3rd and 5th days after wounding, the NOx levels of the tissue strips also decreased in both modalities, but there was no significant alteration between the 3rd and 5th day after wounding. CONCLUSION: It was concluded that EGF affects oral wound healing by downregulating both the lipid peroxidation and NOx levels, and it may thus be considered to be an oxygen radical scavenger.

Evaluation of alginate based mesalazine tablets for intestinal drug delivery.

The aim of this study was to develop the alginate based mesalazine tablets for intestinal delivery. Sodium alginate is a biocompatible, natural polymer with pH-sensitive gel-forming ability. Matrix tablets were prepared with two types of sodium alginate of different amounts. The in vitro release characteristics of mesalazine from alginate tablets were compared with those of the commercial product (Salofalk). X-ray imaging was used to monitor the tablets throughout the gastrointestinal system. Although alginate tablets gave a faster release in an acidic medium compared with the commercial product (Salofalk), the cumulative amount of released drug of the optimum formulation was found to be almost the same as that of the commercial product at the end of 4 h. The alginate type and amount in the matrices played an important role in basic media. The release of the optimum formulation containing low viscosity alginate was found to be almost identical to that of the commercial product in acidic and basic media. Tablets were visualized to determine whether they were located in the terminal ileum or cecum for 3-6 h. Mesalazine-alginate matrix tablet formulations can deliver the drug to the small and large intestine. Thus, the alginate matrix system may be a promising system for the treatment of Crohn's disease involving both the ileum and large intestine.

Rectal and vaginal administration of insulin-chitosan formulations: an experimental study in rabbits.

Insulin is a polypeptide drug and it is degraded by gastrointestinal enzymes, therefore, it cannot be used via oral route readily. There are only parenteral forms available in the market. The aim of this study was to investigate the effect of rectal and vaginal administration of various insulin gel formulations on the blood glucose level as alternative routes in rabbits. Chitosan gel (CH-gel) was used as a carrier; the penetration enhancing effect of sodium taurocholate and dimethyl-beta-cyclodextrin (DM-betaCD) was also investigated. CH-gel provided longer insulin release. The maximum decreasing effect on blood glucose level was observed with insulin-CH-gel containing 5% DM-betaCD. In conclusion, our results indicate that insulin may penetrate well through the rectal and vaginal mucosae from the CH-gel. DM-betaCD was also found to be a useful agent to enhance the penetration of insulin through rectal and vaginal membranes.

Transdermal administration of bromocriptine.

Bromocriptine (BRC) has been mainly used for the inhibition of lactation, treatment of menstrual disorders, Parkinson disease, breast tumours, infertility and brain tumours as a dopamine agonist in clinics. But current BRC formulations have some side effects and bioavailability problems because of hepatic first pass effect. Transdermal application could be an alternative route to overcome all these problem and penetration properties of BRC has not been studied yet. Therefore, it was aimed to investigate the effectiveness of transdermal formulation of BRC which is applicable to the skin. For this purpose, a number of BRC gel formulations (Carbopol-934 (C-934), chitosan (CH) and Gantrez-SP215 (G-SP215) were developed and the effectiveness and bioavailability of the formulations were compared in rabbits. Commercial BRC tablets (Parlodel) were also given to rabbits orally and plasma levels were compared. The effects of two different penetration enhancers, sodium taurocholate (ST) and ethoxydiglycol-Transcutol) (TR) on the BRC penetration were also investigated. The skin samples from the dorsal part of the rabbit were removed after CH gel application and investigated under electron microscope to understand the effects of the gel on the penetration and the possible penetration mechanisms through skin were also discussed. In conclusion, CH gel formulation was found to be the best formulation and comparable blood BRC concentrations were obtained when applied to the rabbit skin. Higher blood levels were obtained with the use of CH. The main penetration process was found to be through transcellular route but some other mechanisms were also found to be incorporated, after microscopic investigation. CH gel was found to be a useful carrier for BRC administration through dermal route and the penetration enhancing effect and the mechanism of CH gel were first established in this study. It was concluded that transdermal delivery of BRC may be a very promising alternative route to the oral route for the treatment.