5.1.4. Cardiovascular Agents

Disorders related to heart and blood vessels are categorized as various cardiovascular diseases such as stroke, heart attack, hypertension, cardiomyopathy, heart arrhythmia, carditis, aortic aneurysms, peripheral artery disease, thromboembolic disease, venous thrombosis and rheumatic, valvular and congenital heart disease [89]. Among these disorders, coronary artery diseases like angina and myocardial infarction are the most common cardiovascular disorders. Nicorandil is widely used against angina or angina pectoris due to its agonistic properties to both ATP-sensitive K+ channel and a polyatomic ion, nitrate, channel [90]. The low bioavailability and slow onset of activities and the major side effects including excess turnover rate and mucosal ulceration have limited the usage of nicorandil as an anti-anginal agent. To overcome these limitations, nicorandil had been electrospun with polymeric nanofibers composed of riboflavin, hyaluronic acid, and PVA to prepare a sublingual dosage for treating angina pectoris. It was expected that the presence of riboflavin in the nanofiber scaffolds would cure mucosal ulceration whereas hyaluronic acid would ensure the quick recovery of inflammation in damaged tissue by reducing the amount of pro-inflammatory cytokines. However, this nano-sized drug-loaded fiber mat was able to sustain the controlled release of nicorandil over a prolonged period of time. The pharmacokinetic study revealed the maintenance of a therapeutic level over a longer period of time and about 4 times more biological half-life of the developed formulation in comparison with marketed nicorandil. Moreover, no mucosal ulceration had been evidenced by the histopathological study at the site of administration for the developed formulation [91].

Carvedilol is another cardiovascular drug that binds and blocks both alpha and beta-adrenergic receptors in an attempt to treat congestive heart failure. Potrˇc et al. (2015) researched electrospun PCL nanofiber scaffolds as a delivery carrier for the oral administration of poorly water-soluble carvedilol. It was observed that the average size of a drug-loaded PCL nanofiber is directly proportional to the amount of loaded drug and the crystallinity of the carvedilol decreased after encapsulation into the PCL nanofiber. The encapsulated drug was partly molecularly interspersed in the PCL nanofiber and in the formation of dispersed nanocrystals to a certain extent. It had been reported that up to 77% of carvedilol was released from the PCL electrospun nanofibers within only 4 h which indicated a significant improvement of the dissolution rate of this poorly water-soluble drug [41]. Hence, electrostatic spinning is a novel nanotechnology-based strategy especially for improving the dissolution rate of water-insoluble drugs.

#### 5.1.5. Gastrointestinal Drugs

Drugs that are used against various gastrointestinal tract or gut or digestive system disorders or ailments to cure or prevent many severe symptoms of the esophagus, stomach, intestines (both small and large), rectum, and anus, are known as GIT drugs. GIT drugs include antidiarrheal, antiemetic, anti-ulcer agents, cathartics, cholagogues and choleretics, emetics, laxative, lipotropic agents, antibacterial and many other types which are frequently prescribed to control gastric juice, regulate gut motility, water flow and improve the digestion of patients [90]. Unfortunately, the inability of GIT drugs as a curative therapy may lead to surgery in the case of serious complications. Hence, finding a new method to improve the pharmacological action of GIT in human physiology is crucial, especially for serious diseases such as inflammatory bowel syndrome-assisted Crohn's disease, gastroesophageal reflux disease or acid reflux disease, irritable bowel syndrome, and peptic ulcer disease that can lead to stomach cancer.

Metoclopramide (4-amino-5-chloro-*N*-[2-(diethylamino) ethyl]-2-methoxybenzamide) is an antidopaminergic benzamide, pharmacologically used as a serotonin receptor agonist. Its inhibitory action on acetylcholinesterase exerts its prokinetic and anti-emetic effect due to its actions on contractility of colonic smooth muscle. Recently, Jaber and co-workers fabricated a core/shell nanofiber

using PVA/PCL to load metoclopramide hydrochloride [92]. The release profile indicated an initial burst release of the loaded drug (about 55% of total release). The reason behind the initial burst release of metoclopramide may indicate the presence of micron or nano-sized pores in the PCL shell.

Designing the control release behavior of hydrophilic molecules such as protein, peptide, nucleic acid or even a drug is a very difficult task. Tiwari et al. proposed a new method by controlling the partition release of two-layer fiber matrix using a core-shell electrospun strategy where the polymer will serve as an outer layer and the encapsulated drug will be in the core. The authors used metoclopramide to represent a hydrophilic drug and loaded it into various monolithic fibers (PCL, PLLA, PLGA, and PVA) as well as core-shell nanofibers such as PVA/PCL, PVA/PLLA, and PVA/PLGA to investigate the control release behavior of metoclopramide loaded as-synthesized nanofibers. The drug release profile data suggested that the controlled release of hydrophilic entities is possible by using core/shell nanofibers and by verifying the physicochemical properties of core/shell solutions. The result also showed a clear difference according to the release characteristics between the monolithic fibers, which are made of hydrophilic and hydrophobic polymers, and core/shell fibers using PCL, PLLA, and PLGA 80/20 shell polymers. The monolithic fibers cannot control the initial burst release of the hydrophilic drug metoclopramide hydrochloride but core/shell electrospun nanofibers can easily regulate the controlled release of incorporated drugs. Thus, electrospun nanofibers would be a promising gastrointestinal drug carrier to achieve controlled release behavior and protect sensitive drugs in a biological pH [93].

#### 5.1.6. Antihistamines

Antihistamine generally works by blocking the physiological activities of histamine, thus, antihistamines are used in the treatment of nasal congestion, sneezing, hives, seasonal hay fever and especially, to relieve the symptoms of various allergies such as dust allergy, cold allergy, allergic rhinitis, indoor and food allergies. For the time being, electrostatic nanofiber scaffolds are being used as a carrier of various antihistamine drugs. One experimental study was designed to incorporate the first-generation antihistamine (H1 receptor antagonist) chlorpheniramine maleate into glutinous rice starch combining polyvinyl alcohol (GRS/PVA) electrospun nanofibers to investigate a drug delivery carrier concept and control release properties of the nanofibers [94]. The hybrid nanofibers (GRS/PVA) offered a biphasic release of loaded-antihistamine in which 60% of initial release had taken place within first 10 min and reached the highest release at about 90% within 120 min of administration. The authors suggested this GRS/PVA nanofiber scaffold as a novel oral antihistamine drug carrier.

Development of fast dissolving delivery systems of therapeutics (FDDST) is an excellent and unique concept especially for those patients who have difficulties swallowing pharmaceutical solid dosage forms. FDDST offers very fast-dissolving solid oral dosage forms that take a few minutes for absorption in the patient's mouth. Thus, FDDST facilitates high drug bioavailability, therapeutic window and exemption of hepatic first-pass elimination. Previously, the electrospinning method was employed to design, develop and evaluate FDDST in which one study proved more than 80% of total ibuprofen release within 20 s [95] whereas another study showed the co-release of caffeine and vitamin B12 at about 100% and 40% respectively within 1 min [96]. However, Loratadine is another effective peripheral histamine H1 receptor inverse agonist and responsible for anti-allergic effects. Nevertheless, its low water solubility, bioavailability and rapid first-pass hepatic effect with mainly CYP3A4 and CYP2D6 (isoforms of cytochrome P450) metabolism systems reduce their usages. In this respect, electrospinning nanofiber-based Loratadine delivery would be the best solution. A few years ago, Akhgari et al. described the impact of few parameters such as the concentration of polymer and antihistamine, and the amount of feed ratio and the voltage on the first dissolving delivery systems for Loratadine. The authors prepared a Loratadine-encapsulated PVP nanofiber scaffold by way of the electrospinning technique and observed a lower feed ratio and low concentration of the polymeric solution with high voltage application produce nano-sized nanofibers with excellent uniformity. The results of this study showed that, to achieve quick solubility and release of antihistamine from

as-prepared nanofibers, the fiber should be a nanometer in size and the antihistamine amount should be smaller [97].

Another example of an antihistamine is Diphenhydramine, a member of the ethanolamine class of histamine H1 receptor antagonists, which is mainly used to treat allergies, nausea, motion sickness, extrapyramidal symptoms and symptoms of a common cold by reversing the effects of histamine on capillaries. It is also used in parkinsonism due to its ability to act as a muscarinic acetylcholine receptor reverse agonist by crossing the blood-brain barrier. In addition, its usage as a sodium channel blocker introduced it as a local anesthetic [90]. However, to produce porous and fast-disintegrating nanofiber scaffolds targeting oral administration, diphenhydramine-incorporated nanofibers were directly electrospun onto a polymeric backing film of hydroxypropylmethylcellulose and glycerol [98]. The physicomechanical characterization data revealed the potency of nanofiber scaffolds in a nanofiber-based oral antihistamine delivery system with the following configurations: high encapsulation efficiency and very short disintegration times (12.8 s). This very short integration time may indicate the large surface area of PVA nanofibers, which were loaded with diphenhydramine.

#### 5.1.7. Contraceptives

For the first time, a composite electrospun nanofiber was fabricated by free-surface electrospinning with various microscale geometries as a carrier of physicochemical diverse medicines including the contraceptive drug progestin levonorgestrel [99]. The as-fabricated PVA nanofibers were capable of encapsulating more than 80% of all matrix formulations except interwoven matrix where an artifact of the processing led to a calculated >150% encapsulation efficiencies for levonorgestrel. The authors checked the solid dispersion of levonorgestrel in the electrospun nanofibers by employing various differential scanning calorimetry analyses. After encapsulation of levonorgestrel, the thermograms of the PVA fabrics did not dramatically change even with high loading of levonorgestrel (17 wt.%). The in vitro release kinetics demonstrated slow and controlled release of levonorgestrel due to its highly hydrophobic nature, where levonorgestrel took 4 h to achieve 100% release from the as-synthesized composite microarchitectures. The idea is that these contraceptive-loaded nanofibers would be inserted into the vaginal mucosal environment to prevent unplanned pregnancy by releasing the appropriate dose of contraceptives into the local cells.
