Current Drug Delivery - Volume 20, Issue 6, 2023

Super Para-magnetic Iron Oxide Nanoparticles (SPIONs) have been manifested for their broad spectrum of applications ranging from biomedical imaging to the treatment of many diseases. Many experiments are being conducted across the globe to especially investigate their potential in the field of targeted treatment for malignant tissues. However, challenges pertaining to the desired delivery of anticancer drugs in the body remain unresolved or unattended. The bare iron oxide nanoparticles are liable to form agglomerates or get easily oxidized in the air which can lead to loss of their magnetism and viability. Moreover, in several reactions, these magnetic nanoparticles leach into the solution/ suspension, making it kinetically unstable. The nanoparticles, further readily metabolize in the stomach pH or are phagocytosed by macrophages. In this article, we address these issues by shedding light on the impact of controlling parameters like size, synthesis method, and surface engineering. After studying the existing literature, it is noted that currently, these magnetically guided delivery systems are being rigorously tested in areas like pancreatic cancer, colon cancer, and prostate cancer, which will be discussed in this review. The fact that the major issue in the conventional treatment of these cancers is intrinsic and acquired drug resistance is a key issue. In this context, the potential of SPIONs as efficient nanotherapeutics is presented. The article provides a deeper insight into the research conducted on these focused areas in cancer. This review also discusses, in brief, the consolidation of artificial intelligence in cancer nanomedicine assuring a better treatment outcome in near future.

Since the discovery of insulin, continuous developments of this peptide have led to better management of diabetes mellitus, thus leading to a decrease in diabetes-related mortality. Despite these developments, we have seen an increase in diabetes cases, which has further necessitated more innovative methods for diabetes management. The subcutaneous administration of insulin remains the mainstay therapy for type 1 diabetes mellitus. However, despite the availability of insulin analogues with improved pharmacokinetics, challenges with conventional administration exist. The challenges associated with insulin injections include hypoglycaemic episodes, needle phobia, and injection-site inflammation, which all have been reported to reduce patient compliance. Ongoing research on diabetes management strives to develop therapies that provide improved glycaemic control with minimal side effects. In part, for these reasons, we have seen an increase in the search and development of alternative insulin delivery systems that are envisaged to circumvent the shortfalls associated with the conventional administration route. Several alternative drug delivery systems, such as oral, pulmonary, buccal, nasal, and transdermal, have been explored in the last century. These efforts have not been without victory, as we have seen the emergence of pulmonary (Exubera and Afrezza) and buccal insulin delivery systems licenced for therapeutic use. Despite the success seen in these two systems, their marketability and popularity have been severely compromised due to reported safety concerns. Although oral insulin delivery has always shown promise in the past decades; however, it was only limited to preclinical trials. The main challenge associated with this delivery route is poor bioavailability, which necessitates high insulin concentration to be administered. Due to recent developments, oral insulin has reached phase 3 clinical trials. It is believed that patients would prefer oral insulin as their preference is often observed for oral antidiabetics over injected ones. In the last decade, transdermal insulin has also gained interest, where delivery of insulin with a concomitant reduction in blood glucose concentration has been demonstrated in vivo. However, at present, there are no clinical studies that have reported the efficacy of transdermal insulin administration. With technological advancement, there is a potential to develop yet another insulin delivery system that would likely enter the markets. As these novel delivery systems have been found to be effective, emerging competing products should be welcome and appreciated.

Proteins and peptides possess considerable potential in treating solid tumors because of their unique properties. At present, there are over 100 peptide-based formulations on the market. Today, peptides and proteins are in more demand due to their selective nature and high target-binding efficiency. Targeting solid tumors with compounds of molecular weight less than 10 kDa are much more desirable because they undergo excessive penetration in view of the fact that they are small sized. The solid tumors have thick tissues and possess excessive interstitial fluid pressure, because of which high molecular compounds cannot enter. The properties of proteins and peptides induce low toxic effects and lessen the major side effects caused by chemical-based drugs. However, their delivery is quite challenging as most proteins and peptides stop functioning therapeutically when following a parenteral route of administration. This paper elaborates on the importance of new age formulations of peptides and proteins followed by their recently documented advancements that increase their stability and delay their metabolism, which helps to target solid tumors.

Proniosomes are the stable carriers used for transdermal application as compared to other vesicular delivery systems like niosomes and liposomes. Oral administration of a drug is associated with severe GIT irritation and first-pass metabolism. The vesicular drug delivery system includes the basic concept of niosomes and proniosomes which describes their mechanism of action, structural formation, interactive study with skin, composition, and method of preparation. Gels contain a high aqueous component as compared to ointment and creams, due to which they can dissolve high concentrations of drugs, and thus help the drug to migrate easily through a vehicle, due to which, gels are considered to be superior in terms of use and patient compliance. This review will focus on the up-to-date research developments in the use of proniosomes, which are applicable to various diseases. Proniosomes are prepared mainly by different concentrations of nonionic surfactants, cholesterol, and lecithin by entrapping hydrophobic as well as hydrophilic drugs. In earlier studies, it was found that the non-ionic surfactants and phospholipids provided higher penetration and it has also been found that some phospholipids have the ability to fluidize the lipid bilayers of the stratum corneum and diffuse through it. In the future, proniosomes may gain more importance in the area of melanoma, brain targeting, protein and peptide drug delivery, gene delivery, hematological drug delivery, and also in cosmetics, and nutraceuticals.

Amorphous solid dispersion (ASD) is a popular concept for improving the dissolution and oral bioavailability of poorly water-soluble drugs. ASD faces two primary challenges of low drug loading and recrystallization upon storage. Several polymeric carriers are used to fabricate a stable ASD formulation with a high drug load. The role of silica in this context has been proven significant. Different types of silica, porous and nonporous, have been used to develop ASD. Amorphous drugs get entrapped into silica pores or adsorbed on their surface. Due to high porosity and wide surface area, silica provides better drug dissolution and high drug loading. Recrystallization of amorphous drugs is inhibited by limited molecular ability inside the delicate pores due to hydrogen bonding with the surface silanol groups. A handful of researches have been published on silica-based ASD, where versatile types of silica have been used. However, the effect of different kinds of silica on product stability and drug loading has been rarely addressed. The present study analyzes multiple porous and nonporous silica types and their distinct role in developing a stable ASD. Emphasis has been given to various types of silica which are commonly used in the pharmaceutical industry.

The conventional oral drug delivery systems face a lot of difficulties in the gastrointestinal tract, such as inappropriate drug release and reduction in the efficacy of the doses, which makes this system less susceptible to the delivery of drug formulation. For the enhancement of therapeutic efficacy and bioavailability of the drug, many efforts have been made. The drug candidates which are not stable at alkaline pH and soluble in acidic medium were selected to increase their therapeutic effectiveness through gastro retentive drug delivery systems (GRDDS). This article discusses various factors which alter the gastro retention time (GRT) of the gastro retentive drug delivery system in the stomach and intestine (duodenum). It emphasizes on the novel approaches made for the delivery and release of drugs with the use of magnetic systems, floating (low-density) systems, super porous hydrogels, raft systems, mucoadhesive systems, high-density systems and expandable systems. Along with the applications, the key aspects of in vivo, in vitro & clinical studies in different approaches to GRDDS have been addressed. In addition, future perspectives have been summarized to reduce gastric transit time in fasting and fed conditions.

The vagina is an essential part of the female reproductive system and offers many potential benefits over conventional drug delivery, including a large surface area for drug absorption, relatively low enzymatic activity, avoiding first-pass effects, and ease of administration. The vaginal mucosal cavity is an effective route for administering therapeutic agents that are intended both for local and systemic administration. The present review provides a comprehensive overview of recent trends and developments in vaginal drug delivery. Marketed formulations and products under clinical study are also reviewed. Various novel vaginal delivery systems have been studied in recent years as effective tools for delivering a range of therapeutic agents to the vagina. These systems offer numerous benefits, including sustained delivery, improved bioavailability, effective permeation, and higher efficacy. The recent focus of the scientific community is on the development of safe and efficient drug delivery systems, such as nanoparticles, microparticles, vesicular systems, vaginal rings, microneedles, etc., for vaginal application. Various factors, such as the physicochemical properties of the drugs, the volume and composition of the vaginal fluid, the pH of the vaginal fluid, the thickness of the vaginal epithelium, and the influence of sexual intercourse may influence the release of drugs from the delivery system and subsequent absorption from the vaginal route. To date, only a limited number of in vivo studies on novel vaginal DDS have been reported. Additionally, drug release kinetics under varying vaginal environments is also not well understood. More research is needed to ensure the suitability, biocompatibility, and therapeutic effectiveness of novel DDS for vaginal delivery. Although numerous strategies and interventions have been developed, clinical translation of these systems remains a challenge. The toxicity of the carrier system is also an important consideration for future clinical applications.

5D & 4D printings are an advanced version of 3D printing class and are one of the most revolutionary and powerful fabrication methods used for preparing innovative structures and solid substances using precise additive manufacturing technology. It captures the imagination of one with its potential to produce flexible designing and fabrication of innovative products with high complexity and speed. This technology with the assistance of AI (Artificial Intelligence) facilitates real-time sensing, adapting to change, and predicting the state of printing. 3D printing works by employing advanced materials utilizing a computer aided design with tomography scan under AI control which deposits printing material in accordance with the nature of a file usually in STL format, but it requires time for printing. This shortcoming can be overcome by 4D printing where smart materials are incorporated with time as 4th dimension. This technique has self-repair and self-assembly properties that will save around 80% of time. Some printed materials are made sensitive to temperature, humidity, light, and other parameters so that they can respond to stimulus, but it’s one limitation of not being able to print complex shapes having curved surfaces can be overcome by utilising 5D printing where additive manufacturing is done by rotation of extruder head and rotation of print bed to print in 5 different axes. This review evaluates the prospective of these techniques with AI interference in medicine and pharmacy, with its effective and efficient production for the required design precision.

Background: Volatile oils and their constituents have been considered major bioactive natural compounds due to their wide therapeutic and biological activities in pharmaceuticals in human healthcare. However, due to their poor solubility, their applications are limited. The inclusion complexation of volatile oils and their volatile constituents with cyclodextrins has emerged as a promising approach for the improvement of aqueous solubility, bioavailability, and stability. Objective: The present review summarizes various research investigations highlighting the complexation of volatile oils and their constituents with cyclodextrins and their derivatives. Additionally, we present an overview of patents published between 1998-2021 to highlight the significance of including volatile oil in cyclodextrins. Methods: The selection of articles for the current review was carried out by using keywords ‘Cyclodextrin’, ‘Essential oil’, ‘Inclusion Complex’, ‘Encapsulation’ and ‘Essential oils/ volatile oils constituents’ in certain specific databases, such as Elsevier (Science Direct), Pubmed Medical subject headings (MeSH) and Medline. Results: A total of 199 studies published were included in the review. In vitro and in vivo studies revealed the efficacy of EOs and their VCs complexed with various types of CD compared to free forms. Conclusion: This review shows the impact of cyclodextrin complexation on the solubility, bioavailability, stability, and biological activities of volatile oils and their constituents.

Background: The formulation of spanlastic vesicles of luliconazole can be used to overcome its poor skin permeation and improve its antifungal efficacy. Objective: In this study, we aimed to enhance the dermal delivery of luliconazole, an antifungal drug, through spanlastic vesicles. Methods: A 2³ regular factorial design was employed, using the Design Expert® software for optimization. The independent variables chosen were Span: Edge activator ratio, type of edge activator, and sonication intensity and their effect on the dependent variables, i.e., entrapment efficiency, particle size, and percentage of drug release after 8h were determined. Spanlastics were formulated by ethanol injection method using Tween 80 as an edge activator. Results: Spanlastics were found to possess sizes in the nano range with entrapment efficiencies between 77 - 88% with optimum zeta potential and polydispersity index indicating a stable formulation. Differential scanning calorimetry, X-ray diffraction, and Fourier transform infrared studies revealed complete encapsulation of the drug within the elastic carriers. The optimized spanlastic formulation was further incorporated into a gel base and was found to be sufficiently viscous, spreadable, homogenous, showed a prolonged release for up to 8h and was also found to be non-irritant. The in-vitro permeation study revealed that the flux value obtained for luliconazole entrapped in the vesicular spanlastics (0.2292 mg/cm².h) was also found to be higher than that of the marketed (0.1302 mg/cm².h) and conventional gel (0.1122 mg/cm².h). The optimized gel formulation was also evaluated for its antimycotic activity. Moreover, the optimized gel formulation also possessed a greater antimycotic activity against Candida albicans. The spanlastics loaded hydrogel formulation was found to have a greater zone of inhibition in comparison to the marketed formulation, thus proving to have optimum antifungal activity against Candida albicans. Conclusion: Collectively, the results revealed that spanlastics could be a potential nanocarrier for wellcontrolled delivery and for targeting deeper skin layers, thus providing new opportunities for dermal treatment.

Aim: Allergy associated with cockroaches are mostly from the American cockroach (Periplaneta americana) and German cockroach (Blattella germanica). The effective and safe treatment for cockroach allergy is Sublingual immunotherapy (SLIT). In this study, SLIT Films containing purified allergen extract of Periplaneta americana were prepared by solvent casting and were evaluated for their efficiency in delivery. Methodology: Cockroach allergen extract was prepared and purified by ultrafiltration and chromatography. The molecular weight of protein content was identified and estimated by SDS- PAGE and ELISA. SLIT films were developed by the Quality by Design (QbD) approach and were evaluated for allergen- excipient compatibility, swelling index, taste, diffusion, in vitro dissolution, local toxicity, and stability analysis. Results: Cockroach allergen protein extracts (cut-off 25-71KDa) were identified by SDS-PAGE and quantified by indirect ELISA and further selected for sublingual film preparation. The indirect ELISA results show a higher optical density (OD) value compared to crude extract. The weight uniformity and thickness of the film were between 13-18 mg and 0.04-0.06 mm. The disintegration time was found to be less than 1 min. The cumulative percentage release was also found to be satisfactory. The local toxicity study indicated no signs of irritation in the buccal mucosa of rabbits. The optimised F3 film had uniform thickness, faster disintegration and drug content within pharmacopeial limits. Ex vivo study revealed better permeability with 90% release of allergen in 7 minutes. The formulation was also stable at room temperature during the study period. Conclusion: SLIT Film containing cockroach allergen from Periplaneta americana was successfully developed and evaluated. SLIT films of cockroach allergen could be more beneficial and convenient for emergency use in patients when compared to subcutaneous immunotherapy. SLIT films provide dose accuracy and are a promising alternative for SCIT and SLIT drops and tablets.

Background: The orally disintegrating tablets (ODTs) are especially suitable for elders and children with dysphagia, who need to be given customized dosages. Objectives: This study aimed to prepare orally disintegrating tablets (ODTs) which can be customized as drug content by using semi-solid 3D printing pressure extrusion technology, with water insoluble and thermally unstable drug loratadine. Methods: The influence of binder concentration, disintegrating agent dosage and ratio mannitol: cellulose on formability and disintegration time was investigated. The properties of orally disintegrating tablets were investigated by ATR-FTIR, XRPD, DSC and SEM. The correlation formula between tablet bottom area and drug content was established. Results: The formulation was optimized, and contained loratadine 3 g, cellulose 4 g, mannitol 2 g, carboxy methyl starch sodium 1g, 6% PVP K30 16 ml. The disintegration time was less than 60 s with infilling percentage of 60%, and the disintegration time was less than 30 s with infilling percentage of 40%. There was no detectable interaction between loratadine and the selected excipients by the analysis of ATR-FTIR, DSC and XRPD. The structure of the tablets was porous, and the drug was dissolved completely within 10 min. The drug content (x) of the tablet and the bottom area (y) of the tablet showed a linear fitting relationship, y = 3.8603x - 0.7176, r² = 0.9993. Conclusion: Semi-solid extrusion of 3D printing technology was applied to prepare loratadine orally disintegrating tablets with customized drug content, which provides an alternative method for the research of customized preparation.

Background: Ketorolac tromethamine (KT) is a non-steroidal anti-inflammatory drug from the heteroaryl acetic acid derivatives family. The most widely used new nanotechnological approaches for topical drug delivery are polymeric nanoparticles (NPs). Objective: Successful results have been obtained with low doses in many treatments, such as cancer, antimicrobial, pain, made with nanoparticle formulations of drug active ingredients. Methods: NPs were prepared using Nano Spray-Dryer. The cytotoxicity of the optimum formulation in BJ (ATCC® CRL-2522™) human fibroblast cells was determined by the WST- 1 method and the gene activity was elucidated by mRNA isolation and real-time polymerase chain reaction (RT-PCR). The in vivo HET- CAM assay was performed for anti-inflammatory activity. Results: NPs presented PDI values lower than 0.5, and therefore particle size distribution was decided to be monodisperse. Positive zeta potential values of NPs highlighted the presence of the cationic ammonium group of Eudragit® RS 100. The release rates observed from KT-NP coded formulations after 24 hours were 78.4% ± 2.9, demonstrating extended release from all formulations, relative to pure KT. The lowest concentration of KT-NP increased fibroblast cell proliferation higher than the highest concentration of KT. The 5-fold increased effect of KT-NP formulation on collagen gene expression compared to KT is also related to the enhanced anti-inflammatory effect in line with the in vivo HET-CAM assay results. Conclusion: With the obtained cell viability, gene expression, and HET-CAM results, it has the hope of a successful nano-topical formulation, especially in both wound healing and anti-inflammatory treatment.