Bibliometric analysis was carried out by collecting data from the Scopus search engine (https://www-scopus-com) on December 24, 2021. Searches for Scopus were carried out using the keywords “ocular” AND “nanoemulsion” OR “in situ gel.” The inclusion criteria for this search were articles published between 2011 and 2021 in English, with the type of document being articles. Then, the data were cleaned and rechecked to avoid data duplication and ensure that the data articles obtained discussed preparations of nanoemulsion for ocular drug delivery systems and/or in situ gels. Abstract and/or article searches were used to validate the right article. After that, the obtained data were exported in the form of a CSV Excel file.

The VOSviewer version 1.6.17 application from Centre for Science and Technology Studies, Leiden University, The Netherlands, which can be downloaded for free at https://www.vosviewer.com/download, was used to analyze the CSV export results. This application was used to examine contributing institutions, sources, authors, papers and co-citation, and keywords co-occurrence. Data cleaning was performed using the thesaurus program in Excel Office to avoid duplication of data or similar terms. Biblioshiny for bibliometrix (R version 4.1.2) from Department of Economics and Statistics, University of Naples Federico II, Italy was also used for data analysis with the Rstudio program, which can be downloaded for free at https://www.rstudio.com/products/rstudio/download. This program analyzes the publication trend, contributing country, contributing source, and contributing author.

The number of documents obtained after searching on the Scopus search engine with the keyword “ocular” AND “nanoemulsion” OR “in situ gel” was 647. The documents were then filtered using inclusion criteria, offering 372 articles. Following the process of ensuring that the filtered articles discussed ocular nanoemulsion preparations and/or in-situ gels, 298 articles were obtained, as shown in Table 1. Fig. 1 presents a flow diagram of the steps of article search.

Figure 1. 

Flow diagram of the steps of article search.

Bibliometric analysis of nanoemulsions and/or in-situ gel ocular preparations was performed to help describe and map knowledge concepts related to advancing research on ophthalmic drug delivery systems using nanoemulsions and/or in-situ gel drug delivery systems using the Scopus database. Performance analysis and science mapping are the two types of bibliometric processing techniques. Performance analysis considers the contributions of research participants from various countries, institutions, sources, and authors who contribute to the productivity of the produced articles (Donthu et al. 2021). Meanwhile, science mapping depicts the relationships between the intellectual aspects of research constituents, such as citation, co-citation, and keyword analyses, as well as bibliographic coupling (Kent Baker et al. 2020).

As shown in Fig. 2, the number of articles appears to have increased in recent years. Table 2 depicts the publication data trends and the average number of citations per article. On average, 27 articles were produced each year, with a relatively high average of 21 citations per article. The highest number of articles on ocular nanoemulsion and in-situ gel preparations were published in 2020 (61), followed by 47 and 31 articles in 2021 and 2019, respectively. The highest average number of citations per article occurred in 2011 (35.4 points), indicating that the 16 articles published in 2011 were cited or used as a reference for 35.4 other research articles. The second-highest average citation per article was in 2016 (31.3 points), followed by the third highest in 2013 (30.8 points). A higher average citation value for each article indicates that, in that year, many articles became references for researchers, and so did their articles in the following years.

Figure 2. 

Annual scientific production of papers since 2011–2021.

Rstudio software was used to analyze the contributing countries. Fig. 3 reveals the collaboration map of the countries involved in the research of ocular nanoemulsions and/or in-situ gel preparations. The more intense the blue color on the map is, the more articles that were published during the 2011–2021 period. The pink line indicates the collaborative relationships of each author in different countries. Collaborative articles from two different countries with the highest frequency (seven times) were between Egypt and Saudi Arabia, India and Saudi Arabia, and the United Kingdom and New Zealand.

Figure 3. 

Country collaboration map from 2011 to 2021 using Rstudio.

The greater the number of citations, the greater the country’s dominance in article publication. Fig. 4 reveals a graph of the most cited countries from the authors’ 39 countries of origin. The three countries with the most citations were India (1180 citations), China (1120 citations), and Egypt (560 citations), indicating these countries’ strong focus on research on nanoemulsion ocular preparations and/or in-situ gels.

Figure 4. 

Most cited country from 2011–2021 using Rstudio.

A bibliometric analysis of the contributing institutions was performed using VOSviewer. This analysis depicts the relationship between institutions that collaborate to produce an article. The total number of organizations or institutions involved in producing articles was 740. To avoid duplication, data cleaning was performed using a thesaurus, which resulted in 618 organizations.

Based on the full counting method, six organizations met the minimum of five (article) publication. These organizations are interconnected in publishing several articles, as shown in Table 3. The Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, presented the most articles (nine in total). This was followed by the Department of Pharmaceutics and Drug Delivery, School of Pharmacy, University of Mississippi; Research Institute of Pharmaceutical Sciences, University of Mississippi; and the Department of Pharmaceutics, School of Pharmacy, Hamadan University of Medical Sciences, which published seven articles in total. The Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, and the Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University published five articles each.

Furthermore, the Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, published the most influential articles when compared the other organizations. This organization had the most citations at 351. Following this were The Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard (156 citations); Department of Pharmaceutics and Drug Delivery, School of Pharmacy, University of Mississippi (123 citations); and Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University (123 citations) as the most influential organizations.

According to the VOSviewer analysis, there are 120 sources or journals that publish articles on preparations of nanoemulsion and/or in-situ gels in ocular drug delivery systems. The more articles were published, the more relevant the source is for publishing articles on ocular nanoemulsion and/or in-situ gel preparation. Table 4 lists the top five data sources that published at least eight articles between 2011 and 2021, namely, the International Journal of Pharmaceutics (25 articles), the Journal of Drug Delivery Science and Technology (14 articles), Pharmaceutical Development & Technology and Pharmaceutics (10 articles), Drug Development and Industrial Pharmacy, and the European Journal of Pharmaceutics and Biopharmaceutics (8 articles). Information about the most relevant sources can assist researchers or scholars in submitting or publishing research reports that correspond to the topics provided in the source or journal (Arifaha et al. 2021).

The “International Journal of Pharmaceutics” had the greatest impact on the development of ocular nanoemulsions and/or in-situ gel preparations with the highest total number of citations (1,030) and the highest average number of citations per article (41.20). This result is consistent with the prediction based on Rstudio analysis results, as shown in Fig. 5. According to the H-index, the “International Journal of Pharmaceutics” had the greatest impact, with an H-index of 17. This result indicates that 17 articles were cited at least 17 times by 17 other scholars. This was followed by “Pharmaceutical Development and Technology” with an H index of 10 and the “Journal of Drug Delivery Science and Technology” with an H index of 7.

Figure 5. 

Highest impact source for ocular nanoemulsion and or in situ-gel drug delivery system using Rstudio.

Fig. 6 illustrate the correlations between author affiliations (AU UN), source (SO), and author’s country of origin (AU CO) in a plot of three fields. This study focused on the top 20 author affiliations, top 20 sources, and top 20 countries of origin that published articles on ocular nanoemulsion and/or in-situ gel preparations. RStudio was used for the analysis using 20 items. A gray line connects the three fields. The size of rectangle indicates the number of related articles in each field. The greater the length of the rectangle is, the greater the number of articles associated with each field

Figure 6. 

Three-fields plot between author affiliations (AU_UN), Source (SO) and author country (AU_CO) using Rstudio.

In line with Table 4 and Fig. 5, Fig. 6 reveals that the International Journal of Pharmaceutics is the most influential journals in the 20 affiliations and 20 countries to publish articles on ocular nanoemulsion and/or in-situ gel preparations. Incoming flow analysis revealed that four of the top 20 affiliations—Shenang Pharmaceutical University, Wenzhou Medical University, Cairo University, and Tianjin University of Traditional Chinese Medicine—submitted articles to this journal. Outgoing flow analysis revealed that this journal published articles by authors from 12 of the 20 most productive countries, namely India, China, Egypt, Spain, Italy, Saudi Arabia, France, the United States of America, the United Kingdom, Indonesia, New Zealand, and Croatia.

Analysis of the contributing author and bibliographic coupling was performed using the Rstudio application and VOSviewer program. The Rstudio application was used to analyze the contribution of the corresponding author and author impact. Corresponding authors submit articles to journal editors and correspond with them via an email address listed on the first page of the article, which is also accessible to other researchers (Peláez-Repiso et al. 2021). Table 5 shows that most of the corresponding authors were from India (82 articles). China (44 articles) and Egypt (28 articles) ranked second and third, respectively. Furthermore, a high number of corresponding authors in a country indicates that the research environment or the country’s resources support the researchers with publishing on nanoemulsion and/or in-situ gels for ocular drug delivery systems.

The countries with the most corresponding authors, India, and China, have the most human resources in the world, and so they are inextricably linked to the problem of ocular disease. India is a developing country with increasing urban migration and a large elderly population on the verge of a dry eye disease epidemic (Donthineni et al. 2019). Over the last two decades, China has seen an increase in the number of people with eye diseases who have lost their vision, and this may continue because of population growth and aging (Wang et al. 2018). As a result, it is not remarkable that these countries have published numerous articles on this subject.

Table 5 also represents the level of collaboration, which consists of intra-country collaboration, also known as single-country publication (SCP), and inter-country collaboration, also known as multiple-country publication (MCP). Corresponding authors from Saudi Arabia have the highest international collaboration and inter-country collaboration ratio of 1. All articles (seven articles) with a corresponding author from Saudi Arabia resulted from international collaborations. Following Saudi Arabia, India (six articles) and Egypt (four articles) had the most international collaborations. MCP paves the way for technological harmonization and expands research opportunities. Comparative studies can be used to investigate scientific production that has an enormous impact on solving global and local ocular problems. Compared to those of other countries, India (76 articles), China (43 articles), and Egypt (24 articles) had the highest intra-country collaborations.

In addition to the author’s impact, Fig. 7 represents the author’s influence, as indicated by the value of the H index. Ali A had the most influence on articles produced on ocular nanoemulsions and/or in-situ gel preparations, with the highest H index of 8, followed by Aqil M and Li X, with an H index of 6. Ali A’s articles were mostly about ocular in-situ gel formulations with in-vitro, in-vivo, and ex-vivo profiles, including irritation tests (Gupta et al. 2013b, 2013a, 2015b, 2015a; Katiyar et al. 2014; Khan et al. 2015; Aslam et al. 2016; Ameeduzzafar et al. 2018a, 2018b). This information is significantly helpful for article writers, including researchers, in designing and discussing the impact of research results.

Figure 7. 

Author local impact based on H using with Rstudio.

The contributing author and research network analyses was carried out between the authors using bibliographic coupling with the full counting method in the VOSviewer application. The full counting method assigns one credit to each contributing author. If there are five authors in a single article, the total number of credits is five (Sivertsen et al. 2019). A bibliographic coupling analysis was performed on the contributing authors with at least two published articles that were linked with other authors; this approach was necessary because if the minimum criteria of one article was used or an analysis on all authors was conducted, the results would indicate that not all authors were connected in the articles created. Consequently, 227 authors were selected based on this approach. There were ten indicated author clusters. Table 7 shows the number of authors in each cluster and the focus of the research themes conducted by the top three authors in each cluster.

A thesaurus was used to clean the data for author name duplication, post which, the number of authors reduced from 1,215 to 1,205. Table 6 shows the top authors who published the most articles that link with other authors about ocular nanoemulsions and in-situ gel preparations. In addition to producing the most influential articles, Ali A. from Jamia Hamdard Faculty of Pharmacy, New Delhi, India, published nine articles between 2011 and 2018, with an average of 30.67 citations per article, who was followed by Mahboobian M.M. from Hamadan University of Medical Sciences in Iran with eight articles (2017–2021). Majumdar S. from the University of Mississippi in the United States and Pan W from Shenyang Pharmaceutical University in China were third, with seven articles (2018–2021).

The number of citations obtained from an article reveals the study with the most significant contribution. The more citations an article receives, the greater its influence on advancing research on preparations with nanoemulsion and/or in-situ gel for ocular drug delivery systems. A total of 298 papers contributed to research on ocular nanoemulsions and/or in-situ gel preparations. Based on the bibliographic coupling analysis with the document analysis unit in VOSviewer, the number of articles with a minimum of one citation was 265. Only 11.07% of articles were not cited by another article and most of these articles were published in 2021, implying that most articles influence those published following their publication. Table 8 lists the top ten most-cited articles. The number of contributing papers is calculated by full counting

The most influential article, titled “In situ gelling systems based on Pluronic F127/Pluronic F68 formulations for ocular drug delivery,” was written by Al Khateb et al. (2016). This study demonstrated that Pluronic F127 and Pluronic F68 at a concentration of 20% w/w in an in-situ gel drug delivery system does not cause mucosal tissue irritation, allowing their efficient application to the eyes; wherein Pluronic F127 20% w/w solution can form a transparent gel, increasing the drug’s residence time (Al Khateb et al. 2016).

“Enhancing and sustaining the topical ocular delivery of fluconazole using chitosan solution and poloxamer/chitosan in-situ forming gel” was the second most influential article with 119 citations (Gratieri et al. 2011). This study aimed to assess the in-situ delivery of a drug using poloxamer 407-chitosan gel to improve corneal permeation and sustained fluconazole release. Fluconazole was released from the poloxamer/chitosan formulation over time, according to the study’s in-vitro drug release evaluation. Ex vivo permeation evaluation of porcine corneas revealed increased permeation at chitosan concentrations ranging from 0.5 to 1.5 percent w/w. The chitosan solution alone demonstrated the highest ex vivo drug permeation. However, the poloxamer/chitosan combination was only comparable in-vivo to the 1.0% chitosan solution. Compared with the simple drug solution, both formulations demonstrated sustained release and a 3.5-fold increase in total fluconazole absorption (Gratieri et al. 2011).

Meanwhile, the third most influential article was “Promising ion-sensitive in-situ ocular nanoemulsion gels of terbinafine hydrochloride: Design, in-vitro characterization, and in-vivo estimation of ocular irritation and drug pharmacokinetics in rabbit aqueous humor,” which had been cited 115 times (Tayel et al. 2013). This study aimed to prepare an in-situ gel nanoemulsion of terbinafine hydrochloride for use in ocular drug delivery systems. Drug-loaded nanoemulsions (0.5%, w/v) were dispersed in gellan gum solution (0.2%, w/w). The in-situ NE gel was transparent, pseudoplastic, and mucoadhesive with a slower zero-order drug release rate. Formula 31 (Miglyol 812-5% w/w, Cremophor EL 18.33% w/w, polyethylene glycol 400-36.67% w/w, gellan gum 0.2% w/w, and water) in-situ NE gel had the least ocular irritation potential and significantly (P, 0.01) better C (max), delayed T (max), prolonged mean residence time, and increased bioavailability (Tayel et al. 2013).

Analysis of co-citation—when two papers are cited by a third paper—revealed the relationship between the cited articles that formed the basic theme of the research. The co-citation relationship between two papers becomes stronger with an increasing number of papers citing both of them (Bamel et al. 2020). Co-citation analysis helps identify the most influential published articles to form thematic clusters (Donthu et al. 2021). Co-citations were analyzed based on a unit analysis of the cited references. Fractional counting was used for this calculation. The co-authored publications were calculated fractionally for each author, with the overall weight of the publication equal to one (Bamel et al. 2020). Therefore, in fractional counting, each publication has the same overall weight to provide balance, consistency, and precision in bibliometric measurements (Sivertsen et al. 2019).

Based on the VOSviewer analysis, the total number of references cited was 11,338. At least one reference cited as many as 504 references, but only 446 articles were connected with each other. Using at least one reference cited by three articles, 112 references were obtained; however, one reference was not connected to the other articles. Therefore, the analysis was carried out on references with a minimum of four citations by other articles to obtain 46 reference articles. As there was duplication of data in the analysis results, cleaning of the data was performed using a thesaurus and 41 articles remained. The top three reference articles that were most cited by articles on ocular nanoemulsions and/or in-situ gel preparation are shown in Table 9.

The most co-citation reference belonged to Urtti (2006). The reference was about topical eye drops wearing off quickly from the eye’s surface, revealing that the absorption time of the drug was short and thus impacting the bioavailability of the drug, which was less than 5%. As a solution, the dosage form can be designed for prolonged action; however, not many patients have received this form. In addition, absorption of the modified preparation can be blocked by the corneal and conjunctival epithelium of the eye (Urtti 2006).

The reference articles were linked to other articles and were divided into six clusters, depicted in different colors on the circle in Fig. 8. Each cluster focuses on a different theme or area of research on ocular nanoemulsions and/or in-situ gel preparations. The red cluster is the largest (11 articles), while the blue cluster is the smallest (2 articles). The size of each circle represents the number of citations. The larger the circle, the more citations an article has received. The distance between the two circles indicates the similarity between their themes; the higher the similarity level, the closer the circles (Bamel et al. 2020). The research focuses on the top three co-citation authors in each cluster with VOSviewer, as shown in table 10.

Figure 8. 

Co-citation network visualization using VOSviewer.

The following analysis examined keyword co-occurrence across all keywords using VOSviewer. This analysis can be used to map current or future research topics on ocular nanoemulsion and/or in situ gel preparations based on the content of the articles written (Donthu et al. 2021). The number of documents that appear using a specific keyword is shown by occurrence. The calculation method used was full counting, so the number of occurrences of keywords in the analysis obtained represents the total occurrence of these keywords in all documents. The All keyword category is made up of author keywords (“article titles,” “abstracts,” and “full texts”) as well as indexed keywords (Arifaha et al. 2021).

The total number of keywords examined was 2,778. The number of keywords used after filtering with the thesaurus was 2,457. The filter process seeks to eliminate duplicate keywords with the same meaning, such as antioxidant and antioxidants, carbopol and carbopol, het-cam and hen’s egg test-cam, and so on. The number of keywords that appeared at least 30 times in the articles found was 68. Then, the manual selection was performed on unrelated or irrelevant to the article’s theme. The analysis did not include keywords of articles, female, human, male, non-human, priority journals, or procedures. The list of keywords and the interpretation of the results obtained can be seen in Table 11 and divided into 3 clusters.

Fig. 9 shows the co-occurrence network based on time division. The most used keyword was “controlled release” (183 occurrences), which appeared in mid-2017. This was followed by “drug delivery system” (170 occurrences) and “drug formulation” (159 occurrences), which began to appear in early 2017. “In vitro studies” began to increase in mid-2017 (141 occurrences) and “gels” appeared in mid-2016 (130 occurrences). Controlled release was the keyword that appeared the most. Prolonged action necessitates controlled drug release from the delivery system to prolong the ocular surface retention time. Controlled release or slow release and/or dissolution of drugs without prolonged retention on the ocular surface is ineffective because it results in poor ocular bioavailability. Therefore, the ocular delivery system must be designed to remain on the ocular surface for an extended period to effectively release the drug dose in the lacrimal fluid. Polymers that exhibit mucoadhesion based on electrostatic interactions or hydrogen bonding can be used to extend the retention time on the ocular surface (Subrizi et al. 2019).

Figure 9. 

Overlay visualization of all keywords using VOSviewer.

Fig. 10 shows the trend of the research topics each year based on author keywords that appeared at least five times in one year from 2011 to 2021 using RStudio. “Nanoemulsion drug delivery systems” began to appear more around 2018–2019, while “in-situ gel preparations” have often appeared since 2011. Low nanoemulsion viscosity can affect the residence time of the preparation on the ocular surface. Therefore, some researchers have modified the preparation by wrapping it in a gel or hydrogel. However, the drawback of this hydrogel form is that the amount of active substance and homogeneity are limited, especially for hydrophobic drugs; therefore, the use of a nanoemulsion delivery system is expected to overcome these problems (Dubald et al. 2018). This has led to the development of ocular in-situ gel preparation research being more varied and dominated by identifying the right gelling agent. The most frequently developed gelling agents are sodium alginate (2014), carbopol (2015), poloxamer (2016), chitosan (2018), and gellan gum (2019).

Figure 10. 

Each year trend topic using RStudio.

Alginate is a brown seaweed-derived anionic, hydrophilic polysaccharide. It is composed of -D-mannuronic acid linked to R-L-guluronic acid units. When sodium alginate comes into contact with the cornea, it can interact with cations, such as Ca²⁺, in the tear film to form a gel (Jumelle et al. 2020). In addition, sodium alginate and gellan gum have been used in conjunction with sodium carboxymethylcellulose (NaCMC) to deliver gatifloxacin against bacterial keratitis in an infected rabbit model. Compared with conventional eye drops, in-situ gel was found to be more effective in treating keratitis (redness, lacrimal secretion, mucoid discharge, response to visual stimulus, and swelling of eyelids) (Kesavan et al. 2016). Surprisingly, a gellan gum (Gelrite) and alginate in-situ gel combination demonstrated a greater capacity to retain a drug on the corneal surface than either gellan gum or alginate in-situ gel alone (Liu et al. 2010). These findings suggest that combining ion-sensitive polymers can improve gelation properties, allowing increased precorneal drug retention on the corneal surface (Jumelle et al. 2020).

Poloxamer 407 (P407) and poloxamer 188 (P188) are the two most frequently used poloxamers in ocular drug delivery owing to their high-water solubility, clarity of aqueous solutions, concentration-dependent viscosity, shear-thinning behavior patterns of the aqueous phase, and safety of use in ocular tissues. The percentage of corneal surface damage in eyes treated with 20% w/w P407 solution was not significantly different from that in eyes treated with saline solution (Soliman et al. 2019). Gupta and Samanta (2010) conducted in-vivo ocular tolerance tests on forskolin-loaded poloxamer-based in-situ gels instilled into rabbit eyes. Inflammatory responses were scored using a modified Draize test, and no significant macroscopic or microscopic reactions were observed in the tested eyes when compared with the contralateral eyes in the same animal.

The active ingredients often used for research on nanoemulsion and/or in-situ gel drug delivery systems are fluconazole (five times in 2014), timolol maleate (five times in 2015), ofloxacin (seven times in 2015), and pilocarpine (five times in 2015), and levofloxacin (8 times, 2016). Concurrently, the types of diseases that are often discussed in the article are glaucoma (25 times, in 2019) and dry eye disease (9 times, in 2020).

Glaucoma was the most studied disease in 2019. It is the leading cause of blindness and it requires long-term therapy (Sall 2000; Silver 2000a; Bhalerao et al. 2020), while 12% of the cases are preventable. It is expected that nearly four million Americans and 80 million people worldwide will have the disease by 2020 (Reeder et al. 2008; Gooch et al. 2012; Mahboobian et al. 2021). Owing to tearing turnover and nasolacrimal drainage, topical dosage forms of drug solutions and suspensions available for the treatment of glaucoma are rapidly eliminated from the precorneal tract, resulting in a drug bioavailability of less than 10% of the administered dose (DeSantis 2000; Silver 2000b; Iester 2008; Bhalerao et al. 2020).

Topical preparations must be used more frequently to overcome drug elimination from the precorneal tract and to achieve desired therapeutic efficacy (Wu et al. 2013; Zhang et al. 2013; Bhalerao et al. 2020). Azopt 1% is an ophthalmic suspension of brinzolamide administered to glaucoma patients every 8–12 hours or 2–3 times per day to effectively control intraocular pressure (Talaei et al. 2020). Patient compliance problems arise due to the required frequency of administration. Furthermore, this formulation has been linked to several side effects, including blurred vision, ocular discomfort (foreign body sensation), blepharitis, and dry eye (Chockalingam et al. 2019; Bhalerao et al. 2020; Talaei et al. 2020).

The in-situ gel-loaded nanoemulsion preparation can be used as an adequate and better alternative preparation than commercial eye drops, and it has exhibited higher permeation with a sustained-release drug profile. It can provide a prolonged therapeutic effect and improve patient compliance due to its less-frequent application and safety. In addition, the in-situ gelling polymer retains the drug for a longer period in the eye because it is not easily washed off or dissolved by tears (Pathak et al. 2013; Morsi et al. 2017). Several studies on nano-ocular preparations with in-situ gel-loaded nanoemulsion delivery systems are shown in Table 12.