Available online on 15.11.2021 at http://jddtonline.info

Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

Copyright  © 2021 The  Author(s): This is an open-access article distributed under the terms of the CC BY-NC 4.0 which permits unrestricted use, distribution, and reproduction in any medium for non-commercial use provided the original author and source are credited

Open Access  Full Text Article                                                                                                                                           Review Article 

Systematic Review on the Effectiveness of Strategies for Increasing Insulin Bioavailability in Oral Route Delivery Systems Based on Manufacturing Techniques and Materials Used

Krisna Adiva Puja , Ningrum Hendri Wahyu , Fimannuha Tamara Laily , Puspita Oktavia Eka* 

Department of Pharmacy, Faculty of Medicine, Brawijaya University, Malang 65145, East Java, Indonesia

INTRODUCTION

Diabetes is a non-communicable disease characterized by hyperglycemia due to impaired insulin secretion, insulin action, or both. Chronic hyperglycemia in diabetes can lead to failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels ¹. Globally, people with diabetes in 2019 are estimated at 9.3% (463 million people), increasing to 10.2% (578 million) in 2030 and 10.9% (700 million) in 2045 ². Meanwhile, in Indonesia, based on Basic Health Research data, people with diabetes increased from 6.9% in 2013 to 8.5% in 2018, so the estimated number of sufferers in Indonesia reaches more than 16 million people (Kemenkes RI, 2018)^2(a). All patients with type 1 diabetes and many patients with type 2 diabetes require insulin therapy to achieve reasonable glycemic control ³.

Insulin is the most effective way to lower blood glucose, allowing the body to maintain glucose within a normal range ⁴. Insulin is given by subcutaneous injection because it can be destroyed by stomach acid if given orally ³. However, daily insulin injections are considered ineffective because they cause pain at the injection site, are inconvenient, uncomfortable, and lead to low patient compliance ⁵. Therefore, many researchers have developed insulin administration via a convenient, non-invasive route such as the oral route. It is recognized as the most convenient and commonly used method of drug administration due to its ease of administration, high patient compliance, cost-effectiveness, minimum sterility constraints, and flexible dosage form design. However, low bioavailability is a significant challenge in designing oral dosage forms ⁶.

The bioavailability of a drug is the portion of the administered dose that reaches the systemic circulation ⁷. Oral bioavailability is influenced by several factors such as water solubility, drug permeability, dissolution rate, first-pass metabolism, pre-systemic metabolism, and susceptibility to efflux mechanisms ⁶. A drug must reach the desired drug concentration in the systemic circulation ⁸. Insulin has low oral bioavailability due to the degradation of proteolytic enzymes and lack of intrinsic permeability through the intestinal epithelium ⁹.

Several strategies have been carried out to develop insulin delivery systems via the oral route. Several reviews of articles related to the development of the oral route of insulin have also been carried out. A review of articles conducted by Singh et al. (2019) reported that oral route insulin bioavailability could be increased through encapsulation to insulin ¹⁰. In addition, Wong et al. (2021) reviewed articles on the characteristics of oral insulin preparation techniques and found that insulin bioavailability can be increased through various insulin preparation techniques used ¹¹. However, there has been no review of articles that analyze the best materials and techniques in the manufacture of insulin that can increase the bioavailability of oral insulin, so this is the background of this study. This study conducted a Systematic Literature Review to determine whether the manufacturing technique and material used to develop oral route insulin therapy can affect insulin bioavailability. The review results are expected to provide information about the best techniques and types of ingredients in increasing the bioavailability of oral insulin. In the future, the results of this study can be helpful to facilitate the development of oral insulin with the best results and quality. To achieve the research objectives, the results of this Systematic Literature Review must be able to answer the following research questions (RQ):

1. Can the manufacturing technique and the type of material used in the delivery system affect the bioavailability of oral insulin?
2. What are the best manufacturing techniques and types of ingredients to increase the bioavailability of oral insulin?

To answer the formulation of these questions requires relevant research results. Therefore, in this Systematic Literature Review, limitations are given to the criteria of the article, namely:

1. Inclusion Criteria (IC 1): Articles published in 2015-2021.
2. Inclusion Criteria (IC 2): The article on insulin research using the oral route is the original article.
3. Inclusion Criteria (IC 3): Articles written in English or Indonesian.
4. Inclusion Criteria (IC 4): Article on the results of an oral insulin study with parameters for measuring bioavailability (insulin levels in plasma and glucose levels in plasma) using in vivo research method.
5. Inclusion Criteria (IC 5): Insulin is formulated in the form of a nanomedicine delivery system (liposome, solid lipid nanoparticle, polymeric nanoparticle, inorganic nanoparticle, insulin emulsion, nanogels).

Thus, not all articles are used to answer this question. Articles that do not meet the data inclusion criteria or articles that contain data on insulin but have the following criteria will not be used to answer research questions. However, it is possible to use it as supporting data only. The article exclusion criteria are as follows:

METHODS

The study was conducted based on the Systematic Literature Review method used by Rowley & Slack (2004) and based on the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) protocol ^12,13 (Figure 1). The research was carried out in 5 stages, namely (a) scanning documents, (b) making documentation, (c) arranging Literature Review, (d) writing Literature Review, and (e) compiling a bibliography. Scanning documents is done by identifying keywords and articles that must be included in the Systematic Literature Review. Documentation is made by listing the references from which the articles were downloaded. Structuring the Literature Review is done by identifying the main themes and then sorting them to select articles. Writing literature according to the themes identified in the previous step was performed. The bibliography is compiled by including all sources referenced in the preparation of the Systematic Literature Review.

The article search begins with determining the combination of keywords that match the formulation of research questions to scan documents on a digital database. The combination of keywords used is insulin AND bioavailability AND “oral administration” OR “oral delivery system” AND liposome OR “solid lipid nanoparticle” OR “polymeric nanoparticle” OR “inorganic nanoparticle” OR “insulin emulsion” OR nanogels. 

Based on article searches that have been carried out through three digital databases, 1000 articles were obtained from Google Scholar, seven articles from Pubmed, and 800 articles from Crossref. The total number of articles obtained is 1807 article titles. The first stage is metadata or combining articles that have been obtained from the three sources in .xlsx format. The next step is initial screening, sorting the early stages of articles with the same title and publisher (duplicate screening). Duplicated articles from 1807 articles are 97 articles. The total number of the article after the duplication was removed was 1710 articles. Based on the screening results through the title and abstract of the article against the suitability of the inclusion and exclusion criteria, it was found that the number of articles that met the inclusion criteria was 77 articles. The results of the article assessment using the Checklist for Quasi-Experimental Studies (Non-Randomized Experimental Studies) from the Joanna Briggs Institute obtained articles that meet the assessment or are eligible are 76 articles.

A description of the article profile was carried out on the selected articles, including article title, author's name, year of publication, publisher, citation per year, manufacturing technique, type of delivery system, formula content, test method, bioavailability test parameters, as well as the resulting bioavailability to be extracted and stored in a format. .xlsx. Figure 2 shows the trend of article publication from year to year. 

Figure 1: Systematic Literature Review Process

Figure 2: Trend of the Number of Articles Each Year in the 2015-2021 Range

The types of delivery systems used vary, including polymeric nanoparticles and lipid nanoparticles. Each country's contribution to the publication of research on the development of oral insulin is shown in Figure 3. Countries were determined based on the authors' affiliation—the country with the highest number of studies in China, followed by India in the second position.

Figure 3: Country Profile of Research Site

All articles have been published in journals with Impact Factors showing that the journal is of high quality and contributes to the research field. Citation analysis is also used to determine the relevance between articles and how many articles are quoted. The citation of an article also shows that the article is of high quality. Table 1 shows the ranking of articles based on citation analysis.

Table 1: Articles by Number of Citations

RESULTS AND DISCUSSIONS

The complete summary results of the 76 selected articles can be seen in Supplementary File 1. Selected articles are classified based on the research questions that will be answered in this study, namely (1) the effect of the technique on increasing oral insulin bioavailability (RQ1), (2) the best manufacturing technique in increasing the bioavailability of oral insulin (RQ2), (3) the effect of the type of substance on increasing the bioavailability of oral insulin (RQ3), and (4) the best type of substance in increasing the bioavailability of oral insulin (RQ4).

Insulin is a high-molecular-weight protein that is highly hydrophilic, so it cannot cross the digestive tract properly due to many barriers. In order to work orally, insulin must pass through three main physiological barriers, namely 1) insulin must be able to withstand a very acidic gastric pH (pH = 1-3) and proteolytic enzymes that can degrade/denature insulin; 2) insulin must be able to penetrate the mucous layer that protects the intestinal epithelial surface, and 3) insulin must be able to pass through the intestinal epithelial cell layer to enter the systemic circulation ¹⁴. Therefore, insulin delivery systems must be designed effectively to protect insulin from obstacles in the digestive tract, biocompatible to maintain the conformational integrity of insulin to remain pharmacologically active, and able to load more insulin in the accurate concentrations that it can control insulin levels for optimal blood glucose ¹⁵.

The manufacturing technique is a factor that plays a role in efforts to increase the bioavailability of oral insulin. The manufacturing technique must pay attention to the physicochemical properties of insulin in order to maintain insulin stability until the end. Based on the review results, the technique used to manufacture an oral insulin delivery system can be seen in Table 2. The most widely used technique is double emulsion solvent evaporation, which is 18.42%. The hydrophilicity and hydrophobicity of the active substance are very important to determine the manufacturing technique used in the delivery system. The double emulsion technique [water in oil in water (w/o/w)], also known as emulsion, is a complex system in which the dispersed phase droplets consist of small dispersed phases. This technique is widely used to encapsulate proteins because it can protect against degradation due to acidic gastric pH and proteolytic enzymes in the small intestine. In addition, this technique can help drugs achieve sustained release, are biocompatible and biodegradable, and can encapsulate two types of hydrophilic and hydrophobic drugs separately and simultaneously. However, this technique has several disadvantages, including the need for high shear stresses and high-pressure homogenization so that the protein tends to denature and form aggregates due to the high shear force and the significant interface exposure between the aqueous and the organic phase. In addition, the resulting particles are relatively heterogeneous, the particle size is sensitive to various parameters of the manufacturing process, and this technique has not had excellent encapsulation efficiency ¹⁶. Like the research that has been done by Chen et al. (2019) resulted in an oral insulin bioavailability of 7.51%, which is still relatively low ¹⁷.

Several ingredients have been reported to increase oral insulin bioavailability, which can be seen in Table 2. Chitosan is the most widely used material in oral insulin delivery systems because it has nontoxic and biocompatible properties, can mediate the opening of tight junctions between epithelial cells reversibly, and can increase permeability via the paracellular pathway. The opening of tight junctions by chitosan is caused by the interaction between chitosan and integrin receptors on the cell membrane, which causes the conformation of integrin receptors which can then damage the tight junction area. The use of chitosan can also prevent nanoparticles from complicated intracellular transport and prevent the enzymatic degradation of insulin in lysosomes ¹⁸. Research conducted by Jafar & Hamid (2019) showed that the use of chitosan polymer could increase the bioavailability of oral insulin by 40.23% ¹⁵.

Based on the results of systematic studies that have been carried out, there are the best techniques and materials based on bioavailability parameters that can be recommended in the development of oral insulin routes. These findings are based on research by Guha et al. (2016) using a mesoporous silica nanoparticles (MSN) delivery system with a layer-by-layer technique coated with a polymer [poly (methacrylic acid-co-vinyl triethoxylsilane)] (PMV). PMV was obtained from the synthesis of methacrylic acid (MAA) and vinyl triethoxylsilane (VTES). PMV polymers are sensitive to pH values so that their release can be targeted in the intestine with the prolonged-release for 6 hours. PMV can protect insulin from the degradation of proteolytic enzymes and gastric acid environment. Encapsulation of insulin with PMV can help insulin cross the intestinal mucosa through paracellular and transcellular transport, then quickly absorbed by intestinal epithelial cells and directly reach the systemic circulation. The layer-by-layer technique is reported to produce a large nanoparticle surface area of 304.3921 m2/g and an adsorption pore width with a smaller dimension of 64.7844 nm to increase insulin absorption to obtain a significantly increased bioavailability of 73.10% ¹⁹.

Table 2: Comprehensive Summary of Oral Insulin Development Articles

CONCLUSION

Oral insulin faces various challenges in the gastrointestinal tract, such as insulin degradation by proteolytic enzymes at acidic gastric pH to lack of insulin permeability in intestinal epithelial cells. Various manufacturing techniques must be adapted to the physicochemical properties of insulin to maintain insulin stability so that it can provide an optimal therapeutic effect. The materials used in the manufacture of 

nanocarriers are very influential in increasing the bioavailability of oral insulin due to their effect in paving the way for insulin across various barriers in the digestive tract. Until now, from various studies of oral insulin that have been developed, it has succeeded in obtaining oral insulin bioavailability of 73.10% achieved by using a mesoporous silica nanoparticles (MSN) delivery system with a layer-by-layer technique coated with a polymer [poly (methacrylic acid-co-vinyl triethoxylsilane)] (PMV)].

SUGGESTIONS

Based on the results of this systematic review, it can then be used as a basis for the development of new oral insulin formulas for bioavailability testing through in vivo studies. Future studies are expected to overcome the three main barriers to oral insulin while having a greater insulin loading capacity to achieve higher bioavailability.

ACKNOWLEDGEMENT

The author would like to thank the Ministry of Education and Culture of the Republic of Indonesia for the funds provided in the 2021 Student Creativity Program activities and Brawijaya University for the facilities provided.

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