A Review on SEDDS for Ulcerative Colitis

Figure 2: Clinical manifestations of UC

3. RISK FACTORS FOR UC:

4. ULCERATIVE COLITIS:

Ulcerative Colitis is a kind of IBD (Inflammatory Bowel Disease). Immune systems reacting oddly to bacteria in the gut, again and again. These flare-ups strike the digestive tract without warning. Though both are long-term gut disorders, their patterns within the bowel lining aren’t identical. One spreads continuously. The other might skip sections.

1. Crohn’s disease

2. Ulcerative Colitis

The lining of the colon and the rectum become inflamed when someone has ulcerative colitis. Ulcerative colitis is an autoimmune disease in which the large intestine’s inner lining becomes inflamed and ulcerated. Even though ulcerative colitis may appear at any age, it often shows up between young adulthood and middle years. The gut tissue swells up, sometimes forming raw sores where healing fails.

Normal liver                    ulcerative liver

Figure 3: Normal liver and ulcerative liver

5. TYPES OF ULCERATIVE COLITIS

There are different types or classifications of ulcerative colitis dependent on the extent and location of the inflammation within the colon. The types of ulcerative colitis include:

1. Ulcerative proctitis

2. Proctosigmoiditis

3. Left-sided Colitis

4. Acute Severe Ulcerative Colitis

1. Ulcerative proctitis: One out of three people with UC deal with ulcerative proctitis. Inflammation shows up just in the rectum - the last part of the big intestine. Usually, it sticks to about 15 centimetres or less. This form doesn’t raise cancer chances.

• Symptoms:  It includes pain in your rectum, bleeding in your rectum, and a sudden need to go to poop, rectal bleeding, urgency.

2. Proctosigmoiditis:  In this type, inflammation spreads beyond the rectum and involves the sigmoid colon, which is the part of the colon right above the rectum.

• Symptoms: are abdominal cramps, bloody diarrhoea, and increased urgency to have bowel movements.

3. Left-sided colitis: Starting at the rectum and moving upward toward the splenic flexure - near the spleen - this form of UC may cause swelling. Inflammation happens here, especially in cases like proctosigmoiditis. That version targets the rectum along with the sigmoid colon, just above it.

• Symptoms:  Loss of appetite, weight loss, pain in belly or bloody diarrhoea

4. Extensive colitis (Pancolitis): This type of UC affects entire colon. Inflammation starts at rectum and goes beyond splenic flexure.

• Symptoms:

1. Diarrhoea (may or may not be bloody)

2. Blood, mucus or pus in your stool

3. Severe belly cramping

4. Fatigue (extreme tiredness)

5. Sudden weight loss

5. Acute Severe Ulcerative Colitis: This is a severe and potentially life-threatening form of UC that affects the entire colon and develops rapidly. It results in dehydration, severe pain, and a significant risk of complications.

• Symptoms:

1. Diarrhoea (may or may not be bloody)

2. Increased bowel movements or episodes of diarrhoea (four or fewer episodes daily)

3. Urgent bowel movements (sudden need to poop)

4. Tenesmus (feeling like you have to poop but being unable to)

5. Mild abdominal (belly) cramping or tenderness

6. Nausea [11]

6. PATHOPHYSIOLOGY OF ULCERATIVE COLITIS

There are both genetic and environmental factors that contribute to IBD, although there is still much to learn about the pathophysiology of ulcerative colitis. Some factors have been repeatedly assessed and shown to be crucial to the development and course of the condition. The primary contributing factors include: a dysregulated immunological response, a compromised epithelial barrier, alterations in the gut microbiome, genetic vulnerability, and the exposome.

6.1 Genetic Factors

There is a significant genetic component to UC. Individuals with a family history of IBD, particularly first-degree relatives with UC, exhibit an increased risk of developing the condition. Multiple genes have been implicated in the susceptibility to UC, including the NOD2/CARD15 gene and the interleukin genes (IL23R and IL10). Although a family history of IBD is present in approximately 25% of UC patients, most cases are sporadic [12]. Identified genetic associations include HLA-DQA1 variants, and genes involved in epithelial barrier integrity (CDH1, LAMB1), immune signalling (TNFRSF15, TNFRSF9, IL1R2, IL8RA/RB, IL7R), and others [13].

6.2 Dysregulation of the Immune System

One of the key elements in the pathogenesis of UC is an abnormal immune response. Normal gut bacteria are mistakenly perceived as foreign invaders, causing the intestinal lining to become chronically inflamed. Immune cells such as T-cells, B-cells, and macrophages infiltrate the gut lining and release pro-inflammatory cytokines. These cytokines are involved in the inflammatory process and further damage the intestinal tissue.

6.3 Intestinal Barrier Dysfunction

When ulcerative colitis is present, the gut wall weakens. Bacteria slip through cracks they normally cannot enter. Once inside, they trigger the immune system. Immune cells jump into action as a result, perpetuating the inflammatory cycle.

6.4 Gut Microbiome Dysbiosis

In healthy individuals, the gut microbiota is predominantly made up of four bacterial phyla — Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria — accounting for roughly 97% of the total. Firmicutes and Bacteroidetes alone represent about 90% of the entire microbial community. These dominant phyla produce short-chain fatty acids (SCFAs), especially butyrate and propionate, through the fermentation of dietary components like non-digestible fibres. SCFAs are vital for preserving intestinal balance and have been shown to regulate immune homeostasis [14].

When ulcerative colitis shows up, that balance shifts — harmful microbes grow more while helpful kinds fade, causing further inflammation. Probiotics appear to benefit individuals with UC mainly by influencing key signalling pathways — such as NF-κB, MAPK, TLR, JAK/STAT, Wnt/β-catenin, and TGF-β — alongside their well-known effects on gut microbiota composition [15].

6.5 Key Inflammatory Signalling Pathways

NF-κB Pathway: The NF-κB transcription factor plays a central role in driving inflammation and immune responses. Evidence indicates that probiotics help dampen intestinal inflammation in UC by suppressing NF-κB pathway activity [16,17].

NLRP3 Inflammasome: Pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) activate the NLRP3 inflammasome, leading to Caspase-1 activation and subsequent release of pro-inflammatory cytokines IL-1β and IL-18, contributing to colonic mucosal inflammation [18].

PI3K/Akt Pathway: In addition to controlling and releasing inflammatory factors, the PI3K/Akt signalling pathway can also indirectly activate the transcription factor NF-κB via phosphorylated IKK. TLR4 signalling triggers the PI3K/Akt signalling pathway and induces downstream mTOR activation [19-20].

The overview of inflammatory signalling pathways involved in UC

Figure 3: Pathophysiological mechanism of ulcerative colitis (UC).

1. The role of NF-κB pathway in Ulcerative Colitis

Figure 4:  Canonical and non-canonical NF-κB signaling pathways [21]

2. NF-κB  in Ulcerative colitis:

Curcumin- SEDDS – blocks IKKβ & p65 nuclear translocation entry

Budesonide-SEDDS- Induces IKBα-locks NF-kB

Quercetin-SEDDS- Blocks IKK+ IkB Stabilisation

Thymoquinone-SEDDS- Inhibits IkB Degradation & NF-kB DNA binding. SEDDS enhances its colonic retention and anti-inflammation potency. Blocks IkB Degradation

7. SELF EMULSIFYING AND SELF MICRO EMULSIFYING DRUG DELIVERY SYSTEM

7.1. Introduction

Oral administration remains the most widely preferred and convenient route of drug delivery. However, more than 40% of new drug candidates exhibit poor water solubility, which presents a significant challenge in oral drug delivery due to inadequate absorption, high intra- and inter-subject variability, and poor dose proportionality [24]. Various formulation strategies have been employed to overcome these limitations, including the use of surfactants, lipids, permeation enhancers, micronization, salt formation, cyclodextrins, nanoparticles, and solid dispersions [25].

Figure 5. Biopharmaceutics classification system

Solubility and permeability are the two fundamental parameters governing drug absorption following oral administration. The Biopharmaceutics Classification System (BCS), developed by Amidon et al. in 1995, classifies drugs into four categories based on these two parameters, as illustrated in Figure 1 [26,27]. Among the four BCS classes, Class II and Class IV drugs are particularly problematic due to their poor water solubility and low oral bioavailability. Consequently, enhancing the dissolution profile of BCS Class II and IV drugs remains one of the most critical challenges in pharmaceutical research.

Since dissolution is considered the rate-limiting step in the absorption of poorly water-soluble drugs [28], achieving efficient self-emulsification through ultra-low oil-water interfacial tension can significantly enhance drug bioavailability and ensure a more consistent and predictable absorption profile from the gastrointestinal tract.

7.1.1. Self-emulsifying drug delivery systems

SEDDS are defined as isotropic mixtures of solid or liquid surfactants, natural or synthetic oils, and/or one or more hydrophilic solvents and co surfactants/solvents [29]. Once more, as previously mentioned, they dilute the drug in the system (aqueous media), such as GI fluids, with mild agitation, forming fine oil-in-water (o/w) emulsions (0.1-100μm) or microemulsions (10-300 nm), which spread easily into the GIT where the movement of the stomach and intestinal fluid provides agitation, creating a self-emulsified system [30].

7.1.2. Properties of SEDDS

• They have the ability to quickly self-emulsify in gastrointestinal fluids and produce a fine o/w emulsion when gently agitated by peristalsis and other gastrointestinal tract movements.
• They are able to successfully add drugs, whether hydrophilic or hydrophobic, to the combination of oil surfactants.
• They are applicable to both liquid and solid dose forms.
• Compared to standard dosage forms, they require a lesser dose of medication.

7.1.3. Advantages associated with SEDDS

• Drug protection from the GIT environment.
• Drug targeting that is specific to a certain GIT absorption window.
• Increased oral bioavailability.
• Consistent medication absorption profile. 
• More effective management of drug delivery characteristics.
• The dosage form's versatility allows it to be utilized with both liquids and solids.
• Predictable treatment because food effects are less variable.
• Drug payloads are substantial.

• Sensitive pharmacological substances are protected.

Table: 1: It shows lipid formulation classification

8. EXCIPIENTS USED IN SEDDS FORMULATION

Self-emulsifying drug delivery systems are made using a lot of excipients. Although co-surfactants can also be utilized, oil and surfactant are essential ingredients. The kind of dose form controls the use of various excipients in SEDDS. SEDDS of different medications have been formulated using a variety of oils, including natural, synthetic, and semi-synthetic. Table 1 lists a few instances of the oils utilized in the commercial products. Table 2 lists the oils utilized in the formulation of SEDDS with various medications.

1. Oils:

Table 2: Type of oils used in marketed SEDDS

Table 3: Type of oils used with different drugs in SEDDS

2. Surfactants

Table 4: Type of surfactants used in marketed SEDDS

Table 5: Type of surfactants used with different drugs in SEDDS

3. Co solvents/Co-surfactants:

Table 6: Type of Co surfactants used in marketed SEDDS

4. Drugs              

Examples: Naproxen, Carbamazepine, Danazol, Ketoconazole, Nifedipine, vitamin E, simvastatin, and mefanimic acid Finasteride

9. SOLID SELF EMULSIFYING DRUG DELIVERY SYSTEM (S--SEDDS)

Although SEDDS are available in both liquid and solid dose forms, solid SEDDS are typically favoured over liquid SEDDS due to their superior stability and simplicity of handling and transportation. A variety of different solid SEDDS, including pellets, microspheres, tablets, beads, implants, and suppositories, have recently been developed.

Table 7. Comparison of SEDDS, SMEDDS, and SNEDDS [33,34].

Table 8: Marketed Preparations of SEDDS.