Pathogenesis of IBD:

IBD is recurring inflammatory condition and chronic condition affects the ileum, colon, or both, and may have connections to systemic symptoms. Although its exact cause is unknown, it seems to involve an immune response influenced by various factors. The main types of IBD are Ulcerative colitis (UC) and Crohn’s disease (CD)¹⁸. These two diseases have unique causes, symptoms, levels of inflammation and gut microbiota composition. Crohn’s disease (CD), the inflammation is intermittent and penetrate in the submucosal areas which can occur to the digestive tract. Ulcerative colitis (UC), inflammation affects only the surface layer of the intestinal lining and is restricted to the region of gut dense bacterial presence, starting at the distal colon and extending upward through the large intestine¹⁹.

Fig no.1 Pathogenesis of IBD²⁰

IBD has genetic element, where the risk of a child developing the condition is higher if one parent has it. Several genes linked to IBD susceptibility, including IL23R, IR12B, STAT3, JAK2 and TYK2 are associated with the interleukin (IL)-23 pathway and are involved in the development of Ulcerative colitis (UC) and Crohn’s disease²¹.

Crohn’s disease (CD) and Ulcerative colitis (UC) both involve overactive immune responses, impacting both innate (e.g., macrophages, neutrophils) and adaptive (e.g., Tand B cells) immune systems. In healthy individuals, immune tolerance to gut microbiota is regulated by various immune cells, including regulatory T cells, B cells, natural killer T cells and dendritic cells, which produce key cytokines and factors like transforming growth factor (TGF)-β, interleukin (IL)-10, interferon (IFN)-α/β and prostaglandin J2. Studies suggest that tumor necrosis factor (TNF) and IL- 12 p40 are crucial in the pathogenesis of Crohn’s disease, whereas T cells are implicated in ulcerative colitis, as evidence by the effectiveness of therapies targeting T cell activity. CD is primarily associated with Th1 and Th17 immune responses, leading to an increase in IL-12, IL-23, IL-27, IFN- and TNF-α. In contrast, UC is linked to a Th immune response, characterized by higher levels of IL-5 and TGF-β^22-23.

Several environmental factors, including diet, smoking, stress, use of medications, appendectomy, hygiene and microbial exposure, can influence the development of inflammatory bowel disease (IBD). Specific microorganisms such as Mycobacterium paratuberculosis, Listeria monocytogenes, Chlamydia trachomatis, Escherichia coli, Cytomegalovirus and Saccharomyces cerevisiae have been proposed as potential contributors to the disease. A Western-style diet, characterized by low fibre intake and high levels of sugar and animal fats, is also considered a potential risk factor for IBD development. Additionally, the composition of the gut microbiota plays a critical role in the onset and progression of IBD^24-25.

Microbes in the digestive system plays a significant role in the development of inflammation. The gut microbiota is essential for maintaining intestinal health. In healthy individuals, the microbiota and the host share a mutually beneficial relationship. The microbes carry out various vital functions, including metabolic processes, protecting the mucus barrier to prevent pathogen invasion, enhancing the integrity of the epithelial layer, and modulating immune responses. These actions help in preserving gut homeostasis and preventing excessive inflammation²⁶.

Ulcerative colitis (UC) is typically marked by the formation of ulcers in the inner lining of the large intestine, often affecting both the proximal colon and the rectum. The condition most commonly impacts the ileocecal region of the digestive tract²⁷. In ulcerative colitis (UC), the risk of developing colorectal cancer is elevated, increased risk is a significant concern for affected individuals²⁸. Ulcerative colitis (UC) can lead to complications such as fistulas, abscesses, bowel narrowing (stenosis), rectal urgency, tenesmus and abnormal lymphoid tissue growth. In contrast, Crohn’s disease (CD) is a chronic inflammatory condition that can affect any part of the digestive tract. Early symptoms of CD often include abdominal pain, fever and diarrhoea containing blood and mucus. In contrast, ulcerative colitis (UC) can be classified into different types depending on the areas of the colon affected, including ulcerative proctitis, pancolitis and proctosigmoiditis^29-30.

Figure no.2 Ulcerative colitis

Figure no.3 Crohn’s disease

Treatment of IBD:

Until the 1930s, effective therapies for inflammatory bowel diseases (IBD) were virtually non-existent. Knowledge about these conditions during the early 20^th century was limited, mirroring the lack of treatment option available at the time. A significant breakthrough came with Nanna Swartz’s development of Sulfasalazine marking the beginning of pharmacological intervention in IBD.

By the 1990s, the landscape of IBD treatment expanded with the introduction of various therapeutic classes, including glucocorticoids and immunomodulators, now referred to as “conventional therapies”. This evolution paved the way for monoclonal antibodies, which had been previously utilized for other medical conditions, such as rheumatologic and oncologic diseases. The initial class of biological therapies, TNF-alpha antagonists (anti-TNF), was quickly followed by integrin antagonists (anti-integrins) and “biological therapies.”

In the 2010s, advances in synthetic technologies led to the development of “small molecules,” demonstrating efficacy through Janus Kinase inhibitors and sphingosine-1-phosphate modulators. These innovations have significantly enriched the therapeutic arsenal against IBD³⁰.

Amino salicylates (5-ASA): 5-ASA works by inhibiting the production of prostaglandins and leukotrienes, while also exerting beneficial effects on the inflammation. When taken orally, 5-ASA is primarily active in the intestine and is rapidly absorbed in upper small intestine, which necessitates its formulation for delayed absorption. Amino-salicylates for IBD includes sulfasalazine, mesalamine, olsalazine and balsalazide^2,31,33.

Corticosteroids: Corticosteroids have been used for IBD treatment since the 1950s and can effectively induce remission when a flare occurs. High doses of corticosteroids are effective in managing acute flare-ups of various types of IBD when other treatments fail to provide adequate relief. However, they are not recommended for long-term maintenance therapy. Drugs such as methylprednisolone, hydrocortisone, budesonide are there in corticosteroids.

Immunomodulators:

Immunomodulators are important for patient with IBD and mainly include cyclosporine, azathioprine, methotrexate, 6-mercaptopurine and tacrolimus.

Biologics:

Biologic primarily consists of inhibitors targeting pro-inflammatory cytokines and integrin antagonists. Inflammatory cytokines TNF-α and IL-12/23 are crucial in the development of IBD. Anti-TNF medications include Certolizumab, Infliximab, golimumab and adalimumab are antibodies to tumor necrosis factor (TNF). Anti-integrin therapy: Drugs include vedolizumab, natalizumab, ustekinumab, risankizumab, etrolizumab.

Small molecule agents:

Medications with a molecular weight under 1 kilodalton. These agents, which are either in use or under development for treatment, are taken orally and lack the immunogenic properties seen with monoclonal antibodies. Drug include tofacitinib, upadacitinib, ozanimod.

Antibiotics:

Antibiotics may emerge as a promising treatment option for IBD due to their potential effects on the composition of the intestinal microbiota. Antibiotics are beneficial in managing Crohn’s disease but their effectiveness is limited in ulcerative colitis, except in cases of toxic colitis^32-35.

Probiotics:

Probiotics are living microorganism offers health benefits when ingested or applied topically. They can assist in reducing apoptosis of epithelial cells and mitigate inflammation in the intestinal mucosa. Various non-pathogenic microorganisms such as commensal Saccharomyces, Escherichia coli and Lactobacillus species are often used as probiotics and may help prevent pouchitis. However, their other potential therapeutic roles remain to be fully established. Additionally, therapeutic use of the parasite Trichuris suis has been explored as a means to enhanced immunity of T2-helper cell, potentially reducing activity of disease in ulcerative colitis^36-37.

Routes of administration for IBD:

Inflammatory bowel disease treatment typically involves combination of medication, surgery and fecal microbiota transplantation. While surgery can provide relief, it doesn’t always eliminate the condition, as many patients experience recurrences that can further compromise their quality of life and lead to additional intestinal damage³⁸. Fecal microbiota transplantation has shown promise, yet challenges remain regarding the prevention of pathogen introduction and the need for improved safety and standardization^39-41.

Drug therapy for IBD predominantly employs oral, intravenous and enema routes. Intravenous administration is particularly beneficial for moderately to severely active cases, as it enhances drug bioavailability and minimizes first-pass metabolism and gastrointestinal irritation. However, it may also lead to systemic toxicity and requires stringent standards for physicochemical properties of formulations.

Rectal administration offers a practical option for mild to moderate IBD, effectively bypassing first-pass metabolism. Nonetheless, it faces challenges such as lower patient adherence, shorter retention times and limited reach within the intestines. Consequently, oral therapies are often favoured due to their high compliance rates among patients.

Oral controlled-release drug delivery systems (CDDS) are engineered to enhance drug availability in the colon while limiting absorption in other parts of the gastrointestinal tract, thereby improving overall distribution throughout the body. This approach shows promise for the effective and safe treatment of IBD^40-41.

Rectal Suppository for IBD Treatment:

Rectal route for IBD treatment is efficient alternative to oral administration. A suppository bypasses issues related to oral administration, such as the first-pass metabolism and the degradation of drugs by stomach enzymes⁵³. Suppositories are preferred over enemas as they deliver the medication directly to the rectum or the adjacent sigmoid colon. They are commonly used as the primary treatment to initiate and maintain remission in inflammatory bowel disease (IBD)⁵⁴.

Suppositories treatment in IBD:

Mesalamine (5-ASA):

Mesalamine suppositories are effective in treating patients with IBD, particularly when the rectum is affected, as well as for those with solitary rectal ulcer syndrome. The best outcomes are observed in patient with distal ulcerative colitis, who account for about 50% of our ulcerative colitis cases. These patients typically experience significant symptom relief within days. By the 6^th week mark, most achieve complete normalization of symptoms along with improved sigmoidoscopic findings and restoration of normal histology. Various formulations are available, including 250mg, 400mg, 500mg and 1000mg, depending on the country. Suppositories are generally well-tolerated and retained, particularly overnight, even in cases of acute distal proctitis and no significant side effects have been reported⁵⁵.

Corticosteroids:

Current guidelines recommended locally administered corticosteroids for patient who do not respond to mesalamine suppositories. It is important to note that rectal corticosteroids lead to remission in approximately 46% of cases and may have potential systemic side effects, including suppression of the hypothalamic-pituitary-adrenal axis. Common topical corticosteroids formulations include budesonide and betamethasone, with variations depending on regional preferences. Budesonide suppositories offer an alternative treatment to mesalamine for the local treatment of ulcerative proctitis⁵⁴.

Tacrolimus:

Tacrolimus suppositories are primarily used for treating ulcerative proctitis, especially when standard treatments such as topical mesalamine and corticosteroids are ineffective. They are regarded as a safe and effective option for patients with treatment-resistant proctitis. Research suggest that tacrolimus can be valuable alternative for individual who do not respond to 5-ASA medications^56-58.

Acetarsol:

Acetarsol is a pentavalent arsenic compound derived from organic arsenic. Introduced as a treatment for proctitis in 1965, acetarsol suppositories were evaluated in randomized, double-blind study by Cornell et al., which included 44 patients with idiopathic proctitis. The participants were divided into two groups: 21 patients received 5mg prednisolone suppositories, and 23 patients received 250mg acetarsol suppositories, both administered twice a week for three weeks. Follow-up evaluations included sigmoidoscopy for 20 patients from each group. The study found that 19 patients (82.6%) in the acetarsol group and 17 patients (80.9%) in the prednisolone group showed endoscopic improvement. Acetarsol suppositories are effective in treating refractory ulcerative proctitis⁵⁴.

Formulation Consideration for Rectal Suppository:

Characteristics of Suppository Base:

1. After reaching equilibrium consistency, most ingredients melt at room temperature, which is 36℃. However, bases with a wider melting range can be used to create eutectic combinations and to add oils, balsams and supplements meant to be used in tropical areas.

2. When applied to delicate or irritated tissues, the base has no adverse effects and is totally harmless.

3. It works well with many different medications.

4. No metastable forms exist for it.

5. Mold lubricants are not necessary because it shrinks sufficiently upon cooling to come free from the mold.

6. There is no sensitization.

7. Its characteristics include wetting and emulsifying.

Types of Suppository Base:

A suppository base is a solid dosage form that is intended to be inserted into the local or systemic absorption when the suppository base melts, dissolves, or softens after being injected. Because it affects medication release, absorption and stability, base selection is crucial.

Cocoa butter (Theobroma oil):

It is extremely emollient, naturally occurring and melts at body temperature. However, the end product may become unstable due to its polymorphism (presence in different crystalline forms⁵⁹. In addition to cocoa butter, there are several other hydrophobic bases known, including Kuva-500, Kuva-300, GHM-3T, GHM-5T, Supporin-M, Butyrol, Salomas and Novata⁶⁰.

The fats are available in different grades with differing melting points, hydroxyl values and other physicochemical properties. Some commercially available semi-synthetic fatty suppositories bases include hard fats such as Massa Estarinum®, Massupol®, Suppocire® and Witepsol®⁵³.

Hydrophilic suppository base:

Glycerinated Base: Rather than melting at body temperature, these substances dissolve in the bodily fluids of the cavity where they are placed⁵⁹. Glycerol- gelatin-based suppositories possess a soft, flexible texture making them well suitable for vaginal use. Rather than melting, they gradually dissolve in the vaginal mucus⁶⁰.

Polyethylene glycol (PEG): These do not melt but do dissolve in bodily fluids. Because PEG bases have flexible melting points, they can be made to fit certain requirement⁵⁹. PEGs with molecular weights ranging from 200 and 600 liquids, while those with molecular weights above 1000 are solid and have wax like consistency⁵³. PEG bases for suppositories often include additional ingredients like surfactants. Two namely used bases are Polybase and PEGblend both of which are blends of polyethylene glycols combined with the emulsifier polysorbate 80⁶⁰.

Surfactants:

Surfactants plays a crucial role in enhancing the release of drugs from suppository bases and improving the overall formulation properties⁶¹. Common surfactants used in suppository formulations include polyoxyethylene sorbitan fatty acid esters (Tween), polyoxyethylene stearates (Myrj) and sorbitan fatty acid esters (Span and Arlacel)⁵³. Polaxamer is non-ionic surfactant used as suppository base to formulate liquid suppository^10-62.

Method of Preparation:

Hand Molding:

The most straightforward and traditional technique for creating suppositories is hand molding. This process involves blending a suppository base with active ingredients, which is first grated and then kneaded using a mortar and pestle until the mixture reaches the plastic consistency. Active ingredients can be finely powdered, dissolved in water, or mixed with a small amount of wool fat to help incorporate them into the base. The mixture is then molded into cylindrical rods of the desired size or into vaginal balls with specific weight. To avoid sticking, starch or talcum powder is applied to the surfaces used for rolling and to the hands. The rods are subsequently cut into portions, with one end tapered. This process is efficient and economical for producing small batches of suppositories.

Compression Molding:

To achieve a more uniform and visually appealing suppository, compression molding can be used. This process involves compressing a cold-grated mixture into the desired shape using a hand-operated device, where a piston applies pressure to the mass inside a cylinder, pushing it into a mold (typically holding three molds at once). Cold compression offers a cleaner, more refined finish than hand molding and helps prevent the settling of insoluble solids in the base. However, it may not be efficient for large-scale production. A potential issue with cold compression in fat-based suppositories is the risk of air entrapment, which can affect weight accuracy and may lead to oxidation of both the base and active ingredients.

Pour Molding:

The pour molding method is the most commonly used technique for manufacturing suppositories, whether in small or large quantities. The process begins by melting the base material, ideally using a water or steam bath to prevent overheating. The active ingredients are then either emulsified or suspended in the melted base. Once combined, the mixture is poured into pre-cooled metal molds, typically made from chrome or nickel, to shape the final suppository.

New Approaches Double Casting Technique:

To ensure a uniform mixture of the drug and base, a specific amount of drug is combined with a quantity of base that is not enough to completely fill the mold cavities. This mixture is poured into the molds, partially filling each cavity. The remaining space is then filled with the melted base. After cooling, the suppositories are removed, mixed again and recast to achieve an even distribution of the active ingredient⁵⁹.

Challenges and Limitations:

While rectal suppositories offer targeted and effective treatment for Inflammatory Bowel Disease particularly for conditions affecting the distal colon and rectum, their use is not without challenges. Several factors can limit their effectiveness and patient adherence.

Many patients face challenges with rectal suppositories due to discomfort and embarrassment associated with their use, as the process involves inserting a suppository into the rectum, which can be particularly difficult for those sensitive about such procedures. Additionally, the frequency of use sometimes requiring multiple applications per day can be inconvenient and further discourage adherence to treatment. Since consistent use is essential for effective disease management, failure to follow the prescribed regimen can lead to worsened symptoms and increased risk of disease flare-ups. Rectal suppositories are most effective for treating inflammation limited to the rectum or lower colon, making them unsuitable for patients with more widespread colonic or small bowel involvement, such as in advanced Crohn's disease. In these cases, alternative treatments, including oral medications, biologics, or systemic therapies, are necessary to manage the disease effectively^44-45.

Recent Advances:

While nanoparticle-based approaches hold significant potential for locally targeting therapy and modulating immune response in IBD. These advanced delivery systems are designed to enhance the efficacy and safety of anti- inflammatory and immunomodulatory agents when administered via suppository. By focusing on localized treatment, these innovative strategies aim to optimize therapeutic outcomes while minimizing systemic side effects⁶³.

Novel delivery systems could improve the effectiveness of tropical tacrolimus. For instance, Seoane-Viano and his co-workers brings innovative self-supporting suppositories of tacrolimus through semisolid extrusion 3D printing. In their follow-up study, they assessed the efficacy of these suppositories in a rodent model of colitis, comparing the result to control animals that received no treatment. This research highlighted the potential benefit of this delivery method, but it did not include comparisons with other interventions or alternative delivery systems⁶⁴.

CONCLUSION:

In conclusion, rectal suppositories offer a targeted and effective treatment for Inflammatory Bowel Disease, particularly for conditions affecting the distal colon and rectum. They provide a practical alternative to oral administration, bypassing issues like first-pass metabolism and the breakdown of active ingredients by stomach enzymes and are most effective for treating inflammation limited to rectum or lower colon. Recent advances in nanoparticle-based approaches aim to enhance the efficacy and safety of anti-inflammatory and immunomodulatory agents when administered via suppository, further optimizing therapeutic outcomes while minimizing systemic side effects.

CONFLICT OF INTEREST:

The authors have no conflicts of interest.

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Received on 06.01.2025 Revised on 10.03.2025

Accepted on 16.04.2025 Published on 08.07.2025

Available online from July 12, 2025

Asian J. Pharm. Tech. 2025; 15(3):261-270.

DOI: 10.52711/2231-5713.2025.00040

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

Drug	Drug Category	Formulation	Excipients	Treatment	Reference
Naproxen	NSAID	Rectal Suppository	Witepsol H15 and Witepsol W35, PEG 2000, PEG 400, PEG 6000, Sodium lauryl sulphate, tween 80, cetylpyridinum chloride	Rheumatic	6
Pentobarbital	Barbiturates	Rectal Suppository	Witepsol W25, oleic acid	Sedatives	7
Artesunate	Anti-malarial	Rectal Suppository	PEG 3350, PEG 1000, Kolliphor P470	Malaria	8
Tolmetin	NSAID	Rectal Suppository	Poloxamer 407 and 188, Methylcellulose, Propylene glycol, PEG 1000, 40000 and 6000, PVP, Witepsol H25, H75 and H15, Tween 80, HPMC, Ethyl chloride, Suppocire A, Soft and hard paraffin	Muco-skeletal Disorders	9
Levosulpiride	Antipsychotic	Rectal Suppository	Poloxamer 407 and 188, Tween 80, Water	Depression	10
Lopinavir	Protease inhibitors	Rectal Suppository	Eudragit RSPO, Pluronic F 127, PEG 3350 and 1500, fattibase	HIV	11
Tramadol HCL	Opioid	Rectal Suppository	PEG 1000,4000,6000, PVP, Beeswax, HPMC, Cocoa butter, methyl paraben, propyl paraben	Pain relief	12
Verapamil	Ca channel blockers	Rectal Suppository	PEG, Witepsol W15, Suppocire, PEG 1500 and 6000	Hypertension	13
Allopurinol	Xanthine oxidase inhibitors.	Rectal Suppository	PEG 4000 and 1000, Suppocire, β-cyclodextrin, sodium salicylate, urea,	Hyperuricemia	14
Furosemide	Diuretics	Rectal Suppository	Witepsol W 15 and W35, Suppocire AML and AP, Massa estarinum B and Massa estarinum BC, Cremophor RH 60, Montanox 60 DF, Solutol HS 15	Oliguria, Oedemas	15
Palcitaxel	Antimicrotubule agents	Vaginal Suppository	PEG 6000, Tween 80, Span 85, Gelucire, Dichloromethane.	Cervical cancer	16
Clotrimazole	Anti-microbial agents	Vaginal Suppository	Lyophilized culture of Lactobacillus, lactic acid bacillus spores	Vaginal cancer	17

Active drug	Route of administration	Formulation	Excipients	Reference
Mesalamine	Oral	Tablet	Eudragite S 100, Cellulose acetate Phthalate, Tween 80, methanol, water, Eudragite RS Eudragite L, Lactose, Dextrose, Talc, Magnesium Stearate, Starch past	42
Dexamethasone	Oral	Tablet	HPMC, Dexamethasone, Eudragite S 100, HPMC	43
udesonide	Oral	Tablet	Poloxamer P188, Croscarmellose sodium (CCS), PVP K30 Sodium Starch Glycolate (SSG) and Dibutyl phthalate (DBP) and Lactose monohydrate	44
Mesalamine	Rectal	Suppository	Polyethylene glycol (PEG 6000), Cocoa butter, Hard Paraffin, Liquid Paraffin, Gelatin, Glycerine, Tween 80, Methyl paraben	45
Mesalamine	Rectal	Foam	Carbopol 974P, Castor oil, Isopentane Dihydrophosphoric acid sodium salt, Sorbitan monolaurate polysorbate 80, Eudragit L100, Eudragit FS 30	46
Budesonide	Rectal	Enema	2,4,6-trinitrobenzenesulfonic acid, sodium azide, dimethyl sulfoxide, 1,4-Dithiothreitol, phosphate buffered saline, lipopolysaccharide, Polyvinylpyrrolidone K30 (PVP)	47
Mesalamine	Rectal	Hydrogel	Collagen, acetic acid, Deionised water, Dextran sodium sulphate	48-49
Hydrocortisone	Oral	Suspension	Leaves of Eryngium foetidum, Manilkara zapota, Murraya koenigii, ethanol	50-51
Azathioprine	Oral	Tablet	Sterculia gum powder, anhydrous lactose, citric acid, magnesium stearate, potassium dihydrogen phosphate, disodium hydrogen phosphate, Eudragit RLPO, Eudragit L 100, Chitosan, PEG 400 and talc	52