A REVIEW ON INFLAMMATORY BOWEL DISEASE-RECENT PHARMACEUTICAL APPROACHES TO COMBAT IT

A REVIEW ON INFLAMMATORY BOWEL DISEASE-RECENT PHARMACEUTICAL APPROACHES TO COMBAT IT

Nihar Ranjan Kar

Centurion University of Technology and Management, Rayagada - 765002, Odisha, India.

ABSTRACT: Inflammatory bowel diseases (IBD) are chronic and relapsing intestinal inflammatory conditions, hallmarked by a disturbance in the bidirectional interaction between gut and brain. IBD is Ulcerative colitis (UC) and Crohn‘s disease (CD). Conventional therapies are inadequate and are associated with several systemic side effects due to lack to localization of active moiety at the inflamed site. Treatment option range from small molecules to macromolecules (peptides, proteins and oligonucleotides) that target multiple therapeutic pathways, and dosed via injectable, oral or the rectal route for local bowel treatment. Conventional therapies are inadequate and are associated with several systemic side effects due to a lack of localization of active moiety at the inflamed site. But colonic drug targeting is a novel, potentially active area of research intended and focused on drug delivery for treating localized disease. Targeted drug delivery to the colon would ensure direct treatment at the disease site, lower dosing, and fewer systemic side effects.

IBD, UC, CD, Colon drug delivery system, Side effects

INTRODUCTION: Inflammatory bowel disease (IBD) is a persistent intestinal inflammatory disease with an unknown etiology. IBD is composed of two specific disease entities: Crohn‘s disorder (CD) and ulcerative colitis (UC). IBD has been idea to be idiopathic however has two fundamental attributable causes that include genetic and environmental factors. The gastrointestinal tract in which this ailment takes place is imperative to the immune system, and the innate and adaptive immune systems are balanced in complicated interactions with intestinal microbes underneath homeostatic conditions ¹.

However, in IBD, this homeostasis is disrupted, and out-of-control intestinal infection is perpetuated. Recently, the pathogenesis of IBD has ended up better understood attributable to advances in genetic and immunologic technology. Moreover, new therapeutic techniques at the moment are being carried out that appropriately target the pathogenesis of IBD. Beyond conventional immune suppressive therapy, the development of organic agents that concentrate on precise disease 2 mechanisms has resulted in extra common and deeper remission in IBD patients, with mucosal healing as a remedy goal of therapy².

Crohn’s Disease: Crohn‘s sickness can affect any part of the GI tract, from the mouth to the anus. It most typically impacts the end of the small intestine, where it joins the beginning of the colon. Crohn‘s disease may appear in patches affecting some areas of the GI tract at the same time as leaving other sections absolutely untouched. In crohn ailment, the inflammation may increase through the entire thickness of the bowel wall ³.

Ulcerative Colitis: Ulcerative colitis is restrained to the big intestine (colon) and the rectum. The inflammation occurs best in the innermost layer of the lining of the intestine. It normally begins in the rectum and decreases colon; however, it might also spread continuously to contain the entire colon ⁴.

Symptoms of IBD: The signs of IBD range from individual to man or woman and may alternate over time. The most common signs and symptoms for CD and UC are common and/or pressing bowel movements, diarrhea, bloody stool, stomachache, and cramping. People with IBD may also file signs and symptoms inclusive of fatigue, lack of appetite, and weight loss. IBD is characterized by times of active disease (flares), while symptoms are present, and instances of remission, while little or no signs are present ⁵.

Causes: The exact cause of IBD stays unknown. Researchers accept as true that an aggregate of four factors causes IBD: a genetic component, an environmental trigger, an imbalance of intestinal bacteria, and a beside-the-point response from the immune device. Immune cells normally defend the frame from infection, but in people with IBD, the immune device mistakes innocent materials inside the gut for foreign materials and launches an attack, ensuing in inflammation ⁶.

Diagnosis: The clinical signs and symptoms of IBD are well described. It is not unusual for sufferers with IBD to describe a protracted diagnostic manner that can take months or years. The key to avoiding such an event is to suspect IBD. Almost all patients with IBD have bowel symptoms (3-5), i.e., Stomach soreness or ache and/or trade of bowel habits (commonly diarrhoea). The substantial majority of patients with such signs and symptoms, however, could have irritable bowel syndrome (IBS) and require less aggressive investigation. The distinguishing features are alarm signs or signs, inclusive of rectal bleeding, weight loss, belly mass, fever, nocturnal signs, etc. ⁷

IBD Complications: In addition to the signs and symptoms of IBD described on the preceding pages, some people develop complications that may require urgent medical care ⁸.

Complications of Ulcerative Colitis Include: ⁹

• Heavy, persistent diarrhoea, rectal bleeding, and pain.
• Perforated bowel-chronic inflammation of the intestine may weaken the intestinal wall to such an extent that a hole develops
• Toxic mega colon-severe inflammation that leads to rapid enlargement of the colon

Complications of Crohn’s Disease Includes: ¹⁰

• Fistula - ulcers on the wall of the intestine that extend and cause a tunnel (fistula) to another part of the intestine, the skin or another organ.
• Stricture - an arrowing of a section of intestine caused by scarring, which can lead to an intestinal blockage.
• Abscess - a collection of pus, which can develop in the abdomen, pelvis, or around the anal area.
• Perforated bowel - chronic inflammation of the intestine may weaken the wall to such an extent that a hole develops.
• Malabsorption and malnutrition, including deficiency of vitamins and minerals.

• Complications outside the GI Tract: ^{11, 12}

• Not all complications of IBD are confined to the GI tract. For reasons that are not entirely understood, some people develop symptoms that are related to the disease but affect other parts of the body. The most common of these complications affect the skin and bones. These extra-intestinal complications may be evident in the:
• Eyes (redness, pain, and itchiness)
• Mouth (sores)
• Joints (swelling and pain)
• Skin (tender bumps, painful ulcerations, and other sores/rashes)
• Bones (osteoporosis)
• Kidney (stones)
• Liver (primary sclerosing cholangitis, hepatitis, and cirrhosis) - occurs rarely

Medical Treatment: There are five main categories of medications used to treat IBD:

Aminosalicylates: These are anti-inflammatory compounds that contain 5-aminosalicylic acid (5-ASA). Examples are sulfasalazine, balsalazide, mesalamine, and olsalazine. These drugs (given orally or rectally) act to decrease inflammation at the wall of the intestine. They are used primarily to treat ulcerative colitis, both to reduce symptoms and maintain remission, but may not be as effective in treating Crohn‘s disease ¹³.

Corticosteroids: These medicinal drugs, which consist of prednisone, prednisolone, and budesonide, affect the body‘s capability to start and maintain an inflammatory process. They preserve the immune system in check. They are powerful for short-time period management of flare-ups. They are not advocated for long-time period, or protection use due to their facet effects, which can include infection, bone loss, weight gain, cataracts, skin fragility, sleep disturbance, and temper swings ¹⁴.

Immunomodulators: This magnificence of medi-cations modifies the interest of the immune system so that it can't purpose ongoing inflammation. Examples consist of azathioprine, 6- mercapto-purine (6- MP), and methotrexate. These capsules are usually used to maintain remission in people who've not answered to other medications or who have most effective spoke back to steroids ¹⁵.

Antibiotics: The antibiotics ciprofloxacin and metronidazole have modest benefits for people with Crohn‘s disease that affects the colon or the area around the anus. They may be used when infections, such as abscesses, occur. There is no substantial scientific evidence to support the use of antibiotics in the treatment of ulcerative colitis ¹⁶.

Biological Therapies: These are the most recently developed treatments for IBD.  Biological therapies are indicated for people with moderately to severely active disease who have not responded well to conventional therapy. Four of these agents (adalimumab, certolizumabpegol, golimumab, and infliximab) target an inflammatory protein called tumor necrosis factor (TNF). Natalizumab and vedolizumab work by blocking certain types of white blood cells from getting into inflamed tissues ¹⁷.

Surgical Treatment: Medication might not correctly control symptoms for all people with IBD, and some human beings with these conditions develop headaches that require surgical operation. After 30 years of disease, up to a 3rd of humans with ulcerative colitis will require surgical operation. The standard surgical operation for ulcerative colitis is the elimination of the colon and rectum. Most patients who have surgical treatment for ulcerative colitis may have a technique known as an ileal pouch-anal anastomosis (IPAA) ¹⁸. In this system, after the whole colon and rectum is removed, the small intestine is hooked up to the anal area, growing a pouch to gather waste. This allows the affected person to pass stool through the anus. Some sufferers who undergo this technique develop complications, along with pouchitis (irritation of the pouch). Some sufferers will want an everlasting ileostomy, in which the fecal waste empties into an external bag attached to the affected person‘s abdomen.

About 70% of human beings with Crohn‘s disease eventually require surgical treatment ¹⁹. Different styles of surgical procedures can be performed for Crohn‘s disease, depending on the cause for surgical treatment, severity of illness, and vicinity of the disease in the intestines. Approximately 30% of sufferers who have a surgical operation for Crohn‘s disease experience recurrence of their signs within three years, and as much as 60% may have a recurrence within ten years ²⁰.

Drug Delivery Strategies for Management of IBD: An ideal drug delivery system for IBD should release the drug at the affected site of the gastrointestinal tract (GIT), preferably the colon, with localization and reduced dosing frequency. Moreover, it should delay the release of the drug in order to achieve the effective concentration required for local action ²¹.

Conventional Targeting Strategies: ²² Conventional strategies studied in the management of IBD rely on the controlled and sustained delivery systems. They basically take advantage of the GIT physiology, particularly the colon. The mechanisms used in these delivery systems can be either based on chemical modification using the prodrug approach or those based on formulation i.e., i) coating with pH-sensitive polymers, ii) Time Released systems, iii) Embedding in poly-saccharide matrices, and iv) Azopolymeric hydrogels.

Prodrug Approaches: Prodrug undergoes in-vivo biotransformation and releases the drug at the desired site. The covalent linkage between the drug and carrier is acted upon by the colonic enzymes, and the drug is bioavailable ²³. Various colonic enzymes are azoreductase, glycosidase, xylosidase, and nitroreductase, etc. Robust and stable series of colon targeting compounds can be generated by conjugation of drugs with cyclodextrins, amino acids, glucuronides, etc. Covalent azo linkages between 5- amino Salicylates (5-ASA) and carrier molecules are the most common prodrugs used in IBD ²⁴. Similar more prodrugs used in the management of IBD are cited in Table 1.

TABLE 1: PRODRUG USED IN IBD

Coating with pH-sensitive Polymers: The ileum and colon exhibit higher pH in the GIT. Dosage form that can collapse at this excessive pH range can be easily centered to colon and latter part of the ileum. Pharmaceutical enterprise has been the usage of this method to regulate dosage paperwork by movie coating pills and capsules with pH touchy biocompatible polymers ²⁵. Enteric coating movies dissolve at intestinal pH and thus hold the drug from the tough acidic pH in stomach 8, acidic bile and microbial degradation. In the process, an prolonged and behind schedule launch profile for the drug is discovered such that it is released only in the intestinal area and increases healing efficacy ²⁶. Commonly used enteric® polymers include derivatives of acrylic acids, co-polymers of methylacrylate (Eudragit), and cellulose polymers together with cellulose acetate trimellate and phthalate displaying a threshold pH within the variety 4.5 -7.0. The gadget has also been prolonged for preparing nanoparticles, microparticles, and pellets. Subsequently, this debris are crammed in tablets. Such delivery systems thus improve the efficacy with site-unique drug release ²⁷.

Time-Dependent Release Systems: Time-dependent launch systems launch pills at predefined time at the favored website of GIT. This technique is predicated on the GI transit time from mouth to colon. Usually, a lag time of 5 hours (h) is considered sufficient for colon delivery because the transit time for a small gut is set 34 h. The lag time relies upon the gastric motility and size of dosage form ²⁸. The dosage forms selectively release the drug either by using osmosis, swelling, or their combination and is unaffected via pH or microbial flora in the gut. Pulsincap^® tool is primarily based on this approach ²⁹. The tool basically has a non-disintegrating half of the tablet body. The open quit of the tablet is locked with a hydrogel plug and then covered with the water-soluble pill cap. The whole pill is then lined with an enteric polymer. Enteric coating avoids premature release in case of variable gastric emptying. On attaining the intestine, the enteric coat dissolves, and the hydrogel plug starts to swell ³⁰. The quantity of hydrogel is adjusted in such a way that it pops out best after the stipulated period of time, and the contents are released at unique web site. In another similar method, a hydrophobic cloth is coated upon the pill with the surfactant ³¹. The hydrophobic admixture retains the potential to rehydrate and re-disperse in aqueous environment in a time immediately proportional to the film thickness. Time clock containing diltiazem hydrochloride even though not available commercially, is a time-dependent launch mechanism with website online unique transport in inflamed ileum or colon ³².

Embedding in Polysaccharide Matrices: Most of the polysaccharides are stable in presence of the GI enzymes. However, they are degraded in colon due to bacterial flora ³³. Amylose, chitosan, chondroitin sulphate, cyclodextrins, dextrans, inulin, guar gum, pectin and locust bean gum, are among those polysaccharides known to be stable in proximal GIT, however, degrades in distal GIT by colonic bacterial flora. The drug is thus released exclusively in the colon. Derivatives of polysaccharides with improved properties, stability, and bioadhesion are being used lately ³⁴.

Azopolymeric Hydrogels: These pH-sensitive hydrogels contain acid side chains and azoaromatic cross-linker that are enzymatically degradable. At acidic pH, the hydrogels do not swell and hence exhibit minimum drug release ³⁵. However, in intestinal pH the hydrogel swells with slow release of the drug. The swelling of the hydrogels exposes the azolinkages to the enzymes. Cleavage of the azobonds releases the drug in colon. Polyanionic-hydrogels made of polyacrylic acids and linked with azo aromatic cross-linkers have been studied for colon targeting ³⁶. These hydrogels yield a minimum release of drug in the stomach. However, in alkaline pH, ionization of the carboxylic groups occurs and the hydrogel swells, exposing the azo cross-links to azoreductase present in colon ³⁷.

CODES^™: CODES^™ utilizes the combination of all approaches used in conventional targeting strategies i.e., pH, time, and bacterial flora ³⁸. The system essentially consists of a trilayered coated tablet with core drug and biodegradable polysaccharides. The drug-containing tablet core is coated with an acid-soluble polymer, viz. Eudragit E ³⁹. This is further coated with a polysaccharide such as lactulose and subsequently coated with an enteric polymer Eudragit L. Eudragit L protects the tablet from the stomach and immediately dissolves after gastric emptying. In colon region, the bacteria flora enzymatically degrade the polysaccharide (lactulose) into organic acid. This further lowers the pH and solubilizes acid-soluble coating ⁴⁰.

Pressure Controlled Drug Delivery System (PCDS): PCDS is based on the fact that the luminal pressure in colon is higher than that found in small intestine. PCDS bears the luminal pressure found in the small intestine but collapses in high colonic pressure ⁴¹. This results in drug release after 3-7 h of oral administration. PCDS are capsule-shaped suppositories coated with water-insoluble polymer ethyl cellulose. Upon oral administration, the suppository base liquefies, and ethyl cellulose forms balloon ⁴². PCDS are not subjected to higher luminal pressure as sufficient fluid content is available in proximal GIT. However, re-absorption of water in colon increases the viscosity of luminal contents resulting in increased intestinal pressure. The increased pressure and high-amplitude colonic peristalsis ruptures the PCDS and release the drug in colon. Some of the products based on this mechanism are available commercially ⁴³.

Osmotic Controlled Systems: This is a well-studied mechanism used for delayed or pulsed delivery. Osmotic gradient arises due to increased water diffusion into the osmotic layer. Drug and osmogen is directly compressed to form a core, and this core is coated with a semipermeable membrane bearing a hole to permit the entry of intestinal fluid ⁴⁴. This driving force results in the release of drugs through laser-drilled holes. This system is essentially controlled by the water diffusion rate into the system and hence shows a constant zero-order release. However, the entire system (OROS-CT) is further coated with an enteric coating so that the drug is not released in upper GIT ⁴⁵.

Multiparticulate Drug Delivery System: Single-unit delivery systems face varied challenges viz., unpredicted disintegration during GI transit with systemic side effects and a reduced bioavailability at the site of action. Systemic side effects of drugs used in IBD is of major concern ⁴⁶. Multiparticulate systems are known for controlled, sustained oral drug release with better chances of local targeting and increased stability in GI conditions due to encapsulation ⁴⁷. Particulate delivery systems show higher adhesion at the site of inflammation due to increased mucus production, enhanced permeability due to disease state, and particle uptake due to a number of immune cells. This phenomenon is found to be size-dependent. Generally, particles in the range of 5–15 μm have enhanced drug residence time in the colon with increased adhesion ⁴⁸. While some reports state that microparticles in a size range of 10– 300 μm target the inflamed tissue in IBD better. Encapsulation of drugs also prevents drug exposure to the P-glycoprotein efflux receptors and to mucosal metabolism, usually Cytochrome P450 3A ⁴⁹. These systems can also be combined with multiple approaches like pH and time. Local bioavailability of the drug thus increases. Multiparticulate systems thus perform better than single-unit systems in-vivo as they can easily spread along the length of the intestine. Thus multi-particulates result in less irritation and prolonged transit in the colon with reproducible release profile ⁵⁰.

Redox Sensitive Polymer Coating: Inflamed tissues in the case of IBD have higher levels of reactive oxygen species (ROS). Thus polymers containing thioketals sensitive to ROS can be used for coating dosage forms so that they get dissolved only in inflamed tissues51. Upon oral administration, the abnormally high levels of ROS will dissolve the polymer and provide site-specific delivery. Increased uptake of redox nanoparticles was also observed in ROS-treated epithelial colonic cells than those with reactive oxygen species untreated cells. A similar observation was seen in-vivo inflamed colon in colitis induced mice model ⁵². Indirectly the ROS decreased, and inflammation also subsided. The dose-response efficacy ousted the positive control 5-ASA. In another example, redox nanoparticles with nitroxide radicals in the core revealed high accumulation in colonic mucosa and cancer tissues ⁵³. Hence no toxicity was observed on long-term oral administration in mice. Nitroxide radicals effectively scavenged ROS and suppressed tumor growth. A combination of redox nanoparticles with irinote can further improve the therapeutic efficacy and suppressed the side effects ⁵⁴.

PHLORAL: PHLORAL is a hybrid pH/ microflora-activated technology developed by some of the investigators who had previously developed COLAL, where it seeks to improve the consistency and accuracy of delivery, as well as assure rapid release of contained drug ⁵⁵. COLAL relies on the controlled swelling of the amylose/ ethylcellulose coating which can be a slow process resulting in a sustained-release mechanism that is not well-suited to fast release in the colon, which leads to better targeting of the whole colon ⁵⁶. PHLORAL aims to resolve these aspects by virtue of a pH and/ or microflora-triggered system as an a-fail safe targeting mechanism. It can be manufactured using conventional pharmaceutical manufacturing equipment and is being applied to several products currently in clinical trials, including an advanced stage trial of a product for the treatment of IBD ⁵⁷. PHLORAL uses methacrylic acid–methyl methacrylate co-polymer (1:2), Eudragit S^™, as its pH-dependent soluble polymer, which starts to dissolve at pH 7.0, and it employs amylose or amylopectin as the microflora degraded polysaccharide. The mixed polymer/ polysaccharide film around a dosage form is applied using fluid bed coating from a solution/ dispersion prepared by mixing appropriate amounts of the amylose dispersion in an organic/aqueous solvent and the enteric polymer solution, to obtain a preferred polysaccharide: polymer ratio ⁵⁸. The optimum pH-dependent polymer: amylose ratio was found to be 7:3, which shows excellent resistance to in vitro drug release at pH 1.2 and pH 6.8 (for up to 12 h), but at pH 7.0 without enzymes or at pH 6.8 in the presence of α-amylase from Bacciluslicheni form, the drug release is initiated at around 3 h and is complete within 4-6 h ⁵⁹. PHLORAL has been verified as superior to purely pH-structured polymer systems in a have a look at in eight wholesome human topics ⁶⁰. Core tablets labeled with technetium-99m (99mTc, 4MBq) had been covered with the PHORAL coating and dosed in a randomized crossover protocol to the topics either fasted or fed (after a 392 kcal breakfast), or 30 minutes prior to the breakfast ⁶¹. Following ordinary meal times, lunch four hours submit dose and dinner 9 h publish dose, the release of the radioactive label from the dosage shape changed into measured in-vivo through γ-scintigraphy. In all cases (no matter feeding status), the label was launched at the goal site, both at the ileocecal junction, the ascending colon, the transverse colon or at the splenicor hepatic flexures ⁶². No dosage forms released any of the labels inside the belly or small intestine, and no dosage shape failed to launch the label in-vivo. This absolutely distinguishes this generation from the purely pH-dependent technologies generally used in setting up colon-centered therapies where, in some of the cases, dosage gadgets didn't release at al ^l63.

MMX^® Technology: A combined delayed-release/ extended-release tablet technology for the delivery of therapeutic agents to the whole colon has been developed, clinically validated in IBD and commercialized (for the glucocorticoid budesonide and the anti-inflammatory mesalazine) ⁶⁴. The technology is described as a multi-matrix structure. Hence MMX tablets consist of a dispersion of drug-containing lipidic granules in a hydrophilic matrix coated with enteric acrylic copolymers. The coating delays the release until the tablet arrives at the intestine, where the coating dissolves and the extended-release drug delivery begins ⁶⁵. Release over the length of the colon allows for the topical application of the drug to the whole bowel surface affected by inflammation ⁶⁶.  The tablet is made by combining drug, a lipophilic matrix-forming agent (for example, stearic acid, stearic acid/carnauba wax mixture or stearic acid/beeswax mixture), and an amphiphilic agent (for example, lecithin or diethylene glycol monomethyl ether), with a binder (low viscosity hydroxypropyl cellulose or povidone) to form granules ⁶⁷. These granules are blended with other non-functional excipients and the hydro-philic matrix-forming excipients (for example, hydroxypropyl cellulose, carbomer, alginate), and optionally additional active ingredient (dependent on dose and drug release profile desired), and tablets are compressed from this blend ⁶⁸. The tablets are then coated with enteric polymers, typically a mixture of methacrylic acid–methyl methacrylate copolymer (1:2) and methacrylic acid–methyl methacrylate copolymer (1:1) ⁶⁹. The innovators of this technology have successfully demonstrated the efficacy of infliximab (anti- TNFα) delivered topically (as an enema) to a very small number of human subjects as a treatment for IBD, and have completed an initial demonstration of the feasibility of incorporating the monoclonal antibody into MMX technology oral dosage forms ⁷⁰.

CONCLUSION: The ever-increasing alarming rate of IBD needs to develop new and sustained efforts in the design of delivery approaches in IBD. Numerous issues such as stability in GIT, bio-distribution, and reduced side-effects need to be addressed to prove their superiority over existing conventional therapies.

ACKNOWLEDGEMENT: Declared none.

CONFLICTS OF INTEREST: The authors declare no conflict of interest, financial or otherwise.

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    Kar NR: A review on inflammatory bowel disease-recent pharmaceutical approaches to combat it. Int J Pharm Sci & Res 2021; 12(7): 3593-01. doi: 10.13040/IJPSR.0975-8232.12(7).3593-01.

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