Alternative Colon Targeted Drug Delivery Approaches for the Treatment of Inflammatory Bowel Disease

 

Prabhat Jain*, Geeta Parkhe

Scan Research Laboratories, Sector A H No. 109, J K Road, Indrapuri, Bhopal, MP 462023.

 

ABSTRACT:

The main purpose of any drug delivery system is to supply a therapeutic amount of drug to a target site in a body, so that the necessary drug concentration can be achieved quickly and then maintained. Targeted drug delivery implies discerning and effective localization of drug into the target at therapeutic concentrations with limited admittance to non-target sites. A targeted drug delivery system is favoured in drugs having low solubility, instability, short half-life, large volume of distribution, reduced absorption, low specificity and low therapeutic index. Targeted drug delivery may afford maximum therapeutic activity by preventing degradation or inactivation of drug during transfer to the target site. Occurrence of inflammatory bowel diseases has enlarged at an alarming rate. The treatment and extent of therapy is determined by the sternness of the circumstances. Conventional therapies are insufficient and are connected with several systemic side effects because of lack to localization of active moiety at the irritated site.  Colon targeted drug delivery is an vigorous area of research for local diseases affecting the colon, as it improves the competence of therapeutics and enables restricted treatment, which reduces universal toxicity. Targeted delivery of therapeutics to the colon is mainly advantageous for the treatment of inflammatory bowel disease (IBD) is a chronic autoimmune disease, which includes ulcerative colitis and Crohn's disease is considered by chronic relapsing inflammation of the gastrointestinal tract. Advances in oral drug delivery plan have considerably enhanced the bioavailability of drugs to the colon; though in order for a drug to have therapeutic efficiency during disease, considerations have to be made for the altered physiology of the gastrointestinal (GI) tract that is connected with GI inflammation. The current review discusses the novel and the latest planned approaches of colonic drug targeting exclusively concentrating the drug at inflamed site and thereby achieving successful treatment routine.

 

 

 

INTRODUCTION:

Inflammatory bowel disease (IBD) is an idiopathic, relapsing disease regarding chronic inflammation of the digestive tract, both in part or entire. The colonic surroundings can be explored for local and systemic release of drugs and other bioactive compounds such as hormones, insulin, vasopressin and other plant ingredients. The colon is the major area of the GIT.

 

The regular colonic disease such as diverticular inflammatory bowel disease (IBD) which includes Crohn’s disease (CD) and ulcerative colitis (UC) among a high prevalence rate in the developed world, among North America noting the maximum frequency of people suffering with CD.¹ Incidence of IBD is from 30 to 70 per100, 000 people for CD and 18-31 per 100,000 for UC and is rising at an alarming rate. Even though, adults are the most regularly diagnosed ones, reports show an important population of paediatric is also being diagnosed with IBD.² In past decades the common pathophysiology of IBD was described on the basis of clinical symptom. The investigators and clinicians are struggled to supply the efficient therapy for IBD due to its dismaying scientific symptom. The causes of IBD is multi factorial and may be resulted from unsuitable activation of mucosal immune system, inflammatory responses, generic factors, candidate genes, chromosome location etc., The transferable organism such as Escherichia coli, measles virus, cytomegalo virus and factor like saturated fats, milk products, allergic foods may also be the cause of the IBD. Common pathophysiology of ulcerative colitis and Crohn’s disease is restricted to large intestine often inflammation and ulcers occurs in the inner lining of the large intestine or in mucosal layer. The UC resulting in diarrhea, blood and pus. CD otherwise called regional enteritis. It involves any part of the GIT from mouth to anus with the inflammation extending by the bowel wall to the serosal outside. Together the diseases used to have waxing and waning intensity and severity.^3-5 CD and UC considerably differ from each. The treatment methods are common to together the diseases. Many more intestinal manifestations are shared by each the diseases occur in adults and youngsters. The sign and symptoms of UC involves diarrhea with the presence of blood and mucus, weight loss, belly ache, painful bowel movements, belly cramps and extra intestinal signs like arthritic knees can be found in children. The pathophysiology of UC confirmed an expanded quantity of colonic sulfate decreasing micro-organism. This can be because of the end result of better awareness of hydrogen sulfide poisonous gasoline. Some reports counseled that sulfur containing pork, alcohol intake additionally improved the disease relapsing in sufferers in remission. UC has no regarded cause and it is treated as autoimmune ailment. The exact etiology of IBD remains unknown.⁶ There is not any remedy for IBD. Therapeutic objectives are aimed in enhancing the patient’s satisfactory of existence by preserving remission, predicting, preventing and treating complications, restoring nutritional deficits, presenting appropriate psychosocial aid and modifying the course in the ones people with competitive disease.⁷ Treatment of IBD majorly consists of anti inflammatory capsules, antibiotics, biologic dealers, immunosuppressants or those for symptomatic relief only.⁷ Commonly, one-of-a-kind paradigms for IBD treatment are followed. The “step-up” paradigm starts first of all with milder pills i.e. Aminosalicylates, immunomodulators (corticosteroids) followed through surgical operation or biologics while step-down, follows the vice versa.⁸ Novel drug transport systems are very successful in the remedy of colonic diseases.  Colon targeted drug delivery system (CTDDS) is not simplest the proper for handing over the drug to the colon for nearby treatment however it's also a most appropriate method for transport of protein and peptide and enhance their bioavailability.⁹ Bioavailability of protein and peptide may be attained if it may be restrained from acid and enzymes within the belly and higher intestine and launched and absorbed inside the colon and defend it from degradation in belly.¹⁰ Degradation of such drug in stomach can be keep away from through using some polymer both alone or in a mixture due to the fact polymer affect the rate of release and absorption of medication and play a crucial position in formulation of CTDDS.¹¹ This assessment particularly focus on targeted drug transport to the colon is extraordinarily desirable for nearby treatment of IBD and distinctive methods for the healing control of IBD encompassing traditional and novel targeting techniques.

 

ANATOMY AND PHYSIOLOGY OF COLON:

The large intestine enlarges from the ileocaecal junction to the anus which is divided into three fundamental components colon, rectum and anal canal. The colon represents caecum, ascending colon, hepatic flexture, transverse colon, splenic flexture, descending colon and sigmoid colon (Fig. 1). The normal length of colon is 1.5 m long; the transverse colon is the longest and most cell component and has a median diameter of approximately 6.5 cm. The wall of colon is along with 4 layers namely the serosa, the muscularisexterna, the submucosa and the mucosa. The serosa is the outside coat of the huge intestine. The muscularisexterna is the principle muscular coat of the massive gut which composed of an inner circular layer of fibers surrounding the bowel and of an outer longitudinal layer. The submucosa is the layer of connective tissue lies right now underneath the mucosa lining the lumen of the colon. The mucosa has 3 components epithelium, lamina propria and muscularis mucosae. Superior mesenteric artery supplies blood to the proximal colon and the inferior mesenteric artery components blood to distal colon.¹²

 

Figure 1 Colon

(Source: http://cisnet.cancer.gov/projections/colorectal/screening.php)

 

Advantages of colon targeting drug delivery system:

·       Colon has fewer peptidase activity so peptides, insulin, oral vaccines, growth hormones can be delivered from this route.

·       Colon is a perfect site for the delivery of agents to treat the local disease of the colon

·       Necessary small drug quantities due to locality targeting.

·       Reduces dosage frequency hence lower cost of expensive drugs.

·       Probable leading to a condensed incidence of side effects and drug interactions.

·       The colon is an attractive site where weakly absorbed drug molecules may have an enhanced bioavailability.

·       Reduce gastric irritation caused by a lot of drugs like NSAIDS.

·       Bypass original first pass metabolism.

·       Comprehensive daytime or night time activity.

·       Improve patient compliance.

·       It has a longer retention time and appears highly responsive to agents that improve the absorption of weakly absorbed drug.¹³

 

Disadvantages of colonic drug delivery:

·       There are variations among individuals with esteem to the pH level in the small intestine and colon which may permit drug release at undesired site. The model of drug release may vary from person to person which may cause ineffective therapy.

·       The pH level in the small intestine and caecum are alike which reduces site specificity of formulation.

·       The major disadvantage of colonic delivery of drug is meagre site specificity.

·       Diet and diseases can affect colonic microflora which can pessimistically affect drug targeting to colon. Nature of food present in GIT can influence drug pharmacokinetics. In diseased circumstances pH level of GIT differs from pH level of healthy volunteers which alters the targeted discharge of formulations which release the drug according to pH of needed site.

·       Enzymatic degradation may be extremely slow which can cause interruption in polymer degradation and thus alters the discharge profile of drugs.

·       Substantial variation in gastric retention time may cause drug discharge at the undesired site in case of time dependent colonic drug delivery system.¹⁴

 

Factors affecting drug absorption from colon:

The colon precise drug delivery primarily precious by two physiological factors, these are pH level and the passage time. The other factors which need to be measured are as follows.¹⁵

1.     Physical characteristic of drug (pka, degree of ionization),

2.     Colonic residence time as detected by gastrointestinal tract motility,

3.     Degradation by bacterial enzymes and by products,

4.     Selective and non-selective bindings to the mucus,

5.     Local physiological actions of drug,

6.     Disease state,

7.   Use of chemical absorption enhancers.

Inter- and intra-challenge variations in gastrointestinal tract pH are stated. Diet, diseased nation and meals consumption influence the pH of the gastrointestinal fluid.^15,16 The average pH values in distinctive place of human GI tract are given in Table 1. One of the essential determinants of absorption of compound from colon is home of formulation in a few particular a part of the colon. The transit time within the small gut is suggested to be pretty steady than the belly and colon. The size of the debris influences the colon transit when dosage paperwork reaches the colon. Small debris surpasses through the colonic location greater slowly than the bigger unit, then again for larger single unit density and size of has no real effect on colonic transit. It has been shown that pellets move faster than the capsules through the ascending colon. So pellets are more favourable than tablets. Table 2 indicates the transit time of stable method in one-of-a-kind region of GI tract.

 

Table 1 Average pH in the GI tract^{14, 16}

 

Table 2 The transit time of dosage forms in GI tract ^{15, 17}

 

GENERAL PATHOPHYSIOLOGY OF IBD:

The pathophysiology of IBD is yet to be uncovered. The IBD is still beneath active research for its reason. The commonplace pathway is the infection of the mucosal lining of the intestinal tract, which causes ulceration, edema, bleeding associated with fluid and electrolyte loss. The researches were aggressive to perceive the gene involved in starting of IBD. The early linkage discovered become on chromosome 16 (IBD 1 gene). The identification of IBD 1 gene publications to the identification of NOD2 gene also called as CARD 15 which became declared as the first gene virtually connected with IBD. This gene additionally has the susceptibility to CD. Studies additionally identified the susceptibility genes on chromosome 5 and 6 (5Q31, 6P21, 19P). CARD 15 is a polymorphic gene worried within the instinctive immune machine, which show 60 specific differences. Three of those variations performed a essential role in IBD development. This way that those genes allowing the IBD to occur, but not a causative source. The predominant factor to be considered here is a presence of genes does no longer increase the ailment, however can also permit the disorder to occur¹⁸ (Fig. 2).

 

Fig. 2 Inflammatory bowel diseases

Source: https://www.hopkinsmedicine.org/inflammatory_bowel_disease_center

 

DIAGNOSIS AND ENDOSCOPY:

H and E biopsy of colonic tissue commonly showing the crypts. Abscess is a hallmark for UC. The initial blood diagnostic assessments entails blood remember test for the estimation of anemia, thrombocytosis, excessive platelet depend, the renal characteristic test, take a look at for persistent diarrhea associated with hypokalemia, hypomagnesemia, liver characteristic take a look at, primary sclerosing cholangitis, X ray, urine evaluation also used as a diagnostic device to study UC. Endoscopy is the nice to be had device to diagnose for UC. The endoscopy reveals the lack of vascular look of the colon and additionally identifies erythema and damaged mucosa, superficial ulceration and pseudopolyps in the colon.¹⁸

 

TREATMENT METHODS FOR IBD AND ITS LIMITATIONS:

Treatment normally based totally on statements of medical records, physical parameters endoscopy, radiology, histology and normal laboratory tests. The take a look at on those reports offers the clean concept approximately IBD and additionally distinguishes the UC and CD, but it's far very hard to differentiate UC and CD in at the least 10% of the populace for them IBD is restricted to the colon.^19,20 Long time supervision of IBD includes the drug therapy and way of life control. Most of the present-day retailers act by using down regulating persistent inflammation inside the intestinal mucosa and cannot cure the ailment. Thus, the safety and discount of remission is still the main aim of the therapy. The remedy of CD and UC are comparable even though now not always identical. Conventional drugs for the remedy of IBD include aminosalicylates, corticosteroids, antibiotics and immunosuppressive agents. Aminosalicylates are the maximum normally used anti-inflammatory tablets to treat moderate to mild energetic CD or UC and to preserve remission.²¹ Administrated orally, rectally or intravenously, corticosteroids are powerful in sufferers with lively CD or UC. Their mighty immunosuppressive outcomes encompass non particular outcomes on the humoral and cellular immune function in addition to extra specific effects on the advent of cytokines and inflammatory mediators.²¹ Antibiotics, especially metronidazole and ciprofloxacine were used to set off remission of CD however are ineffective in UC.^22,23 Another goal is the cytokine imbalance which is also gambling a position within the pathogenesis of the ailment. Several anti-inflammatory cytokines like IL-10, IL-11 and anti- IL-12antibodies, have proved their performance in experimental fashions and clinical research.^24-26 Finally, gene remedy might be a thrilling approach for the IBD-remedy: Intraperitoneal pretreatment of experimental colitis in rats with a recombinant Ad5 vector encoding interleukin-10 prevented colitis.²⁷

 

DRUG DELIVERY STRATEGIES FOR MANAGEMENT OF IBD:

A ideal drug delivery system for IBD should discharge the drug at the affected site of GIT preferably colon with localization and condensed dosing frequency. Moreover, it must delay the discharge of drug in order to attain effective concentration necessary for local action.

 

Conventional targeting strategies:

Conventional strategies studied in the management of IBD rely on the guarded and sustained delivery systems. They essentially take the advantage of the GIT physiology, mostly the colon.²⁸ The mechanisms used in these delivery systems can be both based on chemical modification using the prodrug approach or those based on formulation.

i)   Coating with pH sensitive polymers,

ii) Time Released systems,

iii) Embedding in polysaccharide matrices and

iv) Azopolymeric hydrogels.

 

The approaches are depicted in Fig 3

 

Fig. 3 Conventional delivery approaches in IBD via oral route²⁹

 

Prodrug approaches:

Prodrug undergoes in vivo biotransformation and releases the drug at the required site. The covalent linkage among the drug and carrier is acted upon by the colonic enzymes and drug is bioavailable. A variety of colonic enzymes are azoreductase,³⁰ glycosidase,³¹ xylosidase and nitroreductasev,³² etc. Vigorous and stable series of colon targeting compounds can be generated by conjugation of drugs with cyclodextrins, aminoacids, glucuronides etc. Covalent azo linkages between 5- aminoSalicylates (5-ASA) and carrier molecules are most common prodrugs used in IBD.³³

 

Coating with pH-sensitive polymers:

The ileum and colon exhibit better pH within the GIT.³⁴ Dosage form that may disintegrate at these excessive pH degrees may be in reality focused to colon and latter part of ileum. Pharmaceutical industry has been the usage of this approach to adjust dosage paperwork through film coating drugs and capsules with pH -sensitive biocompatible polymers. Enteric coating films dissolve at intestinal pH and as a result guard the drug from the tough acidic pH in belly, acidic bile and microbial degradation. In this method, an extended and delayed release profile for the drug is located such that it's far launched best within the intestinal location and raise therapeutic efficacy. Commonly used enteric polymers include derivatives of acrylic acids, co-polymers of methylacrylate (Eudragit) and cellulose polymers which include cellulose acetate trimellate and phthalate showing a threshold pH in the range 4.5 -7.0.³³ The system has also been extended for preparing nanoparticles, microparticles and pellets. Subsequently these particles are crammed in pills. Such delivery systems therefore improve the efficacy with site specific drug discharge.³⁵

 

Time dependent release systems:

Time dependent release systems discharge drugs at predefined time at the specified site of GIT^[35]. This method is predicated at the GI transit time from mouth to colon. Usually a lag time of 5 hours (h) is considered enough for colon transport because the transit time for small gut is ready 3-4 h. The lag time is dependent upon the gastric motility and size of dosage form. The dosage paperwork selectively releases the drug either with the aid of osmosis, swelling or their aggregate and is unaltered by way of pH or microbial vegetation inside the intestine. Pulsincap device is based totally on this technique. In another similar technique, a hydrophobic cloth is lined upon the pill with the surfactant. The hydrophobic admixture holds the capability to rehydrate and re-disperse in aqueous environment in a time at once comparative to the film thickness. TIME CLOCK is containing diltiazem hydrochloride even though no longer to be had commercially is a time dependent launch mechanism with site precise shipping in inflamed ileum or colon.³⁶

 

 

Embedding in polysaccharide matrices:

Most of the polysaccharides are constant in presence of the GI enzymes. However, they may be besmirched 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 regarded to be stable in proximal GIT, however mortify in distal GIT by way of colonic bacterial plants and the drug is therefore released exclusively within the colon. Derivatives of polysaccharides with stepped forward residences, stability and bioadhesion are getting used recently.^37,38

 

Azopolymeric hydrogels:

These pH- sensitive hydrogels enclose acid aspect chains and azo aromatic cross-linker that are enzymatically degradable. At acidic pH, the hydrogels do now not swell and therefore exhibit minimal drug discharge. However, in intestinal pH the hydrogel swells with slow discharge of drug. Swelling of the hydrogels exposes the azo linkages to the enzymes. Cleavage of the azo bonds releases the drug in colon.³⁹ Polyanionic hydrogels made from polyacrylic acids and linked with azo aromatic cross linkers were studied for colon concentrated on. These hydrogels yield minimal launch of drug in the belly. However in alkaline pH ionization of the carboxylic businesses happens and the hydrogel swells exposing the azo cross-links to azo reductase found in colon.⁴⁰

 

CODES ™:

CODESTM exploits the mixture of all approaches used in conventional targeting strategies i.e. pH, time and bacterial flora. The system in essence consists of a trilayered coated tablet with core drug and recyclable polysaccharides (Fig 4). The drug containing tablet core is covered with an acid soluble polymer, viz. Eudragit E. This is extra coated with polysaccharide such as lactulose and then coated with an enteric polymer Eudragit L. Eudragit L protects the tablet from stomach and right away dissolves after gastric emptying. In colon area, the bacteria flora enzymatically disgraces the polysaccharide (lactulose) into organic acid. This additional lowers the pH and solubilizes acid soluble coating.⁴¹

 

 

Fig. 4 Mechanisms of CODES™ ²⁸

Novel Strategies:

Conventional targeting approaches discussed above though are planned accurate to target the colon, but the differences in their specificity and discharge profile is not yet definite. Some of the delivery systems constantly release the drug throughout the GIT. Thus these systems show compressed drug accessibility in the colon and probability of systemic adverse effects increases. Development of novel drug delivery systems with exact targeting and release of drug in colon is thus extremely important. Localization of drug would thus raise in inflamed intestinal tissues with improved therapeutic efficacy and condensed adverse effects.²⁹

 

Pressure controlled drug delivery system:

PCDS is based on the fact that the luminal pressure in colon is eminent than that found in small intestine. PCDS bears the luminal pressure establish in small intestine but collapses in high colonic pressure. These results in drug release after 3-7 h of oral administration.³⁵ PCDS are capsule shaped suppositories coated with water insoluble polymer ethyl cellulose. Upon oral administration, the suppository base liquefies and ethyl cellulose forms balloon. PCDS are not subjected to higher luminal pressure as sufficient fluid content is available in proximal GIT. On the other hand, re-absorption of water in colon increases the viscosity of luminal contents resulting in increased intestinal pressure. The enlarged pressure and high-amplitude colonic peristalsis ruptures the PCDS and releases the drug in colon.²⁸

 

Osmotic controlled systems:

This is a well deliberate mechanism used for deferred or pulsed delivery. Osmotic gradient occurs due to improved water diffusion into osmotic layer. Drug and osmogen is directly compressed to form a core and this core is covered with a semi permeable membrane bearing a hole to allow the entry of intestinal fluid. This driving strength results in discharge of drug through laser drilled holes. This system is in essence controlled by the water diffusion rate into the system and hence shows a steady zero order release. However the entire system (OROS-CT) is additional coated with enteric coating so that drug is not released in upper GIT.

 

Multiparticulate drug delivery system:

Single-unit delivery systems face with varied challenges viz., unpredicted disintegration during GI transport with systemic side effects and reduced bioavailability at site of action. ⁴¹ Systemic side effects of drugs used in IBD is of major disquiet. Multiparticulate systems are known for inhibited, continued oral drug discharge with better chances of local targeting and improved stability in GI conditions due to encapsulation.⁴² Particulate delivery systems explain higher adhesion at the site of inflammation due to enlarged mucus production, improved permeability due to disease state and particle uptake due to a number of immune cells. This occurrence is found to be size dependent. Multiparticulate systems thus perform recovered than single unit systems in vivo as they can simply spread along the length of the intestine. Thus multiparticulates result in less irritation and long-lasting transit in the colon with reproducible release profile.⁴³

 

Redox sensitive polymer coating:

Inflamed tissues in case of IBD have superior levels of reactive oxygen species (ROS). Thus polymers containing thioketals sensitive to ROS can be used for covering dosage forms so that they get dissolved only in reddened tissues. Upon oral administration the abnormal high levels of ROS will liquefy the polymer and provide site precise delivery.⁴¹

 

FUTURE PROSPECTS:

Lectin- Carbohydrate targeting:

Lectins are identified for epithelial adhesion due to their sugar binding proteins.³⁵ Lectins get particularly bound to glycolipids or glycoproteins expressed on cell surface membranes of the intestinal mucosa^[44]. They also cause cell incursion via receptor-associated endocytosis, resulting into gathering of drugs in specific M-cells and sub-cellular organelles like lysosomes. Inflammation of colon changes the glycoconjugate appearance pattern.⁴⁵

 

Nutraceuticals:

IBD patients have unfair biodiversity with poor gut microflora and enlarged fungal proportion especially those with CD. Consumption of probiotics such as non-pathogenic E. colinissle, bifidobacteria, Lactobacilli supply valuable belongings like anti-inflammatory, anti-diarrhoea/constipation, anti-microbial and immunomodulation. Inflammatory mediators and proinflammatoy cytokines are down synchronized. E.coli strain nis- Sle1917 has been proved to be as effective as mesalazine (5-ASA) in remission of UC during inhibited trials.⁴¹

 

Bacteria attached nanoparticles:

Immune response increases due to propagation of lymphocytes and macrophages in IBD. Bacteria containing nanoparticles would be simply phagocytosed by these cells. Nanoparticles loaded with anti-inflammatory agents or immune suppressants and close to bacteria would decrease the immunological activity upon phagocytosis of bacteria attached nanoparticle. Bacteria attached to nanoparticles permit specific targeting to immune cells specifically over-expressed in reddened colon tissues. Though the studies are in primitive stage.³⁵

 

 

 

Macrophages:

In difference to the above-mentioned approach macrophages loaded with nanoparticulates ex vivo via phagocytosis can be re-injected into systemic transmission. These macrophages would then be taken to deliver anti-inflammatory agents or immunosuppressive agents. Macrophages by default would be concerned to the site of inflammation. ³⁵

 

CONCLUSION:

The always-increasing shocking rate of IBD requests development of new and continued efforts in design of delivery approaches in IBD. Various issues such as stability in GIT, bio-distribution and reduced side-effects require to be addressed to verify their superiority over existing conventional therapies.

 

CONFLICT OF INTEREST STATEMENT:

The authors declare no conflict of interest in this review article.

 

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Received on 04.12.2019           Modified on 14.02.2020

Accepted on 13.04.2020         © RJPT All right reserved