University of Groningen
Targeting the ileo-colonic region in inflammatory bowel disease
Gareb, Bahez
DOI:
10.33612/diss.155874434
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Publication date: 2021
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Gareb, B. (2021). Targeting the ileo-colonic region in inflammatory bowel disease. University of Groningen. https://doi.org/10.33612/diss.155874434
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General discussion
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General discussion and perspectives
The inflammation in inflammatory bowel disease (IBD) is predominantly localized in the gastrointestinal tract (GIT), although extraintestinal disease manifestations may be observed [1–3]. If the inflammation is limited to the GIT, oral therapy is by far the most preferred route of administration for drugs. Far less preferred routes of administration are subcutaneous injections, intravenous infusions, and rectal drug administration (enemas and suppositories). Treatment options using these unpreferred routes of administration result in lower patient compliance, which is associated with therapy failure [4–6]. Additionally, systemic exposure and drug-related adverse events limit the safety, efficacy, and feasibility of IBD treatments. Collectively these data suggest that oral treatment aimed to maximize the site-specific effects of the drug whilst minimizing systemic and drug-related adverse events hold great potential in the treatment of IBD. However, several challenges related to this approach remain.
First, not all drugs used in the clinical treatment of IBD are appropriate candidates for oral therapy. For instance, highly efficacious therapy consists of therapeutic proteins such as antibodies. These drug candidates degrade upon oral administration under the gastric conditions [7,8]. Moreover, different formulation strategies should be used for biologicals or macromolecules compared to smaller chemical entities in order to realize a stable oral dosage form. The formulation process-induced stresses associated with compounding proteins or macromolecules into tablets may hamper formulation feasibility. Another challenge is the oral drug targeting to specific sites in the GIT since most drug targeting technologies utilize time-dependent release profiles or depend on physiological parameters, which may result in unreproducible drug release profiles. Finally, the release profile of the targeted drug should be well defined and the performance of the dosage form should be robust and reliable in order to achieve the treatment goal. Realizing the desired in vitro release profile is an objective per se, although the greatest challenge is reproducibly realizing the desired release profile in vivo [9–11].
Depending on the IBD severity and type, oral mesalazine or budesonide are effective treatment options in IBD [12,13]. Both drugs are cheap and characterized by topic activity, few systemic side effects, and a good tolerability. Non-responders to either mesalazine or budesonide are generally switched to a combination of oral and rectal therapy or other therapies with systemic effects [12,13]. The former is inconvenient whereas the latter is associated with a greater incidence of side effects. It is therefore important that during diagnosis not only the site of inflammation is characterized, but the topical therapies are also effectively targeted to these sites. However, earlier published in vitro [11,14,15] as well as clinical data [16–19] suggest that none of the commercially available mesalazine and budesonide formulations effectively target the delivery of the drugs to the entire ileo-colonic region in IBD. Furthermore these mesalazine and budesonide formulations do
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not have similar release profiles. This means that combining two commercially available oral formulations containing mesalazine and budesonide will not result in ileo-colonic targeting and the treatment of the same inflamed region by both drugs.
In chapter 2 we developed an ileo-colonic targeted formulation that contained a combination of mesalazine and budesonide. The formulation contained the effective and recommended dose of both compounds [12,13]. We hypothesized that a combination of mesalazine and budesonide with the drug delivery targeted to the ileo-colonic region may be more efficacious than either of the drugs alone, induces a potent site-specific anti-inflammatory effect while minimizing the systemic side effects, and improve patient compliance. Furthermore, if this combination proofs to be effective, it may keep IBD patients on topically active drugs instead of switching these patients to systemically active drugs.
Major challenges of this approach were the targeting of both drugs to the desired site and subsequently realizing similar mesalazine and budesonide release profiles since not only the solubility, but also the dose of both compounds differs significantly. The in vitro results showed that both drugs were targeted to the simulated ileo-colonic region and that the release profiles were similar. We opted for a zero-order release profile so that the content of the formulation is released gradually during ileo-colonic transit.
Since this objective was realized in an in vitro model, the therapeutic efficacy as well as pharmacokinetics (PK) should be confirmed in a clinical trial. The PK analysis should give insight into the in vivo release behavior of the drugs. Furthermore, these studies should relate the efficacy and adverse events to the place in therapy of ileo-colonic IBD. Although studies show that a combination of glucocorticosteroid and aminosalicylate may be more efficacious than either one of the drugs [20–22], it should be investigated whether the combination is effective enough to keep patients on oral topical therapy instead of switching these patients to systemic therapy. An appropriately designed trial should investigate whether the treatment of IBD with the combination preparation is as effective as switching patients that failed monotherapy with budesonide or mesalazine to systemic therapy.
Based on our technical evaluation of the commercially available oral budesonide formulations [16–18], none was considered optimally suited for the treatment of ileo-colonic IBD. Earlier published clinical data [16–19] as well as our own in vitro experiments in chapter 2 and chapter 3 supported this notion. Therefore, we developed ileo-colonic-targeted budesonide formulations that contained a dose of 3 mg or 9 mg in view of increasing the therapeutic efficacy of budesonide in ileo-colonic IBD. The doses were based on the recommended doses by international guidelines [12,13]. Furthermore, we developed two formulations with different doses in view of flexible dosage regimens and the tapering of budesonide after the induction of remission. In chapter 3 we showed that the formulation was targeted to the simulated ileo-colonic region with a release profile characterized by zero-order release kinetics. We opted for a zero-order release profile so that the content of the formulation is released gradually during ileo-colonic transit.
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As with the combination formulation we developed in chapter 2, the efficacy, safety, and PK of the budesonide formulations should be investigated in a clinical trial. Ideally, an appropriately designed clinical trial should investigate the efficacy compared to the currently used budesonide products prescribed for the treatment of ileo-colonic IBD. Furthermore, a clinical trial investigating the efficacy of the novel formulation in left-sided colitis compared to enema treatment should determine whether rectal treatment may for some patient be substituted by oral therapy.
In IBD anti-tumor necrosis factor-alpha (anti-TNF-α) therapy is currently administered systemically as an intravenous infusion or subcutaneous injection. This results in the systemic inhibition of TNF-α whereas the elevated levels of TNF-α are generally localized at the inflamed sites of the GIT [23–29]. Furthermore, studies show that the efficacy of anti-TNF-α is correlated with the tissue concentrations in the GIT as opposed to serum levels alone [29–31]. In chapter 4 we reviewed the available medical literature on localized TNF-α inhibition in IBD. The three objectives were to investigate whether this approach is effective, feasible, and whether the targeted therapy is able to penetrate into the inflamed sites in the GIT.
Most clinical studies discussed in chapter 4 were limited in design as well as sample size. However, several studies showed that local TNF-α inhibition resulted in a clinically favorable and relevant response. This approach showed to be effective even when patients did not respond to conventional therapy or systemically administered anti-TNF-α therapy. Most studies used an invasive method of administration such as (endoscopy-guided) injections of the biologicals in the inflamed regions or anal fistulae. Although this approach is patient unfriendly, an advantage of this approach is the administration of an effective dose to a targeted area. The effects seen in the clinical studies with oral targeted therapy were less unambiguously. Oral targeted anti-TNF-α therapy cannot be compared to local injections since the orally administered drug needs to penetrate into the inflamed sites to become effective. Some clinical studies as well as several animal studies showed that antibodies that were administered locally, could penetrate effectively into the inflamed sites of the GIT. This is an encouraging observation in view of oral targeted therapy with macromolecules such as biologicals. These drugs were investigated without absorption enhancers and it may be worth investigating whether oral targeted therapy with biological or other macromolecules is more efficacious when combined with absorption enhancers, such as bile salts (e.g. sodium deoxycholate or sodium taurocholate), chelators (e.g. salicylates or citric acid), surfactants (e.g. sodium lauryl sulfate or sodium dodecylsulfate), fatty acids (oleic acid or linoleic acid), or liposomes [32–34]. A fine balance between enhancing the penetration of drugs into the inflamed sites on the one hand, and no substantial systemic exposure on the other hand should be investigated.
Most of the animal studies discussed in chapter 4 on local TNF-α inhibition used a more experimental approach in which antibodies, targeted nucleotides, or microorganisms
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were used. For the last two approaches, studies should aim to establish an appropriate dose regimen. Given the mechanism of action, it is likely that there will be no single dose that is suitable for each patient. Furthermore, therapy evaluation and termination strategies should be in place. For instance, if microorganism therapies are used and no clinical response is seen, does this mean that the therapy is ineffective or that an insufficient amount of micro-organisms colonized the colon? Or does it mean that the microorganism does not express the vector in an appropriate amount? The development of suitable methods to investigate these questions may be difficult. Furthermore, how will microorganism therapy be terminated after colonization? Likewise, suitable methods to evaluate the therapeutic efficacy of targeted nucleotides should also be in place before they can be used in an effective and safe manner. More so since the mucosal concentrations of these drugs may not always correlate well with the intracellular drug concentrations of the targeted cells. This may make it difficult to distinguish between an ineffectively targeted drug (intracellular compartment) or an ineffective treatment due to disease severity or other factors that are at play.
Given the available encouraging data in chapter 4 on local TNF-α inhibition, we developed an ileo-colonic targeted infliximab (IFX) formulation in chapter 5.1. The major challenges in developing a tablet containing a monoclonal antibody with a targeted delivery of the drug to the ileo-colonic region are the drug stability and the drug release profile. The stresses associated with the production process of coated tablets may be detrimental to the protein structure. For instance, the mixing of the excipients and the subsequent tableting procedure imposes shear stresses and compaction forces, respectively, on the protein. Furthermore, the coating process exposes the tablet core to solvent and vapor, which may denature the protein. Additionally, proteins are known to easily adsorb to surfaces and excipients [35,36]. Since most of the tablet excipients are generally insoluble, adsorption of IFX to the tablet core excipients may result in incomplete release of the dose after tablet disintegration at the targeted site. All these challenges may result in a tablet formulation that will not meet the preset quality requirements regarding aspects such as drug content, release characteristics, and formulation stability. The IFX stability during compounding and storage was investigated in chapter 5.1. The suitability of different sugar glass matrices in which IFX was incorporated was studied. During this experiment it became evident that the matrix substantially influenced the IFX stability and release behavior. Inulin (IFX-I) was chosen for compounding IFX to ColoPulse-coated tablets (ColoPulse-IFX). Several protein analysis methods were used to investigate the stability and potency of IFX. All these analyses showed no noticeable degradation compared to reference IFX. Furthermore, in vitro experiments showed that the formulation targeted IFX to the simulated ileo-colonic region, where IFX was released in an immediate manner.
Even though the preliminary stability results in chapter 5.1 were encouraging, for ColoPulse-IFX to be a feasible treatment option, the long-term stability still had to be
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investigated. Therefore, we investigated the long-term stability of ColoPulse-IFX stored at room temperature or refrigerated according to ICH guidelines [37] in chapter 5.2. These results showed that the IFX-I and ColoPulse-IFX remained stable and potent during storage at both room temperature and refrigerated up to 6 months and 12 months, respectively. No noticeable changes of the content, tertiary protein structure, and potency were observed compared to reference IFX. Additionally, after the storage period of 12 months at room temperature or refrigerated, the ileo-colonic targeting performance of ColoPulse-IFX was preserved. The data of chapter 5.1 and chapter 5.2 show that ColoPulse-IFX is a feasible treatment option for ileo-colonic IBD.
However, several questions regarding ColoPulse-IFX remain to be investigated. First, the therapeutic efficacy should be investigated in vivo in order to confirm or debunk our hypothesis on site-specific TNF-α inhibition with orally administered IFX in IBD. Second, PK analysis should investigate whether IFX is absorbed after oral treatment and if so, if the absorbed amount is of any clinical relevance. Another question to be answered is whether long-term treatment with oral IFX results in the development of antibodies against IFX or loss of efficacy, which are both observed with systemic IFX therapy [12,13]. We designed a clinical trial to answer these questions and the study protocol, which has been submitted to The Medical Ethics Review Board of the University Medical Center Groningen, was presented in chapter 6.
The stability of all the developed formulations in this thesis were either investigated during an accelerated stability study for 6 months (chapter 2 and chapter 3) or long-term for 12 months (chapter 5.2). However, the extensive long-long-term stability should be investigated stored at room temperature for 36 months, which is generally the shelf-life of tablets. These stability studies should be designed to not only investigate the drug stability, but the drug targeting performance as well to assure the targeting performance of the formulations. To date it is uncertain what the stability of the coating is when stored at room temperature (or refrigerated) for periods longer than 12 months.
The presented research in this thesis is a step towards the clinical use of oral ileo-colonic targeted drugs in the treatment of IBD. The three developed novel formulations are easy to produce on a large scale. Furthermore, drugs that are proven to be efficacious were used within well-defined in vivo targeting objectives. The stability, therapeutic efficacy, and safety of these novel formulations should be investigated in future research. Appropriately designed clinical trials should investigate the therapeutic efficacy and safety of these formulation compared to currently prescribed treatment options in ileo-colonic IBD. These studies should also try to answer the place in therapy of these treatments options in IBD. Finally, the formulation data and approaches presented in this thesis may aid in the development of novel formulations that contain existing or new drugs that aim to target the ileo-colonic region in IBD since we present here formulation strategies of a monoclonal antibody as well as hydrophilic and lipophilic drugs.
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