WO2025222033A1

WO2025222033A1 - Time-controlled payload release capsules

Info

Publication number: WO2025222033A1
Application number: PCT/US2025/025213
Authority: WO
Inventors: Joseph Wang; Amal ABBAS
Original assignee: University of California Berkeley; University of California San Diego UCSD
Current assignee: University of California Berkeley; University of California San Diego UCSD
Priority date: 2024-04-18
Filing date: 2025-04-17
Publication date: 2025-10-23
Anticipated expiration: 2026-10-18

Abstract

Disclosed are capsule devices, systems, and methods for individualized controlled release of multiple payloads. In some aspects, a multi-segment capsule device includes a capsule assembly comprising a body and a cap, wherein the cap is dissolvable in a fluid, and wherein the body includes an enteric coating capable of preventing or slowing dissolution of the body in the fluid; a plurality of capsule segments contained in the capsule assembly comprising at least a first capsule segment and a second capsule segment, wherein each of the plurality of capsule segments includes an interior capable of storing an individual payload substance, and wherein the first capsule segment is adjacent to the cap in the capsule assembly; and at least one enteric barrier positioned between and separating two capsule segments in the capsule assembly, wherein the at least one enteric barrier includes one or more enteric polymers within a matrix material.

Description

TIME-CONTROLLED PAYLOAD RELEASE CAPSULES

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This patent document claims priority to and benefits of U.S. Provisional Patent Application No. 63/636,016, titled “ENTERIC BARRIER DISC AND MULTI-SEGMENT CAPSULE FOR TIME-CONTROLLED DRUG RELEASE” and filed on April 18, 2024, and U.S. Provisional Patent Application No. 63/774,701, titled “ROBOTIC MICROMOTORS FOR ORAL DRUG ADMINISTRATION” and filed on March 19, 2025. The entire contents of the aforementioned patent applications are incorporated by reference as part of the disclosure of this patent document.

TECHNICAL FIELD

[0002] This patent document relates to systems, devices, and processes that use bioengineered micromaterial technologies.

BACKGROUND

[0003] Bioengineered micromaterials involves the design and creation of small (microscopic) materials with specific biological functions for a variety of application, including biosensing, drug delivery, tissue engineering, and others.

SUMMARY

[0004] Disclosed are devices, systems, and methods for time-controlled payload release capsules. Some embodiments of the disclosed devices, systems, and methods include a multisegment capsule with an enteric barrier disc for time-controlled release of one or more drugs. Also, some embodiments of the disclosed devices, systems, and methods include a robotic micromotor payload delivery capsule for time-controlled drug release.

[0005] In some aspects, a device for individualized controlled release of multiple pay loads includes a capsule assembly comprising a body and a cap, wherein the cap is dissolvable in a fluid, and wherein the body includes an enteric coating capable of preventing or slowing dissolution of the body in the fluid; a plurality of capsule segments contained in the capsule assembly comprising at least a first capsule segment and a second capsule segment, wherein each of the plurality of capsule segments includes an interior capable of storing an individual payload substance, and i wherein the first capsule segment is adjacent to the cap in the capsule assembly; and at least one enteric banner positioned between and separating two capsule segments in the capsule assembly, wherein the at least one enteric barrier includes one or more enteric polymers within a matrix material.

[0006] In some aspects, a method for individualized controlled release of multiple payloads includes dissolving, in a fluid, a cap of a multi-segment capsule that comprises the cap and a capsule body, wherein the capsule body contains a plurality of capsule segments and comprises an enteric coating capable of preventing or slowing dissolution of the capsule body in the fluid; exposing, to the fluid, a first capsule segment positioned in the capsule body adjacent to the cap, wherein the first capsule segment is configured to contain a first payload substance; releasing the first payload substance to the fluid from the first capsule segment at a first time after the dissolving of the cap; dissolving an enteric barrier positioned between and separating the first capsule segment from a second capsule segment positioned in the capsule body adjacent to the enteric barrier; exposing, to the fluid, the second capsule segment, wherein the second capsule segment is configured to contain a second payload substance; and releasing the second payload substance to the fluid from the second capsule segment at a second time after the dissolving of the cap using different release kinetics from the releasing of the first payload substance, the different release kinetics including an initial or immediate release of the first payload substance and a sustained release of the second payload substance.

[0007] The subject matter described in this patent document can be implemented in specific ways that provide one or more of the following features.

BRIEF DESCRIPTION OF THE DRAWINGS

[0008] FIG. 1A shows a diagram depicting an example embodiment of a multi-segment capsule device for individualized controlled release of multiple payloads, in accordance with the present technology.

[0009] FIGS. IB- II shows diagrams and images depicting an example embodiment of a multisegment daily capsule for time-controlled release, in accordance with present technology.

[0010] FIGS. 2A-2C show diagrams and images depicting a method for preparing an example embodiment of multi-segment daily capsules, in accordance with the present technology.

[0011] FIG. 2D shows a diagram illustrating an example embodiment of the multi-segment daily capsule in accordance with the present technology.

[0012] FIGS. 3A-3E show diagrams, images, and data plots depicting an example embodiment of a dual dose multi-segment capsule, in accordance with the present technology, used in example implementations for a daily capsule release study.

[0013] FIGS. 4A-4F show diagrams, images, and data plots depicting an example embodiment of a robotic multi-segment capsule, in accordance with the present technology, used in example implementations for a timed-release capsule study.

[0014] FIGS. 5A-5F show diagrams, images, and data plots depicting an example embodiment of magnesium micromotor-based robotic multi-segment capsules, in accordance with the present technology, for pH responsive release of drugs via the multi-segment capsules.

[0015] FIG. 6A shows a diagram illustrating timed release for drugs via an example embodiment of the multi-segment daily capsule, in accordance with the present technology.

[0016] FIG. 6B shows a diagram illustrating an example embodiment of biohybrid algae micromotors that can be incorporated into one or more capsule segments of a multi-segment capsule, in accordance with the present technology.

[0017] FIG. 7 shows a diagram illustrating an example embodiment of a multi-segment capsule, in accordance with the present technology, which enable tailored, time-tunable delivery of multiple drugs and doses throughout the day.

[0018] FIG. 8 shows two comparative data plots depicting Parkinson’s disease medication management of the drug levodopa over the course of a day using conventional oral administration of multiple pills and using oral administration of an example multi- segment daily capsule, in accordance with the present technology.

[0019] FIG. 9 shows an example embodiment of a multi-segment robotic micromotor payload delivery capsule, in accordance with the present technology, for time-controlled drug release of multiple payloads at different times and locations of the gastrointestinal tract of a patient user.

[0020] FIG. 10A shows an example embodiment of a closed-loop sense-act multi-segment capsule, in accordance with the present technology.

[0021] FIG. 10B shows an illustration and data plot illustrating an example implementation of the closed-loop sense-act multi-segment capsule shown in FIG. 10A, providing closed loop dose detection and delivery of the drug levodopa for maintaining the drug concentration levels in a target therapeutic range. [0022] FIG. 11 shows a panel of images from example results of an example implementation of the example embodiment of a multi-segment daily capsule, in accordance with the present technology, depicting dissolution of the capsule in a simulated intestinal fluid of pH 7.4 after full payload release.

[0023] FIG. 12 shows a panel of images, diagrams, and data plots characterizing an example embodiment of a multi-segment daily capsule that contained example fluorescent dyes as payload substances to demonstrate the integrity of each capsule.

[0024] FIG. 13 shows a diagram depicting an example method for fabricating an example embodiment of an enteric barrier, in accordance with the present technology.

DETAILED DESCRIPTION

[0025] Oral drug delivery is the preferred and most convenient route of administration, with adherence to the treatment regime being crucial for the success of therapeutic interventions. It significantly influences patients’ treatment outcomes and long-term health, particularly in chronic conditions such as diabetes and high blood pressure. Managing medication schedules and remembering to take them can be a challenging task, especially for patients on multiple prescriptions like elderly individuals. This complexity intensifies for some conditions such as Parkinson’s and Alzheimer’s, where patients experience memory loss or impairments, and required to follow complex treatment regimens involving multiple drug doses. This significantly increases the risk of accidental overdosing or missed doses.

[0026] Non-compliance not only compromises individual health outcomes but also places a significant burden on healthcare systems. In the U.S., more than 3.8 billion prescriptions are given annually, yet according to the CDC, nearly 50% are taken incorrectly, in terms of timing, dosage, frequency, and duration. Poor compliance with certain drugs that require repetitive dosage such as antibiotics can lead to serious consequences, including antibiotic resistance which causes a mutation in the microbes that allows them to replicate - originating new strains of bacteria that are resistant to conventional antibiotic treatment and spreading the infection. This can lead to an increase in the level of mortality - up to 35,000 people die per year according to the CDC-and increases the overall health cost to over 4 billion dollars per year. This emphasizes the importance of patients’ compliance and the immediate requirement for a new, innovative solution to guarantee the safe and efficient handling of medications, thereby enhancing treatment outcomes and reducing healthcare costs.

[0027] To tackle the issue of poor medical compliance, a range of low-tech to high-tech approaches have been developed. These existing technologies include daily pill organizers, extended-release formulations such as hydrogels capsule, star-shaped capsule, osmotic pump capsule, microneedles patches, medication dispensing systems, smart pill bottles, medication reminder apps, and telehealth devices like wearable sensors for monitoring medication adherence. For instance, the pharmaceutical industry has made advancements in utilizing enteric coating material in sustained drug delivery formulations, e.g., specifically, with the use of pH-responsive enteric materials. These are composed of a copolymer of methacrylic acid and methyl methacrylate, known as Eudragit®S100, which was approved by the FDA. These polymers are widely employed to prolong the release of medication for several hours, serving as a protective layer against the stomach’s acidic environment, and dissolving in the alkaline pH of the intestine. The application of these enteric coatings in commercial formulations such as Asacol®, Naprosyn®, and Pancreaze®, has shown various advantages, including the protection of medication f, sustained release, enhanced therapeutic efficacy, and targeted drug delivery.

[0028] Yet, despite the notable progress in extended-release formulations, patient compliance continues to be a challenge in achieving effective therapeutic outcomes. These include several reasons, such as initial non-adherence, incomplete dosing, or discontinuation of treatment. Effectively managing the timing and frequency of drug intakes is crucial for improving treatment outcomes.

[0029] The disclosed technology is developed to address these issues and the shortcomings of existing and conventional technology approaches.

[0030] Disclosed are devices, systems, and methods for a multi-segment capsule having an enteric barrier for time-controlled release of multiple pay loads.

[0031] In some embodiments, there is provided at least one engineered barrier disc infused with enteric polymer for time-controlled release. The engineered barrier disc(s) is encapsulated in enterically modified capsules to form the multi-segment capsule platform for time-controlled and localized multiple payloads release in the gastrointestinal tract. For example, the capsule can include spatially separated compartment zones, providing the capability of different release kinetics, combining both immediate and sustained release of payloads. This specialized design can ensure the precise delivery of medication in a timely controlled manner, along with the customization of medication regimens of polypharmacy that are specific to individual patients. The automatic release of medication at specific times and locations in the gastrointestinal (GI) tract significantly can enhance treatment compliance, improve therapeutic outcomes, and potentially reduce the overall healthcare burden.

[0032] In some implementations, the enterically modified barrier discs can be configured as timed-controlled and localized-release components employed in multi-segment capsules. For example, the disclosed technology can promote the localization of drug release (or other types of payload release) in the gastrointestinal tract through a customizable time-release capsule that can be taken by a patient, e.g., such as on a daily basis. An exemplary customizable time-release capsule can include a plurality of capsule segments with enterically modified barrier discs configured therebetween to streamline a multi-drug and/or multi-dose treatment routine. For example, in a multi-segment capsule device, each segment is separated with a functional barrier that controls the release time, profile, and location for each drug. By tailoring the density of the enteric polymer within the barrier matrix, the release time of a specific segment is controlled.

[0033] In some embodiments, for example, the exemplary customizable time-release multisegment capsule can include magnesium micromotors into a first segment of the multi-segment capsules that neutralizes the surrounding environment’s pH, enabling further control over the release of the capsule. This can be accomplished through a barrier disk containing a pH-responsive polymer, e.g., such as an anionic methacrylate copolymer ionized above 7.0 pH, which facilitates pH-triggered payload release in the second segment. In some embodiments, for example, the anionic methacrylate copolymer includes Eudragit®S100. By adjusting the amount of pH- responsive polymer in the barrier disc and the weight percentage of Mg micromotors, the dissolution time of this enteric barrier can be customized.

[0034] Ensuring patient compliance is critical for effectiveness of treatment regimens, particularly in polypharmacy where patients are prescribed multiple medication. A common challenge is premature discontinuation of medication, often when patients experience symptom relief. Such issues are addressed by the disclosed time-controlled multi-segment capsule designed for multiple drug intake. The timing of drug release is controlled by the enteric barrier disk. The capsule employs a modified enteric hairier disk to control the timing of drug release, offering both fast and sustained delivery options. This design allows healthcare providers to customize medication schedules according to individual patient needs. The disclosed approach not only simplifies complex medication regimens, commonly seen in treatment conditions like cardiovascular, Parkinson’s, and Alzheimer diseases, but also promises to improve treatment adherence, drug’s therapeutic efficacy, and potentially reduce overall healthcare burden. In some embodiments, for example, Mg micro-stirring robotic capability is introduced in at least one segment, e.g., to further enhance the functionality of the multi-segment daily capsule and serve multiple purposes, including but not limited to: facilitating immediate release for emergency scenarios (e.g., heart attack), acting as microstirrers for improved bioavailability, and/or working as proton pump inhibitors (PPIs). The multi-segment capsule design is configured to provide for both precise timing and localization of drug release in the gastrointestinal tract. Localization can be achieved by modifying the capsule and barriers with a pH-responsive enteric polymer, e.g., allowing for adjustable time and location control.

[0035] In some embodiments, a programmable time-release multi-segment daily capsule is disclosed, which is customized by banner discs with responsive enteric materials. The exemplary programmable time-release multi-segment daily capsule is designed to simplify the treatment regimen and replace the traditional pillbox organizer, e.g., achieving a ‘one capsule per day’ regimen.

[0036] FIG. 1A shows a diagram depicting an example embodiment of a multi-segment capsule device 10 for individualized controlled release of multiple payloads, in accordance with the present technology. The multi-segment capsule device 10 includes a capsule assembly 15 that comprises a body 17 and a cap 19. The cap 19 is configured to be dissolvable in a fluid (e.g., one or more gastrointestinal fluids such as gastric juice (of the stomach), bile, pancreatic juice (released in the small intestine), and/or saliva or mixture thereof). The body 17 includes an enteric coating 18 capable of preventing or slowing dissolution of the body 17 in the fluid. The multi-segment capsule device 10 includes a plurality of capsule segments 20 contained in the capsule assembly 15. In some embodiments, the plurality of capsule segments 20 include at least a first capsule segment 21 and a second capsule segment 22. Each of the plurality of capsule segments 20 includes an interior region 25 capable of storing an individual payload substance. As illustrated in FIG. 1A, the first capsule segment 21 is positioned in the capsule assembly 15 to be adjacent to the cap 19 (and/or may be at least partially encapsulated by the cap 19), and the second capsule segment 22 is positioned in the capsule assembly 15 to be at least partially encompassed by the body 17. While not shown in the diagram of FIG. 1A, the multi-segment capsule device 10 can include a third capsule segment or additional capsule segment(s) among the plurality of capsule segments 20. The multi-segment capsule device 10 includes at least one enteric barrier 30 positioned between and separating two capsule segments of the plurality of capsule segments 20 in the capsule assembly 15. The enteric barrier(s) 30 includes one or more enteric polymers within a matrix material. For example, the one or more enteric polymers can include an anionic methacrylate copolymer ionized above 7.0 pH. In some embodiments, the anionic methacrylate copolymer ionized above 7.0 pH includes a methacrylic acid and methyl methacrylate in a 1 :2 ratio (e.g., EudragitOS 100). For example, the matrix material of the at least one enteric barrier includes one or both of lactose and maltose. In some embodiments, for example, the enteric barrier(s) 30 can be configured as an enteric barrier disc for temporally-controlled release of the individual payload substance in each of the plurality of capsule segments 20.

[0037] In some embodiments of the multi-segment capsule device 10, the enteric coating 18 of the body 17 can include one or more methacrylic acid copolymers. In some embodiments, for example, the enteric coating can include Eudragit®S100. In some embodiments, the enteric coating 18 can include one or more methacrylic acid copolymers mixed with non-enteric materials, such as cellulose (e.g., vegetable cellulose). In some example embodiments, such as for the multisegment capsule device 10 designed for release of the first payload substance in the stomach, the cap 19 may not include an enteric coating 18 and may comprise one or more non-enteric material(s) only (e.g., vegetable cellulose). Yet, in some example embodiments, such as for the multi-segment capsule device 10 designed for release of the first payload substance in the intestines, the cap 19 may include an enteric coating 18, such as one or more methacrylic acid copolymers (e.g., Eudragit®S100). For example, in some implementations, if the target location of the first payload substance is the stomach, the cap 19 can include an unmodified cellulose, allowing it to dissolve in gastric fluid and initiate the payload substance release upon entering the stomach. For example, in other implementations, if the target location of the first payload substance is the intestine, the cap 19 can be modified with an enteric coating to facilitate controlled release.

[0038] In some embodiments of the multi-segment capsule device 10, for example, the enteric coating 18 is a layer applied on the surface of the material structure that forms the body 17 (and/or, the cap 19, for some embodiments). Whereas, in some embodiments of the multi-segment capsule device 10, for example, the enteric coating 18 is integrated with the material structure that forms the body 17 (and/or, the cap 19, for some embodiments). In this approach, the enteric material can include one or more layers within the inner and outer walls of the material structure of the body 17, e.g., forming a sandwich-like structure. To produce such an exemplary integrated enteric coating 18 with the material structure of the body 17 (and/or cap 19), the capsule can undergo a heating process, which might aid in effectively integrating the layers, potentially improving the stability and performance of the enteric properties. This integrated configuration of the enteric coating 18 may enhance resistance to dissolution in the acidic environment of the stomach while allowing the formulation to release the active region (e.g. payload substance within).

[0039] In implementations, for example, the multi-segment capsule device 10 is configured to controllably release a first pay load substance from the first capsule segment 21 at a first release time and controllably release a second payload substance from the second capsule segment 22 at a second release time using different release kinetics. For example, the different release kinetics include an initial release (e.g., immediate release) of the first payload substance and a sustained release of the second payload substance. For instance, the first payload substance can be immediately released upon dissolution of the cap 19 in the fluid (e.g., gastrointestinal fluid(s)), thereby exposing the first capsule segment 21 (e.g., interior of the first capsule segment 21) to the fluid to allow the first payload substance contained therein to the fluid; and the enteric barrier 30 that separates the second capsule segment 22 from the first capsule segment 21 can controllably dissolve over a predetermined time or time range, e.g., based on the concentration of the one or more enteric polymers in the material matrix, such that once the enteric barrier 30 is dissolved, the second capsule segment 22 (e.g., interior of the second capsule segment 22) is exposed to the fluid at the second release time to allow the second payload substance contained therein to the fluid, e.g., in a sustained release.

[0040] In example embodiments of the multi-segment capsule device 10, for example, the interior of each or at least one or some of the plurality of capsule segments 20 includes a hollow region that contains the individual payload substance within. In example embodiments of the multi-segment capsule device 10, for example, the interior of each or at least one or some of the plurality of capsule segments 20 includes a solid region (e.g., dissolvable solid) which integrates the individual payload substance within.

[0041] In some embodiments, for example, the multi-segment capsule device 10 may include a plurality of micromotors that can be contained in at least one capsule segment of the plurality of capsule segments 15. For example, the optional plurality of micromotors can be contained in the first capsule segment 21 . Micromotors are miniature devices capable of converting a type of power into motion, with propulsion mechanisms categorized into chemical, magnetic, optical, acoustic, enzymatic, and biohybrid systems. In some implementations, for example, the optional plurality of micromotors can operate as micro stirrers, such that when released into the fluid, the micromotors induce local hydrodynamics and thereby create a burst release effect of the individual payload substance released from the capsule segment (e.g., first capsule segment 21) that increases propensity of absorption of the individual payload substance into surrounding tissue (e.g., tissue of the gastrointestinal system, such as the stomach wall or duodenum of the small intestine). In some embodiments, the optional plurality of micromotors can include magnesium (Mg) micromotors and/or zinc (Zn) micromotors. In some implementations, for example, when the plurality of Mg micromotors are released from the capsule segment (e.g., first capsule segment 21) to the fluid, the Mg micromotors can neutralize an acidic pH of the fluid (e.g., gastric juice) to which the Mg micromotors are released. The Mg and/or Zn micromotors are biocompatible materials utilize chemical propulsion relying on catalytic reactions. For example, these Mg and/or Zn micromotors react with the gastric acid fluid to produce hydrogen gas, propelling them forward. Mg micromotors also can interact with intestinal bicarbonate ions, enabling targeted drug delivery in the stomach and intestine.

[0042] In some embodiments, for example, the multi-segment capsule device 10 may include a plurality of biohybrid algae micromotors that can be contained in at least one capsule segment of the plurality of capsule segments 15, which can enable targeted drug delivery and cytokine neutralization. For example, when released from the capsule segment into the fluid of a gastrointestinal tract (GI tract), these biohybrid micromotors utilize their natural swimming capabilities, enabling fuel-free, active movement through the GI tract for extended periods. This mobility allows precise localization and prolonged retention at target sites, enhancing drug delivery efficacy. For instance, embedding algae micromotors in pH-sensitive capsules enables site-specific activation and controlled release in designated GI regions, optimizing therapeutic outcomes. For example, biohybrid algae micromotors, such as Chlamydomonas reinhardlii and extremophilic algae, can exhibit high propulsion speeds exceeding 100 pm/s. For instance, C. reinhardtii can propel in intestinal fluid for prolonged durations, e.g., enhancing drug delivery and retention in the GI tract. Moreover, for example, acidophilic algae biohybrid motors maintain high propulsion speeds (e.g., -100 pm/s) across pH gradients, adapting to gastric pH conditions (e.g., ~1.5 pH) and intestinal pH conditions (e.g., -6.5 pH). Such pH resiliency of exemplary biohybrid algae micromotors can enhance the efficiency and effectiveness of the controlled, individual payload substance delivery within the GI tract, e.g., even in harsh GI environments.

[0043] In some example embodiments of the multi-segment capsule device 10 that comprises the plurality of biohybrid algae micromotors, the method to fabricate the exemplary multi-segment capsule device 10 may require modification to load the biohybrid algae micromotors in one or more capsule segment(s) of the plurality of capsule segments 20, e.g., as compared to encapsulating magnesium (Mg) micromotors. An exemplary difference lies in the physical state of the micromotors, i.e., while Mg micromotors are typically in solid form, the biohybrid algae micromotors are typically in liquid form. Therefore, when encapsulating the biohybrid algae micromotors in the capsule segment(s), a higher density of enteric polymer in the barrier and capsule may be used. This is primarily because the liquid form of the algae would enhance the strength of the capsule, ensuring it can adequately protect the contents in an acidic environment.

[0044] These and other example embodiments and implementations of the multi-segment capsule device 10 for individualized controlled release of multiple payloads are described below. [0045] FIGS. IB- II shows diagrams and images depicting an example embodiment of a multisegment daily capsule 100 for time-controlled release, in accordance with present technology. FIG. IB shows a diagram illustrating the multi-segment daily capsule (MSDC) 100, also referred to as MSDC 100 or multi-segment capsule 100. The MSDC 100 includes three segments (e.g., fast segment 110, intermediate segment 120, and slow segment 130) distinguished by their dissolution rate and two enteric barriers 115, 125 of different seeding densities (%w/v), e.g., first enteric barrier 115 (Bl) and second enteric barrier 125 (B2). In the example shown in FIG. IB, the first enteric barrier (Bl) 115 is configured as a low density enteric barrier, and the second enteric bander (B2) 125 is configured as a high density enteric bander. FIG. 1C shows a schematic diagram of an example implementation of the MSDC 100 demonstrating a precise time release of multiple drugs (e.g., DI, D2, and D3) from their conesponding segments, i.e., fast segment 110, intermediate segment 120, and slow segment 130, respectively. FIG. ID shows a diagram depicting an example barrier matrix that is partially protected by an enteric polymer which preserves its structural integrity in the stomach’s acidic condition, whereas a non-protected matrix dissolves once exposed to the gastric pH. FIG. IE shows an image comparing a conventional pill organizer with the example MSDC 100, e.g., illustrating that the example MSDC 100 serves as a convenient alternative, enabling a time-programmed release for three drugs/payloads. FIG. IF shows an image comparing the exemplary Size 3 capsule MSDC 100 to a common coin, scale bar 10 mm. FIG. 1G shows an image of an exemplary MSDC 100 in the palm of a user’s hand. FIG. 1H shows an image depicting the deconstruction of an example embodiment of the daily multisegment capsule platform (e.g., MSDC 100), composed of a vegetable cellulose body coated with enteric material, a non-coated cap, three spatial segments, and two enteric barriers modified by low and high seeding densities of Eudragit®S100 to deliver drugs or payloads at different time frames in the GI tract. FIG. II shows an image of a container holding a plurality of MSDC 100, demonstrating the scalability of MSDC production.

[0046] The exemplary multi-segment daily capsule (MSDC) 100 can function as a platform featuring various payloads in distinct segment including drugs, vitamins, enzymes, and supplements, as illustrated in FIG. 1H. These segments are paired with an enteric barrier that precisely controls the release timing of each payload within the GI tract. The release mechanism of the multi-segment daily capsule 100 in the stomach was studied in example implementations, described herein. The capsule releases the payload of its first segment as the initially scheduled prescription, while the enteric barrier protects the remaining segments from degradation in gastric fluid pH (e.g., pH 1-3). Following a predetermined time interval, in line with the treatment schedule, the second medication begins to release from the subsequent segments. By adjusting the seeding density of the enteric polymer within the barrier matrix, the release time of a specific segment can be controlled, as illustrated in FIGS. IB and 1C. The multi-segment daily capsule is a versatile platform, enabling the incorporation of diverse combinations of medication, pay loads, and supplements. Each one is programmed to be released at a certain time following the treatment plan (FIG. 1C).

[0047] Some example applications of the MSDC 100 can include the following three scenarios. As an example, cases involving multiple conditions where patients require to take medications at different times of the day, such as taking Levothyroxine in the morning for hypothyroidism and Statins at night for high cholesterol. Also, for example, the need for precise dosage frequency to maintain drug concentration within the therapeutic window, aiming to minimize adverse effects, as seen with L-DOPA for Parkinson’s patients or in preventing antibiotic resistance during infections. And, for example, drug-drug interactions where the efficacy of one medication is impacted by another such as iron and calcium supplements. [0048] In some implementations of the multi-segment capsule 10, such as the MSDC 100 or other embodiments disclosed herein, the “smart” multi-segment capsule technology can optimize nutrient and supplement absorption through strategic timing. For instance, the example embodiments of the multi-segment capsule 10 can minimize nutrient interactions. As an example, certain vitamins and minerals compete for absorption in the body, such as iron and calcium. By temporally and/or spatially spacing out their uptake, such competitive interactions can be reduced or eliminated, thereby ensuring each nutrient retains its potency and effectiveness. Also, for instance, the example embodiments of the multi-segment capsule 10 can enable personalized nutrition solutions. As an example, supplement formulations can be customized to meet individual dietary needs, aligning with the growing trend of personalized healthcare. The multi-segment capsule 10 can enable a tailored approach for a user to ensure optimal nutrient uptake and overall health benefits. Also, for instance, the example embodiments of the multi-segment capsule 10 can enhance supplement effectiveness. In order to maximize the benefits of nutritional supplements, it is important to space out competing nutrients to avoid absorption conflicts, to pair synergistic nutrients to enhance bioavailability, and to adjust intake timing to improve overall health outcomes. Calcium can inhibit iron absorption. To avoid this, conventionally, iron supplements are advised to be taken at least two hours apart from calcium-rich foods or supplements. Yet, the multi-segment capsule 10 can be configured to include calcium in the first capsule segment and iron in the second capsule segment, or vice versa, to temporally regulate their release into the user’s gastrointestinal tract and thereby separate their absorption. Also, for instance, the example embodiments of the multi-segment capsule 10 can optimize sports nutrition. As an example, the multi-segment capsule 10 can be configured to combine pre-workout and post-workout supplements into a single capsule to provide staged energy release and support recovery, e.g., making it a convenient and efficient option for athletes. By strategically timing nutrient intake, for example, the multi-segment capsule 10 can enhance absorption, minimize interactions, and maximize the health benefits of your supplements.

[0049] Further enhancing the exemplary “smart” multi-segment capsule technology, microrobots can be incorporated within one or some segments of the capsule. For example, these micromotors can operate as microstirrers to induce local hydrodynamics, which can enhance drug absorption through the gastrointestinal tract, resulting in increased bioavailability and improved overall therapeutic outcomes. The immediate ‘burst’ release is facilitated by embedding biodegradable Mg microparticle engines in the first segment of daily capsule, where tailoring the burst release profiles can be achieved by controlling the loading of the microstirrers into the capsule. This integration into the multi-segment capsule provides added advantages of maximizing therapeutic efficacy through active drug delivery and enhanced absorption. The multisegment capsule can be used in applications that extend beyond the timing the drug release. For example, the multi-segment capsule technology can be used to achieve both timing and localization of treatment within the gut towards efficient and targeted therapy exposed to the gastric pH.

[0050] Example implementations of embodiments of the MSDC 100 were performed based on the following example designs, yielding the following example results.

[0051] An example embodiment of a multi-segment capsule in accordance with the MSDC 100 was designed for precise and controlled release of medication throughout the day. This design can enable combinatorial delivery of medications and can replace conventional prescriptions, simplify treatment plans, improve patient adherence, and enhance therapeutic outcomes. A primary feature of the exemplary multi-segment capsule is the multiple, divided segments of the capsule, e.g., each one containing different drugs or varying dosages of a single drug, programmed to dispense the payload at a specific time.

[0052] This concept is illustrated in FIG. 1C, demonstrating the time-controlled release, where the multi-segment capsule releases pay loads of drug 1, drug 2, and ding 3 (DI, D2, and D3) at a predetermined time. In the exemplary multi-segment capsule, each segment is spatially isolated and efficiently shielded by an enteric barrier disk, which protects the segments from premature degradation or release in a low-pH environment in the stomach (e.g., example enteric barrier discs shown in the image of FIG. 1H).

[0053] In some embodiments, this barrier disk can be made of a lactose and maltose matrix that incorporates a methacrylate-based polymer, such as Eudragit®S100, or other methacrylate- based polymer(s), such as Eudragit®L100, Eudragit®FS30D, Eudragit®L30D-55, and Eudragit®RL and/or RS. The barrier disk may include polylactic acid (PLA), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), shellac, one or more acrylic polymers, pectin, chitosan, alginate, and/or gelatin. This polymer provides the protection of the barrier matrix, while the unprotected part gradually dissolves in the gastric fluid (e.g., illustrating by the diagram of FIG. ID). By varying the density of the enteric polymer (e.g., Eudragit®S 100) within the barrier matrix, for example, the dissolution time of the barrier disk can be altered, thereby allowing precise control over the release timing of each segment’s pay load. This enteric polymer is highly biocompatible and biodegradable. It can be safely degraded and metabolized in the colon at pH > 7 after the full release of the multi-segment capsule payloads, as shown in FIG. 11.

[0054] The design of a daily multi-segment capsule ensures that each segment releases its payload at different rates fast, intermediate, and slow release, thereby allowing for varied release times, as shown in FIG. IB. Controlling the time interval between the release of each segment within the capsule is crucial for enhancing absorption, enabling synergistic drug delivery, and minimizing the risk of drug-drug interactions. For instance, elderly individuals suffering from high blood pressure often rely on beta-blockers as a common treatment option. These medications have been reported to have increased absorption in the evening due to circadian physiological variations. When a multi-segment capsule is programmed to release a beta-blocker in evening time that aligns with the body’s natural rhythm, the therapeutic effect of the medication is enhanced. Therefore, considering the influence of circadian rhythms on aspects of human health and medication efficacy, it is essential to integrate timed control treatment release to optimize treatment outcomes. Similarly, iron supplements are most effectively absorbed on an empty stomach, and their absorption can be hindered by other supplements such as calcium. Using a time-controlled release capsule that dispenses iron during fasting periods, its absorption efficacy is significantly improved.

[0055] In addition, the exemplary multi-segment capsule can facilitate synergistic drug delivery with a combination of common drugs such as clavulanic acid and amoxicillin, and proton pump inhibitors (PPIs) with clarithromycin for treating bacterial infection.

[0056] Precisely timing drug intake can improve pharmacokinetic profiles, ensuring that patients maintain an optimal therapeutic level in the bloodstream, thereby optimizing therapeutic efficacy. This exemplary multi-segment capsule 100 promotes personalized medicine through customizable segments to meet the specific needs of the patient. Such a patient-centered approach enhances the effectiveness of therapeutic administration. In some implementations, for example, the MSDC 100 provides convenience and simplicity in patients’ treatment routines by only having to take one capsule a day, which can provide substantial advancement in healthcare by improving patient compliance and maximizing drug efficacy. In addition, it offers greater portability and functionality compared with traditional pillboxes (see, e.g., FTG. IE and IT).

[0057] FIGS. 2A-2C show diagrams and images depicting a method for preparing an example embodiment of multi-segment daily capsules, in accordance with the present technology. FIG. 2A shows a diagram illustrating the method 200 for preparation of daily multi-segment daily capsules 100. The method includes a process 210 to arrange empty enteric coated capsule bodies into a capsule holder. The method 200 includes a process 220 to fill the capsules with drug-3 (D3). The method 200 includes a process 230 to incorporate barrier-2 into the capsules. The method 200 includes a process 240 to fill the capsules with drug-2 (D2). The method 200 includes a process 250 to incorporate barrier- 1 into the capsules. The method 200 includes a process 260 to fill capsules with drug-1 (DI). The method 200 includes a process 270 to cap and extract the drug- filled and barrier-incorporated capsules. FIG. 2B shows images corresponding to the processes 210-270 from an example implementation of the method 200, depicting the processes for multisegment daily capsule preparation. FIG. 2C shows an image of exemplary multi-segment daily capsules with three model drugs and two barriers prepared by implementation of the method 200. [0058] FIG. 2D shows a diagram illustrating an example embodiment of the multi-segment daily capsule 100, shown as multi-segment capsule 100D, that is configured to have a body 101 and a cap 105 to contain the three segments (e.g., fast segment 110, intermediate segment 120, and slow segment 130 that include the three drugs DI, D2, and D3, respectively) and the two enteric barriers 115, 125 of different seeding. In some embodiments, the body 101 and cap 105 can be made from vegetable cellulose, which can be modified to promote stability and functionality, ensuring effective time-controlled delivery of the contents of the multi-segment capsule 100D. The body 101 and cap 105 can be made of other materials, such as gelatin.

[0059] Example implementations of the multi-segment capsule 100D included enterically modifying the body 101 to maintain its original shape and size under acidic pH. However, in such example implementations, the cap 105 remained unmodified, for example, in order to partially dissolve and detach from the body of the multi-segment capsule, to initiate the release of therapeutic agents. The shape of the multi-segment capsule 100D can allow for ease of oral administration, like a regular capsule. In some embodiments of the multi-segment capsule 100D, the dimensions of the banner 115 and barrier 125 were optimized to 3x 5 mm to fit perfectly into the capsule body, ensuring the prevention of leakage between segments, as shown in FIG. 12. The barriers 115, 125 were seeded with enteric polymer at varying densities to tailor the release time. In the example shown in FIG. 2D, the first barrier 115 has a higher density of enteric polymer than the second barrier (B2) 125. Yet, in other embodiments like that shown in FIG. IB, the first barrier 115 may be configured to have a lower density of enteric polymer than the second barrier 125. The process of seeding the enteric polymer to the barrier discs is illustrated in FIG. 13..

[0060] Example embodiments of the multi-segment capsules 100 can be prepared according to the method 200, described in FIG. 2A. For example, initially, empty, transparent, and enterically coated capsule bodies can be arranged in a capsule tray (process 210). Then, an excipient powder composed of lactose and maltose, for example, can be uniformly ground into a fine powder using a mortar and pestle. In the example experimental implementations, for example, these powders were colored with yellow, green, and red edible food dyes to represent model drugs DI, D2, and D3, respectively. These homogenous powders were measured equally and used to fill each capsule segment. First, the third segment was filled with D3 and compressed using a tamping tool (process 220), followed by the insertion of a high-density enteric barrier to achieve delayed release (process 230). Subsequently, the second segment was loaded with the green excipient D2 (process 240), followed by the placement of a second enteric barrier with low density for intermediate release (process 250). The first segment was filled with yellow excipient DI for the static segment (process 260). The last process was capping, where the capsules were securely sealed to prevent premature release of the payloads (process 270). In some example embodiments of the multisegment capsule 100 that include an engineered micromotor or microrobot, the first segment was filled with yellow excipients with mg micromotors (e.g., 2%, 4%, and 8% of the first segment total weight) to facilitate active release experiments. After the capping process 270, the filled capsules were released from the tray cavities and stored for further analysis and in vitro testing for the example implementations. Some example implementations of the fabrication method 200 can enable efficient and scalable production of 100 capsules per batch, making it highly suitable for large-scale manufacturing. For instance, the example method 200 provides a cost-effective fabrication technique capable of meeting demands for many prescriptions. This is particularly relevant in the United States, where 1 billion prescriptions were reported for outpatient visits in 2019.

[0061] FIGS. 3A-3E show diagrams, images, and data plots depicting an example embodiment of a multi-segment capsule 100, shown as dual dose multi-segment capsule 300, used in example implementations for a daily capsule release study, e.g., for dual administration of two daily dosages. FIG. 3A shows images depicting the deconstruction and design of the exemplary multisegment capsule 300, including panel (a) displaying a plurality of multi-scgmcnt capsules 300 placed in capsule counting device to demonstrate the production capacity; panel (b) showing an image depicting the size (e.g., size 3) of the capsule; panel (c) showing a first side view image of the exemplary multi-segment capsule 300, e.g., highlighting the barrier between the dual drag segments; panel (d) showing a second side view image of the exemplary multi-segment capsule 300, e.g., with two spatially isolated compartments; and panel (e) showing an image featuring the barrier, e.g., having a diameter of 5 mm and height of 3 mm. FIG. 3B shows a schematic illustration of the time-controlled release mechanism of the exemplary multi-segment capsule 300. FIG. 3C shows an illustration and multiple time-lapse images showing the dissolution of multisegment capsules with different enteric barriers densities (e.g., 4%, 6%, and 16% of wt./v%) in 15 mL of simulated gastric fluid under stirring at 100 rpm. FIG. 3D shows a data plot depicting example results from a comparison of dissolution times of the second segment, e.g., colored green, in the dual dose multi-segment capsules 300. FIG. 3E shows images depicting the barrier dissolution of the barrier before and after exposure to gastric fluid (images a and b), microscopic images of the barrier before and after exposure to gastric fluid (images c and d), and scanning electron microscopy (SEM) images of the barrier before and after exposure to gastric fluid (images e and f).

[0062] In vitro testing of example embodiments of the multi-segment capsule 100 were performed. In some example implementations, an example embodiment of the multi-segment capsule comprising two distinct compartments was spatially separated and evaluated. These segments were loaded with excipients colored with food dye to demonstrate the release of the model drugs, DI in yellow and D2 in green. The time-controlled release of the model drugs DI and D2 from the multi-segment capsule was investigated by incorporating barrier disks made from lactose and maltose matrix, which were protected by the enteric polymer Eudragit®S100 at varying densities (4%, 6% and 16% wt./v%).

[0063] To investigate the progression of time-controlled release and the dynamics of release profiles, real-time optical images were captured at different times, as illustrated in FIG. 2C. The multi-segment capsules were tested in simulated gastric fluid (pH 1.3) under stirring at 100 rpm to mimic the speed of bowel movement. The capsule cap started to detach after ~30 minutes, while the capsule body containing all compartments remained intact. The first segment, DI, colored yellow, was released immediately, whereas the second segment in green was shielded by the enteric barrier, preventing degradation or premature release in the highly acidic environment. This example result specifically emphasizes the significance of the barrier function in preserving the second spatial compartment. Images of FIG. 3C clearly show that several hours after the initial release of DI in yellow from the first segment, the second segment successfully retained D2 in green without any release. This effectively demonstrates that the barrier serves its purpose by isolating each segment within the capsule when incorporated.

[0064] Also, the dissolution images of the example dual dose multi-segment capsule 300 of FIG. 3C demonstrates that the second segment’s payload, colored in green, can be tailored based on varying the density of the enteric barriers (e.g., 4%, 6% and 16% Eudragit®S100 density variations as demonstrated in the example implementation). A direct correlation is observed between the barrier’ s density and the delay in release of the second segment. For example, a higher density enteric barrier of 16% Eudragit®S100, results in ~10 hours delayed release of the second segment. Correspondingly, the enteric barrier was characterized both before and after exposure to gastric pH (e.g., pH 1.3) through microscopic images and SEM images. As shown by the images of FIG. 3E, the non-protected matrix of barriers was dissolved and the enteric protected matrix of lactose maltose excipient remained undissolved. This remaining protected matrix will be degraded in the colon at pH >7.

[0065] By controlling the density of the enteric polymer in the banner matrix, the dual dose multi-segment capsule 300 can be configured to precisely control the time of drug delivery for each segment. The in vitro testing conducted here used a size 3 multi-segment capsule (Figure 3 Ab), tested in simulated gastric fluid (pH 1.3). These experiments demonstrated the potential of multi-segment capsules for time-controlled drug release, e.g., which can be utilized by pharmaceutical industry and for prescribed medications.

[0066] In some embodiments, the multi-segment capsule 100 can include a robotic or micromotor contingent to affect motion and/or stirring of surrounding fluid in the environment where the multi-segment capsule 100 undergoes the time-controlled release of the drugs.

[0067] FIGS. 4A-4F show diagrams, images, and data plots depicting an example embodiment of a multi-segment capsule 100, shown as robotic multi-segment capsule 400, used in example implementations for a timed-release capsule study, e.g., for administration of two drug timed dosages. FIG. 4A shows a diagram of an example embodiment of the robotic multi-segment capsule 400 and images depicting characterization of the robotic multi-segment capsule 400, including an SEM image (image a) of a cross section of the 1st segment robotic multi-scgmcnt capsule, an EDX image (image b) illustrating the distribution of elemental Mg (yellow), and a zoomed-in SEM image (image c) of the 1^st segment revealing Mg micromotors (pseudo colored in yellow) embedded within the matrix of 1^st segment. FIG. 4B shows an illustration and data plot illustrating burst profiles of robotic capsule loaded with varying concentrations of Mg microstirrers (0%, 2%, 4%, and 8%) in the first segment. FIG. 4C shows an illustration and data plot of the sequential release profiles of segments 1 and 2 combined with real-time images demonstrating the release of the multi-segment daily capsule release. FIG. 4D shows time-lapse dissolution of 1^st segment in the robotic multi-segment capsule with (e.g., 2%, 4%, and 8% of micro stirrers, by total weight), and 0% static multi-segment capsule. FIG. 4E shows a schematic illustration showing the benefits of incorporating exemplary microstirrers 450 (e.g., in segment 1 of the exemplary robotic multi-segment capsule 400), e.g., to enhance bioavailability of the delivered drugs 490 for uptake. FIG. 4F shows a data plot depicting a comparison of the dissolution time of the 1st segment with varying Mg micromotors loadings and static capsule (i.e., one-way ANOVA, ****/? < 0.0001).

[0068] As demonstrated by both FIG. 3C and FIG. 4D, each segment of an exemplary multisegment capsule has a distinct release profile. The first segment rapidly releases its payload in yellow, while the second one in green provides sustained release. Therefore, the multi-segment facilitates time controlled combinatorial delivery of payloads with different dissolution profiles of immediate and sustained release. This approach holds tremendous benefits for various medical conditions such as chronic disease, pain management, and cardiovascular disorders.

[0069] The innovative design of the disclosed multi-segment capsule technology can be easily adapted to size 000 capsule, measuring 2.2 cm in length and 0.995 cm diameter in diameter, to extend the gastric resident time of multi-segment capsule and make it difficult to pass through the pylorus, which ranges from 1.3-2.0 cm. The use of size 000 capsule prevents passage through the pylorus and prolongs the gastrointestinal residency time.

[0070] Various embodiments of the disclosed multi-segment capsule technology can be configured to have a capsule size in accordance with standard pill capsule sizes, ranging from 000 to 5. Table 1 below shows example sizes of a capsule body for various embodiments of a multisegment capsule in accordance with the present technology. Tabel 1

[0071] FIGS. 5A-5F show diagrams, images, and data plots depicting an example embodiment of magnesium micromotor-based robotic multi-segment capsules 500 for pH responsive release. FIG. 5A shows an illustrative diagram 599 (on right of FIG. 5A) depicting an example Mg/ Au micromotor 550 released from a 1st segment 510 of a robotic multi-segment capsule 500 and use gastric fluid simulant of pH 1.3 as a fuel for propulsion, in which the example Mg/ Au micromotor 550 can neutralize the gastric fluid to facilitate the release 2nd segment 520 in a time-controlled manner. The diagram 598 (on left of FIG. 5A) depicts an example chemical reaction that the example Mg/ Au micromotor 550 undergoes in the gastric fluid at pH 1.3 to neutralizing to pH 7.0. FIG. 5B shows an illustrative diagram depicting the dissolution of the barrier 515 of the example magnesium micromotor-based robotic multi-segment capsules 500 in response to pH environment. FIG. 5C shows optical images of the modified barrier in simulated gastric fluid (SGF) at pH 1.3 and simulated intestinal fluid (SIF) at pH 7.4. FIG. 5D shows a diagram depicting in vitro gastric fluid neutralization dependent on Mg concentration, changing the release of the 2nd segment 520 in green. FIG. 5E shows a data plot demonstrating gastric fluid neutralization occurring in an in vitro SGF, showing dependency on Mg concentration (i.e., a one-way ANOVA, ****p < 0.0001). FIG. 5F shows a data plot demonstrating pH-responsive release of the 2nd segment of the example magnesium micromotor-based robotic multi-segment capsules 500, which is based on Mg concentration, e.g., altering the time of release.

[0072] Example embodiments of a robotic multi- segment capsule was utilized in example in vitro experimental implementations. For example, the integration of the Mg micromotors 450 into the multi-segment capsule 400 represents a substantial advancement in patient healthcare. It combines the time-controlled release of multiple drugs with precision medicine capabilities using micro-robotics technology. As shown in FIG. 4A, the SEM images show a cross-section of the first segment of the multi-segment capsule 400 where microstirrers (e.g., Mg micromotors 450) are embedded. Paired with Energy-dispersive X-ray spectroscopy (EDX) for elemental analysis, these images show the distribution of Mg micromotors 450 embedded in the matrix of the first segment at 8% (w/w), pseudo-colored in yellow for better visualization. The example data demonstrates the dual functionality of Mg micromotors, e.g., by the microstirrers facilitating active drug delivery and by serving as a proton pump inhibitor, demonstrated by the example data in FIG. 4E and illustrated in the diagram of FIG. 5A.

[0073] The example Mg micromotors 450 function as microstirrers, utilizing gastric fluid as fuel for propulsion and generating hydrogen bubbles. These motors propulsion facilitate the immediate disintegration of segment matrix and rapid drug release. This active delivery mechanism causes localized stirring and fluid movement, allowing the micromotors to embed within the mucosal linings of GI tissues (as shown in FIG. 4E). This process not only increases their residence time but also enhances the bioavailability of their therapeutic pay loads. Example in vivo therapeutic benefits of Mg microstirrers are understood to provide significant improvement in treatment efficacy. For instance, Mg micromotors have demonstrated the ability to reduce blood glucose level at lower dosage of metformin. In addition, Mg micromotors enhance iron absorption and improve the release profiles of aspirin, levodopa, paracetamol, and acetaminophen.

[0074] To assess the release of the embedded Mg micromotors 450 from the multi-segment capsule 400 with a 4% enteric barrier, example experiments were conducted to simulate gastric fluid (SGF) with pH at 1.3. First, capsules containing different ratios (e.g., 0%, 2%, 4% and 8% wt) of Mg micromotors were created. FIG. 4D shows time-lapse images of the dissolution of both static multi-segment capsules having no Mg micromotors and robotic multi-segment capsules 400 having embedded Mg micromotors 450, demonstrating varying dissolution rates. The robotic multi-segment capsules 400 exhibited a significantly faster dissolution profile compared to the static capsule. All tested multi-segment capsules 400 had first segments equal in weight but varied in the weight percentage of Mg micromotors. While the first segment of robotic capsules was almost completely dissolved, the first segment of the static capsule retained most of its payload at the same time point. The example multi-segment capsule 400 embedded with 8% Mg micromotors demonstrated the fastest dissolution of the first segment, shown in yellow and displayed an immediate release of the payload among others. Notably, this was three times faster compared to the static multi-segment capsule, shown by the data plot of FIG. 4F. While the first segment released its payload, it was observed that the enteric barrier successfully protected the second segment from dissolving in an acidic pH of SGF.

[0075] The example Mg micromotors 450 include a Mg core and a thin outer layer (e.g., sputtered with a thin gold layer (Au)). In addition to facilitating the active drug delivery of the multi-segment capsules, the Mg micromotors 450 can also function as proton pump inhibitors (PPIs). For example, the Mg micromotors 450 can deplete gastric protons to neutralize the pH, which temporarily alters the local environment. This ability of neutralizing the gastric acid beneficial to work as PPIs, for example, can promote the proper environment for some drug to delivering some drugs, e.g., such as those that subject to premature degradation by the acidity of the gastric fluid, and pH triggered release.

[0076] Some example embodiments of the multi-segment capsules 100 include Mg micromotors configured to neutralize gastric fluid, enabling further control of the release of contents from the multi-segment capsule 100. In some embodiments, this is achieved through barrier disk containing a pH responsive, methacrylate-based polymer, e.g., Eudragit®S100, which facilitates pH-triggered payload release of the second segment. By controlling the seeding density of the pH-responsive polymer and the weight percentage of Mg micromotors, the dissolution rate of enteric barrier can be tailored for the constraints of the desired application. As an example, the Eudragit®S100 polymer chain contains carboxylic groups accounting for 29.2% of its molecular weight, which undergo dissociation after the Mg micromotors neutralize the gastric fluid. This dissociation of carboxylic group affects the dissolution of enteric barrier in neutral pH, as demonstrated in FIG. 5C. Therefore, adjusting the dissolution rate of the enteric barrier enables control of the timing of the release of the second segment.

[0077] The example implementations included in vitro studies on pH neutralization by Mg micromotors and the release of second segment, colored in green, which were conducted with different weight percentage of Mg micromotors (e.g., 0%, 2%, 4%, and 8%) in simulated gastric fluid (pH at 1.3). The rate of pH neutralization by Mg micromotors was monitored by using a pH meter, recording the change in the pH every minute for two hours. The example results indicated that increasing the Mg micromotors concentration accelerated the neutralization process, with pH of the SGF rapidly increasing from 1 .3 to 7.5 within 15 minutes when using 8% Mg micromotors. The time-based graphs of FIG. 5D show the dissolution of multi-segment capsules, particularly the release of second segment, colored green. These images show that the higher percentage of Mg micromotors result in faster release of green payload, attributed to pH-triggered release due to dissolution of the enteric barrier as a result of Mg micromotors’ gastric pH neutralization. The multi-segment capsule embedded with 8% Mg demonstrated the release of the second segment release at 1 hour, whereas capsules with lower Mg content (e.g., 2% and 4%) released their green payload after 130 min and 100 min, respectively, as shown in FIG. 5F.

[0078] FIG. 6A shows a diagram illustrating timed release for drugs via an example embodiment of the multi-segment daily capsule 100. The upper diagram of FIG. 6A shows localization of the multi-segment capsule 100 based on spatial pH variation along the GI tract. The lower diagram of FIG. 6A shows time-controlled release profiles of the multi-segment daily capsule 100. For example, the first payload (e.g., drug 1 or DI) is immediately released from the first capsule segment of the exemplary multi-segment daily capsule 100 in the stomach (e.g., where the cap and structure of the first capsule segment are able to dissolve at the stomach’s pH level (e.g., 1 pH to 3 pH)) at a first time or time range for immediate release (e.g., over > 0 hr to 3 hr). The second payload (e.g., drug 2 or D2) and third payload (e.g., drug 3 or D3) are not able to be exposed or release in the stomach, as the remaining capsules of the multi-segment daily capsule 100 continue through the user’s digestive tract over time. The second capsule segment is able to dissolve in a first region of the small intestine at a second time or time range for sustained release of the second payload, e.g., beginning at 5 hours. The third capsule segment is able to dissolve in a second region of the small intestine at a third time or time range for sustained release of the third payload, e.g., beginning at 9 hours.

[0079] FIG. 6B shows a diagram illustrating an example embodiment of biohybrid algae micromotors 610 that can be incorporated into and controllably released from one or more capsule segments of an example embodiment of a multi-segment capsule 10, shown as multi-segment daily capsule 600. For example, the biohybrid algae micromotors 610 can include one or more pay load substances 605 coupled to an alga 601 having one or more flagellum 603. The biohybrid algae micromotors are contained in at least one capsule segment, such that, when the biohybrid algae micromotors 610 are released from the capsule segment(s) into the fluid of the gastrointestinal tract, the biohybrid algae micromotors 610 are operable to propel in the fluid. For example, the biohybrid algae micromotors 610 are operable to propel in the fluid based on motion of the one or more flagellum 603 at a propulsion speed of at least 80 pm/scc (c.g., at or greater than 100 pm/scc in some implementations). The biohybrid algae micromotors 610 can enhance the performance of the controlled-time delivery and uptake of the payload substance(s) in the gastrointestinal tract by acting as prolonged mixing agents, such that, when released into the fluid, the biohybrid algae micromotors 610 induce absorption of the individual payload substance(s) 605 released from the capsule segment(s) into surrounding tissue of the gastrointestinal tract.

[0080] In some embodiments of the biohybrid algae micromotors 610, for example, simultaneous, active delivery of multiple drugs 605 A, 605B, 605C can be linked to different algae groups. In such embodiments, each group of these biohybrid algae micromotors 610 (also referred to as microswimmers) can deliver its cargo independently, enabling gastrointestinal localization and time-specific release. And, based on the configuration of the multi-segment daily capsule 600, this oral delivery is guided by tailored enteric coating modifications designed to dissolve at different pH values at specific sites along the gastrointestinal tract, providing tunable release profiles and unique pharmacokinetic characteristics. For example, versatility of the multi-segment daily capsule 600 having enteric polymers is particularly beneficial in scenarios requiring the codelivery of multiple drugs within a single pharmaceutical vehicle for enhanced compliance. Such approach is particularly important for treating complex infectious or respiratory diseases, including parasitic infections, and tuberculosis, where the simultaneous administration of multiple antibiotics, painkillers, or therapeutic agents is essential for effective treatment and improved outcomes. For instance, in a respiratory infection scenario requiring an antibiotic, a painkiller, and an antiallergic drug, patients typically need to take these medications at different times of the day to ensure proper therapeutic action. By employing the disclosed multi-algae micromotor platform, all three therapeutic agents could be incorporated into a single pharmaceutical formulation. One- third of the algae could be loaded with the antibiotic and another third loaded with the painkiller, actively transporting it to the intestinal lining for enhanced absorption. Meanwhile, another third of the algae could be loaded with the antiallergic drug, enabling a sustained fashion over time. This strategy allows for spatio-temporal control of drug delivery, reducing the frequency of drug administration and enhancing patient adherence.

[0081] In some implementations, for example, the biohybrid algae micromotors 610, can be loaded with multiple drugs encapsulated within pharmaceutical vehicles, including, but not limited to, doxorubicin and ciprofloxacin. Tn some embodiments, the biohybrid algae micromotors 610 can be modified with macrophage membrane-coated nanoparticlcs, c.g., via click chemistry, such as in example embodiments where the alga 601 is C. reinhardtii. The chemical groups on the surface of C. reinhardtii allow for convenient attachment and loading of a broad range of therapeutic payloads, enabling more versatile and effective treatment strategies. As such, different populations of drug-loaded algae micromotors can be embedded within separate segments of the multi-segment capsule 600 to prevent drug-drug interaction and promote a tunable time release. Upon ingestion, these segments release their contents at different times, providing precise control over the release kinetics of each drug.

[0082] In some implementations with multiple drugs loaded onto the biohybrid algae micromotors 610, for example, each group of these microswimmers can deliver its cargo independently, enabling GI localization and time-specific release. This oral delivery is guided by tailored enteric coating modifications designed to dissolve at different pH values at specific sites along the gastrointestinal (GI) tract, providing tunable release profiles and unique pharmacokinetic characteristics. This approach facilitates precise localization and spontaneous propulsion for sitespecific drug delivery.

[0083] The disclosed oral daily multi-segment capsule platform technology has immense potential to revolutionize drug delivery systems. By allowing for the precise timing and localization of drug release within the gut for multiple medications throughout the day, this technology can improve patient compliance and maximize therapeutic outcomes. Furthermore, the multi-segment capsule platform offers opportunities for personalized medicine as it can be customized to the needs of individual patients by adjusting the number of segments and the sequence of drug release times. This technology represents a major advancement in drug delivery and holds the promise to improve patient health and well-being.

[0084] Researchers have primarily focused on enhancing oral drug delivery formulation through extending the gastric residence time from days to weeks. This has been achieved through various methods, such as employing a geometry-changing strategy through a regular shaped capsule containing a star shape loaded drug device, utilizing polymer properties that can swell and shrink for developing hydrogel capsules as well as implementing osmotic pump technology in capsule design.

[0085] The disclosed technology creates a specially designed multi-segment capsule for advanced therapeutic systems. The multi-segment capsule has the capacity to combine various drugs or payloads, target specific regions within the gut, and provide timed controlled release (like that illustrated in FIG. 6A). Localizing drug delivery to regions of the gastrointestinal (GI) tract is critically important, as drug absorption in the GI tract is influenced by several factors, including microbiota interaction, pH-dependent stability, and enzymatic degradation. By directing drug release towards a desired region, absorption can be enhanced where it most significantly contributes to the most therapeutic efficacy. The multi-segment capsule’s ability to selectively localize the release of desired segments in the GI tract can be achieved by modifying the enteric coating of both capsule body and cap. In addition to localizing drugs, the capsule regulates the drug release time (FIG. 6A). This can be done by adjusting the pH-responsive polymer density within the barrier matrix, which influences the time of the drug release from a designated segment within the GI tract.

[0086] Some medications are more effectively absorbed in the stomach’s acidic environment, while others show higher efficiency when absorbed in the alkaline conditions of the intestine. The disclosed technology is able to address this issue by implementing a multi-segment capsule designed for localized GI tract drug delivery by utilizing the variation of the pH levels across the gastrointestinal tract to (1) deliver to the stomach (2) target the intestine and/or (3) provide a combined release approach in both the stomach and intestine.

[0087] In the stomach, for example, the multi- segment capsule can serve as an effective localized therapy system for treating bacterial infections such as Helicobacter pylori. In this infection, a combined delivery system is essential, starling with proton pump inhibitors (PPI) in the first segment followed by the antibiotic amoxicillin and clarithromycin. In this setup, the PPI is released first to neutralize the gastric acidity, after that time the second segment dispenses amoxicillin, followed by a third segment releases clarithromycin. Such localized treatment offers numerous advantages, including: it can achieve higher local drug concentration, potentially improve eradication rates for H. Pylori, and reduce antibiotic resistance by promoting patient compliance with a simplified treatment regimen by administration of multi-segment capsule replacing the standard triple therapy regimen that usually requires strict timing of multiple dosing and combination of therapy. Localized release in the stomach’s pH is crucial for certain drugs. For example, aspirin, which is a weak acid (acetylsalicylic acid), and iron supplements, often prescribed for iron-deficiency anemia, require an acidic environment to facilitate and better absorbed in upper GI tract of stomach and duodenum.

[0088] The efficient localization and time-controlled release of the multi-segment capsule within the intestine are highly important because of its large surface area, where most drug absorption occurs. Oral site- specific multi- segment drug capsule delivery to certain regions of the intestine can offer targeted treatment options for inflammatory bowel disease, such as colitis, which optimizes the therapeutic effect by targeting the delivery of the medication to the inflamed areas.

[0089] The example embodiments of the multi-segment capsule can be tailored to target both the stomach and intestine for precise drug delivery. This combinatorial delivery system can be engineered to release one segment in the stomach and the other in the intestine. This approach is particularly beneficial for elderly people under cardiovascular treatment and protection plan, where combined therapy includes aspirin, which is absorbed in the stomach, and antihypertensive drugs, such as ACE inhibitors or beta-blockers, which are primarily absorbed in the intestine.

[0090] In some embodiments, the disclosed multi-segment capsule platform technology incorporates and embeds microrobotic stirrers (referred to as microstirrers or microrobots) into multi-segment capsules to facilitate immediate release, which may be vital for emergency conditions/situations such as cardiac arrest. This is due to rapid dissolution and enhanced absorption through tissue impingement by the microrobots. Fast matrix dissolution through the microstirrers has shown several advantages in improving drug delivery and bioavailability, thus enhancing the therapeutic outcomes. For instance, magnesium microrobots can be used in drug delivery applications, e.g., including metformin delivery for diabetes type 2 treatment, L-DOPA, and aspirin. Additionally, these micromotors can alter pH levels, functioning autonomously as proton pump inhibitors (PPIs), which is beneficial in treating ulcers and as part of the treatment regimen for stomach infection. Yet, deployed alone, the magnesium microrobots may not be highly effective or scalable for pharmaceutical products, e.g., as compared to the disclosed multisegment capsule technology.

[0091] For example, by adjusting the weight percentage of Mg micromotors and the seeding density of the pH-responsive polymer in the enteric coating and/or enteric barrier(s) of the exemplary multi-segment capsule device, the dissolution rate of the enteric banner can be adjusted to precisely control the release of drugs in the respective segment (like that illustrated for the example MSDC 100 shown in FIG. ID), e.g. facilitating the pH-responsive release of a following segment in a controlled-timing manner — leveraging pH-responsive mechanisms to enhance targeted payload substance delivery. For some examples, the polymeric chain of methacrylate copolymer containing carboxylic groups dissociates after the Mg micromotors neutralize the gastric fluid. This dissociation of carboxylic groups of the copolymer into carboxylate ions significantly affects the dissolution of the enteric barrier.

[0092] The integration of microrobots into multi-segment capsules offers promising prospects for advancements in the pharmaceutical industry. The multi-segment capsule that incorporate micromotors can improve medication efficacy by increasing bioavailability and modulating the release profile enabling immediate release in some segments while providing sustained release in others. Such technologies hold particular significance for conditions that require combined therapy, such as diabetes, cardiovascular diseases, Parkinson’s disease, arthritis, pain management, and infections. These are notably common among elderly patients who are often on multiple prescriptions.

[0093] The disclosed multi- segment capsule platform technology represents a significant advancement in polypharmacy. The structural design of the capsule creates unique functions to enable time-controlled release and disbursement of payloads in the targeted environment, such as drugs in specific regions of the gastrointestinal tract. The example embodiments of the multisegmented capsule incorporates multiple compartments, each containing distinct payloads, isolated by an enteric barrier. By controlling the concentration of the enteric polymer within the barrier matrix, the time of release can be regulated for a particular payload. As discussed above, example implementations of some example embodiments of the disclosed multi-segment capsules demonstrated the performance of the multi compartment capsule through in vitro testing in simulated gastric fluid at pH (1.3). Implementations of the multi-segment capsules effectively tackles the pressing concern of patient adherence, which is a crucial factor influencing the success and efficacy of any medical treatment and contributes significantly to personalized medicine. The predetermined timed-release mechanism provides a convenient dosing schedule that can replace or eliminate the need for a pillbox organizer, e.g., requiring only one capsule per day for optimal drug delivery. Mg micromotors can be integrated into the multi-segment capsule to improve the bioavailability, uptake, and efficacy of the controlled-release drugs, having a better performance by combining both timed and effective drug delivery. The disclosed multi-segment capsule technology approach is configured to tune the pH-responsive enteric coatings of the capsule body and cap, which can selectively release the drug payload in specific locations of the GI based on the pH gradient.

[0094] In some embodiments, there is provided a multi-segment capsule for drug delivery. The multi-segment capsule comprises at least one enteric barrier. Alternatively, or additionally, the multi-segment capsule comprises at least one micromotor in at least one of the segments of the multi-segment capsule.

[0095] In some embodiments, there is provided a multi-segment capsule comprising an enterically modified banner for use as a medicament. The medicament may be of any forni (e.g., solid, liquid, powder, and/or the like). Alternatively, or additionally, the medicament may be for the purpose of nutrition and/or providing a supplement.

[0096] In some embodiments, there is provided a multi-segment capsule for use in a method for the treatment, wherein the multi-segment capsule is administered. For example, the multisegment capsule may contain a medication that can be also used to tailor the dosage, for example, for illnesses, where more than one time dosage is needed daily and thanks to this multi-segment capsule, one can take one capsule and the segments may dissolve sequentially with the required time delay in between tailored by the density of the enteric barrier, thus, providing the required daily dosage.

[0097] In some embodiments, there is provided an enterically modified barrier for use in a multi-segment capsule comprising a barrier having a composition as disclosed herein. The enteric barriers can have different compositions such that that they dissolve in the stomach or in the intestine or in both sequentially as a function of the pH.

[0098] FIGS. 11-12 show example results from example implementations of the MSDC 100. FIG. 11 shows a panel of images depicting the dissolution of an example embodiment of the MSDC 100 in a simulated intestinal fluid of pH 7.4 after full payload release. FIG. 12 shows a panel of images, diagrams, and data plots characterizing an example embodiment of the MSDC 100 that contained fluorescent dyes as payload substances. FIG. 12, panel A, shows image of an example FITC-Rhodamine capsule; FIG. 12, panel B, shows example fluorescent microscopic images of FITC-Rhodamine capsule separated by barrier disk; FIG. 12, panel C, shows a diagram of an example embodiment of an enteric barrier with a 4% enteric polymer density; and FIG. 12, panel D, shows a time-lapse of FITC-Rhodamine capsule dissolution.

[0099] FIG. 13 shows a diagram depicting an example method for fabricating an example embodiment of the enteric barrier, in accordance with the present technology, such as enteric banders 115, 125. The method can include seeding a barrier structure with enteric polymers through immersion, removal, and drying processes to render the enteric bander. In some embodiments, the bander structures can be formed as barrier discs, e.g., prior to implementation of the seeding method to produce the enteric barriers. For instance, the barrier discs can be formed by first cast molding a barrier structure (e.g., disc) based on a shape and size of a mold; then hardening and extracting the casted barrier structure.

[00100] Also disclosed are devices, systems, and methods for robotic micromotor payload delivery capsules for time-controlled drug release.

[00101] Example embodiments of the robotic micromotor payload delivery capsules can provide a robotic pill system that leverages the efficient propulsion of biological and synthetic micromotors to accelerate pill disintegration and overcome mucosal barriers, increasing bioavailability with lower doses and fewer side effects. In addition, advanced bio-inspired robotic capsules offer enhanced macromolecule bioavailability comparable to the subcutaneous injections. The future of precision medicine is envisioned to be affected by the disclosed robotic micromotorbased capsules, e.g., encapsulating diverse microrobots with unique capabilities within pharmaceutical carriers, thereby offering groundbreaking opportunities for enhanced therapeutic interventions.

[00102] Oral dosage forms, such as tablets and capsules, remain the most convenient and cost- effective method for drug administration, especially for chronic conditions. These formulations can deliver a wide range of therapeutics, including peptides, small molecules, and drug-loaded nanoparticles, with customizable release profiles for optimized outcomes. They also enable targeted treatment in the gastrointestinal tract (GI) by leveraging pH gradients. However, effective drug absorption is often challenged by physiological barriers like digestive enzymes, stomach acidity, and the mucosal barrier, which can degrade drugs or hinder their absorption. Many drugs exhibit poor solubility and permeability in gastrointestinal fluids, which greatly limits their dissolution and absorption. Another crucial factor is gastric transit time since rapid transit can limit the time a drug’s absorption window and reduce its effectiveness. These challenges often lead to suboptimal dosing and lower bioavailability (e.g., the fraction of the drug that enters the systemic circulation and is available to exert its intended biological effect), compromising therapeutic efficacy and risking treatment failure. Thus, innovative strategies are essential to enhance drug absorption and improve therapeutic outcomes.

[00103] FIG. 7 shows a diagram illustrating an example embodiment of a multi-scgmcnt capsule 700, in accordance with the present technology, which enable tailored, time-tunable delivery of multiple drugs and doses throughout the day. The example multi-segment capsule 700 includes a capsule assembly 705 that comprises a body 707 and a cap 709, which the cap 709 is configured to be dissolvable in a fluid (e.g., one or more gastrointestinal fluids such as gastric juice (of the stomach), bile, pancreatic juice (released in the small intestine), and/or saliva or mixture thereof), and the body 707 includes an enteric coating capable of preventing or slowing dissolution of the body 707 in the fluid. The example multi-segment capsule 700 incorporates enteric barriers 715, 725 with varying densities, spatially isolating each segment and facilitating timely programmable precise controlled release of different drug pay loads. The example multi-segment capsule 700 can include robotic micromotors in at least one or some of the capsule segments 710, 720, 730 that also contain the drug levodopa for time-controlled treatment of Parkinson’s disease using a single pill that the Parkinson’s disease patient would orally administer just once a day to manage the effects of Parkinson’s disease. As illustrated in FIG. 7, the multi-segment capsule 700 incorporates robotic micro- stirrers in the first segment 710 to provide immediate therapeutic action and addresses morning “off” periods when symptoms are severe. Subsequent segments deliver intermediate and sustained release doses to maintain therapeutic levels and minimize fluctuations. Such an approach can tackle the complexities of polypharmacy, enabling personalized medication regimens while enhancing therapeutic effectiveness and patient outcomes.

[00104] FIG. 8 shows two comparative data plots 880 and 890 depicting an example Parkinson’s disease patient’s management of the drug levodopa (L-Dopa) over the course of a day. A Parkinson’s disease is a progressive neurodegenerative disorder that causes pain, rigidity, tremors, and postural instability when the patient has an imbalance in dopamine levels in the brain. Levodopa increases dopamine levels, but over time, it can lead to an excess of dopamine, which can cause dyskinesis (involuntary, uncontrolled movements). When levodopa levels taper off over time, the patient is at risk to undergo akinesia (difficulty or inability to initiate voluntary movements, ranging from delayed responses to a complete lack of movement). Data plot 880 depicts the plasma levels of levodopa in a Parkinson’s disease patient when orally administering the standard, conventional multi-pill regime (from pill matrix 888) three times per day to manage dopamine and control the symptoms of Parkinson’s disease. As shown by the data plot 880, the patient should take three doses of the medication at certain times a day to manage levodopa levels to avoid dyskincsis and akinesia. As depicted in the data plot 890, the patient’s use of the multisegment capsule 700 can control the release of three different doses of levodopa throughout the course of the day through a single oral administration of the multi-segment capsule 700 at one time of the day.

[00105] In some embodiments in accordance with the disclosed multi-segment capsule technology, a robotic micromotor payload delivery capsule for time-controlled drug release includes a capsule body comprising at least two segments; a first drug coupled to or mixed with a first set of microrobotic structures comprising at least one of a magnesium (Mg) mirostirrer structure, an algae micromotor, or a zinc (Zn) microtube structure, configured to release from a first segment of the capsule body upon dissolution of an outer wall of the first segment; and a second drug coupled to or mixed with a second set of microrobotic structures comprising at least one of the Mg mirostirrer structure, the algae micromotor, or the Zn microtube structure, configured to release from a second segment of the capsule body upon dissolution of an outer wall of the second segment, wherein the second segment is separated from the first segment by a barrier that protects contents of the second segment during, at least, dissolution of the first segment.

[00106] FIG. 9 shows an example embodiment of a multi-segment robotic micromotor payload delivery capsule 900, in accordance with the present technology, for time-controlled drug release of multiple payloads at different times and locations of the gastrointestinal tract of a patient user. The multi-segment robotic micromotor payload delivery capsule 900 can include the features of any of the example embodiments of the multi-segment capsule 10, such as the plurality of capsule segments (e.g., a first capsule segment 921, a second capsule segment 922, and a third capsule segment 923) separated by one or more enteric barriers 930A, 930B. The multi-segment robotic micromotor payload delivery capsule 900 includes a capsule assembly that comprises a body and a cap, with the cap configured to be dissolvable in a fluid (e.g., one or more gastrointestinal fluids), and the body including an enteric coating capable of preventing or slowing dissolution of the body in the fluid. Each of capsule segments 921, 922, 923 can provide a specific function to the multisegment capsule 900. Each of capsule segments 921, 922, 923 can have different or the same microrobots, including the Zn rocket microrobots (shown as contained in the first capsule segment

921), the Mg microstirrer microrobots (e.g., shown as contained in the second capsule segment

922), and the biohybrid algae microrobots (e.g., shown as contained in the third capsule segment 93), but are not limited to these microrobots shown in the diagram of FIG. 9. Each type of microrobot in the respective segment can release the payload substance contained in the respective capsule segment (e.g., drug) in a different manner.

[00107] For example, the exemplary Zn rocket microrobots can enhance drug penetration upon release from the first capsule segment 921 , the exemplary Mg microstirrer microrobots can provide immediate release and stirring of released drugs, and the exemplary biohybrid algae microrobots can promote sustained release of the released drugs. Notably, each capsule segment can have different or the same embodiment phase and/or configuration (e.g., liquid, solid, gel, nanoparticles, liposomes, macromolecules, micromolecules, micelles, and/or polymer). Encapsulation of materials in the segments is not limited to drugs or medications, as it can also carry any oral devices, such as mechanical devices or sensors.

[00108] Table 2 lists other non-limiting example materials or mechanical devices that can be encapsulated and carried by an example embodiment of the disclosed multi-segment capsule device in accordance with the present technology. Table 2 [00109] FIG. 10A shows an example embodiment of a closed-loop sense-act multi-segment capsule 1000, in accordance with the present technology. The closed-loop sense-act multisegment capsule 1000 includes a capsule assembly 1015 that comprises a body 1017 and a cap 1019. The cap 1019 is configured to be dissolvable in a fluid (e.g., one or more gastrointestinal fluids such as gastric juice (of the stomach), bile, pancreatic juice (released in the small intestine), and/or saliva or mixture thereof). The body 1017 includes an enteric coating 1018 capable of preventing or slowing dissolution of the body 1017 in the fluid. The closed-loop sense-act multisegment capsule 1000 includes a plurality of capsule segments 1020 contained in the capsule assembly 1015. In some embodiments, the plurality of capsule segments 1020 include at least a first capsule segment 1021 and a second capsule segment 1022. Each of the plurality of capsule segments 1020 includes an interior region, i.e., the first capsule segment 1021 having an interior region 1025 A, and the second capsule segment 1022 having an interior region 1025B. The interior regions 1025A, 1025B are capable of storing an individual payload substance and/or a sensor contingent of the closed-loop sense-act multi-segment capsule 1000. As illustrated in FIG. 10A, the first capsule segment 1021 is positioned in the capsule assembly 1015 to be adjacent to the cap 1019 (and/or may be at least partially encapsulated by the cap 1019), and the second capsule segment 1022 is positioned in the capsule assembly 1015 to be at least partially encompassed by the body 1017. While not shown in the diagram of FIG. 10A, the closed-loop sense-act multisegment capsule 1000 can include a third capsule segment or additional capsule segment(s) among the plurality of capsule segments 1020. The closed-loop sense-act multi-segment capsule 1000 includes at least one enteric barrier 1030 positioned between and separating two capsule segments of the plurality of capsule segments 1020 in the capsule assembly 1015. The enteric barrier(s) 1030 can include one or more enteric polymers within a matrix material.

[00110] Example implementations of the closed-loop sense-act multi-segment capsule 1000 can include closed-loop management of disease states characterized by narrow therapeutic windows, drug variability, or nutrient deficiencies, and physiological monitoring of diseases, including but not limited to Parkinson’s Disease, diabetes, cardiovascular disease, inflammatory bowel diseases (IBS), epilepsy, nutritional deficiency disorders, and Gl-related diseases. The sensed data enables remote monitoring by a healthcare provider, caregiver, or external computing device for therapy optimization.

[00111] In some embodiments, a capsule body of the closed-loop sense-act multi-segment capsule 1000 can include a plurality of spatially separated payload-containing capsule segments or reservoirs, configured for sequential, controlled, and/or on-demand release, e.g., within a gastrointestinal (GI) environment. One or more integrated sensing unit can be disposed within the capsule body, where the sensing unit is configured to monitor in situ physiological signals or luminal drug concentrations within the GI tract. In some embodiments, the closed-loop sense-act multi-segment capsule 1000 can include a data processing unit, which can be operably coupled to the sensing unit, configured to process sensor data and determine a release trigger condition based on a predefined therapeutic threshold or physiological signal. In some embodiments of the closed- loop sense-act multi-segment capsule 1000, one or more actuation mechanisms operably associated with the payload-containing reservoirs are configured to release therapeutic or nutritional agents from one or more of the reservoirs in response to the release trigger condition and adjustment of drug release profiles. In some embodiments, a wireless communication module is operably coupled to the data processing module for transmitting sensed data to an external device or receiver, enabling real-time monitoring, feedback control, or adaptive therapeutic adjustment. [00112] Example implementations of the closed-loop sense-act multi-segment capsule 1000 can include one or more of the following features and/or monitoring capabilities. For example, the sensing unit can be configured to detect one or more of: therapeutic drug level(s) (e.g., Levodopa); physiological parameter(s) (e.g., pH, temperature, ORP, pressure); presence and/or level(s) of biomarkers, metabolites (e.g., glucose, lactate, ketones), nutrients (e.g., iron, zinc, magnesium, calcium, vitamins), and/or minerals and electrolytes (e.g., Na⁺, K⁺, CF, Mg²⁺); hormonal level(s), presence and/or level(s) of inflammatory markers (e.g., CRP, Cytokines); presence and/or level(s) of oxidative stress markers (e.g., ROS, ORP); presence and/or level(s) of microbiome metabolites (e.g., SCFA, Bile Acids); presence and/or level(s) of protein or peptide biomarkers; hydration status; GI motility or pressure changes; gas generation (e.g., hydrogen from magnesium reaction); enzyme activities; or others. In some embodiments, the sensor unit of the closed-loop sense-act multi-segment capsule 1000 can include one or more of: electrochemical sensor(s), impedancebased sensor(s), piezoelectric sensor(s), microneedle-based microfluidic sensor(s) (e.g., sampling or real-time sensing), molecularly imprinted polymer (MIP) sensor(s), ion-selective field-effect transistor(s) (ISFET), microfluidic biosensor(s), conductivity sensors, and/or capacitive sensor(s). [00113] In some embodiments, the sensor unit of the closed-loop sense-act multi-segment capsule 1000 can include one or more: biochemical-responsive polymer(s), redox-based sensor(s), voltametric sensor(s), potentiometric sensor(s), nitric oxide (NO) sensor(s), osmolarity sensor(s), conductivity scnsor(s), salinity scnsor(s), accclcromctcr(s) (e.g., for characterizing capsule motion), magnetometer(s) (e.g., for magnetic field tracking), location-tracking sensor(s) (e.g., for pH profile-based or external magnetic field guidance), radio frequency identification ( RFID) and/or near' field communication (NFC) based sensor(s), ultrasound- triggered sensor(s), optical signal sensor(s) (e.g., for in-body tracking), battery-free piezoelectric sensor(s) (e.g., for energy harvesting), fluid-responsive sensor(s), immunosensors (e.g., for antibody-based detection), aptasensor(s) (e.g., DNA/RNA aptamer-based), nanomaterial-enhanced sensors (e.g., graphene, CNT, gold nanoparticle-based sensors), DNA/RNA biosensor(s) (e.g., for genetic material detection), chemical gradient sensor(s) (e.g., for disease state detection), and/or acoustic/vibration- based sensor(s) (e.g., for GI wall movement).

[00114] The closed-loop sense-act multi-segment capsule 1000 can be configured in a variety of capsule sizes, e.g., including but not limited to size 000. The size may be primarily dependent on the intended therapeutic application, required drug payload, sensor configuration, and patientspecific needs. With the continuous advancement in micro- and nanofabrication technologies, particularly through the emergence of nanotechnology-enabled sensor platforms, the sensing and actuation components of the closed-loop sense-act multi-segment capsule 1000 can be miniaturized so as to be configured to a standard capsule size, such as size 000, albeit not limited to this size. For example, highly sensitive biosensors, flexible electronics, and ultra-low power circuits can be manufactured and integrated within smaller capsule formats, without compromising device functionality or performance. Moreover, the example embodiments of the closed-loop sense-act multi-segment capsules 1000 can be adaptable to accommodate various oral drug formulations, including highly potent drugs with low effective doses which require minimal compartment volume for therapeutic efficacy. The ability to deliver drugs with lower dosage requirements, combined with sensor miniaturization, enables use of smart capsules across a broad range of sizes (e.g., from 000 to smaller capsule sizes such as 00, 0, or even customized microcapsule formats). For example, this flexibility allows tailoring the capsule design based on disease indication, patient demographics (e.g., pediatrics, geriatrics), and targeted anatomical location within the gastrointestinal tract, ensuring broad applicability and scalability of this platform for future clinical and commercial translation.

[00115] In some implementations, the closed-loop sense-act multi-segment capsule 1000 can contain the drug levodopa and be used for levodopa dose management for Parkinson’s disease, in which closed-loop scnsc-act multi-scgmcnt capsule 1000 can dynamically adjust Icvodopa release internally (within the patient’s gastrointestinal tract) for optimizing therapeutic outcomes of the levodopa.

[00116] FIG. 10B shows an illustration and data plot illustrating an example implementation of the closed-loop sense-act multi-segment capsule 1000 providing closed loop dose detection and delivery of the drug levodopa for maintaining the drug concentration levels in a target therapeutic range. In some embodiments, the closed-loop sense-act multi-segment capsule 1000 can be engineered to integrate a levodopa monitoring device (e.g., a molecular sensor) and a payload reservoir within multiple segments of the multi-segment capsule so as to be responsive to the drug levels released by the closed-loop sense-act multi-segment capsule 1000 into the patient’s body (e.g., gastrointestinal tract). For example, the molecular sensor could be configured as a target molecule that can detect specific molecules like glucose, ions, pH, proteins, or nucleic acid, or other, and then produce a signal that is readable by a sensor. The closed-loop sense-act multisegment capsule 1000 is a theranostic system envisioned to contribute to maintaining levodopa levels within the therapeutic window for treatment of Parkinson’s disease, e.g., preventing subtherapeutic levels that cause therapeutic failure and overdoses that lead to toxic side effects. Levodopa and Parkinson’s disease are example drugs and disorders for some implementations of the closed- loop sense-act multi-segment capsule 1000, but it is understood that other drugs (and sensor(s)) can be employed by the closed-loop sense-act multi-segment capsule 1000 for treatment of this or other disorders and diseases.

[00117] The disclosed smart multi-segment capsule delivery system can play a transformative and impactful role in healthcare by advancing capsule-based closed-loop systems for ‘sense-act’ theranostic applications. These theranostic systems can combine diagnostic and therapeutic capabilities toward self-regulated therapeutic actions, such as drug delivery based on real-time physiological monitoring, without the need for external stimuli/actuation or human intervention, paving the way for more efficient, precise, and patient-centric healthcare solutions.

[00118] The seamless integration of robotic micromotors with pharmaceutical vehicles offers a versatile powerful personalized approach to drug delivery. This strategy enables on-demand, multi-drug, and site-specific releases tailored to individual patient needs. By combining active propulsion, controlled release, and multi-drug loading, closed-loop therapy, robotic-pill platforms address specific physical constraints within the gastrointestinal tract towards greatly enhanced biocompatibility. Such technological advances arc expected to have a major impact on drug delivery in the coming years and represent a significant step toward personalized and patientcentric drug delivery. The ability of oral robotic pills to enhance the treatment of different diseases should be assessed for evaluating the generalizability of these platforms. With their ability to operate in both gastric and intestinal environments, such robotic pill technology could benefit a wide range of therapeutic applications.

Example Implementations and Payload Substances

[00119] Example embodiments of the disclosed multi-segment capsules, in accordance with the present technology, can be adapted to administer a wide range of orally delivered substances, including but not limited to different dosages of the same active ingredient or multiple active ingredients (e.g., 2, 3, 4, 5, or more) in any combination without limitation. This flexibility applies whether the goal is single-active multiple-dose regimens or multiple-active combinations. For example, single-active multiple-dose regimens can include segregating distinct doses of the same drug into separate segments (e.g., an immediate-release dose plus one or more delayed-release or extended- release doses in a single capsule). For example, multiple- active combinations can include housing two, three, four, or more different active pharmaceutical ingredients (APIs) in physically isolated compartments, each with potentially distinct release profiles (e.g., immediate, delayed, or sustained) to accommodate varying pharmacokinetics, minimize drug-drug interactions, and/or optimize therapeutic efficacy.

[00120] By way of non-limiting examples, substances suitable for multi-segment capsule encapsulation include, but are not limited to:

[00121] 1. Neurological and Psychiatric Medications. Multi-segment capsules can combine immediate-release doses to address acute symptoms with controlled-release doses for sustained management throughout the day (e.g., morning vs. evening compartments). The payload substance can include the following non-limiting examples.

• Alzheimer’s Disease o Cholinesterase Inhibitors (e.g., Donepezil, Rivastigmine) o NMDA Receptor Antagonists (e.g., Memantine) o Investigational beta-amyloid or tau-targeting therapies

• Parkinson’s Disease o Levodopa/Carbidopa (immediate- and controlled-release) o Dopamine Agonists (c.g., Ropinirolc, Pramipcxolc) o MAO-B Inhibitors (e.g., Selegiline) o COMT Inhibitors (e.g., Entacapone)

• Epilepsy I Seizure Disorders o Traditional Agents (e.g., Carbamazepine, Phenytoin, Valproic Acid) o Newer Agents (e.g., Lamotrigine, Levetiracetam)

• Depression and Anxiety o SSRIs (e.g., Fluoxetine, Sertraline) o SNRIs (e.g., Duloxetine) o Tricyclics (e.g., Amitriptyline) o Benzodiazepines (e.g., Diazepam, Alprazolam)

• Psychotic Disorders o Atypical Antipsychotics (e.g., Quetiapine, Olanzapine) o Typical Antipsychotics (e.g., Haloperidol)

• Sleep Disorders o “Z-Drugs” (e.g., Zolpidem) o Other Sedative-Hypnotics (e.g., Eszopiclone)

[00122] 2. Cardiovascular and Metabolic Drugs. Multiple compartments can deliver different doses at specific times (c.g., a higher dose of antihypertensive at night when BP surges, followed by a lower maintenance dose in the morning). The payload substance can include the following non-limiting examples.

• Antihypertensives o ACE Inhibitors (e.g., Lisinopril) o ARBs (e.g., Losartan) o Beta Blockers (e.g., Metoprolol) o Calcium Channel Blockers (e.g., Amlodipine) o Diuretics (e.g., Hydrochlorothiazide)

• Antiarrhythmics o Class I (e.g., Flecainide) o Class III (e.g., Amiodarone, Sotalol) • Antihyperlipidemics o Statins (e.g., Atorvastatin) o Fibrates (e.g., Fenofibrate) o Bile Acid Sequestrants (e.g., Cholestyramine)

• Antidiabetics o Metformin (immediate- and extended-release) o Sulfonylurcas (e.g., Glipizide) o DPP-4 Inhibitors (e.g., Sitagliptin) o SGLT2 Inhibitors (e.g., Canagliflozin) o GLP- 1 Receptor Agonists (oral versions under development)

• Thyroid Hormone Replacement o Levothyroxine (various brand formulations)

[00123] 3. Infectious Diseases. Segmented capsules can combine multiple anti-infective agents (e.g., for HIV or TB regimens) that release sequentially or at different times to maximize therapeutic effect or reduce drug interactions. The pay load substance can include the following non-limiting examples.

• Antibiotics o Penicillins (e.g., Amoxicillin) o Tetracyclines (e.g., Doxycycline) o Fluoroquinolones (e.g., Lcvofloxacin) o Macrolides (e.g., Azithromycin)

• Antituberculars o Isoniazid, Rifampin, Pyrazinamide (in combination therapy)

• Antivirals o HIV Therapies (e.g., Lamivudine, Tenofovir) o Hepatitis Therapies (e.g., Sofosbuvir) o Influenza (e.g., Oseltamivir) o Investigational broad-spectrum antivirals

• Antifungals o Triazoles (e.g., Fluconazole) o Echinocandins (some oral forms in development) [00124] 4. Oncology and Immunomodulatory Agents. Multi-segment capsules can stagger doses of chemotherapy agents, reducing toxicity and simplifying combination regimens. The payload substance can include the following non-limiting examples.

• Oral Chemotherapeutic s o Capecitabine (Xeloda) o Temozolomide (Temodar) o Tyrosine Kinase Inhibitors (e.g., Imatinib, Erlotinib)

• Hormone-Dependent Cancers o Anti-estrogens (e.g., Tamoxifen) o Aromatase Inhibitors (e.g., Anastrozole) o Anti-androgens (e.g., Enzalutamide)

• Immunomodulators o Thalidomide, Lenalidomide (multiple myeloma) o Investigational oral immunotherapies

• Other Investigational o Novel targeted agents, gene therapies, or small-molecule inhibitors

[00125] 5. Gastrointestinal and Hepatic. Multi-segment capsules might separate different layers or pH-based releases, delivering therapy at targeted segments of the GI tract. The payload substance can include the following non-limiting examples.

• Proton Pump Inhibitors (PPIs) o Omeprazole, Esomeprazole

• H2 Receptor Antagonists o Ranitidine (some formulations withdrawn in certain markets) o Famotidine

• Bile Acid Sequestrants o Cholestyramine (sometimes used for Gl issues beyond cholesterol)

• IBD / IBS Treatments o 5-ASA Derivatives (e.g., Mesalamine) o Oral steroids (e.g., Budesonide) in some regimens

• Antiemetics o Ondansetron (ODT / film, or other standard tablets) [00126] 6. Respiratory and Allergy. The payload substance can include the following nonlimiting examples. Segmented capsules can time medication release to align with peak symptom periods (e.g., morning vs. night).

• Asthma / COPD Maintenance o Some oral bronchodilators (e.g., Theophylline) o Leukotriene Inhibitors (e.g., Montelukast)

• Allergy / Antihistamines o Second-generation antihistamines (e.g., Cetirizine, Fexofenadine)

[00127] 7. Musculoskeletal and Anti-Inflammatory. The exemplary multi-segment approach can separate loading doses from maintenance doses or schedule different anti-inflammatories across the day. The payload substance can include the following non-limiting examples.

• NSAIDs o Ibuprofen, Naproxen, Diclofenac

• Disease-Modifying Antirheumatic Drugs (DMARDs) o Methotrexate (some regimens use split dosing in a single day) o JAK inhibitors (e.g., Tofacitinib)

• Osteoporosis Therapies o Bisphosphonates (e.g., Alendronate, but these often have strict administration instructions)

• Gout Management o Allopurinol, Febuxostat

[00128] 8. Analgesics and Pain Management. Combining rapid-onset pain relief with delayed-release forms in a single capsule can improve adherence and control pain more consistently. The payload substance can include the following non-limiting examples.

• Non-Opioid o Acetaminophen (paracetamol) o Various immediate- and extended-release NSAIDs

• Opioid o Extended-release formulations (e.g., Morphine ER, Oxycodone ER)

• Adjuvant Analgesics o Neuropathic pain agents (e.g., Gabapentin, Pregabalin) [00129] 9. Reproductive Health and Hormone Therapy. Multi-segment capsules could adjust hormone release throughout a day or over a multi-day cycle. The payload substance can include the following non-limiting examples.

• Oral Contraceptives o Combined estrogen-progestin pills o Progestin-only pills

• Hormone Replacement Therapy o Estrogens, progestins, or combinations for menopausal symptom relief

[00130] 10. Nutritional and Supplemental Agents. Segmented capsules can keep certain vitamins or minerals physically separated if they interact in solution (e.g., iron and calcium), or deliver them at different times for optimal absorption. The payload substance can include the following non-limiting examples.

• Vitamins o Fat-soluble (A, D, E, K) o Water-soluble (C, B-complex)

• Minerals o Calcium, Magnesium, Iron, Zinc

• Essential Fatty Acids o Omega-3 (EPA/DHA) in certain oral capsules

• Amino Acids / Protein Supplements o Individual amino acids (e.g., L-arginine, L-lysine)

• Herbal and Botanical Supplements (not FDA-approved for strict therapeutic claims) o Turmeric/Curcumin o Ginkgo biloba o St. John’s Wort

• Nutraceuticals o CoQlO, other antioxidants o Probiotics

[00131] 11. Other Notable Categories. The payload substance can include the following nonlimiting examples.

• Immunosuppressants o Tacrolimus, Sirolimus (common in transplant patients)

• Oral Vaccines or Vaccine-Like Preparations o Some are in development (investigational)

• Lifestyle Medications o PDE5 Inhibitors (e.g., Sildenafil) - though typically single-dose usage

• Smoking Cessation o Nicotine replacement therapy in oral forms (e.g., nicotine gum/lozenges; though not typically in capsules) o Bupropion (sustained-release) o Varenicline

[00132] In some implementations, the payload substance(s) of the disclosed multi-segment capsule technology can include representative classes of oral pain-relieving agents. For instance, such agents and substances may be FDA-approved or not, and can be adapted for use in multisegment capsules, with suitable modifications to dosage form, excipient compatibility, and release kinetics.

[00133] Pain relief examples include, but are not limited to:

[00134] 1. Non-Opioid Analgesics

• Acetaminophen (Paracetamol) o Mechanism: Central analgesic and antipyretic activity. o Common Uses: Mild to moderate pain, fever reduction. o FDA Status: Approved for oral use; often co-formulated with opioids (e.g., hydrocodone, oxycodone). o Example Multi-Segment Application: An immediate-release compartment can address acute pain while a second segment provides a delayed or extended release to maintain plasma levels.

• Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) o Mechanism: Inhibition of COX enzymes, reducing prostaglandin synthesis. o Examples:

■ Ibuprofen, Naproxen, Diclofenac (FDA-approved)

■ Celecoxib (COX-2 selective; FDA-approved)

■ Etoricoxib (COX-2 selective; not FDA-approved but used internationally) o Indications: Mild to moderate pain, inflammatory conditions (e.g., arthritis, musculoskeletal injuries). o Example Multi-Segment Application: Separate daytime and nighttime compartments with appropriate dosing intervals to reduce GI side effects and maintain consistent analgesia.

• Salicylates o Acetylsalicylic Acid (Aspirin) o FDA Status: Approved for analgesia, though widely used for antiplatelet activity. o Example Multi-Segment Application: A first segment for immediate symptomatic relief and a second segment combining aspirin with other supportive agents (e.g., gastroprotective).

[00135] 2. Opioid Analgesics. Opioids are commonly indicated for moderate to severe pain.

One skilled in the art will recognize that their potency and pharmacokinetics demand precise formulation to mitigate risks of overdose, tolerance, and dependence.

• Immediate-Release Opioids o Examples: Codeine, Tramadol, Hydrocodone, Oxycodone IR, Morphine IR, Tapentadol IR. o FDA Status: Multiple brand and generic formulations approved. o Example Multi-Segment Application: Initial burst segment for breakthrough pain followed by a sustained-release opioid or co-analgesic in the second segment.

• Extended-Release Opioids o Examples: Oxycodone ER (OxyContin), Morphine ER (MS Contin), Hydromorphonc ER (Exalgo), Tapentadol ER (Nucynta ER), Methadone tablets (for chronic pain). o FDA Status: Various formulations approved, each with REMS (Risk Evaluation and Mitigation Strategy) considerations. o Example Multi-Segment Application: Combine an extended-release opioid with a different analgesic class or an abuse-deterrent agent in a separate compartment.

• Partial Agonists I Mixed Agonist- Antagonists o Buprenorphine (more commonly sublingual or transdermal, but oral forms exist internationally). o Example Multi-Segment Application: Potentially co-formulated with other mild analgesics or adjuncts (c.g., NSAIDs) within separate compartments to reduce abuse potential and manage multiple pain pathways.

[00136] 3. Adjuvant Analgesics for Chronic Pain. Though not primarily classified as analgesics, these agents can significantly enhance pain control, especially in neuropathic pain or fibromyalgia. Examples include:

• Anticonvulsants o Gabapentin, Pregabalin (FDA-approved for postherpetic neuralgia, diabetic neuropathy, fibromyalgia). o Multi-Segment Application: Segregate different doses or combine with a primary analgesic (e.g., NSAID) for 24-hour coverage.

• Antidepressants o Tricyclic Antidepressants (Amitriptyline, Nortriptyline), SNRIs (Duloxetine, Milnacipran). o FDA Status: Duloxetine approved for diabetic neuropathy and fibromyalgia, others used off-label. o Multi-Segment Application: Morning segment for stimulating antidepressant coverage and an evening segment for sleep-enhancing analgesic effect.

• Muscle Relaxants o Cyclobenzaprine, Methocarbamol, Tizanidine. o Multi-Segment Application: Suitable for combined therapy in musculoskeletal pain to reduce spasms, each compartment timed for daytime alertness vs. nighttime sedation.

[00137] 4. Herbal / Alternative Oral Analgesics (e.g., substances not necessarily approved by a regulatory institution, such as the FDA, for strict analgesic claims). For example, the herbal and/or alternative oral analgesics could be placed in a separate compartment to avoid direct interaction with synthetic APIs or to allow different dissolution profiles for complementary effects. Examples include:

• Turmeric/Curcumin, Boswellia Serrata, Willow Bark Extract, CBD (Cannabidiol) Formulations.

[00138] 5. Investigational or Non-Approved Oral Analgesics. For example, segregation allows experimental agents to be released in a controlled manner alongside standard-of-care analgesics, potentially improving patient compliance in clinical trials.

• Novel NSAIDs, Ion Channel Blockers (e.g., Navi.7 inhibitors), TRPV1 Antagonists.

[00139] Anti-cancer drug examples include, but are not limited to:

[00140] 1. Traditional Cytotoxic Chemotherapies

• Capecitabine (Xeloda) o Class: Antimetabolite (prodrug of 5-fluorouracil) o FDA Approval: Yes, indicated for metastatic breast cancer and colorectal cancer. o For example: Frequently used in combination (e.g., with oxaliplatin), activated primarily in tumor tissue, reducing some systemic toxicity.

• Temozolomide (Temodar) o Class: Alkylating agent o FDA Approval: Yes, for glioblastoma multiforme and anaplastic astrocytoma. o For example: Known for crossing the blood-brain barrier, typically administered in multi-day cycles.

• Etoposide (VP- 16) (Oral Form) o Class: Topoisomerase II inhibitor o FDA Approval: IV form widely used; oral form approved for certain indications, though less common. o For example: Often part of combination regimens for small cell lung cancer, testicular cancer.

• Cyclophosphamide (Oral Form) o Class: Alkylating agent o FDA Approval: Yes, though IV administration is more common. o For example: Indicated for various malignancies, including breast cancer, lymphomas, and leukemias.

[00141] 2. Targeted Therapies (Small-Molecule Inhibitors)

• Tyrosine Kinase Inhibitors (TKIs) o Imatinib (Gleevec)

■ Indications: Chronic myeloid leukemia (CML), gastrointestinal stromal tumors (GIST). ■ Mechanism: Inhibits BCR-ABL tyrosine kinase and other kinases.

■ FDA Approval: Yes. o Erlotinib (Tarceva)

■ Indications: Non-small cell lung cancer (NSCLC) with EGFR mutations, pancreatic cancer (in combination).

■ Mechanism: EGFR tyrosine kinase inhibitor.

■ FDA Approval: Yes. o Gefitinib (Iressa)

■ Indications: EGFR-mutant NSCLC.

■ FDA Approval: Approved in various regions, including the U.S.; regulatory history with changes over time. o Sunitinib (Sutent)

■ Indications: Advanced renal cell carcinoma, GIST (after imatinib failure), pancreatic neuroendocrine tumors.

■ Mechanism: Multi-targeted TKI (VEGFR, PDGFR, etc.).

■ FDA Approval: Yes. o Sorafenib (Nexavar)

■ Indications: Hepatocellular carcinoma, renal cell carcinoma, thyroid carcinoma.

■ Mechanism: Multi-kinase inhibitor (VEGFR, PDGFR, RAF kinases).

■ FDA Approval: Yes. o Other TKIs: Lapatinib, Pazopanib, Axitinib, Crizotinib, Ceritinib, Alectinib, and numerous next-generation agents targeting distinct oncogenic pathways.

• Poly (ADP-ribose) Polymerase (PARP) Inhibitors o Olaparib (Lynparza), Rucaparib (Rubraca), Niraparib (Zejula), Talazoparib (Talzenna) o Indications: Ovarian, breast, prostate cancers (especially those with BRCA mutations). o Mechanism: Inhibit DNA repair in cancer cells with existing DNA repair pathway deficiencies. o FDA Approval: Yes, for multiple indications; approvals vary based on specific mutation profiles and tumor types.

• BRAF/MEK Inhibitors o Vemurafenib (Zelboraf), Dabrafenib (Tafinlar)

■ Indications: BRAF V600E-positive melanoma, sometimes other BRAF- mutant tumors. o Trametinib (Mekinist), Cobimetinib (Cotellic)

■ Indications: Typically used in combination with BRAF inhibitors for advanced melanoma. o Mechanism: Block aberrant MAPK pathway signaling. o FDA Approval: Yes, multiple combination regimens authorized.

• Other Targeted Agents o mTOR Inhibitors (e.g., Everolimus [Afinitor]) for renal cell carcinoma, breast cancer, neuroendocrine tumors. o Hedgehog Pathway Inhibitors (e.g., Vismodegib) for basal cell carcinoma. o IDH Inhibitors (e.g., Ivosidenib, Enasidenib) for IDH-mutated acute myeloid leukemia.

[00142] 3. Hormone-Dependent Cancers

• Anti-Estrogens / SERMs o Tamoxifen

■ Indication: Estrogen receptor (ER)-positive breast cancer.

■ FDA Approval: Yes. o Raloxifene

■ Indication: Primarily osteoporosis prevention; also reduces risk of invasive breast cancer in postmenopausal women.

• Aromatase Inhibitors o Anastrozole, Letrozole, Exemestane o Mechanism: Inhibit estrogen production in postmenopausal patients. o FDA Approval: Yes, for ER-positive breast cancer.

• Anti-Androgens o Enzalutamide (Xtandi), Apalutamide (Erleada), Darolutamide (Nubeqa) o Indications: Metastatic castration-resistant prostate cancer (mCRPC). o Mechanism: Block androgen receptor signaling. o FDA Approval: Yes, for advanced prostate cancer.

• Androgen Synthesis Inhibitors o Abiraterone Acetate (Zytiga) o Mechanism: Inhibits CYP17, reducing androgen production in prostate cancer. o FDA Approval: Yes.

[00143] 4. Immunomodulatory Agents o Immunomodulatory Drugs (IMiDs) o Thalidomide, Lenalidomide (Revlimid), Pomalidomide (Pomalyst) o Indications: Multiple myeloma, myelodysplastic syndromes, certain lymphomas. o Mechanism: Modulate immune response and angiogenesis; can induce malignant cell apoptosis. o FDA Approval: Yes, with REMS programs due to teratogenic risk. o Other Investigational Oral Immunotherapies o Checkpoint Inhibitors typically administered IV, but various oral immunomodulators are under development targeting alternative pathways.

[00144] 5. Other Investigational or Non- Approved Agents

• Novel Tyrosine Kinase Inhibitors o Next-generation EGFR, ALK, or other mutation- specific inhibitors. o May be approved in certain regions (e.g., EMA approvals) but not yet FDA- approved.

• Cyclin-Dependent Kinase (CDK) Inhibitors (Oral Investigational Formulations) o While FDA approvals exist for CDK4/6 inhibitors like Palbociclib, Ribociclib, and Abemaciclib in metastatic breast cancer, ongoing research explores additional indications and next-generation compounds.

• Epigenetic Modulators o Histone deacetylase (HD AC) inhibitors, DNA methyltransferase (DNMT) inhibitors, or LSD1 inhibitors in various stages of clinical trials.

Gene-Specific Targeted Agents o Agents that target rare mutations (e.g., RET fusions, NTRK fusions), some already FDA-approved but with limited populations. o Ongoing research may yield oral formulations for additional gene targets.

[00145] Example drugs for cardiovascular disease include, but are not limited to:

[00146] 1. Antihypertensives, including:

[00147] A. Renin-Angiotensin System (RAS) Inhibitors, including:

• Angiotensin-Converting Enzyme (ACE) Inhibitors o Representative Generic Names:

■ Benazepril (Lotensin)

■ Captopril (Capoten)

■ Enalapril (Vasotec)

■ Fosinopril (Monopril)

■ Lisinopril (Prinivil, Zestril)

■ Moexipril (Univasc)

■ Perindopril (Aceon)

■ Quinapril (Accupril)

■ Ramipril (Altace)

■ Trandolapril (Mavik) o Mechanism: Inhibit conversion of angiotensin I to angiotensin II, lowering vasoconstriction and aldosterone release. o FDA Status: Widely approved for hypertension, heart failure, post-myocardial infarction (MI), diabetic nephropathy.

• Angiotensin II Receptor Blockers (ARBs) o Representative Generic Names:

■ Azilsartan (Edarbi)

■ Candcsartan (Atacand)

■ Eprosartan (Teveten)

■ Irbesartan (Avapro)

■ Losartan (Cozaar)

■ Olmesartan (Benicar)

■ Telmisartan (Micardis) ■ Valsartan (Diovan) o Mechanism: Selective blockade of the angiotensin II type 1 (ATI) receptor. o FDA Status: Approved for hypertension, heart failure, diabetic nephropathy.

• Direct Renin Inhibitors o Aliskiren (Tekturna) o Mechanism: Directly inhibits renin, reducing formation of angiotensin I and II. o FDA Status: Approved for hypertension, though usage is relatively limited.

[00148] B. Beta Blockers, including:

• Nonselective (pi- and P2-) o Propranolol (Inderal) o Nadolol (Corgard) o Timolol (Blocadren; more commonly eyedrop for glaucoma, but oral forms exist) o Sotalol (Betapace; also a Class III antiarrhythmic) o Pindolol (Visken)

• Cardioselective (pi) Beta Blockers o Atenolol (Tenormin) o Betaxolol (Kerlone) o Bisoprolol (Zebeta) o Metoprolol (Lopressor, Toprol-XL) o Acebutolol (Sectral) o Nebivolol (Bystolic) - also has nitric oxide-mediated vasodilatory effect.

• Mixed/Additional Properties o Carvedilol (Coreg) - also blocks al receptors. o Labetalol (Trandate) - nonselective P + selective al blockade.

[00149] C. Calcium Channel Blockers (CCBs), including:

• Dihydropyridines o Amlodipine (Norvasc) o Felodipine (Plendil) o Isradipine (DynaCirc) o Nicardipine (Cardene; more often IV, but oral capsules exist) o Nifedipine (Procardia, Adalat) o Nimodipine (Nimotop; typically for subarachnoid hemorrhage, but still an oral dihydropyridinc) o Nisoldipine (Sular) o Lercanidipine, Lacidipine, Cilnidipine (primarily outside the U.S.)

• Non-Dihydropyridines o Diltiazem (Cardizem, Dilacor) o Verapamil (Calan, Isoptin) o Mechanism: Primarily reduce heart rate and contractility (more cardiac effects) plus mild vasodilation.

[00150] D. Diuretics, including:

• Thiazide and Thiazide-Like Diuretics o Hydrochlorothiazide (HCTZ) (Microzide) o Chlorthalidone (Thalitone) o Indapamide (Lozol) o Metolazone (Zaroxolyn)

• Loop Diuretics o Furosemide (Lasix) o Bumetanide (Bumex) o Torsemide (Demadex) o Ethacrynic Acid (Edecrin) - used when sulfa allergy is present.

• Potassium-Sparing Diuretics o Aldosterone Antagonists:

■ Spironolactone (Aldactone)

■ Eplerenone (Inspra) o Direct Epithelial Sodium Channel (ENaC) Inhibitors:

■ Amiloride (Midamor)

■ Triamterene (Dyrenium)

[00151] E. Centrally Acting Agents, including:

• Clonidine (Catapres)

• Methyldopa (Aldomet)

• Guanfacine (Tenex) • Moxonidine (Available in some regions outside the U.S.)

• Mechanism: Reduce sympathetic outflow from the CNS, lowering blood pressure.

[00152] F. Direct Vasodilators, including:

• Hydralazine (Apresoline)

• Minoxidil (Loniten) - potent vasodilator, used in severe or resistant hypertension.

• Diazoxide (historical use, mostly IV; some oral forms in the past).

[00153] Further example drugs for cardiovascular disease include, but are not limited to:

[00154] 2. Anti-Dyslipidemics, including:

[00155] A. HMG-CoA Reductase Inhibitors (Statins)

• Lovastatin (Mevacor)

• Simvastatin (Zocor)

• Pravastatin (Pravachol)

• Fluvastatin (Lescol)

• Atorvastatin (Lipitor)

• Rosuvastatin (Crestor)

• Pitavastatin (Livalo)

• Example Mechanism: Inhibit hepatic cholesterol synthesis; first-line for LDL reduction.

[00156] B. Bile Acid Sequestrants

• Cholestyramine (Questran)

• Colestipol (Colestid)

• Colesevelam (Welchol)

• Mechanism: Bind bile acids in the gut, forcing increased conversion of cholesterol to bile acids.

[00157] C. Fibrates

• Gemfibrozil (Lopid)

• Fenofibrate (Tricor, Lipofen)

• Fenofibric Acid (Trilipix)

• Mechanism: PPAR-a activation, significantly lowering triglycerides and modestly lowering LDL.

[00158] D. Niacin (Vitamin B3)

• Immediate-release, extended-release (Niaspan), and sustained-release forms. • Mechanism: Reduces hepatic VLDL secretion, lowering LDL and triglycerides while raising HDL.

• Use limited by flushing, hyperglycemia, hepatotoxicity at higher doses.

[00159] E. Cholesterol Absorption Inhibitors

• Ezetimibe (Zetia)

• Mechanism: Inhibits NPC1L1 transporter in the intestine, blocking dietary and biliary cholesterol uptake.

[00160] F. Omega-3 Fatty Acids

• Icosapent Ethyl (Vascepa) - purified EPA, indicated for high triglycerides and CV risk reduction.

• Omega-3-Acid Ethyl Esters (Lovaza) - mixture of EPA/DHA.

• Mechanism: Decrease hepatic triglyceride production.

[00161] G. Other / Investigational

• Bempedoic Acid (Nexletol) - ACL (ATP citrate lyase) inhibitor for LDL reduction in statin-intolerant patients.

• PCSK9 Inhibitors -injectable (e.g., Alirocumab, Evolocumab) and/or oral

[00162] Further example drugs for cardiovascular disease include, but are not limited to:

[00163] 3. Anti-Anginal I Ischemic Heart Disease Agents, including:

[00164] A. Oral Nitrates

• Iso sorbide Mononitrate (Imdur)

• Isosorbide Dinitrate (Isordil)

• Mechanism: Nitric oxide donor, dilates veins (reducing preload) and, to a lesser extent, arteries.

[00165] B. Ranolazine (Ranexa)

• Mechanism: Inhibits late inward sodium current, reducing calcium overload in cardiac myocytes.

• FDA Status: Approved for chronic angina.

[00166] C. Nicorandil

• Mechanism: Nitrate-like effect and K_ATP channel opening, used in some countries for angina.

[00167] Further example drugs for cardiovascular disease include, but are not limited to: [00168] 4. Antiarrhythmics, including:

[00169] A. Class I (Sodium Channel Blockers)

• Class IA o Quinidine (various salts) o Procainamide (mostly IV in U.S.; limited oral use) o Disopyramide (Norpace)

• Class IB o Mexiletine (Mexitil) - oral analogue of lidocaine.

• Class IC o Flecainide (Tambocor) o Propafenone (Rythmol) [00170] B. Class II (Beta Blockers)

[00171] C. Class III (Potassium Channel Blockers)

• Amiodarone (Cordarone, Pacerone) - also has Class I, II, and IV effects.

• Sotalol (Betapace) - combined P-blocking and Class III action.

• Dofetilide (Tikosyn) - pure Class III agent.

• Dronedarone (Multaq) - structurally similar to amiodarone, used for atrial fibrillation.

[00172] D. Class IV (Calcium Channel Blockers)

• Verapamil (Calan, Isoptin)

• Diltiazem (Cardizem)

• Mechanism: Slow AV nodal conduction, used for rate control in SVT, AF.

[00173] E. Other Notables

• Digoxin (Lanoxin) - a cardiac glycoside; negative chronotropc, positive inotropc, often used for rate control in AF or in heart failure.

• Ivabradine (Corlanor) - specifically lowers heart rate by inhibiting the funny current (If) in SA node (approved for HF, sometimes off-label for sinus tachyarrhythmias).

[00174] Further example drugs for cardiovascular disease include, but are not limited to:

[00175] 5. Heart Failure Therapies, including:

[00176] A. ARNI (Angiotensin Receptor-Neprilysin Inhibitor)

• Sacubitril/Valsartan (Entresto) - FDA-approved for HFrEF, showing mortality benefit vs. ACE inhibitor alone. [00177] B. SGLT2 Inhibitors (for HF)

• Dapagliflozin (Farxiga)

• Empagliflozin (Jardiance)

• Canagliflozin (Invokana) - primarily for T2DM but studied in HF.

• Mechanism: Increase glucosuria, reduce preload/afterload, beneficial hemodynamic and metabolic effects.

[00178] C. Hydralazine + Isosorbide Dinitrate (BiDil)

• Specifically FDA-approved in self-identified African American patients with HFrEF or those intolerant to ACE inhibitors/ARBs.

[00179] D. Mineralocorticoid Receptor Antagonists

• Spironolactone and Eplerenone (as noted above in diuretics) - proven mortality benefit in HFrEF.

[00180] E. Beta Blockers with HF Indication

• Carvedilol, Metoprolol Succinate ER, Bisoprolol - specifically indicated for HFrEF due to strong evidence of mortality benefit.

[00181] F. Other Adjuncts

• Digoxin - reduces hospitalizations, helps control heart rate in AF.

• Ivabradine - for patients with chronic HF who remain tachycardic despite beta-blockade.

[00182] Further example drugs for cardiovascular disease include, but are not limited to:

[00183] 6. Anticoagulants and Antiplatelets (Oral), including:

[00184] A. Vitamin K Antagonists

• Warfarin (Coumadin, Jantoven) - requires INR monitoring, narrow therapeutic index.

[00185] B. Direct Oral Anticoagulants (DOACs)

• Direct Thrombin Inhibitor o Dabigatran (Pradaxa)

• Factor Xa Inhibitors o Rivaroxaban (Xarelto) o Apixaban (Eliquis) o Edoxaban (Savaysa)

• Example Indications: Stroke prevention in atrial fibrillation (non- valvular-), VTE treatment, prophylaxis post-orthopedic surgery. [00186] C. Oral Antiplatelet Agents

• Aspirin (low-dose, e.g., 81 mg in the U.S.) - comerstone of secondary prevention for coronary artery disease, stroke.

• P2Y 12 Inhibitors o Clopidogrel (Plavix) o Prasugrel (Effient) o Ticagrclor (Brilinta; technically not a prodrug, but still taken orally) o Indications: Dual antiplatelet therapy (DAPT) post-stent placement or acute coronary syndromes.

[00187] D. Other Oral Agents

• Dipyridamole (Persantine) - often combined with aspirin (Aggrenox) for stroke prevention.

[00188] Further example drugs for cardiovascular disease include, but are not limited to:

[00189] 7. Miscellaneous and Regionally Approved CV Agents, including:

[00190] A. Anti-Obesity Agents (Relevant for CVD risk)

• Orlistat (Xenical, Alli)

• Phentermine/Topiramate ER (Qsymia)

• Naltrexone/Bupropion (Contrave)

• Liraglutide (Saxenda) / Semaglutide (Wegovy) - though many GLP-1 analogs are injectables, oral semaglutide (Rybelsus) exists for T2DM (with potential CV benefits).

[00191] B. Pulmonary Arterial Hypertension (PAH) Agents (Some used off-label or regionspecific)

• Bosentan (Tracleer) - Endothelin receptor antagonist (ERA) (oral).

• Ambrisentan (Letairis) - ERA (oral).

• Macitentan (Opsumit) - ERA (oral).

[00192] C. Vasodilators / Niche Uses

• Molsidomine - used in some countries for angina (similar to nitrates).

• Cilostazol (Pletal) - PDE3 inhibitor for intermittent claudication in peripheral artery disease (PAD), also has antiplatelet properties.

[00193] D. Investigational or Non-FD A- Approved Agents • Novel PDE inhibitors, novel vasodilators, next-generation RAAS modulators, or PCSK9 small-molcculc inhibitors (in development) - these may appear in clinical trials and could be approved in certain regions.

[00194] Example orally available anti-infective agents for lung infections include, but are not limited to:

[00195] 1. Antibiotics for Common Bacterial Respiratory Infections, including:

• Macrolides o Azithromycin (Zithromax) o Clarithromycin (Biaxin) o Mechanism: Inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit. o Indications: Community-acquired pneumonia, bronchitis, atypical infections (Mycoplasma, Chlamydophila). o FDA Status: Approved in many regions.

• Penicillins I Penicillin Combinations o Amoxicillin ± Clavulanate (Amoxil, Augmentin) o Ampicillin ± Sulbactam (Unasyn, though more common IV) o Mechanism: Inhibit bacterial cell wall synthesis; clavulanate or sulbactam inhibit P-lactamase. o Indications: Mild to moderate communi ty-acquired pneumonia, acute exacerbations of chronic bronchitis. o FDA Status: Approved; widely used.

• Cephalosporins (Select Oral Forms) o Cefdinir (Omnicef) o Cefpodoxime (Vantin) o Cefuroxime axetil (Ceftin) o Mechanism: Beta-lactams that block cell wall synthesis. o Indications: Various respiratory infections including pneumonia and bronchitis. o FDA Status: Approved.

• Fluoroquinolones o Levofloxacin (Levaquin) o Moxifloxacin (Avelox) o Ciprofloxacin (Cipro) - less ideal for typical pneumonia, but used for Gramnegative coverage. o Mechanism: Inhibit bacterial DNA gyrase and topoisomerase IV. o Indications: Bacterial pneumonia (especially “respiratory fluoroquinolones” like levofloxacin, moxifloxacin). o FDA Status: Approved but with cautions about resistance and adverse events.

• Tetracyclines o Doxycycline (Vibramycin) o Mechanism: Inhibits protein synthesis by binding to 30S ribosomal subunit. o Indications: Community-acquired pneumonia, atypical pathogens, COPD exacerbations. o FDA Status: Approved.

• Other Oral Antibiotics o Linezolid (Zyvox) - Effective against some resistant Gram-positive organisms (MRS A), though typically used cautiously. o Tedizolid (Sivextro) - Similar to linezolid, primarily for skin infections but possible off-label for pneumonia.

[001961 2. Anti-Tubercular Agents, including:

• Isoniazid (INH)

• Rifampin (RIF)

• Pyrazinamide (PZA)

• Ethambutol (EMB)

• Rifabutin, Rifapentine (longer half-lives than rifampin) o Mechanism: Target various aspects of Mycobacterium tuberculosis cell wall synthesis or protein synthesis. o Indications: First-line or adjunct TB therapy; typically used in combination regimens. o FDA/Global Status: Widely endorsed by WHO and many national health agencies for active TB treatment, latent TB prophylaxis (INH, RIF in specific regimens).

[00197] 3. Antifungals (for Pulmonary Fungal Infections), including: • Azoles o Fluconazole (Diflucan) - primarily for Candida, limited lung usage but occasionally for certain infections. o Itraconazole (Sporanox) - useful for histoplasmosis, blastomycosis. o Posaconazole (Noxafil), Voriconazole (Vfend) - often have IV/oral forms, used in Aspergillus infections; oral forms are critical for step-down therapy. o Isavuconazole (Cresemba) - broader-spectrum, used for invasive aspergillosis and mucormycosis. o Mechanism: Inhibit fungal cytochrome P450 enzyme, blocking ergosterol synthesis. o FDA Status: Varies by agent; many with proven efficacy for specific invasive fungal infections.

• Allylamines o Terbinafine (Lamisil) - Typically for dermatophytes; limited lung usage but possible for certain off-label indications.

• Echinocandins - Usually IV (e.g., Caspofungin, Micafungin); oral forms under development, though not widely available.

[00198] 4. Antivirals for Respiratory Viruses, including:

• Oseltamivir (Tamiflu) o Mechanism: Neuraminidase inhibitor for influenza A and B . o Indications: Treatment and prophylaxis of influenza. o FDA Status: Approved.

• Baloxavir Marboxil (Xofluza) o Mechanism: Cap-dependent endonuclease inhibitor (influenza virus replication). o FDA Status: Approved for uncomplicated influenza in certain patient groups.

• Investigational or Non-FD A- Approved Oral Antivirals o Agents targeting respiratory syncytial virus (RSV) or emerging pathogens. o Favipiravir (Avigan) - Approved in some countries for influenza; studied for various viral infections.

[00199] Example orally available agents for lung function/chronic respiratory diseases include, but are not limited to: [00200] 1 . Asthma and COPD, including:

• Leukotriene Modifiers o Montelukast (Singulair) - FDA-approved for asthma, allergic rhinitis. o Zafirlukast (Accolate) - FDA-approved for asthma. o Zileuton (Zyflo) - 5-lipoxygenase inhibitor, less commonly used due to liver monitoring requirements.

• Methylxanthines o Theophylline (Elixophyllin, Theochron) o Mechanism: Inhibits phosphodiesterase, increasing cAMP, causing bronchodilation; also adenosine receptor antagonist. o FDA Status: Older therapy for asthma/COPD, not first-line due to narrow therapeutic index.

• Phosphodiesterase-4 (PDE4) Inhibitors o Roflumilast (Daliresp) o Mechanism: Reduces inflammation via PDE4 inhibition in COPD. o FDA Status: Approved for severe COPD with chronic bronchitis.

• Oral Beta-2 Agonists o Albuterol (Salbutamol) - Typically inhaled; oral forms exist but are less commonly used. o Mctaprotcrcnol (rarely used in modem practice). o Mechanism: Bronchodilation; higher systemic side effects vs. inhaled route.

• Oral Corticosteroids o Prednisone, Prednisolone, Methylprednisolone o Mechanism: Broad anti-inflammatory effect. o FDA Status: Widely used short-term for exacerbations of asthma/COPD; longterm use limited by systemic side effects.

[00201] 2. Cystic Fibrosis (CF) Modulators, including:

• CFTR Potentiators / Correctors o Ivacaftor (Kalydeco) o Lumacaftor/Ivacaftor (Orkambi) o Tezacaftor/Ivacaftor (Symdeko) o Elexacaftor/Tezacaftor/Ivacaftor (Trikafta) o Mechanism: Correct or enhance CFTR protein function in patients with specific mutations. o FDA Status: Approved for CF with qualifying genotypes.

• Mucolytics / Hydrators (Oral forms less common) o Domase alfa is inhaled, not oral. o Hypertonic saline also inhaled. (No widely used oral equivalents for the same function.)

[00202] 3. Asthma and COPD Agents. Although these drugs target pulmonary vasculature more than airway function, they are often considered when discussing lung-related pharmacology.

• Endothelin Receptor Antagonists (ERAs) o Bosentan (Tracleer) - mainly oral. o Ambrisentan (Letairis) - oral. o Macitentan (Opsumit) - oral. o Mechanism: Block endothelin- 1 effects causing pulmonary vasodilation. o FDA/EMA Status: Approved for pulmonary arterial hypertension (PAH).

• Phosphodiesterase-5 (PDE5) Inhibitors o Sildenafil (Revatio) o Tadalafil (Adcirca) o Mechanism: Increase cGMP in pulmonary vasculature, leading to vasodilation. o FDA Status: Approved for PAH.

• Soluble Guanylate Cyclase (sGC) Stimulators o Riociguat (Adempas) - oral, indicated for PAH and chronic thromboembolic pulmonary hypertension (CTEPH).

[00203] 4. Other Oral Agents Influencing Fung Function

• Anticholinergics - Typically inhaled (tiotropium, ipratropium); very limited use in oral form due to systemic side effects.

• Immunosuppressants I Steroid-Sparing Agents (e.g., Methotrexate, Azathioprine): Sometimes used off-label for severe asthma, interstitial lung diseases, but not primarily lung-specific. • Agents for Interstitial Lung Diseases - Two main treatments for idiopathic pulmonary fibrosis are nintedanib and pirfenidone, both orally administered, but typically considered under specialized usage: o Nintedanib (Ofev) - FDA-approved for idiopathic pulmonary fibrosis (IPF), other progressive fibrosing ILDs. o Pirfenidone (Esbriet) - FDA-approved for IPF, has anti-fibrotic, antiinflammatory properties.

[00204] Other oral agents can include, but are not limited to:

• Novel Antibiotics I Antivirals

• Next-Generation CF Therapies (e.g., additional correctors, potentiators, or genetic therapies in oral formulation.)

• Anti-Inflammatory and Immunomodulatory (e.g., oral biologies or small molecules (e.g., JAK inhibitors) for severe asthma or chronic lung inflammation.)

• Phage Therapy (e.g., oral phage cocktails for drug-resistant bacterial infections.)

[00205] The disclosed embodiments of the multi-segment capsule technology are able to provide several advantages for oncology. Some examples include: combination therapy: many oncology regimens require multiple agents with different mechanisms; and multi- segment capsules can compartmentalize chemically incompatible APIs or different release schedules. Some examples include: patient compliance: oral therapies simplify the administration schedule versus frequent IV infusions; combining them in a single, multi-segment dosage form further decreases pill burden. Some examples include: phased or delayed release: some agents can benefit from time- staggered dosing (e.g., morning vs. evening compartments) to minimize toxicity or optimize synergy. Some examples include: global applicability: the capsule design can be adapted to regionally approved drugs or investigational agents, supporting clinical trials and personalized medicine approaches.

[00206] In some example embodiments, a multi-segment capsule comprises: (i) segmented compartments, (ii) time-controlled release mechanisms, and (iii) active ingredient compatibility. Segmented Compartments: One or more barriers or internal walls physically dividing the capsule interior into at least two segments. Each segment can house an individual dose form (e.g., powder, granule, mini-tablet, or liquid-filled micro-container (oil-based or aqueous), micropellets, coated beads, or microcapsules, semi-solid dispersions or gels, lyophilized or freeze-dried substances, multiparticulate systems with distinct release profiles). By selecting the appropriate dose form for each compartment whether it be a rapidly dissolving powder or a coated bead designed for delayed release the manufacturer can control the timing and rate of API or supplement delivery independently for each segment. Time-Controlled Release Mechanisms: By using distinct coatings or encapsulating materials (e.g., enteric polymers, pH-sensitive polymers, hydrogels), the release from each segment can be triggered at different pH levels or delayed by differing polymer erosion profiles. Active Ingredient Compatibility: Where multiple APIs are placed in the same capsule, the segment walls and sealing measures protect against unwanted interactions. In some cases, a desiccant or moisture-absorbing layer may be added to enhance stability.

[00207] Various configurations are possible, including biphasic release, (ii) separate APIs, and (iii) nutrient-drug combinations. Biphasic Release: An immediate burst release for rapid therapeutic effect in one segment, followed by a sustained-release profile in the second segment. Separate APIs: Two distinct active agents enclosed separately to avoid chemical incompatibilities, yet delivered in a single capsule to improve patient compliance. Nutrient-Drug Combinations: A vitamin or mineral supplement in one segment, paired with a prescription medication in another, timed to reduce negative absorption interactions.

[00208] Example advantages and industrial applications of the disclosed technology can include, but are not limited to: (1) improved patient compliance; (2) optimized pharmacokinetics; (3) reduced material footprint; and (4) versatility. Improved Patient Compliance: A single capsule containing multiple doses or multiple active compounds reduces the complexity of regimens, potentially leading to better adherence. Optimized Pharmacokinetics: Precise timing or sitespecific release may improve therapeutic outcomes by aligning drug availability with biological rhythms or disease cycles (e.g., Parkinson’s “wearing off’ phenomena, circadian blood pressure patterns). Reduced Material Footprint: Fewer separate capsules or tablets lessen packaging and may benefit manufacturing efficiency. Versatility: The design is adaptable across a broad range of clinical applications (e.g., monotherapy, combination therapy, prophylactic-therapeutic pairs, or drug-nutrient pairs).

[00209] Example embodiments can include, but are not limited to, the following. Example 1: A two-segment capsule designed to treat Alzheimer’s disease, containing an immediate-release dose of a cholinesterase inhibitor (first segment) and a delayed-release memantine formulation (second segment), providing both initial symptom control and sustained cognitive support. Example 2: A three-segment capsule for oncology patients undergoing combination therapy, with each segment containing a different chemotherapeutic agent set to release at 8-hour intervals, thereby simplifying complex dosing protocols over a 24-hour period. Example 3: A dual-segment capsule combining a morning dose of a beta blocker in the first compartment and an evening dose in the second, timed to release in accordance with known circadian variations in blood pressure. [00210] In an illustrative example, a multi-segment capsule is employed to deliver two therapeutic agents, Drug A and Drug B, or a second dose of Drug A in phased doses. Each segment possesses a distinct release profile to achieve a controlled, sequential administration. Various analytical techniques, including high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LC-MS/MS), immunoassays, or UV-visible spectrophotometry, can be used to measure the plasma concentrations of each drug and confirm release kinetics.

[00211] For this illustrative example, the capsule design can include the following. For the example segment #1 (Immediate-Release Drug A), the formulation can be: x mg of Drug A mixed with a rapidly dissolving carrier; and the release mechanism can be: dissolves in the stomach shortly after ingestion, providing an initial loading dose. For the example segment #2 (Delayed- Release Drug B), the formulation can be: y mg of Drug B or second dose coated or non-coated with an enteric polymer (e.g., Eudragit®); and the release mechanism can be: dissolves in the small intestine at pH > 5.5, avoiding gastric degradation and preventing early co-release with Drug A. For the (optional) example segment #3 (Extended-Release Drug A) [Optional], the formulation can be: x mg of Drug A embedded in a sustained-release matrix (e.g., hydrogel or wax-based); and the release mechanism can be: gradual diffusion over 8-12 hours to maintain therapeutic blood levels once the initial burst from Segment 1 subsides.

[00212] For the example implementation of this illustrative example, multiple (e.g., twelve) adult volunteers diagnosed with mild autoimmune arthritis can participate, and none have previously been exposed to these specific investigational doses. Each participant takes one multisegment capsule per day with breakfast over a 7-day evaluation period. For pharmacokinetic sampling, the implementations can include blood draw times of: 0.5, 1, 2, 4, 8, 12, and 24 hours post-administration on Days 1 and 7. Additional sampling can occur on Days 3 and 5 (through levels) to confirm steady-state kinetics if applicable. Therapeutic Monitoring can include inflammatory markers: Serum levels of C-reactive protein (CRP) and interleukin-6 (IL-6) measured pre-dose (baseline) and again on Days 4 and 7. Symptom Scoring: Each volunteer selfreports pain and stiffness via standardized questionnaires.

[00213] A variety of bioanalytical methods can be used to detect and quantify Drug A and Drug B in plasma or serum. The choice of technique can be based on the chemical properties of the molecules (e.g., molecular’ weight, solubility, stability, protein binding). High-Performance Liquid Chromatography (HPLC) can be used, where its setup may include reverse-phase column (e.g., C18) with a gradient mobile phase of water/acetonitrile containing 0.1% formic acid. Detection can include: UV-visible detector (e.g., at 254 nm if the drugs absorb strongly) or a photodiode array (PDA) for broader spectral analysis. Some advantages can include: reliable, widely available, and suitable if the drugs have strong chromophores and are stable under chromatographic conditions. Liquid Chromatography-Mass Spectrometry (LC-MS/MS) can be used, where its setup may include turbo ion spray interface in positive or negative ion mode, depending on drug ionization characteristics. Some advantage may include: highly sensitive and specific, useful for low-dose regimens or molecules prone to interference in UV-based methods. Immunoassays (e.g., ELISA, RIA) can be used. For instance, if Drug A or Drug B are biologies (e.g., peptides, small proteins) or if immunoassay kits are commercially available. Some advantages include: potential high specificity; feasible in clinical labs. Spectrophotometric or Colorimetric Methods can be used, e.g., particularly for older or highly colored drugs with known absorption maxima. Advantages can include that it has the simplest equipment requirement. However, it has lower specificity compared to LC-MS/MS; sample cleanup often needed to eliminate interferences.

[00214] Example results from the implementations of the illustrative example can include the following. Pharmacokinetic Profiles of Segment 1 (Immediate Release): Plasma Drug A rises within 30-60 minutes, peaking around 1-2 hours. Pharmacokinetic Profiles of Segment 2 (Delayed Release): Plasma Drug B peaks at 4-6 hours, consistent with intestinal transit times. Pharmacokinetic Profiles of Segment 3 (Extended Release): Drug A’s levels remain above the therapeutic threshold from 2-12 hours, tapering off before the next daily dose. Therapeutic Indicators can include Inflammatory Marker Reduction: CRP and IL-6 levels should decrease relative to baseline by Day 7 if Drug A and Drug B exert a combined anti-inflammatory or immunomodulatory effect. Symptom Improvement: Participants may report reduced joint stiffness or pain, suggesting clinical benefit from the phased drug delivery. Safety Assessments can include tolerability, i.e., no severe adverse events expected if total daily doses remain within established safety margins.

Examples

[00215] In some embodiments in accordance with the present technology (example Al), a device for individualized controlled release of multiple payloads includes a capsule assembly comprising a body and a cap, wherein the cap is dissolvable in a fluid, and wherein the body includes an enteric coating capable of preventing or slowing dissolution of the body in the fluid; a plurality of capsule segments contained in the capsule assembly comprising at least a first capsule segment and a second capsule segment, wherein each of the plurality of capsule segments includes an interior capable of storing an individual payload substance, and wherein the first capsule segment is adjacent to the cap in the capsule assembly; and at least one enteric barrier positioned between and separating two capsule segments in the capsule assembly, wherein the at least one enteric barrier includes one or more enteric polymers within a matrix material.

[00216] Example A2 includes the device of example Al or any of examples A1-A24, wherein the device is configured to controllably release a first payload substance from the first capsule segment at a first release time and a second payload substance from the second capsule segment at a second release time using different release kinetics, the different release kinetics including an initial or immediate release of the first payload substance and a sustained release of the second payload substance.

[00217] Example A3 includes the device of example Al or any of examples A1-A24, wherein the interior of each of the plurality of capsule segments includes a hollow region that contains the individual payload substance within.

[00218] Example A4 includes the device of example Al or any of examples A1-A24, wherein the interior of each of the plurality of capsule segments includes a solid region which integrates the individual payload substance within.

[00219] Example A5 includes the device of example Al or any of examples A1-A24, wherein the at least one enteric barrier includes an enteric barrier disc for time-controlled release of one or multiple payload substances contained in the plurality of capsule segments.

[00220] Example A6 includes the device of example Al or any of examples A1-A24, wherein the one or more enteric polymers of the at least one enteric bar ier includes an anionic methacrylate copolymer ionized above 7.0 pH. [00221] Example A7 includes the device of example A6 or any of examples A1-A24, wherein the anionic methacrylate copolymer ionized above 7.0 pH is Eudragit®S100.

[00222] Example A8 includes the device of example Al or any of examples A1-A24, wherein the matrix material of the at least one enteric barrier includes one or both of lactose and maltose.

[00223] Example A9 includes the device of example Al or any of examples A1-A24, further comprising a plurality of magnesium micromotors contained in at least one capsule segment of the plurality of capsule segments, wherein, when the plurality of magnesium micromotors are released from the at least one capsule segment to the fluid, the plurality of magnesium micromotors are operable to neutralize an acidic pH of the fluid to which the plurality of magnesium micromotors are released.

[00224] Example A 10 includes the device of example A9 or any of examples A1-A24, wherein the plurality of magnesium micromotors are contained in the first capsule segment.

[00225] Example Al l includes the device of example A9 or any of examples A1-A24, wherein the plurality of magnesium micromotors operate as microstirrers, when released into the fluid, to induce local hydrodynamics and thereby create a burst release effect of the individual payload substance released from the at least one capsule segment that increases propensity of absorption of the individual payload substance into surrounding tissue across a gastrointestinal tract of a patient user of the device.

[00226] Example A 12 includes the device of example Al or any of examples A1-A24, further comprising a plurality of biohybrid algae micromotors, each comprising one or more nanoparticles coupled to an alga having one or more flagellum, contained in at least one capsule segment of the plurality of capsule segments, wherein, when the plurality of biohybrid algae micromotors are released from the at least one capsule segment into the fluid, the plurality of biohybrid algae micromotors are operable to propel in the fluid.

[00227] Example A 13 includes the device of example A 12 or any of examples A 1 - A24, wherein the plurality of biohybrid algae micromotors are operable to propel in the fluid based on motion of the one or more flagellum at a propulsion speed of at least 80 pm/sec.

[00228] Example A 14 includes the device of example A12 or any of examples A1-A24, wherein the plurality of biohybrid algae micromotors operate as prolonged mixing agents, when released into the fluid, to induce absorption of the individual payload substance released from the at least one capsule segment into surrounding tissue across a gastrointestinal tract of a patient user of the device.

[00229] Example A15 includes the device of example Al or any of examples A1-A24, wherein the plurality of capsule segments contained in the capsule assembly comprises a third capsule segment, and wherein the device is configured to controllably release a first payload substance from the first capsule segment at a first release time, a second payload substance from the second capsule segment at a second release time, and a third payload substance from the third capsule segment at a third release time.

[00230] Example A16 includes the device of example Al 5 or any of examples A1-A24, further comprising a plurality of zinc rocket micromotors contained with a first payload substance in the first capsule segment, wherein, when the plurality of zinc rocket micromotors are released from the first capsule segment to the fluid, the plurality of zinc rocket micromotors are operable to penetrate into surrounding tissue to enhance uptake of the first payload substance are released; a plurality of magnesium microstirrer micromotors contained with a second payload substance in the second capsule segment, wherein, when the plurality of magnesium microstirrer micromotors are released from the second capsule segment to the fluid, the plurality of magnesium microstirrer micromotors are operable to (1) induce local hydrodynamics and thereby create a burst release effect of the second payload substance released from the second capsule segment that increases propensity of absorption of the second payload substance into surrounding tissue and/or (2) neutralize an acidic pH of the fluid where the plurality of magnesium microstirrer micromotors are released; and a plurality of biohybrid algae micromotors contained with a third payload substance in the third capsule segment, wherein, when the plurality of biohybrid algae micromotors are released from the third capsule segment into the fluid, the plurality of biohybrid algae micromotors are operable to propel in the fluid and operate as prolonged mixing agents to induce absorption of the third payload substance into surrounding tissue.

[00231] Example A17 includes the device of example Al or any of examples A1-A24, further comprising a sensor contained in at least one of the capsule segments of the plurality of capsule segments, wherein the sensor is configured to detect a biochemical or physiological condition of its fluidic environment when the at least one capsule segment containing the sensor is exposed to the fluid.

[00232] Example Al 8 includes the device of example A2 or any of examples A1-A24, wherein the device is configured to controllably release a plurality of drugs, wherein the first payload substance includes a first drug and the second payload substance includes a second drug.

[00233] Example A 19 includes the device of example A 18 or any of examples A 1 - A24, wherein the first drug includes levothyroxine, and wherein the second drug includes a statin; or wherein the first drug includes a statin, and wherein the second drug includes levothyroxine.

[00234] Example A20 includes the device of example A2 or any of examples A1-A24, wherein the device is configured to controllably release a plurality of supplements, wherein the first payload substance includes a first supplement and the second payload substance includes a second supplement.

[00235] Example A21 includes the device of example A20 or any of examples A 1 - A24, wherein the first supplement includes calcium and the second supplement includes iron; or wherein the first supplement includes iron and the second supplement includes calcium.

[00236] Example A22 includes the device of example Al or any of examples A1-A24, wherein the fluid includes a gastrointestinal fluid comprising one or more of gastric juice, bile, pancreatic juice, or saliva, or mixture thereof.

[00237] Example A23 includes the device of example Al or any of examples A1-A24, wherein the capsule assembly comprises a vegetable cellulose or a gelatin.

[00238] Example A24 includes the device of example Al or any of examples A1-A23, wherein the capsule assembly includes a capsule size of 000, 00, 0, 1, 2, 3, 4, or 5.

[00239] In some embodiments in accordance with the present technology (example A25), a method for individualized controlled release of multiple payloads includes dissolving, in a fluid, a cap of a multi-segment capsule that comprises the cap and a capsule body, wherein the capsule body contains a plurality of capsule segments and comprises an enteric coating capable of preventing or slowing dissolution of the capsule body in the fluid; exposing, to the fluid, a first capsule segment positioned in the capsule body adjacent to the cap, wherein the first capsule segment is configured to contain a first payload substance; releasing the first payload substance to the fluid from the first capsule segment at a first time after the dissolving of the cap; dissolving an enteric barrier positioned between and separating the first capsule segment from a second capsule segment positioned in the capsule body adjacent to the enteric barrier; exposing, to the fluid, the second capsule segment, wherein the second capsule segment is configured to contain a second pay load substance; and releasing the second pay load substance to the fluid from the second capsule segment at a second time after the dissolving of the cap using different release kinetics from the releasing of the first payload substance, the different release kinetics including an initial or immediate release of the first payload substance and a sustained release of the second payload substance.

[00240] Example A26 includes the method of example A25 or any of examples A25-A32, wherein each of the first capsule segment and the second capsule segment includes an interior capable of storing an individual payload substance, wherein the interior of each capsule segment includes a hollow region that contains the individual payload substance within and/or includes a solid region which integrates the individual payload substance within.

[00241] Example A27 includes the method of example A25 or any of examples A25-A32, further comprising releasing to the fluid a plurality of magnesium micromotors contained in at least one of the first capsule segment or the second capsule segment.

[00242] Example A28 includes the method of example A27 or any of examples A25-A32, comprising neutralizing, by the plurality of magnesium micromotors in the fluid, an acidic pH of the fluid.

[00243] Example A29 includes the method of example A27 or any of examples A25-A32, comprising inducing, by microstirring action of the plurality of magnesium micromotors in the fluid, local hydrodynamics of the fluid and to create a burst release effect of a payload substance released from its respective capsule segment, thereby increasing propensity of absorption of the individual payload substance into surrounding tissue.

[00244] Example A30 includes the method of example A25 or any of examples A25-A32, further comprising releasing to the fluid a plurality of biohybrid algae micromotors contained in at least one of the first capsule segment or the second capsule segment.

[00245] Example A31 includes the method of example A30 or any of examples A25-A32, comprising propelling the plurality of biohybrid algae micromotors in the fluid at a propulsion speed of at least 80 pm/scc.

[00246] Example A32 includes the method of example A30 or any of examples A25-A31, comprising inducing, by propulsion motion of the plurality of biohybrid algae micromotors in the fluid, absorption of a payload substance released from its respective capsule segment into surrounding tissue.

Conclusion

[00247] Implementations of the subject matter and the functional operations described in this patent document can be implemented in various systems, digital electronic circuitry, or in computer software, firmware, or hardware, including the structures disclosed in this specification and their structural equivalents, or in combinations of one or more of them. Implementations of the subject matter described in this specification can be implemented as one or more computer program products, i.e., one or more modules of computer program instructions encoded on a tangible and non-transitory computer readable medium for execution by, or to control the operation of, data processing apparatus. The computer readable medium can be a machine-readable storage device, a machine-readable storage substrate, a memory device, a composition of matter effecting a machine-readable propagated signal, or a combination of one or more of them. The term “data processing unit” or “data processing apparatus” encompasses all apparatus, devices, and machines for processing data, including by way of example a programmable processor, a computer, or multiple processors or computers. The apparatus can include, in addition to hardware, code that creates an execution environment for the computer program in question, e.g., code that constitutes processor firmware, a protocol stack, a database management system, an operating system, or a combination of one or more of them.

[00248] A computer program (also known as a program, software, software application, script, or code) can be written in any form of programming language, including compiled or interpreted languages, and it can be deployed in any form, including as a stand-alone program or as a module, component, subroutine, or other unit suitable for use in a computing environment. A computer program does not necessarily correspond to a file in a file system. A program can be stored in a portion of a file that holds other programs or data (e.g., one or more scripts stored in a markup language document), in a single file dedicated to the program in question, or in multiple coordinated files (e.g., files that store one or more modules, sub programs, or portions of code). A computer program can be deployed to be executed on one computer or on multiple computers that are located at one site or distributed across multiple sites and interconnected by a communication network.

[00249] The processes and logic flows described in this specification can be performed by one or more programmable processors executing one or more computer programs to perform functions by operating on input data and generating output. The processes and logic flows can also be performed by, and apparatus can also be implemented as, special purpose logic circuitry, e.g., an FPGA (field programmable gate array) or an ASIC (application specific integrated circuit). [00250] Processors suitable for the execution of a computer program include, by way of example, both general and special purpose microprocessors, and any one or more processors of any kind of digital computer. Generally, a processor will receive instructions and data from a read only memory or a random access memory or both. The essential elements of a computer are a processor for performing instructions and one or more memory devices for storing instructions and data. Generally, a computer will also include, or be operatively coupled to receive data from or transfer data to, or both, one or more mass storage devices for storing data, e.g., magnetic, magneto optical disks, or optical disks. However, a computer need not have such devices. Computer readable media suitable for storing computer program instructions and data include all forms of nonvolatile memory, media and memory devices, including by way of example semiconductor memory devices, e.g., EPROM, EEPROM, and flash memory devices. The processor and the memory can be supplemented by, or incorporated in, special purpose logic circuitry.

[00251] While this patent document contains many specifics, these should not be construed as limitations on the scope of any invention or of what may be claimed, but rather as descriptions of features that may be specific to particular embodiments of particular inventions. Certain features that are described in this patent document in the context of separate embodiments can also be implemented in combination in a single embodiment. Conversely, various features that are described in the context of a single embodiment can also be implemented in multiple embodiments separately or in any suitable subcombination. Moreover, although features may be described above as acting in certain combinations and even initially claimed as such, one or more features from a claimed combination can in some cases be excised from the combination, and the claimed combination may be directed to a subcombination or variation of a subcombination.

[00252] Similarly, while operations are depicted in the drawings in a particular order, this should not be understood as requiring that such operations be performed in the particular' order shown or in sequential order, or that all illustrated operations be performed, to achieve desirable results. Moreover, the separation of various system components in the embodiments described in this patent document should not be understood as requiring such separation in all embodiments.

[00253] Only a few implementations and examples are described and other implementations, enhancements and variations can be made based on what is described and illustrated in this patent document.

Claims

CLAIMS What is claimed is:

1. A device for individualized controlled release of multiple pay loads, comprising: a capsule assembly comprising a body and a cap, wherein the cap is dissolvable in a fluid, and wherein the body includes an enteric coating capable of preventing or slowing dissolution of the body in the fluid; a plurality of capsule segments contained in the capsule assembly comprising at least a first capsule segment and a second capsule segment, wherein each of the plurality of capsule segments includes an interior capable of storing an individual payload substance, and wherein the first capsule segment is adjacent to the cap in the capsule assembly; and at least one enteric barrier positioned between and separating two capsule segments in the capsule assembly, wherein the at least one enteric barrier includes one or more enteric polymers within a matrix material.

2. The device of claim 1, wherein the device is configured to controllably release a first payload substance from the first capsule segment at a first release time and a second payload substance from the second capsule segment at a second release time using different release kinetics, the different release kinetics including an initial or immediate release of the first payload substance and a sustained release of the second payload substance.

3. The device of claim 1, wherein the interior of each of the plurality of capsule segments includes a hollow region that contains the individual payload substance within.

4. The device of claim 1, wherein the interior of each of the plurality of capsule segments includes a solid region which integrates the individual payload substance within.

5. The device of claim 1, wherein the at least one enteric bander includes an enteric barrier disc for time-controlled release of one or multiple payload substances contained in the plurality of capsule segments.

6. The device of claim 1, wherein the one or more enteric polymers of the at least one enteric barrier includes an anionic methacrylate copolymer ionized above 7.0 pH.

7. The device of claim 6, wherein the anionic methacrylate copolymer ionized above 7.0 pH is EudragitOSlOO.

8. The device of claim 1, wherein the matrix material of the at least one enteric barrier includes one or both of lactose and maltose.

9. The device of claim 1, further comprising: a plurality of magnesium micromotors contained in at least one capsule segment of the plurality of capsule segments, wherein, when the plurality of magnesium micromotors are released from the at least one capsule segment to the fluid, the plurality of magnesium micromotors are operable to neutralize an acidic pH of the fluid to which the plurality of magnesium micromotors are released.

10. The device of claim 9, wherein the plurality of magnesium micromotors are contained in the first capsule segment.

11. The device of claim 9, wherein the plurality of magnesium micromotors operate as microstiners, when released into the fluid, to induce local hydrodynamics and thereby create a burst release effect of the individual payload substance released from the at least one capsule segment that increases propensity of absorption of the individual payload substance into surrounding tissue across a gastrointestinal tract of a patient user of the device.

12. The device of claim 1, further comprising: a plurality of biohybrid algae micromotors, each comprising one or more nanoparticles coupled to an alga having one or more flagellum, contained in at least one capsule segment of the plurality of capsule segments, wherein, when the plurality of biohybrid algae micromotors are released from the at least one capsule segment into the fluid, the plurality of biohybrid algae micromotors are operable to propel in the fluid.

13. The device of claim 12, wherein the plurality of biohybrid algae micromotors are operable to propel in the fluid based on motion of the one or more flagellum at a propulsion speed of at least 80 pm/scc.

14. The device of claim 12, wherein the plurality of biohybrid algae micromotors operate as prolonged mixing agents, when released into the fluid, to induce absorption of the individual payload substance released from the at least one capsule segment into surrounding tissue across a gastrointestinal tract of a patient user of the device.

15. The device of claim 1, wherein the plurality of capsule segments contained in the capsule assembly comprises a third capsule segment, and wherein the device is configured to controllably release a first payload substance from the first capsule segment at a first release time, a second payload substance from the second capsule segment at a second release time, and a third payload substance from the third capsule segment at a third release time.

16. The device of claim 15, further comprising: a plurality of zinc rocket micromotors contained with a first payload substance in the first capsule segment, wherein, when the plurality of zinc rocket micromotors are released from the first capsule segment to the fluid, the plurality of zinc rocket micromotors are operable to penetrate into surrounding tissue to enhance uptake of the first payload substance are released; a plurality of magnesium microstirrer micromotors contained with a second payload substance in the second capsule segment, wherein, when the plurality of magnesium microstirrer micromotors are released from the second capsule segment to the fluid, the plurality of magnesium microstirrer micromotors are operable to (1) induce local hydrodynamics and thereby create a burst release effect of the second payload substance released from the second capsule segment that increases propensity of absorption of the second payload substance into surrounding tissue and/or (2) neutralize an acidic pH of the fluid where the plurality of magnesium microstirrer micromotors are released; and a plurality of biohybrid algae micromotors contained with a third payload substance in the third capsule segment, wherein, when the plurality of biohybrid algae micromotors are released from the third capsule segment into the fluid, the plurality of biohybrid algae micromotors are operable to propel in the fluid and operate as prolonged mixing agents to induce absorption of the third payload substance into surrounding tissue.

17. The device of claim 1, further comprising: a sensor contained in at least one of the capsule segments of the plurality of capsule segments, wherein the sensor is configured to detect a biochemical or physiological condition of its fluidic environment when the at least one capsule segment containing the sensor is exposed to the fluid.

18. The device of claim 2, wherein the device is configured to controllably release a plurality of drugs, wherein the first payload substance includes a first drug and the second payload substance includes a second drug.

19. The device of claim 18, wherein the first drug includes levothyroxine, and wherein the second drug includes a statin; or wherein the first drug includes a statin, and wherein the second drug includes levothyroxine.

20. The device of claim 2, wherein the device is configured to controllably release a plurality of supplements, wherein the first payload substance includes a first supplement and the second payload substance includes a second supplement.

21. The device of claim 20, wherein the first supplement includes calcium and the second supplement includes iron; or wherein the first supplement includes iron and the second supplement includes calcium.

22. The device of claim 1, wherein the fluid includes a gastrointestinal fluid comprising one or more of gastric juice, bile, pancreatic juice, or saliva, or mixture thereof.

23. The device of claim 1, wherein the capsule assembly comprises a vegetable cellulose or a gelatin.

24. The device of claim 1, wherein the capsule assembly includes a capsule size of 000, 00, 0, 1, 2, 3, 4, or 5.

25. A method for individualized controlled release of multiple payloads, comprising: dissolving, in a fluid, a cap of a multi-segment capsule that comprises the cap and a capsule body, wherein the capsule body contains a plurality of capsule segments and comprises an enteric coating capable of preventing or slowing dissolution of the capsule body in the fluid; exposing, to the fluid, a first capsule segment positioned in the capsule body adjacent to the cap, wherein the first capsule segment is configured to contain a first payload substance; releasing the first payload substance to the fluid from the first capsule segment at a first time after the dissolving of the cap; dissolving an enteric barrier positioned between and separating the first capsule segment from a second capsule segment positioned in the capsule body adjacent to the enteric barrier; exposing, to the fluid, the second capsule segment, wherein the second capsule segment is configured to contain a second payload substance; and releasing the second payload substance to the fluid from the second capsule segment at a second time after the dissolving of the cap using different release kinetics from the releasing of the first payload substance, the different release kinetics including an initial or immediate release of the first payload substance and a sustained release of the second payload substance.

26. The method of claim 25, wherein each of the first capsule segment and the second capsule segment includes an interior capable of storing an individual payload substance, wherein the interior of each capsule segment includes a hollow region that contains the individual payload substance within and/or includes a solid region which integrates the individual payload substance within.

27. The method of claim 25, further comprising: releasing to the fluid a plurality of magnesium micromotors contained in at least one of the first capsule segment or the second capsule segment.

28. The method of claim 27, comprising: neutralizing, by the plurality of magnesium micromotors in the fluid, an acidic pH of the fluid.

29. The method of claim 27, comprising: inducing, by microstirring action of the plurality of magnesium micromotors in the fluid, local hydrodynamics of the fluid and to create a burst release effect of a payload substance released from its respective capsule segment, thereby increasing propensity of absorption of the individual payload substance into surrounding tissue.

30. The method of claim 25, further comprising: releasing to the fluid a plurality of biohybrid algae micromotors contained in at least one of the first capsule segment or the second capsule segment.

31. The method of claim 30, comprising: propelling the plurality of biohybrid algae micromotors in the fluid at a propulsion speed of at least 80 pm/sec.

32. The method of claim 30, comprising: inducing, by propulsion motion of the plurality of biohybrid algae micromotors in the fluid, absorption of a payload substance released from its respective capsule segment into surrounding tissue.