Orally ingestible delivery system

Abstract

The invention includes an orally ingestible delivery system for delivering a therapeutic agent to a preselected more distal location within a gastrointestinal (GI) tract of a mammal, where the system includes the therapeutic agent and a differentially disruptable capsule system, wherein the differentially disruptable capsule system is dimensionally adapted for oral ingestion and for passage from a more proximal location in the GI tract to the preselected more distal location and wherein the differentially disruptable capsule system comprises a continuous frangible matrix enclosing the therapeutic agent compartment and having a plurality of areas of material inhomogeneity disposed within the continuous frangible matrix. The invention additionally includes methods of manufacturing the orally ingestible delivery system and methods of employing the system to deliver an effective amount of a therapeutic agent to a patient in need thereof.

Description

ORALLY INGESTIBLE DELIVERY SYSTEMRELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 545,406 filed October 24, 2023. The entire contents of the above application are incorporated by reference herein.FIELD OF THE APPLICATION

[0002] This application relates to orally ingestible delivery systems for drugs, biologies, and other therapeutic agents.BACKGROUND

[0003] Therapeutic agents for treating a medical condition are formulated to optimize the delivery and uptake of the agent when it is administered to a patient. As used herein, “therapeutic agent” is any substance, material, device, organism, or portion thereof, that is delivered to a person or animal to effect a therapeutic intervention. For avoidance of doubt, a therapeutic intervention can include diagnostic interventions and surveillance interventions (i.e., interventions to diagnose and thereby prevent an anticipated disorder, and interventions to gather data about states of wellness or disease, in order to facilitate prevention of an anticipated disorder).

[0004] Routes of delivery for a therapeutic agent can involve the gastrointestinal tract (termed “enteral” or “enteric” administration) or other pathways that do not involve the gastrointestinal tract (termed “parenteral” administration). Intravenous administration is one parenteral delivery route, but there are others: examples include injections into body cavities, muscles, under the skin, into the skin, diffusion through mucous membranes or through the skin, and inhalation. Parenteral administration has certain well-recognized advantages. Most importantly, it allows the therapeutic agent to reach the systemic circulation quickly, without having to navigate the digestive tract, where its effective uptake can be unpredictable due to altered blood flow, low gastrointestinal motility, poor absorption, or effects of first pass metabolism. For these reasons, parenteral mechanisms typically result in greater absolute bioavailability. Moreover, therapeutic agents comprising proteins, peptides, and living organisms like viruses and cells have to date requiredparenteral administration, because they are susceptible to digestion in the stomach, which would render them ineffective.

[0005] While the bioavailability advantages of parenteral administration are important in intensive care and emergency situations, these routes have clear drawbacks for more routine or chronic treatments. Parenteral delivery commonly requires invasive interventions such as needle punctures and infusions that are carried out by skilled personnel using sterile techniques; under other circumstances, parenteral delivery relies on complex mechanisms such as specialized aerosols or pumps. These auxiliary requirements make parenteral delivery costly, inconvenient, and / or unpleasant for patients, especially when the treatment needs to be administered frequently. The need for invasive or technically complicated interventions makes parenteral delivery especially undesirable for certain patient populations, such as pediatric patients and patients in underserved areas that do not have access to the medical facilities for more complex delivery systems.

[0006] Despite these drawbacks, a large number of conditions requiring repeated or widespread treatment, for example chronic conditions, or population-based conditions such as disease prophylaxis via vaccination, are currently treated parenterally, in many cases because the treatment agent is not compatible with enteric - specifically oral - administration. Other conditions not treatable by oral administration are suitable for nonoral routes of enteric administration, for example via rectal delivery (enemas, suppositories, and the like). Examples of rectal delivery include diseases of the colon such as ulcerative colitis, where the active ingredient can act directly on the colon itself, and disorders treated by bacteriotherapy (for example, fecal transplant), where living organism are introduced into the colon to repopulate it with healthy bacteria. For many of these conditions treated parenterally or rectally, oral delivery would be preferable because it is convenient, familiar, and generally well-tolerated by the patient.

[0007] During oral administration, the therapeutic agent passes from the mouth through the esophagus into the stomach, then passing from the stomach into the duodenum and thereafter into the rest of the small intestine. The delivery vehicle for an oral agent needs to have sufficient mechanical integrity to survive passage from the mouth into the stomach, but this involves fairly standard pharmaceutical techniques. The stomach presents more daunting conditions for a drug or biologic. Cells in the stomach mucosa produce hydrochloric acid, leading to an acidic environment in the stomach (pH about 2.0 or less). Furthermore, stomach cells secrete pepsinogen, a proenzyme for pepsin, an enzyme that breaks down proteins. The acid in the stomach hydrolyzes proteins, and further converts the proenzymepepsinogen into its active form pepsin; pepsin digests proteins in the stomach, breaking them down into peptides that are further digested in the small intestine and then absorbed. Small molecules delivered orally are susceptible to hydrolysis by stomach acid. Proteins and peptides delivered orally are not only hydrolyzed by stomach acid, but they are also digested by pepsin. These conditions in the stomach prevent or impair the use of the oral delivery route for many therapeutic agents. There remains a need in the art therefore for improved delivery vehicles for oral administration of therapeutic agents that do not tolerate exposure to stomach conditions, including biopharmaceuticals, living organisms, microdevices, and small molecules. There also exists a need for an alternative to rectal delivery to spare patients the discomfort and inconvenience that this route of administration involves. These improved delivery mechanisms would be particularly advantageous in chronic conditions requiring frequent dosing, or in specialized populations, because of increased patient convenience and acceptance, and decreased complexity and health care cost.SUMMARY

[0008] Disclosed herein, in embodiments, are orally ingestible delivery systems (OIDS) for delivering a therapeutic agent to a preselected more distal location within a GI tract of a mammal, comprising: the therapeutic agent; and a differentially disruptable capsule system (DDCS) containing the therapeutic agent within a therapeutic agent compartment, wherein the differentially disruptable capsule system is dimensionally adapted for oral ingestion and for passage from a more proximal location in the GI tract to the preselected more distal location, wherein the differentially disruptable capsule system comprises a continuous frangible matrix enclosing the therapeutic agent compartment and having a plurality of areas of material inhomogeneity (AMI) disposed within the continuous frangible matrix (CFM), wherein the continuous frangible matrix resists disruption at the more proximal location and is susceptible to disruption at the preselected more distal location, wherein the areas of material inhomogeneity are foci for differential stresses that can propagate within the continuous frangible matrix and predispose the continuous frangible matrix to fracture and potential failure, thereby rendering the continuous matrix susceptible to disruption at the preselected more distal location, and wherein the disruption of the continuous frangible matrix at the preselected more distal location releases the therapeutic agent from the therapeutic agent compartment and discharges the therapeutic agent from the OIDS to reach the preselected more distal location, thereby delivering the therapeutic agent thereto. In embodiments, the preselected more distal location is selected from the group consisting ofthe duodenum, the jejunum, the ileum, and the colon, for example the duodenum; in embodiments, the more proximal location is the stomach. The therapeutic agent can be an immediate release formulation or a modified release formulation, and it can be coated to delay its release within the preselected more distal location after it has been discharged from the OIDS. In embodiments, the therapeutic agent compartment is formed as a void, and it can enclose one or more therapeutic agents which can be suspended in a therapeutic agent compartment matrix. In embodiments, the DDCS contains a plurality of therapeutic agent compartments. In embodiments, the DDCS comprises a plurality of layers, and the plurality of layers can include two or more layers having dissimilar properties. Further disclosed herein are orally ingestible delivery systems as previously described wherein the CFM is acid-resistant. In embodiments, the CFM can comprise an acid-resistant material selected from the group consisting of cellulose, fatty acids, waxes, polyolefins, edible elastomers and natural elastomers. In embodiments, the CFM comprises a moldable hydrophobic or lipophilic material, which can be a wax, for example, a wax that is selected from the group consisting of beeswax, soybean wax, carnauba wax, and candelilla wax. In embodiments, the CFM is formed from ingredients selected from the group consisting of: one or more types of waxes mixed together; one or more waxes mixed with one or more fatty acids; one or more wax or waxes mixed with policosanol; one or more wax or waxes mixed with cholesterol; one or more wax or waxes mixed with a phospholipid and / or with phosphatidylcholine; one or more wax or waxes mixed with essential oils; and one or more waxes mixed with oilsoluble vitamin mixture. Further disclosed herein are orally ingestible delivery systems as previously described wherein the AMI are voids or inclusions. In embodiments, the voids are produced within the CFM as the CFM is being formed. In embodiments, the inclusion becomes a void by being dissolved away to leave a defect in the matrix material, or by generating a gas that expands within the matrix material. In embodiments, the inclusions act as space occupiers, which can comprise a fluid material, and the fluid material can be selected from the group consisting of triglycerides, fatty acids, edible oils, esters derived from vegetable oils, and esters derived from plants; in other embodiments, the inclusions act as stress concentrators. In embodiments, the inclusions are chemically reactive, for example, chemically reactive in stomach acid. In embodiments, the inclusions are minimally soluble in a strongly acidic environment and are more soluble in a neutral or basic environment. In embodiments, inclusions can act as gas formers, and can be selected from the group consisting of calcium carbonate, sodium bicarbonate, potassium bicarbonate, magnesium carbonate, and magnesium particles. Such gas formers can generate a gas that blocks a defectin the matrix, or they can produce a gas in the stomach that is dispersed in the duodenum. In embodiments, the orally ingestible delivery systems as previously described further comprises an outer shell that envelopes the DDCS. In embodiments, the orally ingestible delivery systems as previously described further comprises an enclosing layer disposed internal to the continuous frangible matrix. The enclosing layer can be supplemented with inclusions, and the inclusions can comprise gas-forming substances.

[0009] Also described herein are methods of manufacturing the OIDS as previously described, comprising including the therapeutic agent compartment within the DDCS. In embodiments, the step of including comprises embedding the therapeutic agent within a preformed space in the DDCS. In embodiments, the step of including comprises covering the therapeutic agent by the matrix material of the OIDS without the preliminary formation of a discrete space therein, and the step of covering can take place by a technique selected from the group consisting of coating the therapeutic agent or therapeutic agent compartment with matrix material, curtain-coating the therapeutic agent or therapeutic agent compartment with matrix material, dipping the therapeutic agent or therapeutic agent compartment into matrix material, and spraying matrix material on the therapeutic agent or therapeutic agent compartment.

[0010] Further described herein are methods of delivering an effective amount of a therapeutic agent to a patient in need thereof, comprising: providing the orally ingestible delivery system as described above, wherein the orally ingestible delivery system contains the effective amount of a therapeutic agent; administering the orally ingestible delivery system to the patient by mouth; permitting passage of the orally ingestible delivery system into the stomach; and further permitting passage of the OIDS to a preselected more distal location; wherein the passage of the OIDS from the stomach to the more distal location subjects the continuous frangible matrix to differential stresses that propagate within the DDCS and initiates disruption of the continuous frangible matrix, and wherein the disruption takes place at or before the preselected more distal location and releases the therapeutic agent from the OIDS to reach the preselected more distal location, thereby delivering the effective amount of the therapeutic agent to the patient. In embodiments, the orally ingestible delivery system contains an effective amount of a second therapeutic agent, wherein the therapeutic agent and the second therapeutic agent in combination treat the condition. In embodiments, the step of disruption takes place in the stomach, and in embodiments, the preselected more distal location is the duodenum.BRIEF DESCRIPTION OF FIGURES

[0011] The foregoing and other objects, features and advantages of the invention will be apparent from the following more particular description of preferred embodiments of the invention, as illustrated in the accompanying drawings in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention.

[0012] FIGs. 1A, IB, and 1C depict schematically cross-sections of embodiments of orally ingestible delivery systems.

[0013] FIGs. 2A, 2B and 2C depict schematically a cross-section of the differentially disruptable capsule system of an orally ingestible delivery system.DETAILED DESCRIPTION

[0014] Disclosed herein, in embodiments, are orally ingestible delivery systems for releasing a therapeutic agent within the lumen of the gastrointestinal tract of a patient. As used herein, the term “gastrointestinal tract” includes, but is not limited to, the stomach, the small intestine with its three segments (duodenumjejunum, ileum) and the large intestine, the small intestine and the large intestine collectively being termed the “intestinal tract.” The orally ingestible delivery system (OIDS) disclosed herein is particularly adapted for delivering the therapeutic agent to target areas for absorption within the small or large intestine. In embodiments, the therapeutic agent is delivered within the small intestine; in other embodiments the therapeutic agent is delivered within the large intestine; yet other embodiments can combine points of delivery so that the therapeutic agent is delivered throughout the small intestine, throughout the large intestine or both. In an embodiment, the OIDS comprises an inner therapeutic agent compartment containing one or more therapeutic agents and a differentially disruptable capsule system enclosing the therapeutic agent compartment, wherein the differentially disruptable capsule system resists fluid ingress in the stomach, but is susceptible to fluid ingress in the intestine, so that the stomach fluid is inhibited partially or completely from passing through the capsule system to access the therapeutic agent compartment, but the intestinal fluid is permitted to pass through the capsule system to access the therapeutic agent compartment. In such an embodiment, the contents of the therapeutic agent compartment are relatively or absolutely protected from exposure to stomach acid so that they pass relatively intact into the intestine, where the therapeutic agent compartment is reached by and penetrated by the intestinal fluid so that the therapeutic agent is released within the intestinal tract. In other embodiments, thedifferentially disruptable capsule system is designed to permit a certain preselected degree of fluid ingress in the stomach, but considerably more fluid ingress in the intestine. This arrangement can allow the stomach acid to initiate the digestion or destruction of inner layers within the OIDS, such as digestion of the therapeutic compartment enclosing the therapeutic agent, with subsequent digestion, disruption, or destruction of such structures in the small intestine leading to the release profile for the therapeutic agent in the desired area of the intestinal tract.

[0015] In more detail, the orally ingestible delivery system is ingested by mouth, and then passes into the esophagus and thence into the stomach. In embodiments, the OIDS disclosed herein is designed to retain designated degrees of integrity as it passes through the stomach. In embodiments, the delivery system disclosed herein remains substantially intact as it passes through the stomach, thereafter, decomposing or being digested or being otherwise disrupted at some point distal to the stomach, or it remains substantially intact as it passes through the stomach, resisting the ingress of stomach fluids but becoming permeable to fluids in the intestinal tract. In embodiments, the delivery system is designed to retain at least a portion of its integrity within the stomach, with any loss of integrity in the stomach or distal to the stomach being incorporated into the design. In embodiments, the differentially disruptable capsule system is designed to commence its decomposition, digestion, or other disruption within the stomach, optionally with the release of some or all of a therapeutic agent encased within the system or embedded within the walls of the differentially disruptable capsule system itself. In embodiments an outer shell or coating is provided external to the differentially disruptable capsule system that can be formulated to dissolve partially in the stomach to allow further fine-tuning of the release profile. While this structure is referred to in the singular as an outer shell (also referred to as an external shell), it is understood that there can be a plurality of outer (external) shells, which can have the same or different properties. Advantageously, a plurality of outer (external) shells can have differential effects on the disruption of the differentially disruptable capsule system, and / or can have differential effects on the release of the therapeutic agent from the OIDS.

[0016] As used herein, the term “differentially disruptable capsule system” applies to that layer of the orally ingestible delivery system that encloses the therapeutic agent compartment and undergoes a different degree of disruption in the stomach and in the intestinal tract. This feature, whereby the delivery system has a preselected degree of resistance to disruption and subsequent fluid ingress in the stomach and has a different, preselected degree of resistanceto disruption and subsequent fluid ingress in the intestine, is referred to herein as being “differentially disruptable.”

[0017] Preferably the feature of differential disruptability impairs disruption of the capsule as it passes through the stomach, allowing more significant disruption within the intestinal tract. Even more preferably, the feature of differential disruptability allows the more significant disruption within the intestinal tract to take place at a preselected location within the intestinal tract or in a preselected region of the intestinal tract. Regions of the intestinal tract include anatomically recognized regions such as the duodenum, the jejunum, the ileum, and the colon, or subregions thereof, such as the proximal or distal duodenumjejunum, ileum, or colon, or the rectum.

[0018] In an embodiment, the differentially disruptable capsule system (also known as the “capsule”) is designed to undergo different degrees of disruption (whether mechanical disruption or disruption based on encounter with chemical or biological agents that impair its integrity) in one or more regions of the gastrointestinal tract (for example, stomach and / or duodenum). As used herein, the term “disruption” includes any and all processes that impair the integrity of the capsule, whether from mechanical forces within the gut such as peristalsis, or from chemical influences, such as different pH environments or by encounter with proteolytic or other digestive enzymes, or by interactions with gut bacteria, or by activity of external forces such as electromagnetic waves or acoustic waves that affect its structure). The term “disruption” includes without limitation processes such as digestion, decomposition, physical or chemical damage, dissolution, or destruction by any other means that affects the integrity of the structure.

[0019] In an embodiment, the differentially disruptable capsule system passes through the stomach with minimal, if any, disruption but is susceptible to disruption within the duodenum. In other embodiments, the disruption of the capsule commences in the stomach by encounter with one disrupting agent (e.g., acidic pH or proteolytic enzymes), but progresses in the duodenum to encounter other disrupting agents (e.g., other proteolytic enzymes or acidic pH), resulting in the differential deterioration and destruction of the capsule. In embodiments, such a capsular system susceptible to differential disruption can contain disparate elements or components that impart the different types of susceptibilities; advantageously, such disparate elements are included within a single structure comprised within or forming the differentially disruptable capsule system, for example, they can be arranged locally or topically (e.g., in regions or in layers), or they can be distributed within asingle capsular matrix that supports all of the components involved with the disruptive incursions.

[0020] An alternative mechanism for imparting differentially disruptable properties to the capsule system can involve ways to control the passage of fluid into and through the capsule without an initial disruption of the capsule itself, or with only minimal initial disruption. The capsule can be constructed to allow fluid intentionally to pass into its matrix, which could then lead to swelling, dissolving, or frank breakdown, or the capsule can be subject to minor degrees of disruption, either of which can permit an ingress of fluid into the capsule that can cause the capsule to swell. With sufficient swelling, the capsule is subject to stresses that cause deformation and ultimate failure of the capsule itself. The swellable properties of the capsule can be engineered so that it remains substantially intact as it passes through the stomach, only to rupture after it reaches the intestine.

[0021] As used herein, the indefinite articles “a” or “an” are intended to mean “one or more” unless otherwise specified. Other terms used herein may be defined separately or as part of a particular description wherein the term as used in a specific context.A. Orally ingestible delivery systems generally

[0022] Features and exemplary embodiments of an OIDS are described below in more detail and are illustrated by certain of the following Figures. As shown in the cross-sections of an OIDS as depicted in FIGs. 1 A, IB, and 1C, the OIDS comprises a differentially disruptable capsule system surrounding one or more therapeutic agent compartments.

[0023] In the embodiment shown in FIG. 1 A, the OIDS 100a comprises a therapeutic agent compartment 102a containing a therapeutic agent, surrounded by a differentially disruptable capsule system 104a. While the Figures show the DDCS as a single-layered structure, it is understood that the DDCS can be formed from multiple layers, with each layer similar or dissimilar to the others. For example, the DDCS can be formed as a two-layer capsular structure, a multilayer capsular structure, or a one-layer capsular structure having uniform or dissimilar properties. For example, the DDCS can be formed as a single asymmetric layer with variable properties so that the outer aspect of the single layer has more hydrophobic properties while the inner aspect has a predominance of proteinaceous components that are susceptible to protease digestion. In another embodiment, the DDCS can be a multilayer structure comprising a top layer that can be hydrophobic, intended to impart acid resistance. Other structural components can be combined (whether separate layers, integrated layers, or enclosed / coated / encapsulated therapeutic agents within the therapeutic agent compartment) to form a single DDCS.

[0024] As used herein, the term “therapeutic agent compartment” refers to a designated locus (whether a space or void left within the capsular matrix of the differentially disruptable capsule system 104a or a shaped form factor included therein) containing a deposit of the therapeutic agent. In more detail, the term “therapeutic agent compartment” refers to any locus containing the therapeutic agent within the differentially disruptable capsule system 104a, whether the therapeutic agent is inserted into a preformed space within the orally ingestible delivery system that acts as the therapeutic agent compartment, or whether the therapeutic agent is covered by (e.g., encased, enveloped, or enrobed with) the matrix material of the orally ingestible delivery system without the preliminary formation of a discrete space within which the therapeutic agent is directed to reside, or otherwise.

[0025] In more detail, the OIDS comprises a therapeutic agent included within a therapeutic agent compartment, which is included within a DDCS, as described below in more detail. The therapeutic agent is therefore included within the DDCS, for example by being embedded in the pre-formed DDCS or by being enrobed with the frangible matrix material that will comprise the DDCS. In either case, the space occupied within the OIDS by the therapeutic agent is termed the therapeutic agent compartment. The OIDS thus comprises both the therapeutic agent compartment and the DDCS. A number of techniques result in the therapeutic agent compartment or the therapeutic agent becoming included within the DDCS, in accordance with the principles of the invention. Non-limiting examples of suitable methods of manufacture are provided below, although other methods of manufacture as envisioned by skilled artisans are also within the scope of the invention.

[0026] In embodiments, the DDCS can be pre-formed with interior voids that are included within or enveloped by the matrix material as the DDCS is being formed, wherein such interior void or voids can receive the therapeutic agent. For example, the orally ingestible delivery system can be pre-formed with an interior cavity into which a fluid therapeutic agent can be injected or inserted. Such a preformed cavity can have other layers of protection or controlled release besides those integral to the differentially disruptable capsule system 104a. In other embodiments, the DDCS can be formed around a pre-existing therapeutic agent compartment containing the therapeutic agent. For example, a third party can produce the therapeutic agent with its own enclosure and / or coating(s), such as a capsule having optional layers of coatings, which can then be presented for inclusion within the orally ingestible delivery system, for example, by forming the differentially disruptable capsule system 104a around it, or by encasing or including it within a preformed differentially disruptable capsule system, or by enrobing or dipping the third partytherapeutic agent with its own enclosure and / or coating(s) in the materials that will form the capsular matrix of the differentially disruptable capsule system. Without limitation, techniques such as coating or curtain-coating the therapeutic agent or therapeutic agent compartment, dipping the therapeutic agent or therapeutic agent compartment into matrix material, spraying the matrix material on the therapeutic agent or therapeutic agent compartment, and the like, can be utilized to cover the therapeutic agent with the capsular matrix, thereby including the therapeutic agent within the OIDS. In all these situations, whether the space is preformed within the orally ingestible delivery system or whether the differentially disruptable capsule system is formed to cover, envelop, or otherwise enclose a therapeutic agent, for example a therapeutic agent having its own enclosure and / or coating(s), the discretely defined locus of residence for the therapeutic agent is deemed the therapeutic agent compartment.

[0027] A therapeutic agent compartment can be formed in any configuration suitable for the retention of the solid, liquid, or semisolid therapeutic agent within the orally ingestible delivery system 100a as shown schematically in FIG. 1A and as will be further described in connection with FIGS. IB and 1C below. In embodiments, the therapeutic compartment is formed from the therapeutic agent itself, which is shaped in a solid or semi-solid mass. In other embodiments, the therapeutic agent compartment 102a can be formed as a discrete enclosure with its own walls, or it can be initially constructed as a void that encloses the therapeutic agent, to which the therapeutic agent is added separately. The enclosure for the therapeutic agent compartment 102a can comprise a simple membrane such as a gelatin capsule within which the therapeutic agent can be deployed. In certain embodiments, the wall of the therapeutic agent compartment can be engineered to have specific properties for regulating the dispersal of the therapeutic agent.

[0028] In certain embodiments, for example, as illustrated in FIG. 1 A, there can be an additional enclosing layer 108a disposed internal to the continuous frangible matrix and external to the therapeutic agent compartment 102a or its contents, to provide such a boundary that provides specific properties for regulating the release of the therapeutic agent. The enclosing layer 108a can be engineered to provide a modification of the therapeutic agent’s release profile, or provide mechanical protection, or provide further resistance against proteases that may penetrate the differentially disruptable capsule system 104a. In embodiments, the optional enclosing layer 108a is intended to modify in some way the delivery of the therapeutic agent from the therapeutic agent compartment 102a. For example, the optional enclosing layer 108a can be formed from materials intended to have controlledrelease properties. Such materials are familiar to skilled artisans in the field of pharmaceutical manufacture, and can include without limitation materials that are safe for oral administration such as shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2- hydroxymethacrylate, methacrylate hydrogels, 1,3 butylene glycol, ethylene glycol methacrylate, and / or polyethylene glycols, and combinations thereof.

[0029] In embodiments, the optional enclosing layer 108a is supplemented with inclusions. In embodiments, this enclosing layer 108a can contain within its substance or can bear upon its inner or outer surface a plurality of inclusions (not shown), which can behave similarly or dissimilarly from those included within the matrix material of the differentially disruptable capsule system. In embodiments, the inclusions can act as stress concentrators, space occupiers, and / or gas formers, similar to the behavior of inclusions that are embedded in the capsule matrix (as described below in more detail). In other embodiments, the inclusions themselves can be deployed as an inner lining of the therapeutic agent compartment 102a, so that the inclusions themselves constitute the optional enclosing layer 108a. In yet other embodiments, the inclusions can form all or part of a coating around the therapeutic agent itself before it is introduced into the therapeutic agent compartment 102a.

[0030] When the inclusions that form all or part of the optional enclosing layer 108a act as gas formers, they can comprise substances that react preferentially with the acid medium in the stomach or the alkaline medium in the duodenum. For example, suitable gas-forming substances can include carbon-dioxide formers such as calcium carbonate (including precipitated calcium carbonate (PCC), sodium bicarbonate, potassium bicarbonate, magnesium carbonate, and the like, or hydrogen formers such as magnesium particles and the like). Such materials, upon contact with small amounts of stomach acid, form gases, either carbon dioxide or hydrogen; these gases when formed at the level of the optional enclosing layer 108a can act as gas barriers to protect the optional enclosing layer 108a or the contents of the therapeutic agent compartment 102a from contact with acid that has penetrated the overlying capsule. In more detail, such gases can remain where they are formed and prevent further incursion of stomach acid into or through the optional enclosing layer 108a, and / or they can percolate through those defects in the capsule that allowed the incursion of stomach acid and form a gas barrier to limit further acid ingress. For example, gases thus formed can act to block pinholes in the overlying capsule and prevent furtherstomach acid from passing through them to reach the therapeutic agent compartment 102a. In yet other embodiments, gas formers that produce gases upon contact with the alkaline fluid in the duodenum can act to slow the passage of duodenal juices into the therapeutic agent compartment 102a, thereby affecting the release of the therapeutic agent compartment 102a within the duodenum and more distally within the gastrointestinal tract.

[0031] In other embodiments, the optional enclosing layer 108a can have a minimal effect on release properties, such as a gelatin or other pharmaceutically acceptable capsule, but can be selected to afford a convenient way to facilitate handling of the therapeutic agent during the process of manufacturing the overall orally ingestible delivery system 100a. However, in other embodiments, the therapeutic agent compartment 102a can be formed as a void (not shown) within which the therapeutic agent resides, without additional enclosing layers apart from those provided by the capsular matrix of the differentially disruptable capsule system 104a itself.

[0032] As shown in more detail in FIG. 1 A, and as also described with reference to FIGs. 2A and 2B below, the differentially disruptable capsule system 104a comprises a plurality of inclusions 112a embedded in a supporting matrix 116a. While the inclusions 112a are shown in FIG. 1 A as arranged in a geometric pattern within the matrix 116a, it is understood that they can be distributed in any pattern throughout the matrix and can be distributed randomly. The orally ingestible delivery system 100a as disclosed herein can be designed to remain substantially intact in the stomach but then to permit sufficient disruption in the intestine or to allow sufficient intestinal fluid ingress that the contents of the therapeutic agent chamber 102a can be released from the orally ingestible delivery system 100a at a selected location distal to the stomach. The distribution, amount, and nature of the inclusions 112a are properties that are engineered in order to provide the differentially disruptable capsule system 104a with these features of differential disruptability during its transit through the stomach and the duodenum, as described below in more detail.

[0033] In embodiments, an external shell 110a can be provided around the differentially disruptable capsule system 104a to permit more fine tuning of the release profile for the therapeutic agent. The external shell 110a can be itself engineered to slow or prevent the exposure of the differentially disruptable capsule system 104a to stomach juices; following the dissolution of the external shell 110a, the differentially disruptable capsule system 104a can then undergo the differential disruption contemplated by the invention. As mentioned previously, the orally ingestible delivery system 100a as disclosed herein is designed to be differentially disruptable, remaining substantially intact in the stomach but then permittingsufficient disruption in the intestine or sufficient intestinal fluid ingress that the some or all of the contents of the therapeutic agent chamber 102a can be released from the orally ingestible delivery system 100a at a selected location distal to the stomach. Hence, an external shell 110a can be provided to limit or to selectively permit the ingress of any and all fluids, whether stomach fluids (i.e., liquid secretions produced in the stomach) or intestinal fluids (i.e., liquid secretions produced by the pancreas, liver, or intestine that reside in the intestinal tract), thereby allowing such fluids to pass through the differentially disruptable capsule system 104a at an intended time after the ingestion of the orally ingestible delivery system 100a, and thus to access the contents of the therapeutic agent chamber 102a. The complete or partial dissolution of the outer shell in a particular area (for example, the stomach) allows the surrounding secretions to access the differentially disruptable capsule system matrix and initiate its dissolution, thereby exposing the inclusions within the matrix and extending the dissolution throughout the matrix layer, as described in more detail herein.

[0034] In embodiments, the external shell 110a can contain within its substance or can bear upon its inner or outer surface a plurality of inclusions (not shown), which can behave similarly or dissimilarly from those included within the matrix material of the differentially disruptable capsule system. In embodiments, the inclusions can act as stress concentrators, space occupiers, and / or gas formers, similar to the behavior of inclusions that are embedded in the capsule matrix (as described below in more detail). In embodiments, the inclusions themselves can be deployed as an outer lining or coating over the capsule 104a, so that the inclusions themselves contribute to the barrier properties of the external shell 110a, or constitute the external shell 110a in whole or in part.

[0035] When the inclusions that form all or part of the external shell 110a act as gas formers, they can comprise substances that react preferentially with the acid medium in the stomach, forming gas that remains on the surface of the capsule to offer an additional layer of protection during passage through the stomach. For example, suitable gas-forming substances can include carbon-dioxide formers such as calcium carbonate (including precipitated calcium carbonate (PCC)), sodium bicarbonate, potassium bicarbonate, magnesium carbonate, and the like, or hydrogen formers such as magnesium particles and the like). Such materials, upon contact with small amounts stomach acid, form gases, either carbon dioxide or hydrogen; these gases when formed at the level of the external shell 110a can act as gas barriers to protect the underlying capsule from contact with acid that has penetrated the external shell 110a. For example, such gases can remain where they are formed and prevent further incursion of stomach acid into or through the external shell 110a,or they can form a gas layer over all or part of the external shell 110a or capsule to afford extra protection to the dispersible capsule. For example, gases thus formed can act to block pinholes in the overlying external shell 110a and prevent further stomach acid from passing through, thereby reinforcing the external shell 110a as the OIDS pass through the stomach.

[0036] Suitable materials for the external shell 110a include, without limitation, those substances for enteric coatings that are familiar to skilled artisans, for example, cellulose derivatives such as cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate succinate, cellulose acetate succinate, carboxy methyl ethyl cellulose, methylcellulose phthalate, hydroxypropyl methylcellulose phthalate, and ethylhydroxy cellulose phthalate; vinyl polymers, such as polyvinyl acetate phthalate, vinyl acetate-maleic anhydride copolymer; polyacrylates; and polymethacrylates such as methyl acrylate-methacrylic acid copolymer, methacrylate-methacrylic acid-octyl acrylate copolymer; and styrene-maleic monoester copolymer, any of which can be used alone or in combination. Certain of these materials are pH sensitive, including as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, and acrylic copolymers, such as have been commercialized as part of the EUDRAGIT® family (Rohm Pharma) of coatings.

[0037] In embodiments, multiple therapeutic agent compartments can be provided within the OIDS, for example as shown in FIG. IB. FIG. IB depicts an OIDS 100b comprising a differentially disruptable capsule system 104b having similar features to that shown in FIG.1 A, where similar numbers represent similar structures. For example, the differentially disruptable capsule system 104b is shown as containing a plurality of inclusions 112b and surrounded by an outer shell 110b. However, the OIDS 100b shown in FIG. IB depicts a plurality of therapeutic agent compartments 102b within the differentially disruptable capsule matrix, each containing a therapeutic agent that can be the same as or different than the others. In embodiments involving multiple therapeutic agent compartments 102b containing different therapeutic agents, the various therapeutic agents can be selected to work sequentially or simultaneously. To manufacture the embodiment of an OIDS as shown in FIG. IB, the therapeutic agent or agents can be formulated initially and then can be enclosed within same matrix material that forms the differentially disruptable capsule system 104b, with the space(s) that the one or more therapeutic agents occupy each being termed a therapeutic agent compartment 102b. Advantageously, a plurality of therapeutic agent compartments can be included, with each containing the same or different therapeutic agents. As shown in the embodiment depicted in FIG. IB, one therapeutic agent compartment cancontain a first therapeutic agent, and a second therapeutic agent compartment can contain a second therapeutic agent, both of which have different therapeutic effects, and which can optionally act synergistically, such combinations can thus provide two or more therapeutic agents to a patient in the same delivery system. As another example, one therapeutic agent compartment can contain a first therapeutic agent, and another therapeutic agent compartment can contain a second therapeutic agent, where the second therapeutic agent enhances the effect of the first therapeutic agent without itself having an independent therapeutic effect. As an example, a probiotic therapeutic agent can be delivered in one therapeutic agent compartment and a prebiotic substance can be delivered in another therapeutic agent compartment, with the prebiotic agent having no independent therapeutic effect but rather acting to enhance the effectiveness of the probiotic substance.

[0038] In embodiments such as those depicted in FIG. IB, each therapeutic agent compartment 102b can be provided with its own enveloping layer (each labeled 108b), which can be the same as or different from other enveloping layers for other therapeutic agent compartments; in embodiments, the outer enveloping layer 108b is absent for some or all of the therapeutic agent compartments 102b. As described previously, an outer enveloping layer 108b for a therapeutic agent compartment 102b can provide numerous advantages, and can permit fine-tuning of structural properties and release characteristics for the therapeutic agent compartments 102b. An outer enveloping layer or coating 108b can be provided, for example, to modify the release profile of the therapeutic agent compartment 102b, or to enhance its uptake or its therapeutic effects, or to enhance the mechanical stability of the therapeutic agent compartment 102b if it is to be released as a separate structure from the orally-ingestible delivery system 100b to permit a delayed release of its contents at a different site in the gastrointestinal tract. As shown in FIG. IB, the differentially disruptable capsule matrix surrounds the plurality of therapeutic agent compartments 102b, similar to the depictions in FIG. 1 A.

[0039] In some embodiments, such as the one depicted in FIG. 1C, an OIDS 100c comprising a differentially disruptable capsule system 104c and a therapeutic agent compartment 102c can be constructed, wherein the main therapeutic agent compartment 102c contains multiple deposits of therapeutic agents (all labeled 120) that are enclosed within. Optionally, some or all of the multiple deposits of therapeutic agents 120 can be provided with an encapsuling layer 114 for each, which can be the same or different among the multiple deposits. In embodiments, the multiple deposits of therapeutic agents 120 can be suspended in a therapeutic agent compartment matrix 118 within the therapeutic agentcompartment 102c with or without an encapsulating agent 114. The therapeutic agent compartment matrix 118 can be formed of any substance that can support or suspend the multiple deposits of therapeutic agents 112, for example hydrocolloids such as guar, alginate, gelatin, and the like, or chitosan or other hydrogels that can be crosslinked. Hydrocolloids and hydrogels are desirable as matrices for therapeutic agents having more hydrophobic properties, for example, medications suspended or solubilized in oil or otherwise rendered hydrophobic: such deposits of therapeutic agents can be suspended in the hydrophilic matrix analogous to an oil-in-water emulsion. In embodiments, the hydrophilic matrix comprises a protein or a polysaccharide, and the hydrophilic matrix can possess hydrocolloid properties. In embodiments, the protein is a gelatin. A more hydrophilic therapeutic agent can be suspended in a matrix having less hydrophilicity. Depending on the therapeutic agents that are involved, and the desired chemistry for the overall OIDS, the matrix 118 within the therapeutic agent compartment 102c can be more or less hydrophilic. In embodiments, the supporting therapeutic agent compartment matrix 118 within the therapeutic agent compartment is optional or minimal, or the therapeutic agent compartment matrix 118 itself can be a therapeutic agent. In embodiments, the therapeutic agent compartment 102c is a void within the differentially disruptable capsule system 104c, with multiple deposits of the therapeutic agent contained within the void. An optional inner enclosure 108c around the therapeutic agent compartment 102c, for example a capsule, can encase the multiple deposits of the therapeutic agent 112 and can further provide for additional fine-tuning of therapeutic agent release following the disruption of the differentially disruptable capsule system. As mentioned previously, in embodiments of an OIDS 100c having multiple therapeutic agent deposits 114 within the therapeutic agent compartment 102c, each therapeutic agent deposit 114 within the therapeutic agent compartment 102c can have its own optional system of coatings or enveloping agents 118, for example to provide mechanical stability after its release from the orally ingestible delivery system 100c, or to modify its release profile, or to enhance its uptake or its therapeutic effects. The therapeutic agent thus formulated, for example with a system of enveloping layers, can be inserted intact into the therapeutic agent compartment 102c with its release properties provided by its own formulation; in such embodiments, the therapeutic agent’s formulation can add to or modify the overall orally ingestible delivery system’s effect on the therapeutic agent’s release profile. In such embodiments, for example, the therapeutic agent with its appropriate release-modifying formulation can be inserted into an empty therapeutic agent compartment 102c, i.e., a therapeutic agent compartment 102cformed as a void without special walls or other envelopments apart, although the void can itself be enveloped by an optional inner enclosure 108c, all as depicted in FIG. 1C.

[0040] Advantageously, in the embodiment depicted in FIG. 1C, a single therapeutic agent compartment 102c can be fabricated that contains a combination of therapeutic agents, thus making available two or more therapeutic agents to a patient in the same delivery system. In this embodiment, the therapeutic agent compartment 102c can be manufactured separately, for example by a pharmaceutical company, and can be provided to a different manufacturer for enclosure in the delivery system provided by the OIDS. Such an arrangement would allow the pharmaceutical company providing the therapeutic agent(s) to retain fine control over the release profiles of the agents enclosed within the therapeutic agent compartment 102c, while the delivery system manufacturer would retain control over the dissolution profile for the overall differentially disruptable capsule system.

[0041] Similar to the OIDS depicted in FIG. IB, the OIDS shown in FIG. 1C can permit the dispensation of two or more different therapeutic agents, wherein one agent enhances the effect of the other without having an independent therapeutic effect. As an example, a probiotic therapeutic agent can be provided at the same time as a prebiotic therapeutic agent, with the prebiotic agent intended to enhance the effectiveness of the probiotic substance. As mentioned previously, single-pill combinations are recognized as valuable tools for managing chronic conditions like asthma, diabetes, hypertension, and dyslipidemia.Because of its ability to survive passage through the stomach, the OIDS disclosed herein can offer the advantages of combination therapies for therapeutic agents that previously had required parenteral administration, by including combinations of therapeutic agents within a single therapeutic agent compartment.

[0042] The OIDS shown in FIG. IB and the OIDS shown in FIG. 1C both permit the delivery of two or more different therapeutic agents in a single pill. Single-pill combinations are recognized as valuable tools for managing chronic conditions like asthma, diabetes, hypertension, and dyslipidemia. Because of their ability to survive passage through the stomach, orally ingestible delivery systems as shown in FIGs. IB and 1C can offer the advantages of combination therapies for therapeutic agents that previously had required parenteral administration, by including multiple therapeutic agents each within its own therapeutic agent compartment, with each therapeutic agent compartment surrounded by the differentially disruptable capsule system of the present invention. It is understood that multiple therapeutic agents can be contained within a single therapeutic agent compartment,as shown in FIG. 1C, or can be deployed within its own therapeutic agent compartment, as shown in FIG. IB.B. Differentially disruptable capsule matrices and embedded inclusions

[0043] Central to the advantageous properties of the OIDS is the differentially disruptable capsule within which the therapeutic agent compartment(s) reside. While engineered modifications of the therapeutic agent compartment and the therapeutic agents themselves can be employed to affect the rate of effective release at different locations in the gastrointestinal tract, the differentially disruptable capsule system component of the OIDS provides substantial control over the protection of therapeutic agents in the stomach milieu and their subsequent, targeted release in the intestines.

[0044] Accordingly, the differentially disruptable capsule system can be formulated to resist disruption in the stomach and to permit disruption in the duodenum, or to permit some controlled disruption in the stomach, followed by further disruption in the duodenum. In embodiments, this can be accomplished by forming the differentially disruptable capsule system so that it has two distinct properties: (1) it resists hydrolysis in the low pH environment of the stomach, and resists digestion from stomach enzymes, thus resisting disruption in the stomach; and (2) it is susceptible to disruption in the intestine.

[0045] The differentially disruptable capsule system comprises a combination of a supportive matrix and a plurality of inclusions embedded therein. The supportive matrix is designed to be relatively frangible, allowing it to be disrupted in the intestine and potentially allowing its disruption to commence in the stomach. As used herein, the term “frangible” refers to the capability of a material or a structure to be broken, ruptured, disrupted, or otherwise to have its integrity impaired. A frangible substance need not be easily breached; instead, it can have sufficient mechanical strength to resist a variety of forces, while it is capable of being fractured or damaged by a particular stress or combination of stresses or being exposed to a certain chemistry. In embodiments, the frangible materials and structures disclosed herein are engineered in such a way as to resist certain stresses, but to undergo preprogrammed or planned disruption when exposed to other internal or external stresses or chemical reactions. This engineered frangibility can allow the acid-resistant matrix, for example, to withstand the mechanical stresses within the stomach, but to permit sufficient deterioration in its mechanical integrity to allow for its disruption so that therapeutic agent compartment can be accessed by stomach and / or intestinal juices. The OIDS as disclosed herein attains a desirable degree of frangibility for the differentially disruptable capsulesystem by embedding a plurality of inclusions within the matrix material, as discussed below in more detail.1. Matrix materials

[0046] In embodiments, the differentially disruptable capsule matrix can be formed from a moldable hydrophobic or lipophilic material, for example a waxy or fatty capsular acid- resistant matrix material that is relatively unaffected by stomach juices, such as beeswax, carnauba wax, candelilla wax or the like, or mixtures thereof. In embodiments, a matrix material can be selected that can be emulsified away in the duodenum by the bile salts.

[0047] A variety of materials can be used to create the acid-resistant capsular matrix of the differentially disruptable capsule system, for example acid-resistant materials such as cellulose, fatty acids, waxes, polyolefins, edible or natural elastomers (such as natural latexes, couma macrocarpa, tunu, jelutong, or chicle), and the like. In embodiments, a waxy substance is advantageous, both providing acid resistance and also sufficient frangibility that it can be disrupted before or as the OIDS enters the duodenum. In an embodiment, a waxy substance such as beeswax, soybean wax, carnauba wax, candelilla wax, and the like, or mixtures thereof, can be used as the base substrate for the acid-resistant capsular matrix. As used herein, the term “wax” refers to any hydrocarbon that is lipophilic and a malleable solid near ambient temperatures, typically having a melting point above about 40°C. As examples, waxes can include long-chain aliphatic hydrocarbons typically having 20-40 carbon atoms per molecule, or fatty acid / alcohol esters typically containing from 12-32 carbon atoms per molecule, such as myricyl cerotate, found in beeswax and carnauba wax.

[0048] Certain types of waxes are more hydrophilic than others and can be used themselves or blended with other forms of wax to create a material with advantageous properties. In embodiments, for example, the blended formulation can be more efficiently emulsified with the addition of other materials that act as emulsification promoters or can otherwise affect the surface tension or physical properties of the coating layer.

[0049] In embodiments, other components can be admixed into the capsular matrix to improve its performance. For example, the capsular matrix can be modified with other materials such as surfactants or oils to enhance desirable properties or can otherwise be modified to alter its mechanical characteristics. Examples of ingredients that can be mixed together to form the capsular matrix substance include (1) one or more types of waxes mixed together (for example, two waxes can be selected that offer a high-temperature stable coating); (2) one or more waxes mixed with one or more fatty acids; (3) one or more wax or waxes mixed with policosanol; (4) one or more wax or waxes mixed with cholesterol; (5)one or more wax or waxes mixed with a phospholipid and / or with phosphatidylcholine; (6) one or more wax or waxes mixed with essential oils (e.g., from orange peel or from other flowers, or extracts such as limonene, pinene, and the like); and (7) one or more waxes mixed with oil-soluble vitamin mixture such as vitamin A and / or E. Suitable waxes include candelilla wax, carnauba wax, and beeswax, none of which are soluble in acid. Other examples within the scope of the invention can be identified by practitioners of skill in the art, using no more than routine experimentation, and any the above ingredients in combination.

[0050] In embodiments, coatings can be applied to the entire system to improve the ingestibility of the system, to improve its palatability, or to protect it from mechanical trauma. For example, confectioner’s glaze or pharmaceutical glaze can provide a glossy finish and protective coating around the entire device. Such coatings are well-known in the formulation field. Such coatings can be formed from natural ingredients, such as shellac (formed from insect excretions) and carnauba wax. As would be understood by skilled artisans, the decomposition time of the capsular matrix can be further adjusted by adding coatings on top of it, for example a coating possessing delayed release or extended-release properties when exposed to stomach acid and / or proteases. Techniques for forming such layers are well-known in the art. In embodiments, the delivery system can be coated with a lubricious and / or pleasant-tasting coating (e.g., confectioner’s glaze, carnauba wax, gelatin, mucilage, and the like) that make its ingestion easier.

[0051] In embodiments, the differentially disruptable capsule system can comprise multiple layers having different degrees of chemical responsiveness to the conditions in the stomach and the intestine, or different degrees of mechanical or chemical vulnerability. In other embodiments, the differentially disruptable capsule system can be formed as a single layer enclosing the therapeutic agent compartment but having asymmetrical properties. In embodiments, the layer can then be formed as a gradient between two regions having different properties, for example with a more hydrophobic, acid-resistant outer region and an inner, more hydrophilic inner region (or vice versa). Such an arrangement can include more of the waxy or hydrophobic polymer in the mixture on the outer region, and a more proteinbased or hydrophilic polymer in the mixture on the inner region (or vice versa). In embodiments, an asymmetrical layer can be formed using temperature gradients that produce a gradient of two dissimilar components in the layer.2. Areas of material inhomogeneity

[0052] In embodiments, areas of material inhomogeneity, such as inclusions or voids, can be introduced into the capsular matrix formulation to become disposed within the continuous frangible matrix enclosing the therapeutic agent compartment. As used herein, the term “continuous” refers to the substantial physical integrity of the matrix as it encloses the therapeutic agent compartment. Moreover, the continuous frangible matrix is initially continuous, but can experience progressively more areas of discontinuity as the differentially permeable capsular system encounters the physical and chemical conditions in the stomach and small intestine. It is anticipated that the continuous frangible matrix will become discontinuous at some point in its progression through the gastrointestinal tract, so that the contents of the therapeutic agent compartment can be released as intended. The continuity of the frangible matrix does not preclude different regions within the matrix from having different physical or chemical properties or from containing areas of material homogeneity, any of which may contribute to the frangibility of the matrix. Nor does the continuity of the frangible matrix preclude scattered voids or other engineered defects from inclusion, so long as the frangible matrix remains substantially physically intact as it encloses the therapeutic agent compartment.

[0053] Voids can be created within the matrix material, and inclusions can be embedded in the matrix material. As used herein, the noun “void” refers to a space within the material. As used herein, the noun “inclusion” refers to a material different than the material of the capsular matrix that is embedded as a small, discrete deposit of any shape or aspect ratio within the capsular matrix material, where the material forming the inclusion has different stiffness properties than the capsular matrix material and is typically more rigid. Without being bound by theory, it is understood that an inhomogeneity in a material such as an inclusion, a void, or some other sort of defect in the material produces an area of stress concentration that increases the risk of the material’s failure at that site. Moreover, an inclusion can become a void, for example if it is dissolved away to leave a defect behind in the matrix material; in addition, an inclusion can generate a void or a defect in the matrix material if it is a gas-former that produces a gas that is able to expand within the matrix material itself to deform it, thereby producing a void. Areas of material inhomogeneity such as inclusions and voids can generate a stress gradient that affects the stress-strain properties of the material and its resistance to cumulative damage, which can lead to fatigue failures. Cyclic plastic deformation and damage progression occur in the reverse / cyclic plastic zone that is produced around the inclusion. Multiphase materials having different stress-strainregions can accumulate microstructural damage, inhomogeneous deformation, deformation localization and failure. The presence of inclusions or voids thus may result in inhomogeneous stress states in the capsular matrix material that can cause cracks and fractures in the matrix and subsequent mechanical failure.

[0054] As described above, inclusions or voids act as areas of material inhomogeneity that can act as stress concentrators, space occupiers, and gas formers. In embodiments, inclusions can exhibit one or more of these functional behaviors, acting as one or more of stress concentrators, space occupiers, or gas formers. Multiple inclusion materials that exhibit different functional behaviors can be incorporated in the matrix, or a single type of inclusion can be incorporated in the matrix so as to perform several different functions within the matrix, i.e., acting as acting as one or more of stress concentrators, space occupiers, or gas formers.

[0055] In embodiments, the presence, distribution, size, and morphological characteristics of inclusions can be selected based on their mechanical effects as stress concentrators to produce desired frangibility in the coating material being used to produce the differentially disruptable capsule system. Areas of weakness related to the presence of inclusions in the matrix material described herein thus can be deliberately engineered to predispose it to fracture and potential failure when subjected to stresses such as agitation in the stomach or intestine. Fractures or other disruptions that ensue can then allow the ingress of surrounding fluids, whether stomach fluids or duodenal fluids. Ingress of fluids can cause further damage to the matrix material by causing swelling in the matrix in addition to furtherance of fracture patterns. Moreover, fluids that penetrate the differentially disruptable capsule system can reach the therapeutic agent compartment, leading to the release of such agents from their compartment or compartments in a desired location in the gastrointestinal system.

[0056] In embodiments, inclusions embedded in the capsular matrix material can serve as space-occupiers, thereby reducing the amount of the hydrophobic capsular matrix material available to act as load-bearing elements of the differentially disruptable capsule system. It is understood that the inclusions occupy space within the matrix, decreasing the effective thickness and strength of the matrix layer, allowing the propagation of differential stresses, and thereby rendering the matrix more frangible. This space-occupying effect is separate from, and in addition to, the effect of the inclusions as stress concentrators. Inclusions act as space-occupiers by residing within the waxy layer so that the wax, as the continuous layer of the matrix, forms very thin walls above and between the space-occupying particles. Spaceoccupiers can be distributed in any pattern or amount, but close packing will maximize theirweakening effect on the coating. With a higher loading of space-occupying particles (loading is likely to range anywhere from 0 - 99% by weight, and likely 25-80% by weight), the amount of capsular matrix material between the particles would become increasingly thin, until the particles reach a percolation threshold at which all inclusion particles are touching. These thin walls that are formed in the capsular matrix are more susceptible to external stresses such as agitation in the stomach or intestine, while still offering a certain degree of protection in the low pH environment of the stomach. Ultimately, these spaceoccupiers can help the wax break away much more quickly and efficiently.

[0057] Both solid and fluid materials can act as space occupiers, taking up volume within the capsular matrix and reducing the thickness of matrix walls remaining between the space occupiers so that the capsular matrix material overall is thinner, or less strong, or otherwise less resistant to the degree of stress that would be encountered during passage through the gastrointestinal tract. Exemplary fluid materials suitable for use as space occupiers can include non-polar materials such as triglycerides, fatty acids, edible oils, and esters derived from edible oils, vegetable oils, or plants, provided that the selected space occupiers are not soluble in the capsular matrix material itself. In embodiments, medium chain fatty acids are desirable. Exemplary edible oils containing medium chain fatty acids include coconut oil, MCT oil, palm kernel oil, laurel oil, and other oils containing caproic acid, caprylic acid, capric acid, or lauric acid. Useful materials also include triglycerides and esters produced from edible oils, for example caprylic and capric acid ester products such as CAPTEX® products, NEOBEE® products, MIGLYOL® products, and the like. Other edible oils, including long or short chain fatty acids, can also be used, such as olive oil, palm oil, soybean oil, canola oil, corn oil, peanut oil, avocado oil, mustard oil, rice bran oil, safflower oil, sesame oil, sunflower oil, almond oil, flaxseed oil, cottonseed oil, grapeseed oil, butter, margarine lard, linseed oil, hemp oil, macadamia oil, pumpkin seed oil, walnut oil, tallow, tea seed oil, hazelnut oil, acai palm oil, jambu oil, graviola oil, tucuma oil, Brazil nut oil, carapa oil, buriti oil, passion fruit oil, pracaxi oil, solarium oil, cocoa butter oil, pecan oil, perilla oil, vitamin A oil, vitamin E oil, cod liver oil, shark liver oil, krill oil, or fish oil from fish such as herring, sardines, tuna, anchovies, mackerel, and salmon, and the like. In embodiments, the space-occupying fluid can itself contain therapeutic agents, which would be released with the dispersal of the fluid in the intestine. In certain embodiments, the space-occupying fluid is a fat or an oil that is thermally sensitive, so that it is a liquid when it is introduced into the matrix, but so that it solidifies as the system cools; such a material may solidify at room temperature, for example, and re-liquify at body temperature, or it may be aliquid that solidifies as it cools and that remains a solid at body temperature. Such a material would be a hybrid space-occupier: a fluid at certain temperatures and a solid at others, offering mechanical protection in either case.

[0058] In addition to acting as space-occupiers and as stress concentrators, certain embedded inclusions are chemically reactive, so that they respond to an encounter with the acidic or basic environments in the stomach or duodenum, or so that they are affected by the enzymes in these regions. Preferably, at least some of inclusions in the continuous frangible matrix are chemically reactive. Materials acting as chemically reactive inclusions can comprise any material that undergoes a change of state or a chemical reaction when it encounters the environment of the stomach or of the duodenum. For example, certain materials can dissolve in acids, or in neutral fluids, or in alkali. Contact of these reactive materials with other reactants can yield a product such as a gas that can block a defect in the matrix, or can yield a solution that causes the inclusion to be washed out of the matrix, leaving behind a void that increases the frangibility of the matrix in that location. Chemically reactive substances useful as chemically reactive inclusions include, without limitation, substances being insoluble or minimally soluble in strongly acidic environments such as the stomach while being more soluble in neutral or higher pH, such as that environment in the duodenum. Examples of such are benzoic acid, bile acid, salicylic acid, citric acid, boric acid, and tartaric acid. Long chain fatty acids in their acid form may also be used, where the selected material is insoluble in a highly acidic environment but becomes soluble in neutral to alkaline pH environments that are also rich in emulsifying bile salts, such as within the duodenum. Such fatty acids may include palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, myristoleic acid, palmitoleic acid, sapienic acid, elaidic acid, vaccenic acid, linoelaidic acid, arachidonic acid, eicosapentaenoic acid erucic acid, docosahexaenoic acid, and the like. In other embodiments, inclusions can be selected that are relatively susceptible to and reactive in a low pH environment such as stomach acid. For example, bicarbonate can be used to form inclusions that exert mechanical effects on the matrix as stress concentrators and as space occupiers, but bicarbonate is also reactive if it contacts stomach acid, forming carbon dioxide gas that can act as a barrier to further ingress of stomach acid. In embodiments, inclusions that are more susceptible to stomach acid and enzymes, for example proteins, sugars, salts, and the like, can be positioned towards the outer aspect of the matrix, while inclusions that are more susceptible to intestinal juices can be positioned towards the inner aspect of the matrix, an arrangement that would allow for differential disruption of the matrix, depending on theanatomical location of the OIDS. Inclusions can be selected for their susceptibility to stomach juices, or for their susceptibility to intestinal juices, or both; inclusions can be formed from the same or from different materials; inclusions can be provided in the same amounts throughout the matrix, or in different amounts selected either randomly or deliberately, for example, with larger inclusions deployed towards the interior or exterior of the matrix. Other arrangements for inclusions and variations of inclusion patterns can be envisioned by skilled artisans, based on the objective of the OIDS for delivering the therapeutic agent within the gastrointestinal tract.

[0059] Reactive inclusions that form a gas in certain chemical environments (called “gas formers”) are particularly advantageous for producing desirable differential disruption in the capsule matrix. Bicarbonate inclusions in the matrix can form CO2upon contact with stomach acid, for example if there is a small defect in the matrix that allows the stomach acid to penetrate it and reach the inclusions. The stomach acid produces the gaseous CO2from the bicarbonate, and the gaseous CO2permeates the matrix defect and prevents the incursion of further stomach acid. Besides weakening the structure of the overall capsular matrix by occupying space therein, and besides whatever concentration-dependent weakening effect they have as stress concentrators before they react to produce gas, embedded deposits or particles of gas-forming materials can have an additional weakening effect after they react to produce gas within the capsular matrix, because the presence of gases within the matrix is itself an inhomogeneity in the material, which can produce a stress concentration effect. As used herein, the term “gas former” or “gas-forming substance” refers to a material selected so that it produces a gas when it reacts with acid, such as is found in the gastric juice, or with alkali, such as is found in the duodenum. Of particular advantage is a gas-forming substance that generates carbon dioxide upon exposure to the hydrochloric acid in the stomach. Gasforming substances (e.g., carbon-dioxide formers such as calcium carbonate (including precipitated calcium carbonate (PCC)), sodium bicarbonate, potassium bicarbonate, magnesium carbonate, and the like, or hydrogen formers such as magnesium particles and the like) exist as solid materials or in other physical states that can, in embodiments, be deposited in the capsular matrix to release carbon dioxide when exposed to stomach acid. In an embodiment, the gas-forming substance can be inserted directly in the matrix itself, or it can be embedded in a digestible polymer or small molecule carrier that is disposed within the capsular matrix, so that upon contact with stomach acid the carrier decomposes and exposes the embedded gas-forming substance to react with the stomach acid; in other embodiments, the gas-forming substance can be embedded directly in the capsular matrix.Alternatively, or in addition, gas formers can produce gases upon contact with the alkaline fluid in the duodenum. Gas forming inclusions can be included in the frangible capsular matrix instead of or in addition to other reactive or non-reactive inclusions.

[0060] FIG. 2A illustrates schematically an arrangement of inclusions embedded within the differentially disruptable capsule system of an OIDS. This Figure shows a partial cross section of an OIDS 200a having a differentially disruptable capsule system 202a enclosing a therapeutic agent compartment 204a. As shown, the differentially disruptable capsule system 202a comprises an acid-resistant capsular matrix 208a with multiple inclusions 210a, 212a, 214a embedded therein. As shown for exemplary purposes, there are different types of inclusions, including those that react in an acid environment (210a), those that are unreactive in acidic or in alkaline environments (212a), and those that are reactive in alkaline environments (214a); it is understood, however, that any particular OIDS can contain any of the types of inclusions or none at all Those inclusion materials that are reactive in acid or alkaline environments can be gas-formers.

[0061] FIG. 2B depicts the same OIDS 200b cross-section as shown in FIG. 2A, with the inclusions 210b, 212b, and 214b embedded within the differentially disruptable capsule system 202b. As shown in FIG. 2B, however, there is a break 218 in the integrity of the capsular matrix 208b, allowing the stomach fluid 220 to penetrate it. While the depicted capsular matrix 208b is itself impervious to the chemical effects of the stomach fluid, its integrity is nonetheless affected by the mechanical damage.

[0062] Moreover, as shown in FIG. 2C, the stomach fluid 220c can encounter the acid- responsive gas formers 210c, for example, carbon-di oxide formers such as calcium carbonate (including precipitated calcium carbonate (PCC)), sodium bicarbonate, potassium bicarbonate, magnesium carbonate, and the like) or hydrogen formers such as magnesium particles and the like, and converts these solid inclusions into bubbles of gas 222c. Neither the non-reactive inclusions 212c nor the alkali-reactive inclusions 214c respond to the stomach acid exposure by forming gas bubbles. In embodiments, the embedded inclusions are predominately acid-reactive inclusions, which can dissolve in contact with acid, and which can form gases. In other embodiments, the embedded inclusions are predominately pH neutral -reactive or base-reactive inclusions, intended for dissolution in more distal sections of the gastrointestinal tract. In embodiments, gas bubbles formed by gas forming inclusions 222c can cause further structural damage to the capsular matrix 208c by their formation and expansion; these gas bubbles can also offer some resistance to further effects of stomach fluid 220c by acting as a physical and chemical barrier that blocks the gastricacid from further entry. In embodiments, the gas bubbles 222c can coalesce or spread through the damaged area of the capsular matrix 208c, and are capable of forming a dispersible acid barrier (not shown), using mechanisms that have been described in U.S. Patent Application Publication No. 20210113476A1 (U.S. Application No. 17 / 075,030, filed October 20, 2020), the contents of which are incorporated by reference in their entirety.

[0063] As depicted schematically in FIG. 2C, if the capsular matrix 208c encounters mechanical stress in the stomach, minimal damage to the matrix can create voids and / or can permit the penetration of stomach juices. If the stomach acid encounters gas-forming substances 210c within the capsular matrix 208c, the resulting production of gas can stress the matrix 208c from within, damaging it further. In addition, gas that is generated within the matrix, for example when a chemically reactive inclusion encounters stomach acid and forms CO2, can produce voids in the matrix material, which can act themselves as stress concentrators; voids can also be generated from the dissolution of non-gas-forming inclusions. This process can perpetuate itself throughout the OIDS 200c as it passes through the stomach, weakening the matrix substance while simultaneously generating protective gas such as CO2 that can prevent the further penetration of stomach acid into the matrix. In embodiments, the balance between mechanical forces and gas generation allows the OIDS 200c to pass through the stomach with therapeutic agent compartment 204c protected; following passage through the stomach, the OIDS will enter the duodenum, where the basic environment will dispel the protective CO2 and allow the duodenal juices to enter the matrix, erode it, and ultimately release the therapeutic agent from the therapeutic agent compartment.

[0064] While FIGs. 2B and 2C both show a therapeutic agent compartment (204b and 204c respectively), in the depicted embodiments there is no incursion of stomach fluid 220b / 220c into that region, as the differentially disruptable capsule system 202b / c remains substantially intact. It is recognized that in certain embodiments, especially with a large number of gas formers or other inclusions sensitive to stomach acid 210b / c, there could be sufficient disruption of the capsular matrix layer 208b / c that it loses its integrity, permitting the stomach fluid to access the therapeutic agent within the therapeutic agent compartment. In embodiments, as shown in FIG. 2C, the gas bubbles 222c that are produced by the encounter of the gas formers 210c with the stomach juice 220c can be scattered throughout the capsular matrix 208c where the stomach juice 220c has contacted them, potentially exacerbating the weakening of the matrix layer 208c.

[0065] In other embodiments, not shown in FIG. 2C, the formation of gas can itself act as a barrier to further intrusion of stomach acid if it is in sufficient amount to produce a dispersible gas barrier (not shown), substantially as described in the aforesaid U.S. Patent Application 17 / 075,030, the contents of which is incorporated herein by reference, thus counteracting or even preventing any weakening effects due to the gas formation process. As described in the ‘030 Application, a barrier formed by the presence of gas bubbles within or on top of the capsular matrix layer is termed “dispersible” because it can be dispersed in the duodenum as it dissolves in the neutral duodenal secretions and reacts with the bicarbonates contained in the pancreatic secretions. Thus, any gas barrier formed by the reaction of the gas formers in the stomach can offer protection to the capsular matrix 208c while in the stomach without preventing the effects of bile salts and pancreatic enzymes that are secreted into the duodenum, and without preventing them from accessing the therapeutic agent compartment 204c.

[0066] While using gas formers as embedded inclusions offers an additional mechanism for tuning the differential disruptability of the capsule, other types of inclusions can be incorporated in the capsular matrix along with or as substitutes for gas formers. Such inclusions can include materials that dissolve in an acid or alkaline environment, but without the production of gas. An inclusion soluble in an alkaline environment will resist stomach acid during the OIDS’s passage through the stomach but will dissolve rapidly when it encounters the higher pH in the duodenum. The behavior of such substances, such as solid forms of acids, can accelerate the breakdown of the differentially disruptable capsule system in the duodenum as these deposits within the capsular matrix dissolve, substituting weak, fluid-filled areas or voids for solid particles. Similarly, a solid particle soluble in an acid environment can accelerate the breakdown of the differentially disruptable capsule system in the stomach by a similar mechanism, instead of or in addition to the effects of gas formers within the capsular matrix. In embodiments, combinations of inclusions can be used, with some being more susceptible to breakdown in the acid environment and others being more susceptible to breakdown in an alkaline environment. The use of both types of inclusions (acid-sensitive and alkali-sensitive) or a set of inclusions having a spectrum of acid- and alkali-sensitivities, can allow tuning of the effect of the differentially disruptable capsule system on the release of the therapeutic agent.

[0067] As an alternative to depositing inclusions in the capsular matrix, a similar effect can be produced by creating gas pockets or voids within the matrix as the matrix is being formed, for example by foaming it or otherwise introducing gas within the matrix material.By occupying space within the capsular matrix, these gas pockets reduce the amount of matrix material available to provide structural support. Instead, the capsular matrix is filled with empty spaces that detract from its overall strength. Such a honeycombed matrix structure will be more susceptible to disruption. Air pockets can be produced by adding a material to the capsular matrix during its formulation that forms gas upon mixing with the molten hydrophobic material, such as the wax or fat composition that comprises the matrix. For example, beeswax is slightly acidic, and when sodium bicarbonate is added to it, CO2 is formed within the capsular matrix as it is being formulated. The resulting formulation, as it hardens, will contain gas bubbles. When the capsular matrix is used to form the OIDS, whether by coating the therapeutic agent compartment, dipping the therapeutic agent compartment into the matrix, spraying the matrix or otherwise, the molten matrix material can contain the gas bubbles within it; as the matrix material hardens, the bubbles remain within, weakening the overall strength of the matrix layer. A benefit of this gas inclusion approach is that breakthrough may occur more quickly in the duodenum due to the lack of any extra material blocking the pathway to the drug or inner drug compartment.C. Therapeutic agents and methods of treatment

[0068] The therapeutic agent(s) included in the OIDS can be formulated as solids, semisolids, liquids, gels, or any combination thereof. As described previously, the one or more therapeutic agent compartments can contain one or more therapeutic agents (in any known state or dosage form, e.g., pills, granules, powder, liquid, etc.), with or without other covering layers. For example, the therapeutic agent(s) in the therapeutic agent compartment can be enclosed by protease-digestible layers such as gelatin, or by other protective, prolonged-release or delayed-release coatings familiar in the pharmaceutical art.

[0069] In embodiments, therapeutic agents are pharmaceutical, nutraceutical (i.e., a pharmaceutical alternative claiming physiological benefits), or diagnostic agents that are formulated for delivery in a liquid, semi-solid, or solid form, or any combination thereof. Solid forms can include powders, pellets, crystals, and the like. Semi-solid forms can include slurries, pastes, gels, gums, and the like. Formulations of therapeutic agents can be produced using familiar techniques in the art, including excipients designed to enhance their physical properties, their uptake rates, their delayed or controlled release, and the like. The therapeutic agents can be enclosed in other membranes or layers intended to encapsulate them, protect them from dissolution, prolong their release, or other adaptations familiar to skilled artisans.

[0070] In more detail, therapeutic agents for deployment within the OIDS described herein can be formulated as dosage forms for immediate release or for modified release. As used herein, the term "dosage form" denotes any form of a formulation that contains an amount of a therapeutic agent sufficient to achieve a desired therapeutic effect with a single administration (i.e., a “a therapeutically effective amount.”). A dosage form may be engineered to provide an immediate release of the active pharmaceutical ingredient, or a modified release of the active pharmaceutical ingredient, or a combination of release patterns.

[0071] As used herein, the term “immediate release” refers to a formulation, dosage form or delivery system in which the active pharmaceutical ingredient (API) is released from the dosage form with a rapid dissolution profile attained promptly after administration. While the term “immediate release” often refers simply to highly soluble APIs, comparable immediate release profiles can be achieved with less soluble therapeutic agents if excipients such as surfactants are added to the formulation to enhance drug dissolution. A therapeutic agent delivered via the orally ingestible delivery system and intended for immediate release can pass across the intestinal mucosal boundary via mechanisms such as passive diffusion or active transport, reaching its highest plasma level (termed Cmax) in a fairly short time (termed Tmax). Immediate release dosage forms usually release the therapeutic agent in a single action, following a first-order kinetics profile in which the rate of the process is proportional to the concentration of the therapeutic agent.

[0072] To counteract the disadvantages of immediate release dosage forms, or to achieve discrete therapeutic results, dosage forms can be designed that modify the release profile of the therapeutic agent. As used herein, the term “modified release” for a formulation or a composition refers to any dosage form that delivers the therapeutic agent at a rate that differs from immediate release as described above. Modified release dosage forms have drugrelease characteristics that differ from immediate release dosage forms in time course or in release location. Modified dosage forms can be further classified as “delayed release,” wherein the drug is released at a point in time and / or at a location that differs from the time and location of initial administration, and “extended release,” wherein the drug’s release is prolonged over time as compared to an immediate release version.

[0073] In embodiments, therapeutic agents used with the orally ingestible delivery systems described herein can be further coated (e.g., with enteric coatings) to delay release of the therapeutic agent within the preselected more distal location of the GI tract even after it has been discharged from the delivery system itself. Delayed release modifications can allow atherapeutic agent released from the delivery system in the small intestine to pass further along the gastrointestinal tract, for uptake at a preselected anatomical location. For example, an oral dosage form can be enteric-coated, to delay release of the medication until the formulation has passed through the stomach, or until the drug has passed through the gastrointestinal tract to the colon. Typically, extended-release dosage forms are formulated in such a manner as to make the therapeutic agent available over an extended period of time following administration. Extended-release dosage forms can be further characterized as sustained release or controlled release. Sustained release systems maintain the rate of drug release over a prolonged period of time. Sustained release dosage forms can permit the therapeutic agent to release gradually, for example, along the entire small intestine, resulting in a prolonged period for absorption and a consequent prolonged interval of drug concentration in the therapeutic range. Sustained release dosage forms commonly use various polymers that coat granules or tablets, or that form a matrix within which the drug is dissolved or dispersed. Controlled release systems offer a sustained release profile but are engineered to provide a predictably constant plasma concentration of the therapeutic agent that is independent of the biological environment of application. Although the various approaches to modified release dosage forms are not interchangeable, they all have in common the tendency to prolong the time that a drug is in the therapeutic range following a single administration, while decreasing the potential for peaks and troughs in plasma levels that would increase toxicity or decrease therapeutic efficacy. Other approaches to delivery of therapeutic agents can be employed to achieve desirable plasma levels of the agent or agents. For example, two therapeutic agent doses can be combined in one dosage form, with each dose formulated to achieve a different timing for delivery, or two different therapeutic agents can be combined in the dosage form. By adjusting the release profiles of the doses (either the same agent or different agents), the temporal distribution of the one or more agents can be optimized. Additives and formulations to facilitate sustained or controlled release are well-known in the art. For example, polymeric materials such as sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and hydroxyethylcellulose, or other cellulose ethers can be used for formulation.

[0074] Dosage forms can be formulated with enteric coats to tune sustained release. Coating materials familiar in the art include polymers with a pH-dependent solubility (i.e., pH-controlled release), polymers with a slow or pH-dependent rate of swelling, dissolution or erosion (i.e., time-controlled release), polymers that are degraded by enzymes (i.e., enzyme-controlled release) and polymers that form firm layers that are destroyed by anincrease in pressure (i.e., pressure-controlled release). Tablets can be coated using known methods to form osmotically controlled release tablets. Formulations for delivery in the small intestine and the colon include enteric coated systems, based, e.g., on methacrylate copolymers such as poly(methacrylic acid, methyl methacrylate), which are only soluble at pH 6 and above, so that the polymer only begins to dissolve upon release from the orally ingestible delivery system into the small intestine. The site where such polymer formulations disintegrate is dependent on the rate of intestinal transit and the amount of polymer present. For example, a relatively thick polymer coating can be used for delivery to the colon, while a thinner layer will be adequate if a quicker dissolution of the coating is desirable. Polymers capable of providing site-specific colonic delivery can also be used, wherein the polymer relies on the bacterial flora of the large bowel to provide enzymatic degradation of the polymer coat and hence release of the drug. For example, azopolymers, glycosides and a variety of naturally available and modified polysaccharides can be used in such formulations.

[0075] Multiple therapeutic agents can be delivered using the orally ingestible delivery system described herein. In embodiments, the multiple therapeutic agents can be attached together, enclosed within a single matrix or covering layer, or otherwise integrated into a single structure that can then be enclosed within a therapeutic agent compartment within the OIDS. In other embodiments, several different dosage forms can be enclosed within a single therapeutic agent compartment, each having its own enclosure and its own delivery properties. If two or more therapeutic agents are delivered, advantageously each can be provided to release a therapeutically effective amount to effect the overall therapeutic objective of the OIDS; it is understood that the two or more therapeutic agents can act synergistically so that their combined administration via the OIDS requires a different dosage for one or both therapeutic agents when administered together, in contrast to the dosage that would be required if each were delivered individually.

[0076] Without limitation, a therapeutic agent can be provided in single or multiple dosage forms, optionally formulated for delayed or extended release, and then enveloped by the orally ingestible delivery systems described herein, with such agents either mixed together or isolated from each other completely or partially, for example by disposing each agent within its own compartment inside the therapeutic agent compartment, or by encasing each agent in its own membrane with particular parameters for breakdown and drug release. Single agents or multiple agents within a therapeutic agent compartment can be formulated as pellets to be contained within capsules or within other enveloping media. In embodiments, onetherapeutic agent can be coated on the surface of a second therapeutic agent either as a single form factor or as a plurality of bilayer coated capsules, and the two-layer medication structure(s) are disposed within the therapeutic agent compartment. The combination of two therapeutic agents in one form factor can achieve bimodal pharmacokinetic release of the two agents, as required by a patient’s treatment plan. Alternatively, or in addition, an external enteric coating can be provided that dissolves more distally in the intestine, allowing delayed release. In embodiments, a combination of therapeutic agents can be delivered by the orally ingestible delivery system, where the combination of therapeutic agents is complementary or synergistic. For example, a combination of treatment agents can be provided for treating diabetes and other glucose regulation disorders, for example a peptide like an incretin (e.g., exenatide) and a small molecule like a biguanide compound (e.g., metformin). In embodiments, a small molecule therapeutic agent can be dissolved in the matrix, while an insoluble or larger-scale therapeutic agent is dispersed in packets throughout the matrix. Dosage preparations of the two agents can be titrated so that appropriate blood levels and therapeutic efficacy is attained.

[0077] As another example, a combination of living organisms and nutrient substances can be contained within a single orally ingestible delivery system (whether intended for pharmaceutical or nutraceutical use), such as probiotic bacteria and prebiotic substances that are synergistic or complementary to each other. Prebiotic substances, as the term is used herein, include non-digestible or minimally digestible food ingredients that can selectively stimulate the growth and / or activity of one or a limited number of bacteria residing in or coming to reside in the intestinal tract, and can include, more broadly, substrates that are selectively used by microorganisms to confer a health benefit on the host. Prebiotic substances can include materials such as undigestible fibers (e.g., galacto-oligosaccharides, fructo-oligosaccharides, oligofructose, chicory fiber, inulin, and the like), which can provide a supportive milieu for the probiotic organisms being introduced. Other prebiotic substances can include natural or partially hydrolyzed collagen and other proteins that can act as supportive milieu for probiotic organisms and / or that have independent nutraceutical effects.

[0078] Both the probiotic organisms and the prebiotic substances can benefit from the transit through the stomach into the intestinal tract afforded by the orally ingestible delivery system; the properties of the orally ingestible delivery system and the packaging of the therapeutic agents it contains can be further optimized to deliver the prebiotic substances and the probiotic organisms to a preselected destination in the large or small intestine. In embodiments, a single orally ingestible delivery system can contain an optimizedcombination of prebiotic substances and probiotic organisms designed to facilitate biome growth and maintenance while minimizing side effects; the combination of prebiotic substances and probiotic organisms can be delivered together within the therapeutic agent compartment of the orally ingestible delivery system. The combination of prebiotics and probiotics administered together can also act as a synbiotic, understood to be a product combining the prebiotic substance and the probiotic organisms so that they interact synergistically to improving survival and implantation of living microbes in the gastrointestinal tract by selectively stimulating their growth and / or metabolism. The probiotic strains used in synbiotic formulations can include Lactobacilli, Bifidobacteria spp, S. boulardii, B. coagulans and the like, while the major prebiotics used include oligosaccharides like fructooligosaccharide, galacto-oligosaccharide, xylose-oligosaccharide, inulin, prebiotics from natural sources like chicory and yacon roots, and the like.

[0079] The physical proximity of the prebiotic substances and the probiotic organisms can be engineered within the orally ingestible delivery system to maximize downstream interaction of the two therapeutic agents. In embodiments, probiotic organisms and prebiotic substances can be delivered separately in discrete orally ingestible delivery systems, e.g., for example, with one system adapted for delivering probiotic organisms, and a separate system adapted for delivering prebiotic substances; in this example, the two delivery systems can be administered simultaneously or sequentially, based on the patient’s clinical needs. In yet other embodiments, probiotic organisms can be formulated in combination with other substances besides prebiotic ingredients to enhance the viability of the probiotic organisms or to augment their therapeutic effect, and these combinations can be within the orally ingestible delivery system. Preparations using living organisms such as probiotic bacteria can be formulated using conventional methods, for example into pellet form, with optional enteric coatings to tune their delivery to preselected areas of the intestine; in other embodiments, preparations containing lyophilized living bacteria can be pelletized and encased in enteric coating substances to facilitate their delivery to the designated target site within the intestine. As would be understood by skilled artisans, other formulations using multiple pellets containing probiotic organisms can be envisioned, for example a formulation process that mixes the probiotic-loaded pellets with cushioning agents (microcrystalline cellulose, lactose monohydrate, com starch, porous calcium, and the like) and compresses the mixture into tablets that can then be contained within the therapeutic agent compartment of the orally ingestible delivery system.

[0080] Therapeutic agents can be specially formulated to optimize aspects of their pharmacokinetics as they are released from the orally ingestible delivery systems described herein. Using the OIDS, certain therapeutic agents can be delivered in an intact or an active or an activatable form into the small intestine, for example, from whence they must be taken up through the intestinal mucosa so that they can reach the systemic circulation to exert their desired effect. In an embodiment, this can be accomplished by formulating the therapeutic agent or agents in a liquid or gel matrix so that they are taken up by endocytosis (including without limitation, phagocytosis, pinocytosis and potocytosis) and are thereby transported in vesicles across the cells of the intestinal villi to enter the circulation. Following the therapeutic agent’s uptake by endocytosis, it travels across the intestinal cell for discharge into the extracellular fluid within the intestinal wall, from whence it can enter the lymphatics and / or the systemic circulation.

[0081] For certain therapeutic agents’ formulations, the therapeutic agent itself can first be dissolved in an aqueous medium, for example, a water-soluble protein in a hydrophilic environment such as a viscous matrix loaded with oligosaccharides to minimize water content of the solution. The aqueous medium can be pH buffered and contain other protective excipients as would be found in a formulation of the protein for parenteral administration, along with one or more oligosaccharides, e.g., inulin, trehalose, dextran, and the like. The aqueous medium can then be admixed in an oil phase to form a water-in-oil emulsion, wherein the aqueous droplets are suspended within the oily matrix. The oil phase can include edible oils and fats familiar in the art, for example, coconut oil, palm oil, olive oil, omega-3 and -6 containing fish oils, and the like, and / or their corresponding monoglycerides or long-chain fatty acids (or mixtures thereof). Using known techniques in pharmaceutical formulation and engineering such as ultrasonic vibration and homogenization, the aqueous phase and the oil phase can be combined so that the oil phase contains ultrafine nanodroplets (e.g., from tens to hundreds of nanometers in diameter) of the aqueous phase as the starting oil phase. Edible surfactants such as lecithin and phospholipids can be employed to stabilize the emulsions. Upon release of this therapeutic agent formulation from the orally ingestible delivery system, the oily material containing the aqueous nanodroplets can be ingested by the small intestine through transcytosis; in addition, while the oily phase is susceptible to the action of lipases within the small intestine, it protects the therapeutic agent in the nanodroplets from the enzymatic action of intestinal proteases in the intestine. As a consequence, the aqueous nanodroplets within the oilymatrix can be taken up by the small intestine and delivered across the mucosa into the extracellular fluid for further absorption into the systemic circulation.

[0082] The oil-based vehicle can transport other types of therapeutic agents without their inclusion in aqueous nanodroplets. For example, lyophilized protein particles can be durably suspended in the oil matrix and carried along within the oil as it is taken up by the small intestine following its release from the orally ingestible delivery system. Similarly, living organisms can be suspended in an oily matrix alone, or can be contained within a viscous aqueous matrix that is then emulsified with the oily matrix to form a water-in-oil emulsion containing aqueous nanodroplets bearing the living organisms within, with the aqueous nanodroplets being suspended within the oily matrix. In certain embodiments, the aqueous nanodroplets can also contain nutrients to preserve and protect the living cells; in other embodiments, the aqueous nanodroplets can contain other organisms instead of living cells, for example virus particles, lyophilized cells, and the like.

[0083] Other combinations for treatment can be readily envisioned by skilled artisans, for conditions such as cancer treatment, or treatment of HIV, where the treatment requires a plurality of drugs having different pharmacokinetic properties and different dosages. Encasing the drug combinations having different properties (e.g., solid, semi-solid, gelled, emulsions, single phase aqueous vehicles, oil vehicles, and the like) within the orally ingestible delivery system allows them to bypass the stomach and its effects on the different therapeutic agents and be delivered to designated target areas, permitting more focused, specific, and / or predictable absorption distal to the stomach.

[0084] Therapeutic systems and methods of treatment as disclosed herein are suitable for a wide range of illnesses, diseases, and health or wellness conditions (collectively, “conditions”). As used herein, the terms "treatment," "treating," "therapy," "therapeutic" and the like refer to interventions that are intended to cure, heal, alleviate, improve, remedy, or otherwise beneficially affect a disorder or a condition that impacts the well-being of a patient. As used herein, the term “patient” refers to a human or non-human animal experiencing a condition for which a treatment is desirable. It is particularly advantageous to deliver therapeutic agents via the orally ingestible delivery system as described herein for those therapeutic agents that would otherwise require parenteral administration because of their susceptibility to breakdown in the stomach. For example, certain small molecules undergo hydrolysis when exposed to acid in the stomach, and related structures, are susceptible to enzymatic attack in the stomach via its proteases; therapeutic formulations comprising these molecules typically require parenteral administration. As yet anotherexample, preparations containing beneficial bacteria (“probiotics”) or other living organisms are vulnerable to damage in the stomach, reducing the number of viable bacteria cells or other viable cells (as applicable) that ultimately reach the colon or other intestinal target. For example, although various coating strategies and tablet preparations are under investigation to protect probiotics when they are administered orally, preparations containing viable bacterial cells are commonly delivered by enema to ensure that they reach the colon in a healthy state. The systems and methods described herein offer an alternative route of delivery and / or a better milieu for conveying viable cells to their intestinal destination for these fragile but important therapeutic agents.

[0085] As an additional benefit, the orally ingestible delivery system protects the stomach from therapeutic agents that could harm it. Certain classes of drugs, for example corticosteroids or non-steroidal anti-inflammatory agents, inflict well-recognized damage on the stomach lining, causing gastritis and ulcer formation. Bypassing the stomach can help protect this organ from these effects, while allowing the therapeutic agent to exert its beneficial effects in a non-destructive manner.

[0086] Without limitation, a wide variety of therapeutic agents are suitable for administration using an orally ingestible delivery system as described herein. Certain of these therapeutic agents are currently available in oral dosage forms, for example various antibiotics, antiviral agents, antiparasitic agents, immune suppression agents, and the like. Use of the orally ingestible delivery system disclosed herein can offer other advantages, for example it can improve pharmacokinetics and prevent gastric-related side effects. Other therapeutic agents not currently available for oral administration, in particular peptides and proteins that are susceptible to breakdown in the stomach, can be advantageously delivered orally using the orally ingestible delivery system disclosed herein. Further description of the therapeutic uses of the orally ingestible delivery system is provided below, with specific exemplification of its use with therapeutic agents that are currently available for oral ingestion, and with therapeutic agents that are currently not available for oral ingestion and are presently delivered parenterally or transrectally. The orally ingestible delivery systems disclosed herein are suitable to replace current delivery mechanisms for, without limitation, orally ingested therapeutic agents, parenterally delivered therapeutic agents, and rectally delivered therapeutic agents.

[0087] While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that variouschanges in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

[0088] The patent and scientific literature referred to herein establishes the knowledge that is available to those with skill in the art. All United States patents and published or unpublished United States patent applications cited herein are incorporated by reference. All published foreign patents and patent applications cited herein are hereby incorporated by reference. All other published references, documents, manuscripts and scientific literature cited herein are hereby incorporated by reference. The relevant teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety.

Claims

CLAIMSWhat is claimed is:

1. An orally ingestible delivery system (OIDS) for delivering a therapeutic agent to a preselected more distal location within a gastrointestinal (GI) tract of a mammal, comprising: the therapeutic agent; and a differentially disruptable capsule system containing the therapeutic agent within a therapeutic agent compartment, wherein the differentially disruptable capsule system is dimensionally adapted for oral ingestion and for passage from a more proximal location in the GI tract to the preselected more distal location, wherein the differentially disruptable capsule system comprises a continuous frangible matrix enclosing the therapeutic agent compartment and having a plurality of areas of material inhomogeneity disposed within the continuous frangible matrix, wherein the continuous frangible matrix resists disruption at the more proximal location and is susceptible to disruption at the preselected more distal location, wherein the areas of material inhomogeneity are foci for differential stresses that propagate within the continuous frangible matrix and predispose the continuous frangible matrix to fracture and potential failure, thereby rendering the continuous matrix susceptible to disruption at the preselected more distal location, and wherein the disruption of the continuous frangible matrix at the preselected more distal location releases the therapeutic agent from the therapeutic agent compartment and discharges the therapeutic agent from the OIDS to reach the preselected more distal location, thereby delivering the therapeutic agent thereto.

2. The OIDS of claim 1, wherein the preselected more distal location is selected from the group consisting of the duodenum, the jejunum, the ileum, and the colon.

3. The OIDS of claim 2, wherein the preselected more distal location is the duodenum.

4. The OIDS of claim 1, wherein the more proximal location is the stomach.

5. The OIDS of claim 1, wherein the therapeutic agent is an immediate release formulation.

6. The OIDS of claim 1, wherein the therapeutic agent is a modified release formulation.

7. The OIDS of claim 1, wherein the therapeutic agent is coated to delay its release within the preselected more distal location after it has been discharged from the OIDS.

8. The OIDS of claim 1, wherein the therapeutic agent compartment is formed as a void.

9. The OIDS of claim 1, wherein the therapeutic agent compartment encloses one or more therapeutic agents.

10. The OIDS of claim 9, wherein the one or more therapeutic agents are suspended in a therapeutic agent compartment matrix.

11. The OIDS of claim 1, wherein the differentially disruptable capsule system contains a plurality of therapeutic agent compartments.

12. The OIDS of claim 1, wherein the differentially disruptable capsule system comprises a plurality of layers.

13. The OIDS of claim 12, wherein the plurality of layers includes two or more layers having dissimilar properties.

14. The OIDS of claim 1, wherein the continuous frangible matrix is acid-resistant.

15. The OIDS of claim 14, wherein the continuous frangible matrix comprises an acid- resistant material selected from the group consisting of cellulose, fatty acids, waxes, polyolefins, edible elastomers and natural elastomers.

16. The OIDS of claim 1, wherein the continuous frangible matrix comprises a moldable hydrophobic or lipophilic material.

17. The OIDS of claim 16, wherein the moldable hydrophobic or lipophilic material is a wax.

18. The OIDS of claim 17, wherein the wax is selected from the group consisting of beeswax, soybean wax, carnauba wax, and candelilla wax.

19. The OIDS of claim 1, wherein the continuous frangible matrix is formed from ingredients selected from the group consisting of: one or more types of waxes mixed together; one or more waxes mixed with one or more fatty acids; one or more wax or waxes mixed with policosanol; one or more wax or waxes mixed with cholesterol; one or more wax or waxes mixed with a phospholipid and / or with phosphatidylcholine; one or more wax or waxes mixed with essential oils; and one or more waxes mixed with oil-soluble vitamin mixture.

20. The OIDS of claim 1, wherein the areas of material inhomogeneity are voids or inclusions.

21. The OIDS of claim 20, wherein the voids are produced within the continuous frangible matrix as the continuous frangible matrix is being formed.

22. The OIDS of claim 20, wherein the inclusions become voids by being dissolved away to leave a defect in the matrix material, or by generating a gas that expands within the matrix material to deform it.

23. The OIDS of claim 20, wherein the inclusions act as stress concentrators.

24. The OIDS of claim 20, wherein the inclusions act as space occupiers.

25. The OIDS of claim 24, wherein the space occupiers comprise a fluid material.

26. The OIDS of claim 25, wherein the fluid material is selected from the group consisting of triglycerides, fatty acids, edible oils, esters derived from vegetable oils, and esters derived from plants.

27. The OIDS of claim 20, wherein the inclusions are chemically reactive.

28. The OIDS of claim 27, wherein the inclusions are minimally soluble in a strongly acidic environment and are more soluble in a neutral or basic environment.

29. The OIDS of claim 27, wherein the inclusions are reactive in stomach acid.

30. The OIDS of claim 29, wherein the inclusions act as gas formers.

31. The OIDS of claim 30, wherein the inclusions are selected from the group consisting of calcium carbonate, sodium bicarbonate, potassium bicarbonate, magnesium carbonate, and magnesium particles.

32. The OIDS of claim 30, wherein the gas formers generate a gas that blocks a defect in the matrix.

33. The OIDS of claim 1, further comprising an outer shell that envelopes the differentially disruptable capsule system.

34. The OIDS of claim 1, further comprising an enclosing layer disposed internal to the continuous frangible matrix.

35. The OIDS of claim 34, wherein the enclosing layer is supplemented with inclusions.

36. The OIDS of claim 35, wherein the inclusions comprise gas-forming substances.

37. A method of manufacturing the OIDS of claim 1, comprising including the therapeutic agent compartment within the differentially disruptable capsule system.

38. The method of claim 37, wherein the step of including comprises embedding the therapeutic agent within a preformed space in the differentially disruptable capsule system.

39. The method of claim 37, wherein the step of including comprises covering the therapeutic agent by the matrix material of the OIDS without the preliminary formation of a discrete space therein.

40. The method of claim 39, wherein the step of covering takes place by a technique selected from the group consisting of coating the therapeutic agent or therapeutic agent compartment with matrix material, curtain-coating the therapeutic agent or therapeutic agent compartment with matrix material, dipping the therapeutic agent or therapeuticagent compartment into matrix material, and spraying matrix material on the therapeutic agent or therapeutic agent compartment.

41. A method of delivering an effective amount of a therapeutic agent to a patient in need thereof, comprising: providing the OIDS of claim 1, wherein the OIDS contains the effective amount of the therapeutic agent; administering the OIDS to the patient by mouth; permitting passage of the OIDS into the stomach; and further permitting passage of the OIDS to a preselected more distal location; wherein the passage of the OIDS from the stomach to the more distal location subjects the continuous frangible matrix to differential stresses that propagate within the DDCS and initiates disruption of the continuous frangible matrix, and wherein the disruption takes place at or before the preselected more distal location and releases the therapeutic agent from the OIDS to reach the preselected more distal location, thereby delivering the effective amount of the therapeutic agent to the patient.

42. The method of claim 41, wherein the OIDS contains a second therapeutic agent, and wherein the OIDS releases a therapeutically effective amount of the second agent.

43. The method of claim 41, wherein the step of disruption takes place in the stomach.

44. The method of claim 41, wherein the preselected more distal location is the duodenum.

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