Orally Ingestible Delivery Systems

Abstract

The present invention includes an ingestible delivery system for releasing a therapeutic agent in the intestine of a mammal, the system comprising a therapeutic agent and a differentially permeable capsule system containing the therapeutic agent in a therapeutic agent compartment, the differentially permeable capsule system dimensionally adapted for oral ingestion and passage through the mammal's stomach and thereafter into the intestine, the differentially permeable capsule system comprising an acid-resistant shell and a dispersible acid barrier, the dispersible acid barrier being formed when the ingestible delivery system is in the stomach; the dispersible acid barrier dispersing in the intestine, thereby allowing enzymes in the intestine to reach the therapeutic agent compartment. The present invention also includes methods for making the system and methods for its use.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Application No. 62 / 923,783, filed October 21, 2019, U.S. Provisional Application No. 62 / 950,527, filed December 19, 2019, U.S. Provisional Application No. 62 / 981,651, filed February 26, 2020, U.S. Provisional Application No. 63 / 010,132, filed April 15, 2020, U.S. Provisional Application No. 63 / 058,231, filed July 29, 2020, and U.S. Provisional Application No. 63 / 088,070, filed October 6, 2020. The entire contents of the above applications are incorporated herein by reference.

[0002] Field of application This application relates to an ingestible delivery system for drugs, biologics or other therapeutic agents. [Background technology]

[0003] background Therapeutic agents for treating medical conditions are formulated to optimize delivery and uptake of the agent when administered to patients.As used herein, "therapeutic agent" refers to any substance, material, device, organism or part thereof that is delivered to humans or animals to effect therapeutic intervention.For the avoidance of doubt, therapeutic intervention can include diagnostic intervention and surveillance intervention (i.e., intervention for diagnosing and thereby preventing expected disorders, and intervention for collecting data about health or disease states to facilitate the prevention of expected disorders).

[0004] Pharmacokinetics is a branch of pharmacology that deals with the movement of pharmaceutical or biological therapeutic agents into, through and out of the body: their absorption, distribution, metabolism and excretion. Bioavailability is a subcategory of absorption that refers to the amount of administered therapeutic agent that reaches the systemic circulation. When a drug is administered intravenously, by definition, the entire dose enters the systemic circulation and has 100% bioavailability. Drugs administered by other routes than intravenous (i.e., oral, intramuscular, subcutaneous, transdermal, sublingual, rectal, etc.) typically have lower absorption and therefore lower bioavailability (i.e., less of the administered dose reaches the circulation and therefore less is distributed to target organs and cells). Bioavailability is measured by pharmacokinetic studies that measure the plasma concentration of the drug versus time; the dose-adjusted area under the curve for this plasma concentration versus time curve indicates the bioavailability. The bioavailability of a drug delivered via a non-intravenous route compared to its bioavailability when administered intravenously is referred to as its absolute bioavailability.

[0005] Routes of delivery for therapeutic agents may include the gastrointestinal tract (referred to as "enteral" or "enteric" administration) or other routes that do not involve the gastrointestinal tract (referred to as "parenteral" administration). Intravenous administration is one parenteral delivery route, but there are others: examples include injection into a body cavity, muscle, under the skin, into the skin, diffusion through or through mucous membranes, and inhalation. Parenteral administration has certain well-understood advantages. Most importantly, it allows the therapeutic agent to reach the systemic circulation rapidly without having to go through the digestive tract, where effective uptake of the therapeutic agent can be unpredictable due to the effects of altered blood flow, low gastrointestinal motility, poor absorption, or first pass metabolism. For these reasons, parenteral mechanisms typically result in greater absolute bioavailability. Furthermore, therapeutic agents, including proteins, peptides, and living organisms such as viruses and cells, have required parenteral administration to date because of their susceptibility to digestion in the stomach, which would render the therapeutic agent ineffective.

[0006] Although the bioavailability advantages of parenteral administration are important in intensive care and emergency situations, these routes have distinct disadvantages for more routine or chronic treatments. Parenteral delivery generally requires invasive interventions such as needle puncture and injection, performed by skilled personnel using sterile techniques; in other situations, parenteral delivery relies on complex mechanisms such as specialized aerosols or pumps. These auxiliary requirements make parenteral delivery expensive, inconvenient and / or unwelcome for patients, especially when treatment needs to be administered frequently. The need for invasive or technically complex interventions makes parenteral delivery particularly undesirable for certain patient populations, such as pediatric patients and patients in underserved areas who do not have access to medical facilities for more complex delivery systems.

[0007] Despite these drawbacks, many conditions that require repeated and extensive treatment, such as chronic conditions, or population-based conditions such as disease prevention by vaccination, are currently treated parenterally, since in many cases the therapeutic agent is not compatible with enteral, specifically oral, administration. Other conditions that are not treatable by oral administration are suitable for the parenteral route via enteral administration, such as rectal delivery (enemas, suppositories, etc.). Examples of rectal delivery include diseases of the colon, such as ulcerative colitis, in which the active ingredient can act directly on the colon itself, and disorders that are treated by bacteriotherapy (e.g. fecal transplants), in which live organisms are introduced into the colon and allowed to grow there with healthy bacteria. For many of these conditions that are treated parenterally or rectally, oral delivery is preferred, as it is convenient, well known, and generally well tolerated by patients.

[0008] During oral administration, therapeutic agents pass from the mouth through the esophagus to the stomach, then from the stomach to the duodenum and then to the rest of the small intestine. A delivery vehicle for an oral agent needs to have sufficient mechanical integrity to survive the passage from the mouth to the stomach, which involves fairly standard pharmaceutical techniques. The stomach presents more challenging conditions for drugs or biologics. Cells in the gastric mucosa produce hydrochloric acid, resulting in an acidic environment (pH approx. 1.0) in the stomach. In addition, gastric cells secrete pepsinogen, a proenzyme of pepsin, an enzyme that breaks down proteins. Acid in the stomach hydrolyzes proteins and further converts the proenzyme pepsinogen to 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 gastric acid. Orally delivered proteins and peptides are not only hydrolyzed by gastric acid, but are also digested by pepsin. These conditions within the stomach prevent or impair the use of the oral delivery route for many therapeutic agents.

[0009] When developing pharmaceuticals and biopharmaceuticals to treat chronic or population-specific conditions, it is desirable to avoid the drawbacks associated with their delivery forms. A wide range of disorders, from insulin-dependent diabetes to chronic inflammatory diseases, can be treated with pharmaceuticals and biopharmaceuticals administered parenterally. Other disorders require broad treatment measures across large populations, such as vaccines, or require access to populations, such as children, who may find it difficult to tolerate parenteral administration. Certain disorders may only be treated with drugs delivered rectally at present. Even though these delivery forms are expensive and have drawbacks, they currently remain the only option for these drugs, as they cannot survive passage through the stomach.

[0010] Therefore, there remains a need in the art for improved delivery vehicles for oral administration of therapeutic agents, such as biopharmaceuticals, living organisms, microdevices and small molecules, that do not tolerate exposure to gastric conditions.There is also a need for alternatives to rectal delivery, so that patients are not subjected to the discomfort and inconvenience that this administration route involves.These improved delivery mechanisms are particularly advantageous in chronic conditions or special populations that require frequent dosing, because of the increased convenience and tolerance of patients, and the reduced complexity and cost of health care.

[0011] Therefore, there remains a further need in the art for improved delivery vehicles for oral administration of therapeutic agents, such as biopharmaceuticals, live organisms, microdevices and small molecules, that do not tolerate exposure to gastric conditions. There is also a need for alternatives to rectal delivery to avoid subjecting patients to the discomfort and inconvenience that this route of administration involves. These improved delivery mechanisms are particularly advantageous in chronic conditions or special populations that require frequent dosing, for increased patient convenience and acceptance, and reduced complexity and health care costs. Advantageously, the improved delivery vehicles can be optimized for easy ingestion, for example, in a palatable and easy-to-eat dosage form or environment. Edible forms of pharmaceutical products, such as vitamins as "gummies", cough drops as lozenges, calcium and vitamin D in chocolate and caramel, are well known in the art. Improving the consistency and flavor of the delivery vehicle can improve its overall acceptability by patients, especially for populations that are unwilling or unable to swallow tablets. It is further advantageous to provide the delivery vehicle in a food item that facilitates ingestion. For example, delivery vehicles that may be added to liquids, gels, or semi-solid media such as soups, beverages, milkshakes, ice cream, yogurt, jellies, etc. are attractive to consumers and easy to swallow. Such improved delivery mechanisms are particularly desirable in special populations such as children or patients with dysphagia, for those conditions requiring frequent dosing, or for increased patient convenience and tolerance, as well as reduced complications and health care costs. Summary of the Invention

[0012] Summary of the Invention In one aspect, the present invention relates to an ingestible delivery system for releasing a therapeutic agent in the intestine of a mammal comprising a therapeutic agent and a differentially permeable capsule system comprising the therapeutic agent in a therapeutic agent compartment, wherein the differentially permeable capsule system is dimensionally adapted for oral ingestion and passage through the stomach and thereafter into the intestine of a mammal; the differentially permeable capsule system comprises an acid resistant shell and a dispersible acid barrier; the dispersible acid barrier is deployed at a location selected from the group consisting of an exterior surface of the acid resistant shell, an interior surface within the acid resistant shell, and an underlying region below the acid resistant shell, wherein the dispersible acid barrier inhibits contact of the acid resistant shell with gastric fluids in the stomach; the dispersible acid barrier is formed when the ingestible delivery system is in the stomach; and the dispersible acid barrier disperses in the intestine, thereby allowing enzymes in the intestine to reach the therapeutic agent compartment.

[0013] In a further aspect, the invention relates to an orally ingestible delivery system, wherein the acid resistant shell is an acid resistant protease digestible membrane. In yet a further aspect, the acid resistant shell comprises or consists essentially of a waxy substance. In a further aspect, the acid resistant shell comprises fiber, and optionally the fiber is digestible or hydrolyzable.

[0014] In yet a further aspect, the dispersible acid barrier is a gas barrier, e.g., the gas barrier may be formed by reaction of gastric acid with a gas generator, the gas generator being disposed on at least one of the exterior surface of the acid-resistant shell, the interior surface within the acid-resistant shell, and the lower region below the acid-resistant shell; optionally, the acid-resistant shell is perforated by a system of pores containing a deposit of the gas generator. In one aspect, the gas barrier comprises carbon dioxide. In yet a further embodiment, the gas barrier is dispersed by the interaction of carbon dioxide with bicarbonate in the intestine.

[0015] In a further aspect, the acid-resistant shell comprises a space-occupying fluid or a space-occupying solid. The space-occupying fluid or the space-occupying solid can be disposed, for example, in the pore system. In some aspects, the space-occupying fluid is a non-polar liquid. In yet a further aspect, the space-occupying solid reacts with gastric fluid to create a second space-occupying fluid that comprises a liquid or a gas; for example, the space-occupying solid comprises solid bicarbonate, and the gas comprises carbon dioxide.

[0016] The present invention also includes a method of delivering a therapeutic agent to the intestine of a mammal, comprising providing an ingestible delivery system as described herein; administering the ingestible delivery system to the mammal through the mouth; the ingestible delivery system passes through the stomach, and the ingestible delivery system is exposed to gastric acid that interacts with the ingestible delivery system to form a dispersive acid barrier; the ingestible delivery system then passes through the intestine, and the dispersive acid barrier disperses due to interaction with intestinal fluid, which penetrates the acid-resistant shell, which then disperses and releases the therapeutic agent from the therapeutic agent compartment; thereby delivering the therapeutic agent to the intestine. In some aspects, the intestinal fluid compromises the integrity of the acid-resistant shell, thereby facilitating the release of the therapeutic agent from the therapeutic agent compartment. In certain further aspects, the therapeutic agent is susceptible to degradation in the stomach. The therapeutic agent can be a protein or peptide or a living organism.

[0017] The invention also encompasses a method of delivering an effective amount of a therapeutic agent to a patient in need thereof, the method comprising: providing an orally ingestible delivery system as described herein, wherein the orally ingestible delivery system comprises an effective amount of a therapeutic agent; administering the orally ingestible delivery system to the patient through the mouth; the orally ingestible delivery system passes through the patient's stomach such that the orally ingestible delivery system is exposed to gastric acid which interacts with the orally ingestible delivery system to form a dispersible acid barrier; the orally ingestible delivery system then passes through the patient's intestine such that the dispersible acid barrier disperses due to interaction with intestinal fluid which penetrates the acid resistant shell such that the dispersible acid barrier disperses, releasing the therapeutic agent from the therapeutic agent compartment, thereby delivering an effective amount of the therapeutic agent to the patient.

[0018] In certain aspects, the patient is being treated with a therapeutic agent for a condition selected from the group consisting of cancer, a metabolic disorder, an allergic disorder, a hormonal disorder, a dermatological disorder, a cardiovascular disorder, a respiratory disorder, a hematological disorder, a musculoskeletal disorder, an inflammatory disorder, a rheumatic disorder, an autoimmune disorder, a gastrointestinal disorder, a urological disorder, a sexual and reproductive disorder, a neurological disorder, and a genetic disorder.

[0019] The present invention further encompasses an orally ingestible delivery system comprising an acid-resistant shell around the therapeutic agent compartment, and further comprising a space-occupying fluid or solid disposed at a location selected from the group consisting of an exterior surface of the acid-resistant shell, an interior surface within the acid-resistant shell, and an underlying region below the acid-resistant shell, where the space-occupying fluid or solid provides a mechanical barrier to the penetration of the acid-resistant shell by gastric acid. In one aspect, the acid-resistant shell is perforated by a system of pores; optionally, at least a portion of the space-occupying fluid or solid is present within the system of pores. In a further aspect, the therapeutic agent compartment is dimensionally adapted to contain a deliverable therapeutic agent; for example, the therapeutic agent compartment is void. In yet a further aspect, the therapeutic agent compartment contains a deliverable therapeutic agent, and optionally, the deliverable therapeutic agent comprises at least one therapeutic agent. In one aspect, the space-occupying fluid or solid is an acid-reactive substance. For example, the acid-reactive material can include a gas-forming material that produces or releases a gas upon contact with hydrochloric acid in the stomach, the gas providing a mechanical obstacle to penetration of the acid-resistant shell by the stomach acid. In one aspect, the gas is carbon dioxide.

[0020] The invention also includes an ingestible delivery system comprising a digestible capsule system surrounding a therapeutic agent compartment, wherein the digestible capsule system comprises an acid resistant shell and a dispersible acid barrier; the dispersible acid barrier is disposed at a location selected from the group consisting of an exterior surface of the acid resistant shell, an interior surface within the acid resistant shell, and an underlying region beneath the acid resistant shell; the dispersible acid barrier prevents at least one of acids and enzymes from reaching and compromising the integrity of the therapeutic agent compartment; once formed, the dispersible acid barrier is dispersible upon exposure to components of duodenal fluid; and the therapeutic agent compartment comprises a deliverable therapeutic agent. In some aspects, the dispersible acid barrier comprises a space occupying solid or a space occupying fluid. In some aspects, the space occupying fluid is a gas. In yet a further aspect, the space-occupying solid or space-occupying fluid comprises an acid-reactive substance; optionally, the space-occupying solid or space-occupying fluid creates a second space-occupying material upon contact with acid in the stomach, the second space-occupying material forming, in whole or in part, a dispersible acid barrier; and / or further optionally, the second space-occupying material is a gas. In yet a further aspect, the integrity of the therapeutic compartment is compromised by enzymatic activity, and then the dispersible acid barrier disperses. In a further aspect, the component of the duodenal fluid is bicarbonate or bile salt.

[0021] The present invention also includes a method of delivering a therapeutic agent to the intestine of a mammal, the method comprising: providing an ingestible delivery system as described above; administering the ingestible delivery system to a mammal through the mouth; exposing the ingestible delivery system to an acid before, during or after administering the ingestible delivery system through the mouth, where the acid forms a second space-occupying fluid that interacts with the acid-reactive space-occupying fluid or space-occupying solid to form a dispersive acid barrier; passing the ingestible delivery system through the stomach of the mammal to the intestine; and contacting the ingestible delivery system with duodenal fluid, where components of the duodenal fluid disperse the dispersive acid barrier, thereby exposing the ingestible delivery system to enzymatic activity in the intestine, which compromises the integrity of the therapeutic agent compartment, thereby releasing the therapeutic agent from the therapeutic agent compartment and delivering the therapeutic agent to the intestine. In one aspect, the ingestible delivery system is exposed to an acid after administering the ingestible delivery system through the mouth, where the acid is gastric acid. The present invention also includes a method for manufacturing a differentially permeable capsule system, comprising the steps of providing an acid-resistant shell; and fixing one or more deposits of an acid-reactive material to the acid-resistant shell or embedding one or more deposits of an acid-reactive material within the acid-resistant shell, wherein the deposits are located at a location selected from the group consisting of an outer surface of the acid-resistant shell, an inner surface within the acid-resistant shell, and a lower region below the acid-resistant shell. The acid-resistant shell may include fibers or may include a waxy material. In some aspects, the acid-resistant shell is perforated by a system of pores; optionally, the deposits are located at least partially within the system of pores. In certain further aspects, the acid-reactive material includes a gas-generating material; optionally, the gas-generating material forms carbon dioxide upon exposure to hydrochloric acid. In yet a further aspect, the method further includes forming the acid-resistant shell to surround a therapeutic agent compartment, the therapeutic agent compartment being dimensionally adapted to include a deliverable therapeutic agent. The method may further include including a deliverable therapeutic agent in the therapeutic agent compartment.

[0022] The invention further includes an ingestible delivery system for releasing a therapeutic agent into the intestine of a mammal comprising a therapeutic agent and a digestible capsule system containing the therapeutic agent in a therapeutic agent compartment, the digestible capsule system being dimensionally adapted for oral ingestion and passage through the stomach and thereafter into the intestine of the mammal, the digestible capsule system comprising an acid resistant protease digestible membrane and a dispersible acid barrier; the dispersible acid barrier is disposed at a location selected from the group consisting of an exterior surface of the acid-resistant protease digestible membrane and an interior region within the acid-resistant protease digestible membrane, the dispersible acid barrier inhibiting contact with gastric fluids in the stomach; The dispersible acid barrier forms in the stomach and disperses in the intestine, exposing the acid-resistant protease digestible membrane to enzymatic activity in the intestine; The acid-resistant protease digestible membrane, exposed to enzymatic activity in the intestine, is wholly or partially digested by the enzymatic activity, thereby releasing the therapeutic agent in the intestine.

[0023] In one aspect, the acid-resistant protease digestible membrane comprises an inner protease digestible layer and an outer acid-resistant layer. In a further aspect, the dispersible acid barrier disposed on the outer surface of the acid-resistant protease digestible membrane or within the inner region of the acid-resistant protease digestible membrane is a gas barrier. The gas barrier may be formed, for example, by reaction of gastric acid with a gas-generating substance, the gas-generating substance being contained within the inner region of the acid-resistant protease digestible membrane. Optionally, the acid-resistant protease digestible membrane is perforated by a system of pores containing a deposit of gas-generating substance, and the reaction of gastric acid with the gas-generating substance results in the gas barrier. In a further aspect, the gas barrier comprises carbon dioxide. In yet a further aspect, the gas barrier is dispersed by the interaction of carbon dioxide with bicarbonate in the intestine. In yet further aspects, the dispersible acid barrier disposed on the exterior surface of the acid-resistant protease digestible membrane or within the interior region of the acid-resistant protease digestible membrane comprises a space-occupying fluid or solid, such as a non-polar liquid. In some aspects, the space-occupying fluid or solid is disposed within a system of pores and / or the space-occupying solid reacts with gastric fluids to create a space-occupying fluid that comprises a liquid or a gas. In a specific aspect, the space-occupying solid comprises solid bicarbonate and the gas is carbon dioxide.

[0024] The present invention includes a method for delivering a therapeutic agent to the intestine of a mammal, the method comprising the steps of: providing an ingestible delivery system as described herein; administering the ingestible delivery system to a mammal through the mouth; allowing the ingestible delivery system to pass into the stomach, where the ingestible delivery system is exposed to gastric acid that interacts with the ingestible delivery system to form a dispersive acid barrier in and / or on the ingestible delivery system; and allowing the ingestible delivery system to pass further into the intestine, where the dispersive acid barrier is dispersed by interaction with secretions in the intestine, and enzyme activity in the intestine contacts the acid-resistant protease digestible membrane, which then disperses the dispersive acid barrier, thereby compromising the integrity of the acid-resistant protease digestible membrane and allowing the therapeutic agent contained therein to be excreted; thereby delivering the therapeutic agent to the intestine.In one aspect, the therapeutic agent, for example a protein or peptide, is susceptible to degradation in the stomach.In a further aspect, the therapeutic agent is a living organism.

[0025] In yet a further aspect, the present invention relates to a method of delivering an effective amount of a therapeutic agent to a patient in need thereof, the method comprising the steps of: providing an ingestible delivery system as described herein, wherein the ingestible delivery system comprises an effective amount of a therapeutic agent; administering the ingestible delivery system to the patient through the mouth; allowing passage of the ingestible delivery system into the patient's stomach, wherein the ingestible delivery system is exposed to gastric acid which interacts with the ingestible delivery system to form a dispersive acid barrier; and allowing further passage of the ingestible delivery system into the patient's intestine, wherein the dispersive acid barrier is dispersed by interaction with intestinal secretions and enzymatic activity in the intestine contacts the acid-resistant protease digestible membrane which then disperses the dispersive acid barrier, thereby compromising the integrity of the acid-resistant protease digestible membrane and allowing evacuation of the therapeutic agent from the therapeutic agent compartment; thereby delivering an effective amount of the therapeutic agent to the patient. In certain aspects, the patient is being treated with a therapeutic agent for a condition selected from the group consisting of cancer, a metabolic disorder, an allergic disorder, a hormonal disorder, a dermatological disorder, a cardiovascular disorder, a respiratory disorder, a hematological disorder, a musculoskeletal disorder, an inflammatory disorder, a rheumatic disorder, an autoimmune disorder, a gastrointestinal disorder, a urological disorder, a sexual and reproductive disorder, a neurological disorder, and a genetic disorder.

[0026] The present invention further encompasses an ingestible delivery system comprising a digestible capsule system surrounding a therapeutic compartment, where the therapeutic compartment is dimensionally adapted to contain a deliverable therapeutic agent, and the digestible capsule system comprises an acid-resistant protease digestible membrane in which a space-occupying fluid or solid is disposed. In some aspects, the therapeutic compartment is hollow. In still further aspects, the therapeutic compartment comprises a deliverable therapeutic agent, e.g., the deliverable therapeutic agent comprises at least one therapeutic agent. In still further aspects, the acid-resistant protease digestible membrane is perforated by a system of pores. In some embodiments, the acid-resistant protease digestible membrane comprises an inner protease digestible layer and an outer acid-resistant layer, where the system of pores is disposed in whole or in part within the outer acid-resistant layer. In further aspects, at least a portion of the space-occupying fluid or solid is present within the system of pores.

[0027] The present invention further includes an ingestible delivery system comprising a digestible capsule system around a therapeutic compartment, wherein the digestible capsule system comprises an acid-resistant protease digestible membrane and a dispersible acid barrier, the dispersible acid barrier being formed on or within at least one of the outer surface of the acid-resistant protease digestible membrane and the inner system of pores contained within the acid-resistant protease digestible membrane; the dispersible acid barrier prevents at least one of acid and enzyme from reaching and compromising the integrity of the therapeutic compartment; once formed, the dispersible acid barrier is dispersed by exposure to components of duodenal fluid; the therapeutic compartment comprises a deliverable therapeutic agent. In one aspect, the dispersible acid barrier comprises a space-occupying solid or fluid. The space-occupying solid or fluid creates a second space-occupying material upon contact with, for example, stomach acid, which in whole or in part forms the dispersible acid barrier. In yet a further aspect, the integrity of the therapeutic compartment is compromised by enzymatic activity, after which the dispersible acid barrier is dispersed. In a further embodiment, the duodenal fluid component is a bicarbonate or a bile salt.

[0028] The invention also encompasses a method of delivering a therapeutic agent to the intestine of a mammal, the method comprising: providing an ingestible delivery system as described above; administering the ingestible delivery system to a mammal through the mouth; exposing the ingestible delivery system to an acid before, during or after administering the ingestible delivery system through the mouth, where the acid interacts with the acid-reactive material disposed within the acid-resistant protease digestible membrane, thereby creating a space-occupying fluid that forms a dispersible acid barrier; passing the ingestible delivery system through the stomach of the mammal and into the duodenum; and contacting the ingestible delivery system with duodenal fluid, where components of the duodenal fluid disperse the dispersible acid barrier, thereby exposing the ingestible delivery system to enzymatic activity in the intestine, which enzymatic activity compromises the integrity of the therapeutic agent compartment, thereby releasing the therapeutic agent from the therapeutic agent compartment and delivering the therapeutic agent to the intestine. In one aspect, the orally ingestible delivery system is exposed to an acid following the step of administering the orally ingestible delivery system through the mouth, and the acid is gastric acid.

[0029] In an embodiment, disclosed herein is an orally ingestible delivery system for releasing a therapeutic agent in the intestine of a mammal, comprising a therapeutic agent and a digestible capsule system comprising the therapeutic agent in a therapeutic agent chamber, the digestible capsule system being dimensionally adapted for oral digestion and passage through the stomach and thereafter into the intestine of the mammal, the digestible capsule system comprising an acid-resistant protease digestible membrane and a dispersible gas barrier, the dispersible gas barrier being disposed, in whole or in part, on an outer surface of the acid-resistant protease digestible membrane, the dispersible gas barrier inhibiting contact with gastric fluids in the stomach, the dispersible gas barrier being formed in the stomach and dispersed in the intestine to expose the acid-resistant protease digestible membrane to enzymatic activity in the intestine, the acid-resistant protease digestible membrane being exposed to enzymatic activity in the intestine being digested, in whole or in part, by the enzymatic activity, thereby releasing the therapeutic agent in the intestine. In an embodiment, the acid-resistant protease digestible membrane comprises an inner protease digestible layer and an outer acid-resistant layer. In embodiments, the acid-resistant protease digestible membrane is perforated by a system of pores containing a deposit of a gas generating substance, and reaction of the gas generating substance with gastric acid produces a gas that accumulates to form a dispersible gas barrier, in embodiments, the gas comprises carbon dioxide, and the dispersible gas barrier is dispersed in the intestine by interaction of the carbon dioxide with bicarbonate.

[0030] In an embodiment, a method for delivering a therapeutic agent to the intestine of a mammal is further disclosed herein, the method comprising the steps of: providing an ingestible delivery system comprising an acid-resistant protease digestible membrane and a therapeutic agent chamber comprising a therapeutic agent; administering the ingestible delivery system to a mammal through the mouth; allowing the ingestible delivery system to pass through to the stomach, where the ingestible delivery system is exposed to gastric acid that interacts with the ingestible delivery system to form a dispersible gas barrier in and / or on the ingestible delivery system, and allowing the ingestible delivery system to pass further through to the intestine, where the dispersible gas barrier is dispersed by interaction with bicarbonate secretions in the intestine, and the enzyme activity in the intestine contacts the acid-resistant protease digestible membrane and impairs its integrity and the integrity of the therapeutic agent chamber, thereby allowing the excretion of the therapeutic agent contained therein and delivering the therapeutic agent to the intestine.In an embodiment, the therapeutic agent is susceptible to degradation in the stomach.In an embodiment, the therapeutic agent is a protein or peptide or a living organism. In an embodiment, also disclosed herein is a method of delivering an effective amount of a therapeutic agent to a patient in need thereof, the method comprising the steps of providing an ingestible delivery system comprising an acid-resistant protease digestible membrane and a therapeutic agent chamber comprising an effective amount of a therapeutic agent, administering the ingestible delivery system to the patient through the mouth, allowing passage of the ingestible delivery system into the patient's stomach, where the ingestible delivery system is exposed to gastric acid which interacts with the ingestible delivery system to form a dispersible gas barrier; and allowing further passage of the ingestible delivery system into the patient's intestine, where the dispersible gas barrier is dispersed by interaction with bicarbonate secretions in the intestine, and enzymatic activity in the intestine interacts with the acid-resistant protease digestible membrane and compromises its integrity, thereby releasing the therapeutic agent from the therapeutic agent chamber to deliver an effective amount of the therapeutic agent to the patient. In embodiments, the patient is receiving treatment with a therapeutic agent for a condition selected from the group consisting of cancer, a metabolic disorder, an allergic disorder, a hormonal disorder, a dermatological disorder, a cardiovascular disorder, a respiratory disorder, a hematological disorder, a musculoskeletal disorder, an inflammatory disorder, a rheumatic disorder, an autoimmune disorder, a disorder due to hormonal imbalance, a gastrointestinal disorder, a urological disorder, a sexual and reproductive disorder, a neurological disorder, and a genetic disorder.

[0031] In embodiments, an ingestible delivery system is also disclosed herein that includes a digestible capsule system surrounding a therapeutic agent chamber, where the therapeutic agent chamber is dimensionally adapted to contain a deliverable therapeutic agent, and the digestible capsule system includes an acid-resistant protease digestible membrane in which a gas generator is disposed. In embodiments, the therapeutic agent chamber is hollow, and in embodiments, the therapeutic agent chamber contains a deliverable therapeutic agent that includes at least one therapeutic agent. In embodiments, the acid-resistant protease digestible membrane is perforated by a system of pores. In embodiments, the acid-resistant protease digestible membrane includes two layers, an inner protease digestible layer and an outer acid-resistant layer, and the system of pores is disposed within the outer acid-resistant layer. In embodiments, at least a portion of the gas generator is present within the system of pores.

[0032] In an embodiment, further disclosed herein is an ingestible delivery system that includes a digestible capsule system around a therapeutic agent chamber, wherein the therapeutic agent chamber includes a deliverable therapeutic agent; an acid-resistant protease digestible membrane; and a dispersible gas barrier, the dispersible gas barrier being formed on or in at least one of the outer surface of the acid-resistant protease digestible membrane and the inner system of holes contained within the acid-resistant protease digestible membrane, and the dispersible gas barrier prevents at least one of acid and enzyme from reaching the therapeutic agent chamber and compromising its integrity.In an embodiment, the dispersible gas barrier is formed by contact with acid, and once formed, the dispersible gas barrier is dispersible by exposure to a neutral or basic environment.In an embodiment, the integrity of the therapeutic acid chamber is compromised by enzyme activity, and then the dispersible gas barrier is dispersed.

[0033] In embodiments, a method of delivering a therapeutic agent to the intestine of a mammal is also disclosed herein, the method comprising the steps of providing an ingestible delivery system as described above; administering the ingestible delivery system to a mammal through the mouth; exposing the ingestible delivery system to an acid before, during or after administering the ingestible delivery system through the mouth, where the acid interacts with a gas generating material integrated within the ingestible delivery system, thereby creating a dispersible gas barrier; passing the ingestible delivery system through the stomach of the mammal and into the intestine; and contacting the ingestible delivery system with neutral or basic secretions in the intestine, where the neutral or basic secretions in the intestine disperse the dispersible gas barrier, thereby exposing the ingestible delivery system to enzymatic activity in the intestine, which compromises the integrity of the therapeutic agent chamber, thereby releasing the therapeutic agent from the therapeutic agent and delivering the therapeutic agent to the intestine. In embodiments, the orally ingestible delivery system is exposed to acid following the step of administering the orally ingestible delivery system through the mouth, and the acid is gastric acid. [Brief description of the drawings]

[0034] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] FIG. 1 shows a schematic of an embodiment of an ingestible delivery system. [Diagram 2] FIG. 2 shows a schematic of a portion of an embodiment of an ingestible delivery system in cross-section. [Diagram 3] FIG. 3 shows a schematic of a portion of an embodiment of an ingestible delivery system in cross-section. [Figure 4] FIG. 4 shows a schematic of a portion of an embodiment of an ingestible delivery system in cross-section. [Diagram 5] FIG. 5 shows a schematic of a portion of an embodiment of an ingestible delivery system in cross-section. [Figure 6] FIG. 6 shows a schematic of a portion of an embodiment of an ingestible delivery system in cross-section. [Figure 7] FIG. 7 shows a schematic of a portion of an embodiment of an ingestible delivery system in cross-section. [Figure 8] FIG. 8 shows a schematic of a portion of an embodiment of an ingestible delivery system in cross-section. [Figure 9]FIG. 9 shows a schematic of a portion of an embodiment of an ingestible delivery system in cross-section. [Figure 10] FIG. 10 shows a schematic of a portion of an embodiment of an ingestible delivery system in cross-section. [Figure 11] FIG. 11 shows a schematic of a portion of an embodiment of an ingestible delivery system in cross-section. [Figure 12] FIG. 12 is a schematic of a portion of an embodiment of an ingestible delivery system in cross-section. [Figure 13] FIG. 13 is a schematic of a portion of an embodiment of an ingestible delivery system in cross-section. [Figure 14] FIG. 14 shows a schematic of an embodiment of an ingestible delivery system in cross-section. [Figure 15] FIG. 15 shows a schematic of an embodiment of an ingestible delivery system in cross-section. [Figure 16] FIG. 16 shows a schematic of an embodiment of an ingestible delivery system in cross-section after a period of residence in the stomach. [Figure 17] FIG. 17 shows a schematic of an embodiment of an ingestible delivery system in cross-section after a period of residence in the stomach. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] Detailed Description As used herein, the indefinite article "a" or "an" is intended to mean "one or more" unless specified otherwise.

[0036] In an embodiment, disclosed herein is an ingestible delivery system for releasing therapeutic agent into 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 divisions (duodenum, jejunum, ileum) and the large intestine, which are collectively referred to as "intestinal tract". The ingestible delivery system disclosed herein is particularly adapted to deliver therapeutic agent to a target area for absorption in the small intestine or large intestine. In an embodiment, the therapeutic agent is delivered into the small intestine; in other embodiments, the therapeutic agent is delivered into the large intestine; yet other embodiments may combine delivery points so that the therapeutic agent is delivered throughout the small intestine, the large intestine, or both.

[0037] A. Orally Ingestible Delivery Systems and Methods of Manufacture 1. Common Oral Delivery Systems: Passage to the Stomach The delivery system disclosed herein is designed to retain a specified degree of integrity as it passes through the stomach. In embodiments, the delivery system disclosed herein remains substantially intact as it passes through the stomach and is subsequently degraded or digested at some point distal to the stomach, or remains substantially intact as it passes through the stomach and resists the ingress of gastric fluids but becomes permeable to intestinal fluids.

[0038] This feature causes the delivery system to have a preselected degree of resistance to ingress of fluids in the stomach, and the different preselected degree of resistance to ingress of fluids in the intestine is referred to herein as being "differentially permeable." In one embodiment, an orally ingestible delivery system (OIDS) includes a differentially permeable capsule system that is resistant to ingress of fluids in the stomach but susceptible to ingress of fluids in the intestine, such that gastric fluids are inhibited from accessing the therapeutic agent compartment through the capsule system, but intestinal fluids are permitted to access the therapeutic agent compartment through the capsule system. In such an embodiment, the contents of the therapeutic agent compartment are protected from exposure to gastric acid so that the contents pass relatively intact to the intestine, where the therapeutic agent compartment is reached and penetrated by intestinal fluids such that the therapeutic agent is released into the intestinal tract.

[0039] As used herein, the term "digest" and related lexical units that include this term refer to the destruction, decomposition, disintegration, processing, or loss of structural integrity caused by exposure to enzymes, acids, or other physiological agents as they act on orally ingested materials in the gastrointestinal tract. The term "digestion" as used herein simply refers to the mechanical and / or chemical breakdown of orally ingested materials, not their subsequent absorption or excretion. In embodiments, the orally ingestible delivery system passes through the stomach without any significant or any digestion, and then releases the therapeutic agent in the duodenum or jejunum or ileum. In other embodiments, the orally ingestible delivery system passes through the stomach and a portion of the small intestine without any significant or any digestion, and then releases the therapeutic agent in the colon.

[0040] More specifically, an ingestible delivery system is ingested through the mouth and then passes into the esophagus and then into the stomach. In an embodiment, the delivery system is designed to retain at least a portion of its integrity in the stomach, and any loss of integrity in the stomach or distal to the stomach is incorporated into the design. For example, the shell or coating around the ingestible delivery system described below can be formulated to be partially dissolved in the stomach. In other embodiments, the entire ingestible delivery system is designed to begin its degradation or digestion in the stomach, releasing some or all of the therapeutic agent that is optionally enveloped in the system or embedded within the walls of the system itself. As used herein, the term "differentially permeable capsule system" refers to the structure of an ingestible delivery system that has different permeabilities in the stomach and intestinal tract. In one embodiment, the capsule is designed to undergo digestion in one or more locations in the gastrointestinal tract (e.g., stomach and / or duodenum). In one embodiment, the differentially permeable capsule system passes through the stomach with minimal, if any, digestion, but is susceptible to digestion in the duodenum. The features and exemplary embodiments of the differentially permeable capsule system are described in more detail below and illustrated by the following specific figures. For the purpose of clarity, the term "differentially permeable capsule system" encompasses "digestible capsule system" or "selectively digestible capsule system" as described herein. One way that the differentially permeable capsule system can provide a different degree of resistance to the ingress of fluid in the stomach versus the intestine is by allowing a different degree of digestion of the capsule-like layer(s) in the stomach compared to the intestine. Other ways to provide the capsule system with differentially permeable properties can include mechanisms for inhibiting the passage of fluid to and through the capsule when the capsule is in the stomach, and for allowing the passage of fluid to and through the capsule when the capsule is in the intestine, where such mechanisms can be a substitute for or supplement the digestion of the capsule itself.

[0041] 1 illustrates in cross-section an embodiment of an orally ingestible delivery system 100 after its digestion and a period of residence in the stomach. As shown, the orally ingestible delivery system 100 includes a differentially permeable (e.g., digestible) capsule system 104 that confines a therapeutic agent within a therapeutic agent compartment 102. The therapeutic agent compartment 102 may be formed as a separate enclosure with its own wall, or may be formed as one or more orally ingestible delivery systems within the differentially permeable capsule system 104 for containing the therapeutic agent, or may be formed in any other configuration suitable for retaining a solid, liquid, or semi-solid therapeutic agent within the orally ingestible delivery system 100.

[0042] Although this and subsequent figures show the therapeutic agent compartment 102 as a single compartment, it is understood that there may be one, two or more therapeutic agent compartments 102 disposed within the orally ingestible delivery system, each compartment containing a therapeutic agent that may be the same as or different from the others.

[0043] As used herein, the term "therapeutic agent compartment" refers to the location of a therapeutic agent, whether the therapeutic agent is inserted into a preformed space within the orally ingestible delivery system that serves as the therapeutic agent compartment, or the therapeutic agent is enveloped or coated in an outer layer of the orally ingestible delivery system without the formation of a separate space in which the therapeutic agent is oriented to reside. For example, an orally ingestible delivery system may be preformed with an internal cavity into which a fluid therapeutic agent may be injected. Such preformed cavities may have other layers of protection or controlled release in addition to those integrated into the differentially permeable (e.g., digestible) capsule system 104. Or as another example, a third party may create a therapeutic agent with its own enclosure and / or coating(s), for example, in a capsule with any layer of coating, whereby such therapeutic agent forming agent may be presented for inclusion within an orally ingestible delivery system, for example, by forming a differentially permeable capsule system 104 around it, or by encasing it within a preformed differentially permeable capsule system, or by coating or immersing a third therapeutic agent with its own enclosure and / or coating(s) within the material that forms the differentially permeable capsule system. In all these situations, whether a space is preformed within the orally ingestible delivery system or a differentially permeable capsule system is formed to cover, encase or surround a therapeutic agent with its own enclosure and / or coating(s), the location of the presence of the therapeutic agent is referred to as a "therapeutic agent compartment."

[0044] Although the figures provided herein show a single therapeutic compartment, it is understood that there can be multiple therapeutic compartments disposed within the orally ingestible delivery system, where the contents of each compartment can be the same or different. For example, one therapeutic compartment can contain a first therapeutic agent, and another therapeutic compartment can contain a second therapeutic agent, both of which act synergistically but have different therapeutic effects: such a combination can thus provide the patient with two or more therapeutic agents in the same delivery system. As another example, one therapeutic agent can contain a first therapeutic agent, and another therapeutic compartment can contain a second therapeutic agent, where the second therapeutic agent enhances the effect of the first therapeutic agent, which does not have an independent therapeutic effect by itself. As an example, a probiotic therapeutic agent can be delivered within one therapeutic compartment, and a prebiotic substance can be delivered within another therapeutic compartment, where the prebiotic substance is intended to enhance the effectiveness of the probiotic substance. Single pill combinations are recognized as valuable tools for managing chronic conditions such as asthma, diabetes, hypertension, and dyslipidemia. Because of its ability to survive passage through the stomach, the orally ingestible delivery system disclosed herein may offer the advantage of combination therapy for therapeutic agents that previously required parenteral administration.

[0045] As shown in Figure 1, the differentially permeable (e.g., digestible) capsule system 104 includes an acid-resistant shell 108 (e.g., an acid-resistant protease digestible membrane) on or within which a dispersible acid barrier 110 is disposed. As used herein, the term "acid-resistant shell" refers to a structural layer of the orally ingestible delivery system 100 that is resistant to the hydrolytic effects of stomach acid. The construction of the acid-resistant shell is described in more detail below in connection with the following figures. If the acid-resistant shell 108 completely prevented the inflow and through-passage of stomach fluids, it would prevent digestion of the orally ingestible delivery system 100 in the stomach and could further impair, delay or prevent digestion in the intestinal tract. However, the orally ingestible delivery system 100 is intended to be differentially permeable, remaining substantially intact in the stomach, but then allowing sufficient digestion in the intestine or sufficient intestinal fluid inflow such that the contents of the therapeutic agent chamber 102 can be released from the orally ingestible delivery system 100 at a selected location distal to the stomach.

[0046] As such, the acid-resistant shell may be constructed to allow the inflow of all fluids, whether gastric fluids (i.e., liquid secretions produced within the stomach) or intestinal fluids (i.e., liquid secretions produced by the pancreas, liver, or intestines present in the intestinal tract), which structurally allows such fluids to pass through the acid-resistant shell and access the contents of the therapeutic agent chamber 102. However, this indiscriminate fluid passage through the acid-resistant shell in both the stomach and small intestine is prevented by the dispersive acid barrier 110. The dispersive acid barrier 110 forms in the stomach and prevents gastric fluids from passing to and / or through the acid-resistant shell 108, as described in detail below. Then, as the orally ingestible delivery system 100 passes into the intestine, the dispersive acid barrier 110 disperses, allowing intestinal fluids to pass to and through the acid-resistant shell 108, ultimately accessing the contents of the therapeutic agent chamber 102, and optionally causing partial or complete destruction of the remainder of the orally ingestible delivery system 100.

[0047] The dispersive acid barrier 110 shown in this figure is disposed on the surface of the acid-resistant shell 108 (e.g., an acid-resistant protease digestible membrane), however, it is understood that the dispersive acid barrier 110 may also or instead be disposed within the acid-resistant shell 108, such as within pores or channels in the acid-resistant shell 108 or even underneath the acid-resistant shell 108. Certain of these locations for the dispersive acid barrier are shown in the figure. As used herein, the term "dispersive acid barrier" refers to a physical obstacle formed from fluids or solid particles (whether integrated or isolated) that prevents the ingress of gastric acid into and / or through the acid-resistant shell 108. As used herein, a substance referred to as a "fluid" is a state of matter that includes gas or liquid phase materials, i.e., any substance that flows or deforms under applied shear stress. As used more generally, the term "barrier" refers to any physical obstacle that blocks passage or prevents or inhibits movement or action, such as a physical obstacle that prevents / inhibits gastric acid from entering the therapeutic agent chamber 102 or prevents / inhibits acid from contacting the exterior or interior surfaces of the acid-resistant shell 108.

[0048] More specifically, the dispersible acid barrier 110 may be disposed on the outside of the acid-resistant shell 108 (e.g., an acid-resistant protease digestible membrane) as shown, or may be disposed within the acid-resistant shell 108 (not shown), or both, to protect the acid-resistant shell 108 from contact (in whole or in part) with stomach acid. It is understood that the dispersible acid barrier 110 on the surface of the acid-resistant shell 108 may comprise a different material than the dispersible acid barrier disposed within the acid-resistant shell 108, and that these different compositions of dispersible acid barriers may coexist within a single orally ingestible delivery system 100. As used herein, the terms "dispersible," "disperse," and the like refer, without limitation, to those processes by which a barrier (whether gas, liquid, or solid) is dispelled, decomposed, dissolved, scattered, dissipated, destroyed, chemically altered, or otherwise removed from or reduced in its original location in a manner that affects its physical properties and / or integrity. The term includes the process of dissolution, which occurs when the barrier components (e.g., CO2 gas bubbles produced in the stomach to form an acid barrier) equilibrate in a more pH neutral solution, such as one found in the duodenum, and form conjugate acids (e.g., carbonic acid). The term also includes processes such as emulsification, solubilization, hydrolysis, etc., which occur when the barrier components (e.g., oils, waxes, or other hydrophilic fluids or solids) encounter bile salts, lipases, etc. in the duodenum. In embodiments, the dispersible acid barrier 110, once formed, may provide a hydrophobic outer layer as shown that protects the underlying acid-resistant shell 108 from further contact with gastric acid. In other embodiments, the dispersible acid barrier 110 may provide a mechanical obstacle within the acid-resistant shell 108 to inhibit the penetration of gastric acid into the acid-resistant shell 108 itself.

[0049] The dispersible acid barrier 110 may, in embodiments, be formed by a reaction between a gas generator (not shown) embedded or otherwise disposed within or in contiguous with the acid-resistant shell 108 (e.g., an acid-resistant protease digestible membrane), as described in more detail below. As used herein, the term "gas generator" refers to a material that produces gas when reacted with acid in gastric fluids. An example of a gas generator is solid bicarbonate particles that form carbon dioxide gas upon contact with gastric acid, although other examples will be apparent to those skilled in the art. The carbon dioxide gas may form a dispersible acid barrier 110 within and / or on top of the acid-resistant shell, as described in more detail below, that acts to prevent further ingress of gastric acid, but is dispersible in the duodenum due to the pH difference between the stomach and the duodenum.

[0050] As shown in this and other figures, the dispersible acid barrier 110 may be present on the surface of the acid-resistant shell 108 (e.g., an acid-resistant protease digestible membrane), and any extension or beginning of the dispersible acid barrier 110 within the acid-resistant shell 108 is not shown; however, in other embodiments (e.g., those shown in Figures 8-11), the dispersible acid barrier 110 is formed within the acid-resistant shell 108, either extending outward to form a continuous or discontinuous barrier layer on the surface or remaining contained within the acid-resistant shell 108, or both. In still other embodiments, the dispersible acid barrier 110 is formed from materials disposed in a separate layer within or adjacent to the acid-resistant shell 108 that form a fluid barrier within the acid-resistant shell 108 itself in response to contact with gastric acid.

[0051] The acid-resistant shell 108 (e.g., an acid-resistant protease digestible membrane) may be formed as a bilayer membrane, a monolayer membrane, or a multilayer membrane, as described in more detail below. In one embodiment, the acid-resistant shell 108 is formed of a hydrophobic layer that confers acid resistance. This may be combined with other components (whether a separate layer, an integral layer, or a therapeutic agent surrounded / coated / encapsulated within the therapeutic agent compartment 102) to form a differentially permeable (e.g., digestible) capsule system 104. For example, the acid-resistant shell 108 may be formed around an inner proteinaceous layer that is protease digestible (e.g., an acid-resistant protease digestible membrane); in this embodiment, the acid-resistant shell 108 may be perforated by a series of pores or channels that are blocked or protected by the dispersible acid barrier 110, such that gastric or duodenal fluid may pass through these pores or channels when the dispersible acid barrier 110 is dispersed, thereby gaining access to the inner proteinaceous layer to affect its digestion. In another embodiment, the acid-resistant shell 108 is formed as a single asymmetric layer with varying properties, such that the outer surface of the single layer has more hydrophobic properties, while the inner surface has a predominance of proteinaceous components that are susceptible to protease digestion.

[0052] These embodiments of the acid-resistant shell 108 surrounding or including an internal protease digestible layer may be referred to as an "acid-resistant protease digestible membrane." As used herein, the term "acid-resistant protease digestible membrane" refers to an acid-resistant shell 108 that structurally includes a protease digestible component, either as a separate layer or as an integrated layer. It is understood that the presence of the acid-resistant shell 108 and the protease digestible component together forming a single acid-resistant protease digestible membrane is consistent with the function of an acid-resistant protease digestible membrane within a differentially permeable (e.g., digestible) capsule system 104, with each of these two features adding a different factor of differential permeability. More specifically, the acid-resistant shell provides acid resistance and prevents or delays digestion of the differentially permeable capsule system 104 in the stomach, while the protease digestible component is digestible in the duodenum. The protease digestible component is also digestible in the stomach, but the dispersible acid barrier 110 (shown in this and subsequent figures) prevents gastric enzymes from reaching the protease digestible component. Thus, the system with the acid resistant shell 108 and the protease digestible component forms a differentially permeable capsule system 104, allowing differential passage of gastric and duodenal fluids into the orally ingestible delivery system 100. As used herein, the term "acid resistant shell" may include the acid resistant characteristics of an integrated acid resistant protease digestible membrane, or may refer to an acid resistant layer alone.

[0053] In some embodiments, the acid-resistant shell 108 or acid-resistant protease digestible membrane includes other layers to provide structural support or elastic resiliency, to impart other advantageous properties, such as layers that add mechanical strength or stability, including, for example, an embedded biodegradable structural support, or an outer layer that is digested in the stomach to provide mechanical protection as it passes through the mouth and esophagus, or a mesh layer disposed in whole or in part over the outer surface of the acid-resistant shell.

[0054] Figure 2 shows a section of an orally ingestible delivery system 200 as shown in Figure 1, where the section of Figure 2 is taken at line A-A' shown in Figure 1. As seen in Figure 2, a differentially permeable (e.g., digestible) capsule system 204 encloses a therapeutic agent within a therapeutic agent compartment 202. As described in more detail below, the therapeutic agent compartment 202 may contain one or more deliverable therapeutic agents (pills, granules, powders, liquids, etc.), with or without other coating layers. For example, the therapeutic agent(s) within the therapeutic agent compartment may be surrounded by a protease digestible layer, such as gelatin, or other protective or delayed release coating well known in the pharmaceutical arts.

[0055] The differentially permeable (e.g., digestible) capsule system 204 includes an acid resistant shell 208 (e.g., an acid resistant protease digestible membrane) and a dispersible acid barrier 210, shown here on a surface of the acid resistant shell 208. As shown in FIG. 2, the acid resistant shell 208 may be formed as a single layer, although, as noted above, other configurations of the acid resistant shell may be envisioned, which may include a protease digestible component to form an acid resistant protease digestible membrane. As shown, the acid resistant shell 208 is perforated by a system of pores 212 disposed throughout the layer, with certain pores opening to the interior and in fluid communication with the therapeutic agent compartment 202 and other pores opening to the exterior and in fluid communication with the dispersible acid barrier 210. The system of pores 212 interconnect such that the system of pores 212 provides fluid communication between the exterior surface of the acid resistant shell 208 and the therapeutic agent compartment 202. In embodiments, the pores are arranged within the acid-resistant shell 208 in a lattice or network system, with the pore channels intersecting within the membrane itself. More specifically, the system of pores 212 through the acid-resistant shell 208 can be straight, curvilinear, tortuous, separated, intersecting, or any configuration that provides access through the acid-resistant shell 208 to ultimately provide access to the therapeutic agent compartment 202. In embodiments, the pores can be less tortuous and more straight, allowing for more direct passage from the exterior face of the acid-resistant shell 208 to the therapeutic agent compartment 202. In other embodiments (not shown in this figure), the pores can be non-intersecting, for example arranged as multiple of a single channel that does not communicate. In embodiments, the pores within the system of pores 212 are dimensioned to have a micron-scale entry diameter, for example, about 10 microns, or about 1 to about 10 microns, or about 100 nm to about 10 microns, although other pore sizes, shapes, and configurations can be designed. 2 shows a system of pores 212 with no contents, entrances deflected by the externally disposed dispersible acid barrier 210, it is understood that the pores themselves may contain some form of dispersible acid barrier material (not shown), whether fluid or solid, the presence of which may supplement or replace the dispersible acid barrier 210 disposed on the surface of the acid-resistant shell 208. The dispersible acid barrier material within the pores may be the same or different from the dispersible acid barrier 210 formed on the surface of the acid-resistant shell 208.

[0056] In some embodiments, the acid-resistant shell 208 (e.g., an acid-resistant protease digestible membrane) may be formed uniformly or homogeneously, with pores 212 dispersed therein. In other embodiments, the acid-resistant shell 208 may be formed from a mixture of discontinuous acid-resistant particles, droplets, fibers, etc., which are positioned sufficiently proximate or juxtaposed to one another to form a barrier layer that prevents or impedes the influx of fluids from the surrounding environment.

[0057] 3 shows an embodiment of an ingestible delivery system 300 after ingestion thereof and after a period of residence in the stomach. A differentially permeable (e.g., digestible) capsule system 304 including an acid resistant shell 308 and a dispersible acid barrier 310 (shown here on a surface of the acid resistant shell 308) surrounds a therapeutic agent compartment 302 within which one or more therapeutic agents 306 are disposed.

[0058] More specifically, the acid-resistant shell 308 (e.g., acid-resistant protease digestible membrane) provides an outer acid-resistant layer that can be formed of any material that is resistant to the hydrolytic activity of gastric acid. In one embodiment, waxy materials such as beeswax, soy wax, carnauba wax, etc. can be used as the substrate material for the outer acid-resistant layer. As used herein, the term "wax" refers to any hydrocarbon that is a lipophilic and malleable solid near ambient temperatures, typically with a melting point greater than about 40°C. By way of example, the wax can include long chain aliphatic hydrocarbons, typically having 20-40 carbon atoms per molecule, or fatty acid / alcohol esters, typically containing 12-32 carbon atoms per molecule, such as myricyl cerotate, found in beeswax and carnauba wax.

[0059] The therapeutic agent(s) 306 may be formulated as a solid, semi-solid, liquid, gel, or some combination thereof. As shown in this figure, the therapeutic agent 306 is surrounded by the therapeutic agent compartment 302, where the therapeutic agent compartment 302 may be formed with a wall or additional layer covering the therapeutic agent 306. In embodiments, the therapeutic agent 306 may be present within a walled therapeutic agent compartment 302, where the wall is intended to modify the delivery of the therapeutic agent 306 from the orally ingestible delivery system 300 in some manner. The walls of the therapeutic agent compartment 302 may be designed to provide modification of the release of the therapeutic agent 306 or to provide mechanical protection or to provide additional resistance to proteases that may penetrate the acid resistant shell 308. In other embodiments, the therapeutic agent compartment 302 is hollow, without an additional surrounding layer, within which the therapeutic agent 306 resides. In embodiments, the therapeutic agent 306 may be present within the therapeutic agent compartment 302 without a separate covering layer.

[0060] In embodiments, one or more therapeutic agents 306 may be present within the therapeutic agent compartment 302, each with its own covering layer; if the deliverable therapeutic agent includes multiple therapeutic agents, separate covering layers may be provided surrounding two or more of the therapeutic agents. A single or multiple therapeutic agents may be present within the therapeutic agent compartment 302, collectively comprising the deliverable therapeutic agent. As used herein, the term "deliverable therapeutic agent" refers to the entire contents of the therapeutic agent compartment 302, which may include multiple therapeutic agents packaged separately or a therapeutic agent and a supportive environment or other variation in dosage form for one or more therapeutic agents 306 as a separate unit. In embodiments, each therapeutic agent 306 within the therapeutic agent compartment 302 may have its own system of covering layers, for example, to provide mechanical stability after its release from the orally ingestible delivery system 300, or to modify its release characteristics, or to enhance its uptake or its therapeutic effect. In such embodiments, the therapeutic agent 306 so formulated, for example with a system of covering layers, may be inserted intact into the therapeutic agent compartment 302, and no special modification of the orally ingestible delivery system is necessary to optimize the release of the therapeutic agent 306, since the formulation itself provides its release profile. In such a situation, the therapeutic agent 306 with its appropriate modified release formulation may be inserted into an empty therapeutic agent compartment 302, i.e., the therapeutic agent compartment 302 is formed as a hollow, with no special walls or other coverings apart from the acid resistant shell 308 and its components, and optionally including the inner protease digestible layer 314. The membrane formed by combining the acid resistant shell and the inner protease digestible components may be referred to as an acid resistant protease digestible membrane, which in the illustrated embodiment includes the acid resistant shell 308 and inner protease digestible layer 314. Alternatively or additionally, the therapeutic agent 306 having a suitable modified release formulation may be coated, covered or otherwise encased by or in an acid resistant shell 308, which, when these processes place an acid resistant shell 308 around the therapeutic agent 306 or deliverable therapeutic agent, in effect forms a therapeutic agent compartment 302. In embodiments, the therapeutic agent 306 may be a solid, liquid or gel, and may optionally be encased within a protease digestible layer 314, such as a gelatin capsule.In the embodiment shown, the protease digestible layer 314 serves as the outer wall of the therapeutic agent compartment 302. In other embodiments, the protease digestible layer 314 is not present. In the embodiment shown in Figure 3, the acid-resistant shell 308 of the differentially permeable (e.g., digestible) capsule system 304 can surround the optional inner protease digestible layer 314, with the two layers together forming an acid-resistant protease digestible membrane. In embodiments, the outer acid-resistant shell 308 is insensitive or only minimally sensitive to the effects of stomach acid, while in other embodiments, the outer acid-resistant shell 308 is relatively insensitive to the effects of stomach acid as compared to any protease digestible layer 314. In the embodiment shown, the exterior acid-resistant shell 308 is perforated by a system of pores 312 disposed in the layer 308, with certain pores open on the exterior face of the acid-resistant shell 308 in contact with the dispersible acid barrier 310 and certain pores open to the interior face of the acid-resistant shell 308 in contact with the protease digestible layer 314. As shown in Figure 3, the system of pores 312 only penetrates the acid-resistant shell 308, with some or all of the pores also communicating with the exterior face of the acid-resistant shell 308 and with the protease digestible layer 314. In an embodiment, the pores are disposed within the acid-resistant shell 308 in a lattice or network system, with the pore channels intersecting each other within the acid-resistant shell 308. More specifically, system of pores 312 through acid-resistant shell 308 can be straight, curvilinear, serpentine, separated, intersecting, or any configuration that provides access through acid-resistant shell 308, with some or all of the pores being contiguous on inner protease digestible layer 314. In other embodiments (not shown in this figure), the pores can be non-intersecting, e.g., arranged as multiple of a single channel without communicating. In embodiments, the pores in system of pores 312 are sized to have an entry diameter on the micron scale, e.g., an entry diameter of about 10 microns or about 1 to about 10 microns.

[0061] As previously described, in embodiments, the dispersible acid barrier 310 on the surface of the acid-resistant shell 308 may prevent the ingress of gastric acid into the pore system; in other embodiments, the pores may contain a dispersible acid barrier material (not shown), whether fluid or solid, which prevents the ingress of gastric acid and may replace or supplement the dispersible acid barrier 310 disposed on the surface of the acid-resistant shell 308 (e.g., an acid-resistant protease digestible membrane). It is understood that the dispersible acid barrier material within the pores may be the same or different from the dispersible acid barrier 310 formed on the surface of the acid-resistant shell 308.

[0062] As shown in Figure 3, the acid-resistant shell 308 (e.g., an acid-resistant protease digestible membrane) has an irregular surface. Without being limited to theory, it is understood that the irregularity of the membrane surface may take advantage of the phenomenon of surface tension and improve adhesion of fluids (i.e., gas or liquid) or solid particles to the surface, thereby making the dispersive acid barrier more robust. Although the dispersive acid barrier 310 is shown in this figure as having continuity across the surface of the acid-resistant shell 308, the dispersive acid barrier 310 may be discontinuous in any arrangement, such as being present only in grooves or recesses in the acid-resistant shell 308, or in areas surrounding the opening of holes into the exterior surface of the acid-resistant shell 308, or in any other configuration that enhances its function of preventing gastric fluids from contacting the acid-resistant shell 308. As previously described, the dispersible acid barrier 310 is shown only on the surface of the acid-resistant shell 308, but a dispersible acid barrier may also be formed and maintained within the pore system 312, as shown in subsequent figures.

[0063] As previously described, the orally ingestible delivery system 300 will reside in the stomach after ingestion where it will encounter acids and enzymes in the gastric fluids. When the orally ingestible delivery system 300 enters the stomach, it will be covered with gastric acid which will interact with the characteristics of the delivery system as described herein and below. As a result of encountering gastric acid, the system shown in FIG. 3 will form a dispersible acid barrier 310 on its surface. In embodiments, the orally ingestible delivery system 300 may encounter an acidic environment prior to its ingestion and will respond similarly to how it responds to gastric acid. In embodiments where a dispersible acid barrier 310 will form after encountering acid, the orally ingestible delivery system 300 may be pre-treated with acid prior to reaching the stomach to enhance the formation of the dispersible acid barrier 310. For example, the orally ingestible delivery system 300 may be provided in an acidic environment for ingestion or swallowed with an acidic liquid, gel or solid. Under these conditions, such pre-treatment with acid will initiate mechanisms for creating a dispersible acid barrier both before and after the orally ingestible delivery system reaches the stomach. It will be appreciated that if the orally ingestible delivery system 300 is exposed to acid before reaching the stomach, further contact with stomach acid may continue the process of creating a dispersible acid barrier 310 .

[0064] The particular mechanism by which the orally ingestible delivery system interacts with gastric or other acids is illustrated generally and in more detail in FIGS.

[0065] As shown in FIG. 4, the orally ingestible delivery system 400 is exposed to gastric fluids 416, including acids and gastric enzymes, whether prior to ingestion, during ingestion, or as it enters the stomach. As previously described and illustrated in FIGS. 1 and 2, the orally ingestible delivery system 400 includes an acid-resistant shell 408 (e.g., an acid-resistant protease digestible membrane) around the therapeutic agent compartment 402. In embodiments, the surface of the acid-resistant shell 408 may be coated with a soluble or digestible coating (not shown) that erodes rapidly in the stomach, such as a coating made of gelatin, polysaccharide, or some other digestible biopolymer. Such a coating may provide mechanical protection to the orally ingestible delivery system 400 during its storage, handling, and oral ingestion. In other embodiments, the coating may be formed as a mesh or network of elongated elements or fibers to provide structural stability, durability, or elasticity. In embodiments, the coating may protect the underlying components until the coating is eroded, damaged, or destroyed in the stomach. For example, a gas generator may be placed under the coating and on top of the acid-resistant shell so that as the coating degrades it reacts with stomach acid, thereby forming a layer of gas (not shown) that protects the exterior surface of the acid-resistant shell 408.

[0066] In embodiments, agents may be added to the acid-resistant shell 408 (e.g., an acid-resistant protease digestible membrane) or any full or partial covering applied thereto to enhance its strength or elasticity despite the mechanical stresses in the stomach. For example, the strength or elasticity of the acid-resistant shell 408 may be improved by adding substances such as polyisobutylene or other equivalent agents to the matrix used to form this layer, as described in more detail below. In other embodiments, the acid-resistant shell 408 shown here as a single layer may be constructed of multiple layers or combined with other layers, for example as described in FIG. 3, where an outer acid-resistant layer covers an inner protease digestible layer to form a single acid-resistant protease digestible membrane.

[0067] As shown in the embodiment shown, acid-resistant shell 408 (e.g., an acid-resistant protease digestible membrane) has a network of intersecting pores 412 within its matrix that penetrate to and diffuse throughout the matrix of the exterior surface of acid-resistant shell 408. In an embodiment, acid-resistant shell 408 can be perfused with a deposit of gas generating material, and contact of the gas generating material with stomach acid causes gas to be released from the gas generating material within the outer acid-resistant layer.

[0068] In the embodiment shown, the pores 412 themselves are not completely blocked by the barrier-forming material 422 throughout the entire network of pores. Thus, when acid 416 (e.g., in gastric fluid) first encounters the pores 412 that penetrate the outer surface of the acid-resistant shell 408 (i.e., before the formation of any dispersible acid barrier), it can enter the pores and diffuse through the pores, encountering deposits 422a of barrier-forming material dispersed within the pores and, optionally, deposits 422b of barrier-forming material dispersed within the matrix of the acid-resistant shell 408. Upon encountering gastric acid in the gastric fluid 416, these deposits 422a and / or 422b react with the acids and / or enzymes in the gastric fluid, creating the acid barrier layer shown in the previous figures. In embodiments, barrier-forming material 422a and / or 422b may be preferentially located at the more superficial sides of pores 412 and the matrix such that any gastric acid entering pores 412 will fairly quickly encounter barrier-forming material 422a and / or 422b and form a gas that prevents further ingress of gastric acid, thereby protecting the underlying therapeutic agent from the effects of gastric fluid 416.

[0069] In embodiments, barrier-forming materials 422a and 422b may be gas-forming materials that produce or release gas upon contact with hydrochloric acid in the stomach. By way of example, barrier-forming materials 422a and / or 422b may include bicarbonate crystals that form carbon dioxide upon contact with gastric acid in gastric fluid 416, which enters pores 412 and optionally becomes present on the surface of acid-resistant shell 408 (e.g., acid-resistant protease digestible membrane), where the presence of carbon dioxide acts as a dispersive acid barrier, mechanically preventing further exposure of acid-resistant shell 408 to gastric fluid, either by coating its surface, blocking pores or other channels in acid-resistant shell 408, or both. Such barrier-forming materials are referred to herein as "gas-forming materials" when their encounter with hydrochloric acid forms a gas. By way of example, carbonate-containing materials, including but not limited to metal carbonates such as calcium carbonate (e.g., precipitated calcium carbonate (PCC)), sodium bicarbonate, potassium bicarbonate, magnesium carbonate, etc.), are gas-forming materials since they form carbon dioxide when encountered with hydrochloric acid, as are hydrogen formers such as magnesium particulates.

[0070] The barrier-forming material may be concentrated in the pores 422a or dispersed in the matrix 422b, as shown in the figure, or both. For example, the barrier-forming material may also be randomly scattered in the deposit 422b through the acid-resistant shell 408 instead of or in addition to the barrier-forming material included 422a. Thus, the barrier-forming material comes into contact with gastric acid in the gastric fluid 416 as it enters the pores or penetrates the acid-resistant shell 408 (e.g., an acid-resistant protease digestible membrane), or both. A dispersible acid barrier 408 formed by contact of the barrier-forming material with gastric acid contained in the gastric fluid 416 may enter the pores from the matrix if the barrier-forming material is disposed in the matrix 422b, or a dispersible acid barrier may be formed within the pores if the barrier-forming material is included in the pores 422a.

[0071] In embodiments, additional barrier-forming materials may be dispersed within other components of orally ingestible delivery system 400, such as within a gas-producing layer (not shown) added between two or more layers of an acid-resistant shell (not shown) or below acid-resistant shell 408, or as separate deposits contained within therapeutic agent compartment 402, or within the therapeutic agent or deliverable therapeutic agent itself. It is understood that the barrier-forming materials dispersed in various locations, such as within deposits 422a within pores 412 and deposits 422b within the matrix, or within other components of orally ingestible delivery system 400, may comprise different substances or formulations.

[0072] In this figure, the acid-resistant shell 408 (e.g., an acid-resistant protease digestible membrane) includes multiple deposits 422a and 422b of a barrier-forming material dispersed throughout the acid-resistant shell 408. Some of the deposits 422a reside within the pores or partially contact the pores in the pore system, while other deposits 422b are encased within the material of the acid-resistant shell 408 without contacting the pores. In certain embodiments, the pores in the pore system 412 are constructed to be hollow, and the deposits 422a of the barrier-forming material are accessible to gastric fluids 416 that reside therein or otherwise enter the hollow pores. In still other embodiments (not shown), some or all of the pore system 412 may include a paste or oil, such as an edible oil, in which the deposits 422a may be dispersed. Such oils may have a viscosity tailored to retain the oil within the pores, and the oils may be selected to resist oxidation, hydrolysis and other deleterious processes that may affect durability and shelf life. For example, an unsaturated oil or oil blend may be selected. Filling the pore system 412 with a paste or oil may provide additional protection to the acid-resistant shell 408 to prevent ingress of fluids from the stomach, thereby preventing stomach acid and enzymes from encountering the membrane 408 from within. In other embodiments, the configuration for the pores may be patterned with digestible material scattered throughout the acid-resistant shell 408 as it is formed and disposed over the therapeutic agent compartment or over the therapeutic agent itself. As part of the same process to form the acid-resistant shell 408, the barrier-forming substances may be scattered throughout the matrix in a random pattern, or they may be attached to fibers (not shown) that are dispersed within the matrix and / or within the pores. In embodiments, the fibers are digestible or hydrolyzable, so that when they are digested or hydrolyzed, the acid of the acidic environment 416 comes into contact with the barrier-forming substances, which are thereby activated to produce a fluid that fills the pores or ingestible delivery system that remains after digestion of the fibers. Some of the fluid produced by the barrier-forming material may pass through the pores and become present on the surface of the acid-resistant shell 408 as a dispersible acid barrier (not shown).The dispersive acid barrier thus formed (including the outer fluid layer and the pore-filling fluid) prevents additional acid 416 from re-entering the acid-resistant shell 408 and affecting its digestion.

[0073] As shown in Fig. 4, the barrier-forming substances 422a and 422b have not yet come into contact with any acid in the gastric fluid 416, and therefore no fluid has yet formed that would become a dispersible acid barrier penetrating and covering the acid-resistant shell 408. By describing the system and its mechanism of activation in more detail with respect to Fig. 4: first, the acid in the gastric fluid 416 enters the pore system 412 (e.g., in the stomach, hydrochloric acid comes into contact with the barrier-forming substances in the pores and / or in the matrix of the acid-resistant shell 408); then, after contact with the acid, the deposit 422a forms a fluid that forms a dispersible acid barrier in the pores and on the surface; the surface components of the dispersible acid barrier are already shown in Figs. 1, 2, 3 and 5, but are not shown in Fig. 4.

[0074] 4 shows a plurality of deposits 422a and 422b that are substantially similar in size, it is understood that the size of deposits 422a and 422b can be similar or vary, and that the deposits can be regularly or randomly distributed throughout the matrix of acid-resistant shell 408 (e.g., an acid-resistant protease digestible membrane) and within the pores of pore system 412. When a particular deposit 422b is entirely encased within the matrix of acid-resistant shell 408, a porous fiber or other medium that allows for liquid transport can be embedded within the matrix in contact with the pores, such that acid can enter the pores and be carried into and within the matrix of acid-resistant shell 408, such acid contacting deposits 422b embedded in the matrix; fluids produced by contact of acid with deposits 422b can be expelled from the matrix and enter through channels into the pores or ingestible delivery system previously occupied by the porous fiber or other medium. This reaction between the barrier-forming material and the stomach acid results in the production of a fluid (not shown) that crosses the system of pores 412, in some cases blocking the pores entirely, remaining within the pores due to surface tension forces, and in other cases being expelled from the system of pores and becoming deposited on the surface of the acid-resistant shell 408. These bubbles or droplets of fluid may coalesce on the surface of the acid-resistant shell 408 to form a dispersive acid barrier thereon as shown in the other figures. Although the dispersive acid barrier layer has been shown as continuous or nearly continuous in the previous figures, it will be understood that the bubbles or droplets (whether separate or confluent) that form the dispersive acid barrier (i.e., fluid-filled pores) may be regionally separated and produce their barrier effect. For example, the bubbles or droplets (whether separate or confluent) may be localized at the opening of the pore and act as a "cap" on the pore without diffusing onto the remaining surface of the acid-resistant shell 408. Or for example, bubbles or droplets of fluid (whether separate or merging) may also or alternatively reside within grooves or irregularities on the surface of the acid-resistant shell 408, retaining their attachment due to surface tension.Other arrangements of fluid bubbles or droplets (whether separate or combined) on the membrane surface and / or within the pores can be envisioned to be consistent with the role of a dispersive acid barrier, i.e., providing a mechanical obstacle protecting the acid-resistant shell 408 in the stomach while dispersing in the duodenum to allow duodenal enzymes to access and dissolve the membrane.

[0075] Modifications of the acid-resistant shell 408 (e.g., acid-resistant protease digestible membrane) can be made to enhance the attachment or localization of droplets or bubbles (whether separate or combined) on its surface. For example, fibers contained within the matrix of the acid-resistant shell 408 can be positioned to protrude from its surface to trap droplets or bubbles (whether separate or combined) on the surface in specific areas and enhance their attachment. Such fibers (not shown) can be scattered or differentially positioned throughout the matrix in a regular pattern so that they are preferentially positioned on the exterior surface of the acid-resistant shell 408. In other embodiments, fibers that function to trap or hold droplets or bubbles (whether separate or combined) can be attached or positioned separately on the exterior surface of the acid-resistant shell 408 without them being embedded within the matrix, or they can be concentrated around the openings of the pore system 412. In embodiments, a barrier-forming material may be disposed on or at a surface portion of the acid-resistant shell 408 to facilitate the production of a dispersible acid barrier on the membrane surface.

[0076] FIG. 5 shows another embodiment of a cross-section of an ingestible delivery system 500 when the ingestible delivery system is exposed to an acid-containing fluid 516 (e.g., gastric fluid containing acid and gastric enzymes). In the embodiment shown, an acid-resistant shell (e.g., an acid-resistant protease digestible membrane) 508 surrounds the therapeutic agent compartment 502. The acid-resistant shell 508 may be formed discontinuously, where islands or droplets or chunks of acid-resistant material 518 are placed on top of each other to form a solidified layer. For example, when the solidified layer is formed by spraying, islands or droplets or chunks of acid-resistant material 518, such as sprayed particulate matter in suspension, may be placed on top of each other and adjacent to each other as discontinuous chunks of liquid, solid or gel to form a substantially solid layer of acid-resistant shell 508. Channels, hollows or holes 512 are formed during the placement process when the sprayed material 518 is layered or otherwise placed in contact with each other without fully integrating. These channels, hollows or holes 512 may penetrate completely through the acid-resistant shell 508 , potentially allowing external acid-containing fluid 516 to reach the therapeutic agent compartment 502 .

[0077] In the embodiment shown, an inner erodible layer 514, e.g., a layer of acid-digestible or protease-digestible material, is interposed between the acid-resistant shell 508 and the therapeutic agent compartment 502. In embodiments, the combination of the acid-resistant shell 508 and the inner erodible layer 514 forms an acid-resistant, protease-digestible membrane when the inner erodible layer is protease-digestible. As used herein, "erodible layer" refers to any layer included as a structural component of an orally ingestible delivery system that degrades upon exposure to the physical or chemical conditions in the stomach or intestinal tract, e.g., a protease-digestible layer, an acid-hydrolyzable layer, or any other material that can be digested or otherwise destroyed or damaged by the physical or chemical conditions in the stomach or intestinal tract.

[0078] As shown in this figure, multiple barrier-forming substances 522, e.g., gas-forming substances, are embedded in this layer 514. These barrier-forming substances 522 can be released or activated when they encounter acid leaking through the acid-resistant shell 508 (e.g., an acid-resistant protease digestible membrane) or gas from the acid-containing fluid 516. For example, if bicarbonate crystals are placed in the erodible layer 514 as barrier-forming substances, they can be converted to carbon dioxide gas upon encounter with gastric acid, and the carbon dioxide so formed can create a dispersive acid barrier as follows: As mentioned above, the acid-containing fluid 516 can access the inner erodible layer 514 by penetrating channels, hollows, or holes 512 present in the acid-resistant shell 508 as gaps between droplets 518 that are sprayed or otherwise placed on top of each other, without completely merging. Carbon dioxide gas (not shown) released from deposits of barrier-forming material 522 (e.g., bicarbonate crystals) within the corrodible layer 514 may then expand to fill (partially or completely) the channels, hollows or pores 512, filling them sufficiently to prevent further ingress of the acid-containing fluid 516.

[0079] 5 shows the inner erodible layer 514 with the barrier-forming material 522 substantially surrounded by the inner erodible layer, although other arrangements of the barrier-forming material 522 that minimize or eliminate a separate inner erodible layer 514 can be envisioned. For example, the inner erodible layer 514 can be a thin layer to which the barrier-forming material 522 is attached (on or below) rather than embedded therein. In other embodiments (not shown), the erodible layer 514 can be disposed within the acid-resistant shell 508 at any level and can include a barrier-forming material that can be released within the acid-resistant shell 508 upon their encounter with the acid-containing fluid 516. The inner erodible layer 514 can be a network or mesh and the barrier-forming material 522 can be attached thereto or disposed within the interstices of such network or mesh. In the absence of the internal erodible layer 514, the barrier-forming material 522 may be integrated into the therapeutic agent compartment 502, for example forming a coating around the deliverable therapeutic agent or surrounded by the therapeutic agent compartment 502 as a liquid or solid around the deliverable therapeutic agent itself. In these situations, the same mechanism is involved, whereby the external acid-containing fluid 516 leaks through gaps 512 in the acid-resistant shell 508 and accesses the barrier-forming material 522. However, in such embodiments, the acid-containing fluid penetrates the therapeutic agent compartment itself, where the acid activates the barrier-forming material contained therein.

[0080] In other embodiments, as shown in FIG. 6, a barrier-forming material 622 (shown diagrammatically and not to scale) may be disposed within the matrix of the acid-resistant shell 608 (e.g., an acid-resistant protease-digestible membrane), either in the interstices 612 as shown, or within a network or mesh of islands or droplets or clumps of acid-resistant material 618 (not shown). In FIG. 6, the erodible layer 614 does not include any barrier-forming material, but instead is simply disposed below the acid-resistant shell 608 and on top of the therapeutic agent compartment 602. In embodiments, the combination of the acid-resistant shell 608 and the inner erodible layer 614 forms an acid-resistant protease-digestible membrane when the inner erodible layer is protease-digestible. The erodible layer 614 may also be omitted, with the barrier-forming material 622 within the acid-resistant shell 608 providing sufficient barrier protection against the ingress of acid-containing fluid 616 to protect the deliverable therapeutic agent within the therapeutic agent compartment 602.

[0081] In embodiments, the orally ingestible delivery system may be coated with a soluble or digestible coating (not shown) that is rapidly eroded in the stomach, such as a coating made of gelatin, polysaccharides, or some other digestible biopolymer, as shown, for example, in Figures 5 and 6 and subsequent figures. Such a coating may provide mechanical protection to the orally ingestible delivery system during its storage, handling, and ingestion. In embodiments, the coating may protect the underlying components until the coating is eroded, damaged, or destroyed in the stomach. For example, gas generators may be placed under the coating or on top of the acid-resistant shell (e.g., an acid-resistant protease digestible membrane) so that they can react with stomach acid as the coating degrades, thereby forming a layer of gas (not shown) that protects the exterior surface of the acid-resistant shell 608.

[0082] In other embodiments, the coating may be formed as a mesh or network of elongated elements or fibers to provide structural stability, durability or elasticity. In embodiments, agents may be added to the acid-resistant shell (e.g., acid-resistant protease digestible membrane) or any full or partial covering applied thereto to enhance its strength or elasticity despite mechanical stresses in the stomach. For example, the strength or elasticity of the acid-resistant shell may be improved by adding a substance such as polyisobutylene or other equivalent agent to the matrix used to form this layer, as described in more detail below. In other embodiments, the acid-resistant shell shown as a single layer in Figures 4, 5 and 6 may be constructed with multiple layers or combined with other layers to provide advantageous properties. Other options for the creation of acid-resistant shells are described in more detail below.

[0083] 2. Common Oral Delivery Systems: Passage to the Duodenum As previously described, when the orally ingestible delivery system encounters an acidic environment, for example when it enters the stomach, the dispersible acid barrier that is formed protects the underlying acid-resistant shell (e.g., acid-resistant protease digestible membrane) from the action of gastric acid and enzymes. The dispersible acid barrier, whether internal, external, or both, acts mechanically to separate the acid-resistant shell from both acid and proteases. Thus, the orally ingestible delivery system can pass through the stomach, with the therapeutic agent being substantially intact within the therapeutic agent compartment, despite the stomach environment with its low pH and abundant digestive enzymes.

[0084] However, oral ingestible delivery systems can be adapted to release therapeutic agents, which can have therapeutic effects after passing through the stomach. This differential sensitivity to conditions in the stomach and duodenum characterizes OIDS as comprising differentially permeable (e.g., digestible) capsule systems. This selectivity allows OIDS to survive the stomach with the therapeutic agent relatively intact, and then release the therapeutic agent in the duodenum or elsewhere in the gastrointestinal system.

[0085] The first step of the release of the therapeutic agent is the dispersion of the dispersible acid barrier in the duodenum. The dispersible acid barrier can be a gas, such as carbon dioxide, generated in the stomach as described above. When carbon dioxide encounters bicarbonate released in the pancreas by the duodenum, it is dispersed and the mechanical protection it provides disappears. With the dispersion of the external dispersible acid barrier (if any), the external and / or internal surface of the acid-resistant shell (e.g., acid-resistant protease digestible membrane) is directly exposed to the enzymes of the duodenum. With the dispersion of the internal dispersible acid barrier, these enzymes can enter the pores that penetrate the acid-resistant shell of the differentially permeable (e.g., digestible) capsule system. For a single-layer differentially permeable capsule system, the entry of duodenal enzymes allows the digestion of the membrane from within the pores. For example, for a bilayer or multilayer differentially permeable capsule system that includes an acid-resistant shell and a protease-digestible component (thereby forming an acid-resistant protease-digestible membrane) or another form of erodible inner layer, the entry of duodenal enzymes allows these agents to reach and digest the erodible inner layer in addition to their digestive activity carried out within the pores. For example, for a multilayer differentially permeable capsule system with an outer acid-resistant layer and an inner erodible layer, the digestion and subsequent disintegration of the inner erodible layer can strip the outer acid-resistant layer of its structural support, causing it to deteriorate. With the deterioration of the outer acid-resistant layer, there can be increased contact between the duodenal enzymes and the erodible layer, so that the digestion of this layer can be accelerated.

[0086] The dispersive acid barrier formed by the space-occupying fluid or solid behaves similarly when the orally ingestible delivery system passes through the stomach to the duodenum. As described above, the space-occupying fluid or solid is selected to provide or contribute to the dispersive acid barrier, so that it is resistant to gastric acid, but dispersible (e.g., soluble) in the duodenum. As an example, the non-polar oil selected as the space-occupying fluid cannot be altered by gastric acid, and will remain in the pores of the orally ingestible delivery system when it is placed back. However, when the device enters the duodenum, bile salts and lipases disperse (now emulsify or digest) the non-polar oil, so that it is removed from the pores of the device, thereby opening them to the entry of duodenal proteases, which can destroy the device sufficiently to release the therapeutic agent therein. As another example, space-occupying solids can be placed in the pores, so that these solids are not affected by gastric acid, or they can respond to gastric acid by forming other space occupants, whether solid, liquid, or gas. The space-occupying solids themselves may disperse in response to duodenal fluid (as seen with carbon dioxide gas dispersing as either a gas or a fluid following its reaction with bicarbonate in the duodenum), or solid reaction products formed in the stomach may be susceptible to the action of duodenal fluid, resulting in their dispersion. As with space-occupying gases, dispersion in the intestine with space-occupying fluids or solids allows ingress of digestive fluids from the duodenum into the pores of the ingestible delivery system; this access allows digestive fluids such as proteases to further act on the acid-resistant shell (e.g., an acid-resistant protease digestible membrane) of the ingestible delivery system, destroying it sufficiently so that the therapeutic agent is released.

[0087] More specifically, digestive enzymes are produced in the stomach as well as the pancreas, which delivers them to the duodenum via the pancreatic duct. The main enzyme produced in the stomach is pepsin, which is responsible for initiating the breakdown of proteins in food. Pepsin is formed by cleavage of the precursor pepsinogen by gastric acid. The stomach also produces lipases, which initiate the hydrolysis of lipids in the stomach contents, which then pass into the duodenum. As mentioned above, the dispersive acid barrier formed on the surface and / or within the pores of the orally ingestible delivery system protects the underlying acid-resistant shell from the action of all of these enzymes.

[0088] Once the ingestible delivery system enters the duodenum, it encounters a different environment. The pancreas delivers bicarbonate to the duodenum, which neutralizes the acidic pH of the gastric chyme. The pancreas also delivers protease precursors to the duodenum, where they are activated to form the proteases trypsin and chymotrypsin. Other pancreatic enzymes include carboxypeptidases, pancreatic lipases, phospholipases, sterol esterases, and some elastases and nucleases. The acid-resistant shell (e.g., acid-resistant protease digestible membrane) itself is designed to resist the action of acids, such as gastric acid, but it is also designed to be corrosive. The ingestible delivery system loses its dispersive acid barrier when it encounters the duodenal environment. For example, if the dispersible acid barrier is formed of a gas-generating material such as bicarbonate solid that generates carbon dioxide in the stomach, the gas (e.g., carbon dioxide) provides mechanical protection while in the stomach. However, in the duodenum, the carbon dioxide is removed by the bicarbonate in the duodenum, thereby dispersing the mechanical protection that carbon dioxide provides while in the low pH stomach environment. At this point, the acid-resistant shell is exposed to the action of various enzymes, especially proteases, in the duodenum. Proteases may damage the acid-resistant shell and / or they may penetrate the acid-resistant shell and attack the inner layer of the orally ingestible delivery system around the therapeutic agent(s).

[0089] Similarly, if the dispersive acid barrier is formed by a space-occupying fluid or solid that is resistant to the activity of gastric fluid, the ingestible delivery system will pass through the stomach relatively intact. The space-occupying fluid or solid is selected to be dispersible in the duodenum; that is, the activity of duodenal enzymes, bile salts, bicarbonates, etc. is intended to affect the space-occupying fluid or solid, resulting in its dispersion. For example, a space-occupying non-polar fluid such as edible oil may be minimally affected by gastric conditions, but may become dispersed because it may be emulsified by bile salts in the duodenum, digested by duodenal lipase, and / or destabilized by pH changes. With the loss of the dispersive acid barrier, whether provided by a fluid (liquid or gas) or a solid, the acid-resistant shell (e.g., an acid-resistant protease digestible membrane) is exposed at its outer surface to digestive enzymes in the duodenum, which may begin to attack the protein components of this membrane. As noted above, in addition to this external attack, the acid-resistant shell and underlying layers of the orally ingestible delivery system can be attacked from the inside.

[0090] The release of the therapeutic agent or deliverable therapeutic agent from the therapeutic agent compartment can begin when the pores of the acid-resistant shell (e.g., an acid-resistant protease digestible membrane) are penetrated by acid and appropriately opened. The process can be accelerated as the acid-resistant shell degrades and loses its integrity. The rate of degradation of the acid-resistant shell can be controlled by engineering the structure of this membrane, as described in more detail below. Furthermore, the therapeutic agent or agent within the deliverable therapeutic agent can be formulated to promote or delay its / their release in its / their active form, or to protect it / them from the action of digestive enzymes that it / they encounter in the duodenum after the surrounding acid-resistant shell is breached. For example, the therapeutic agent can be formulated with a protease inhibitor that protects the therapeutic agent from the action of proteases or delays their effects. As used herein, the term "inhibit" and related lexical units that include this term refer to an action or process that impedes, inhibits, delays, interferes with, or prevents another action or process. Other formulations for delayed release in the intestinal tract are well known in the art. In other embodiments, the therapeutic agent in the therapeutic agent compartment may be surrounded by a protective liquid or solid capsule that provides additional engineered protection and / or delays release in the intestinal tract. The therapeutic agent may be formulated as a solid, liquid, gel or lyophilized formulation. In embodiments, the therapeutic agent may be a single agent (e.g., active pharmaceutical ingredient ("API")) or a combination of agents (e.g., two or more APIs, or one or more APIs combined with non-pharmaceutical substances that are intended to interact with the API(s) and promote their efficacy, or a collection of living organisms and their supporting environment); such combinations may include a deliverable therapeutic agent.

[0091] 3. Orally Ingestible Delivery Systems: General Structure for Acid-Resistant Shells More specifically, the acid-resistant shells (e.g., acid-resistant protease digestible membranes) disclosed herein can be formed of confluent, continuous or discontinuous component materials and any combination thereof. As an example, the acid-resistant shell can be formed uniformly of a single acid-resistant material. As shown in the previous figures, such a uniform acid-resistant shell can be perforated by a series of holes blocked by a dispersive acid barrier that allow gastric fluid access otherwise through the acid-resistant shell to reach the therapeutic compartment. As another example, the acid-resistant shell can be formed of discontinuous acid-resistant elements that are proximate or positioned close to each other, such as a series of wax droplets that are added to each other to form adjacent, adjacent or stacked layers of particles with channels or gaps between the individual solid droplets. The solid elements can be stacked, woven or positioned next to each other, for example, by a spray process that disperses wax droplets to form cobblestone-like layers or multi-layered films. Channels between the separate opposing elements are formed as the individual particles are deposited, and the channels can allow gas or liquid to pass through the membrane in either direction (inside-out or outside-in). In embodiments, the acid-resistant shell formed of discontinuous elements can be formed of fibers that are laminated, air-laid, dry-laid, wet-laid, spun-melted, woven, or otherwise arranged proximate to one another, where the fibers are arranged in such a way that they can escape from channels or passages between them that can allow gas or liquid to pass through. In embodiments, the fiber network can be air-laid, and wax is sprayed simultaneously to bond or adhere the fiber network together. In one embodiment, non-acid water-soluble fibers such as psyllium seed husk, cellulose fibers, lignin, etc. can be used. In other embodiments, the fibers are arranged in such a way that they are susceptible to dissolution and can escape from channels or passages in the acid-resistant shell when the fibers are dissolved.

[0092] As previously described, the barrier-forming material can be disposed in the gaps between the elements of the acid-resistant shell or within the elements of the acid-resistant shell, or both. In one embodiment, insoluble fibers can be used to form the acid-resistant shell, and can be combined with a material such as wax to provide a more uniform resistance to acid. For example, in an embodiment, acid-resistant or acid-soluble fibers can be stirred into molten wax to form a suspension, and then the fiber-bearing wax suspension can be formed into an acid-resistant shell layer. Alternatively, such fibers can be coated with wax or similar material before being used in the network, or the fibers can be aligned in the network and then sprayed or otherwise coated with wax or similar material.

[0093] In embodiments, the barrier-forming substances can be disposed within the wax layer or they can be attached to the fibers with wax coating. To form a suitable acid-resistant shell layer using this technique, the wax-coated fibers carrying the barrier-forming substances can be expected to adhere to each other without the need for a separate adhesive or other fastening technique. The wax-coated fibers can also contain the barrier-forming substances embedded in the fibers themselves. For example, the fibers can simply be stirred into a solution of water and sodium bicarbonate, allowing the fibers to be immersed in the water and dissolved sodium bicarbonate. The fibers can then be removed and dried, and sodium bicarbonate crystals will form again within the fibers to act as the barrier-forming substance. In other embodiments, wax can be used to coat acid-insoluble or acid-soluble fibers, and the fibers can contain the barrier-forming substance. When the fibers dissolve, the barrier-forming substance produces a barrier material (e.g., carbon dioxide gas) that fills the space occupied by the fibers before their dissolution.

[0094] In one embodiment, fibers can be prepared for use in forming an acid-resistant shell layer by coating a selected type of fiber, such as an acid-insoluble fiber, with a layer of soluble gas-forming solid, which is then covered with an outer layer of wax. When the outer layer of wax is penetrated, acid can access the layer of gas-forming solid (e.g., sodium bicarbonate), dissolve them, and release gas (e.g., carbon dioxide) that can exit from the hollow behind where the gas-forming solid was previously. In another embodiment, fibers can be combined with gas-forming solids or other solids, which are attached to the outside of the fiber or embedded or entrained within the fiber, or inserted into the acid-resistant shell proximal to the fiber without being attached to or integrated within it. If the fiber is acid-soluble, it can be corroded upon contact with acid, and during that process the fiber acts as a conduit to guide the acid to contact the solid. Upon contact with acid, the gas-forming solids can release gas, which then occupy the space where the fibers and solids were previously present. That is, the space is first occupied by the acid-soluble fibers, the solids are filled with gas, and then prevent further acid ingress. If the fibers are acid-resistant and have gas-forming or other solids attached to their exterior or embedded or contained within them, such fibers can still act as conduits to allow acid to contact the solids: acid can flow along the exterior surface of the acid-resistant fibers (e.g., by capillary action), so that it comes into contact with the proximal solids. Upon contact with acid, the gas-forming solids can release gas, which then occupy the space where the solids were previously present. The acid-resistant fibers remain intact, but the gas released from the gas-forming solids occupies the space where these solids were previously present. In embodiments, the gas-forming solids located proximal to or within the fibers can be accompanied by starch or other materials that can swell when contacted with gastric acid. Upon contact with gastric acid, such swellable materials increase in volume and expand the space around them, potentially creating a larger volume within which released gas can reside and / or creating more defined or more accessible channels for solids or gases or both.

[0095] Fibers, whether acid-resistant or acid-soluble, can only act as a conduit for gastric acid if they come into contact with acid. Therefore, the fibers must come into contact with the acid in some way. Several methods for providing this contact can be envisioned by those skilled in the art. For example, parts of the fiber can be exposed on the outer surface of the acid-resistant membrane, so that the acid can contact these exposed parts. As another example, if the acid-resistant membrane is coated with a protease digestible layer, the fiber is temporarily coated with such a layer until it is digested; digestion of the protease digestible layer then follows, exposing the fiber to gastric acid and allowing the fiber to act as a conduit. The presence of an outer layer coating the exposed parts of the fiber can be used to fine-tune the process of gas generation within the acid-resistant membrane. Similarly, an inner layer of the acid-resistant membrane can be positioned to prevent further excursion of acid through this layer into the therapeutic compartment.

[0096] As another approach, solid channels can be created in the acid-resistant shell by adding solid particles to the wax layer alone, or with water mixed with surfactant or surfactant alone. As an example, starch and calcium carbonate powder can be mixed together and liquid surfactant can be added to create a paste. This paste can be added directly to the wax phase. Since starch or calcium carbonate powder is only mixed with surfactant and wax, neither dissolves; therefore, these solids remain intact in the wax, allowing the formation of channels thereafter as follows. After contact with gastric acid, the starch in the paste can dissolve and swell, potentially expanding the space it occupies and / or forming more defined or more accessible channels for calcium carbonate; calcium carbonate from the original paste deposit can then react with gastric acid to generate gas. Here, this gas can act as a barrier that is trapped inside the channel. So, upon contact with duodenal fluid, the gas can be removed and the channel is exposed to the interior region of the device. As mentioned above, starch can be replaced by gelatin powder, pectin, xanthan gum, carrageenan or any other hydrocolloid or material that can dissolve and swell when in contact with water or stomach acid. Additionally, any liquid surfactant can be used to create a paste, or powdered surfactant can be used, simply mixed with other powdered materials, and also combined with waxes.

[0097] In embodiments, two or more different solids can be embedded in the matrix of the acid-resistant shell, and the different solids perform different functions. For example, one material can act as a gas generator, as described below. A second material can interact with the gas bubbles formed and hold them in a specific location within the matrix, for example, by surface tension attraction or other physical or chemical forces. A first gas generator can be used that forms gas upon contact with gastric fluid, and a second gas generator can be used that forms gas only upon contact with duodenal fluid. Other embodiments with different arrangements of solids within the acid-resistant shell can be envisioned by those skilled in the art.

[0098] In an embodiment, as described herein, the barrier-forming material can be a gas-generating material. Particularly advantageous are gas-generating materials that generate carbon dioxide when exposed to hydrochloric acid in the stomach. Gas-generating materials (e.g., carbon dioxide formers such as calcium carbonate (including precipitated calcium carbonate (PCC)), sodium bicarbonate, potassium bicarbonate, magnesium carbonate and other metal carbonates, or hydrogen formers such as magnesium particles) can exist as solid materials or other physical states, and in an embodiment, can be embedded in the acid-resistant shell or embedded in its pores, so that they generate carbon dioxide or other gases when exposed to gastric acid. In one embodiment, gas-generating materials can be embedded in a digestible polymer or small molecule matrix and intertwined with the wall-forming material of the acid-resistant shell, so that when contacted with gastric acid, the matrix decomposes to expose the embedded gas-generating material to react with gastric acid.

[0099] Carbon dioxide, as produced by certain gas generating substances, is particularly advantageous as a major component of the dispersible acid barrier because it dissolves in the natural secretions of the intestine and reacts with bicarbonate released into the duodenum by pancreatic secretions. This feature allows the carbon dioxide gas barrier formed in the stomach by the action of gastric acid on the gas generating substance to disperse rapidly into the duodenum, allowing the influx of various pancreatic enzymes into an acid-resistant shell (e.g., an acid-resistant protease digestible membrane), as described in more detail below.

[0100] When the barrier-forming substances are gas-generating substances, they protect the orally ingestible capsule system from the effects of stomach acid: while the orally ingestible capsule system is in the stomach, fluids are prevented from accessing the acid-resistant shell (e.g., an acid-resistant protease-digestible membrane) and from entering the pores by a dispersive acid barrier formed from gas, which covers the capsule system as a continuous layer or discontinuous phase and / or is present within the pores themselves. In either case, the dispersive acid barrier formed from the gas-generating substance creates a gas-fluid interface with the liquid in the stomach, preventing it from entering some or all of the pores. Some or all of the pore openings on the surface of the membrane can be mechanically protected from the entry of fluids in the stomach by a dispersive acid barrier formed from the gas-generating substance, so that gastric acid cannot access the inside of the acid-resistant shell. When the dispersive acid barrier is formed from the gas-generating substance, gas bubbles can also become present within the system of pores as well, or alternatively, form a separate gas barrier within the pores themselves. Although the gas bubbles are shown in the figures as separate bubbles, it is understood that the gas bubbles will coalesce to occupy some or substantially all of the space within the pores; this coalescence is expected when gas is formed from the gas-generating material and expands within the pores. The gas within the pores therefore acts as a mechanical barrier to the ingress of gastric acid after the initial ingress of gas triggers the formation of gas from the gas-forming material. Furthermore, to the extent that a dispersive acid barrier formed from the gas-generating material is present on the surface of the acid-resistant shell, this barrier prevents gastric acid from contacting the exterior face of the membrane.

[0101] In other embodiments, the barrier-forming material described herein can be a space-occupying solid or fluid (i.e., any fluid, whether gas or liquid) instead of or in addition to a gas-generating material. In embodiments, the pores in the matrix can be partially or completely filled with a solid and / or fluid that provides a mechanical barrier to the influx of gastric acid. For example, the pores can contain a non-polar fluid in liquid form, such as an edible oil, that does not react with or dissolve in gastric acid, thereby blocking gastric acid from entering the pores. Such a material remains intact in place as the orally ingestible delivery system traverses the stomach, but is dispersible in the duodenum when bile salts emulsify the fluid and then disperse it. In embodiments, a solid can be placed in the pores instead of or in addition to a non-polar fluid. In embodiments, the solid or liquid can add a mechanical impediment to the influx of acid and / or can be reactive with gastric acid to contribute to barrier formation. In embodiments, an acid-reactive liquid or solid can interact with gastric acid to form a space-occupying material that provides a mechanical barrier to further influx of gastric acid. For example, solid bicarbonate particles may be acid-reactive solids that interact with gastric acid to form carbon dioxide bubbles that then provide their own mechanical protection to the system as previously described. As another example, non-polar materials such as waxes or gels may act as space-occupying solids, but can be transformed into space-occupying liquids at body temperature or when exposed to the action of gastric acid or enzymes. Substances that form another substance upon contact with acid are referred to as "acid-reactive substances."

[0102] Certain of these embodiments (barrier-forming materials that are gas generators and barrier-forming materials that are space-occupying solids or fluids) are discussed below with reference to Figures 7-13. When gas generators (e.g., bicarbonate crystals) encounter gastric acid, they produce a gas (e.g., carbon dioxide) that fills the pores and displaces the hydrochloric acid from the channels or pores. In embodiments, the gas may traverse the outer acid-resistant layer to reach the surface of the acid-resistant shell (e.g., an acid-resistant protease digestible membrane) and form a dispersive acid barrier thereon. In other embodiments, the released gas may migrate throughout the system of pores, filling them completely or partially and forming a dispersive acid barrier therein. In still other embodiments, the released gas may fill the pores more or less completely and form a layer of gas on the surface. The gas within the pores and / or the layer of gas on the surface (in certain cases concentrated around the external openings of the pores or channels) prevents further influx of gas into the outer acid-resistant layer, thereby protecting the inner erodible layer from contact with gastric fluids.

[0103] In embodiments, the acid-resistant shell (e.g., acid-resistant protease digestible membrane) comprises channels or pores that allow gastric acid to reach the gas-generating material contained therein and also allow the gas(es) released from the gas-generating material to reach the surface. In embodiments, the acid-resistant shell (e.g., acid-resistant protease digestible membrane) can be formed by the gas-generating material embedded therein, which creates pores upon activation of the gas-generating material; alternatively or additionally, the pores can be mechanically created. Mechanically forming channels or pores can include, for example, drilling holes in the layer with microneedles after it is placed, so that a direct path is created that allows gastric acid to enter the layer and reach at least some of the gas-generating material placed therein. In embodiments, the porous structure of the acid-resistant shell can be created by 3-D printing or other techniques that simultaneously form hollow and solid regions of the matrix, so that a porous network is formed within the matrix. In other embodiments, the acid-resistant shell can be formed by embedding a gas-generating substance therein, and then the pores can be chemically created. For example, chemically creating channels or pores can occur when there are acid-digestible elongated structures, such as filaments or fibers, dispersed within the layer, which are corroded or digested by gastric acid, leaving behind hollows through which gastric acid can infiltrate the layer. For example, the acid-resistant shell can be formed by embedding a gas-generating substance therein and dispersing a hydrophilic substance (fibers or other inclusions, polymers, etc.) throughout the matrix, so that the hydrophilic substance can provide a conduit for gastric acid to enter the matrix and react with the gas-generating substance; in embodiments, the hydrophilic substance is selected so that they are hydrolyzable by gastric acid, creating hollows within the matrix, allowing the gas produced by the gas-generating substance to escape from the matrix, as described above, to form a dispersive acid barrier on the surface of the acid-resistant shell.

[0104] In embodiments, differentially permeable (e.g., digestible) capsule systems can be formed as a single layer surrounding a therapeutic compartment but with asymmetric properties. If the properties of such a single layer structure include both acid resistance and protease digestibility, the structure can be considered to be an acid-resistant protease digestible membrane. For example, such a layer can include a naturally derived polymer such as gelatin or an engineered polymeric matrix with embedded space-occupying solids or fluids, or gas-generating substances such as bicarbonate crystals therein, using the techniques described above. The layer can then be formed as a gradient with a more hydrophobic, acid-resistant exterior region and an internal, more hydrophilic interior region. For example, the layer can include more waxy or hydrophobic polymers in the mixture on the exterior region and more protein-based or hydrophilic polymers in the mixture on the interior region. In embodiments, an asymmetric layer can be formed using a temperature gradient that creates a gradient of two dissimilar components within the layer. In embodiments, an asymmetric layer can be formed by a temperature gradient. The layer is placed between two layers of dissimilar temperatures. Between the two temperature boundaries is the temperature as a function of position in the bulk layer, and any slice in the bulk layer has a small layer of temperature T(z). The preferred mixture distribution of the two dissimilar components is a function of temperature. This means that if T(z) is different for each layer at z, the mixture of components C1 and C2 will be different from other z locations, and so throughout the bulk layer of finite thickness at location z along the thickness, there will be a different mixture ratio of C1 and C2. If the layer is then "frozen" at that location by gradual cooling, the z-dependent mixture ratio will remain intact, so the mixture of C1 and C2 will not be uniform throughout.

[0105] In embodiments, a one-layer differentially permeable (e.g., digestible) capsule system can be created that has a combination of properties, such as behavior similar to a system with an external acid-resistant shell and an internal erodible layer. A single blended layer that includes an erodible material and an acid-resistant material (e.g., gelatin and a waxy matrix) can be formed with the two components blended together and a space-occupying fluid or solid or gas-generating material disposed therein. Digestion of the erodible material by stomach acid creates channels that allow the acid to access the barrier-forming material and activate or release them. When gas is produced from the gas-generating material or space-occupying fluid is released from its deposit, it fills the channels and optionally reaches the surface of the layer, creating an internal and external dispersive acid barrier as previously described. Alternatively or additionally, a gas-producing layer and / or a layer of space-occupying fluid can be disposed within a single blended layer, so that when gastric acid reaches it, which corrodes the erodible portion of the single blended layer, the barrier-forming layer will generate gas or release fluid, respectively. Reinforcing materials, as described in more detail herein, may be added to the single compounded layer to add strength and / or resilience.

[0106] In embodiments, for example, a one-layer differentially permeable (e.g., digestible) capsule system can be formed from a mixture of a water-swellable, acid hydrolyzable, and / or protease digestible phase and a water-resistant and hydrolysis-resistant phase; this one-layer system encloses the therapeutic agent or deliverable therapeutic agent. In embodiments, the water-swellable, acid hydrolyzable, and / or protease digestible phase can include polysaccharides, proteins, or some combination thereof. Polysaccharides well known in the art, such as starches (such as tapioca, rice, and corn), glycogen, inulin, pectin, xanthan gum, carrageenan, gum arabic, agar, alginates, and the like, can be used in this phase. In embodiments, polysaccharides with hydrocolloid properties can be selected for their ability to swell upon exposure to water. Proteins, such as gelatin, wheat gluten, corn zein, soy protein, whey protein, and mung bean protein, can be used in this phase to form a water-swellable protein solution. Gas generating materials or space occupying fluids may be dispersed within this phase, similar to the distribution of other materials described herein. The water insoluble, acid resistant phase may be formed from a variety of materials, such as cellulose, fatty acids, waxes, polyolefins, edible / natural elastomers (e.g., natural latex, couma macrocarpa, tunu, jelutong, or chicle). The water insoluble, acid resistant phase may also include non-digestible food grade materials, such as fibers intended to improve the strength and durability of the layer.

[0107] 7 shows an embodiment of an orally ingestible delivery system 700 that diagrammatically illustrates an external dispersible acid barrier 710 comprising gas bubbles on the surface of an acid-resistant shell 708 (e.g., an acid-resistant protease digestible membrane) formed by a mechanism using a gas-generating barrier-forming material as described above, and an internal dispersible acid barrier 716 formed within a system of pores 712 by the same mechanism. The orally ingestible delivery system 700 shown in this figure is exposed to gastric acid during residence in the stomach. As a result, the gas-generating material (not shown) originally dispersed within the system of pores 712 reacts in whole or in part with the gastric acid to produce gas bubbles 720 within the system of pores 712 that occupy and block the system of pores 712, forming the internal dispersible acid barrier 716 (although diagrammatically shown in this figure as a linear arrangement of three gas bubbles within the system of pores, it will be understood that this internal dispersible acid barrier 716 may be designed to fill all or substantially all of the pores to provide a more adequate barrier effect). As described in more detail below, gas bubbles 720 within pore system 712 may combine to form a robust internal dispersive acid barrier 716; and gas bubbles 720 may traverse pore system 712 and reach the surface of acid-resistant shell 708 where the gas bubbles form external dispersive acid barrier 710. Although only a few gas bubbles 720 are shown in this figure, it is understood that multiple gas bubbles may be produced to partially or completely occupy pore system 712, thereby blocking pore system 712 sufficiently to provide internal dispersive acid barrier 716. In embodiments, unreacted deposits of gas generating material 722 may remain within the matrix of acid-resistant shell 708 or within pore system 712 (not shown); in other embodiments, there are no unreacted deposits of gas generating material within pore system 712, as these gas generating materials have all reacted to produce gas bubbles 720.

[0108] 7, an acid-resistant shell 708 may be used with an internally disposed inner erodible layer 714, where the therapeutic agent compartment 702 is disposed within the inner erodible layer 714, effectively creating a two-layer differentially permeable (e.g., digestible) capsule system; if the inner erodible layer 714 is protease digestible, the combination of the acid-resistant shell 708 and the inner erodible layer 714 forms an acid-resistant, protease-digestible membrane. As in the embodiment shown, in a two-layer differentially permeable capsule system, the inner erodible layer 714 is protected from the action of gastric fluids by the protective effect of the gas bubbles 720 formed within the pores and / or the external dispersible acid barrier 710. In an embodiment not shown in this figure, the erodible layer 714 may include a barrier-forming material, such as a gas-generating material, as shown within the acid-resistant shell 708. In other embodiments not shown in this figure, the acid-resistant shell may be formed as a single layer with a similar system of pores within its matrix, but is not combined with the internal erodible layer 714. In still other embodiments, the acid-resistant shell 708 may include other layers within itself or be combined with other layers to impart other advantageous properties. For example, layers may be added to increase mechanical strength or stability, including embedded biodegradable structural support, such as fibers or an internal mesh structure to add strength, or an embedded biodegradable layer that includes additional barrier-forming materials that may react when exposed to conditions in the stomach or intestine, or an external layer that is digested or dispersed in the stomach to provide mechanical protection during passage through the mouth and esophagus. In other embodiments, an external layer may be provided on top of the acid-resistant shell 708 in the form of a network or mesh of elastic fibers that shield and protect the capsule as it is advanced by peristalsis in the stomach. Other such layers at any level (top, bottom, or middle) of the acid-resistant shell may be envisioned by one of skill in the art.

[0109] 7, some of the gas bubbles 720 produced by contact of the gas generating material deposit with gastric acid remain within the pore system 712 (thereby forming an internal dispersive acid barrier 716), while other gas bubbles 720 exit the pore system and form an external dispersive acid barrier 710 present on the surface of the acid resistant shell 708 (e.g., an acid resistant protease digestible membrane). As used herein, the term "dispersive acid barrier" includes the external dispersive acid barrier 710 disposed on the exterior surface of the acid resistant shell 708, and further includes any single or combined gas bubbles 720 or other dispersive barrier material present within the pore system 712 (i.e., internal dispersive acid barrier 716). In the embodiment shown, both the external dispersible acid barrier 710 and the gas bubbles 720 within the pores 712 (i.e., the internal dispersible acid barrier 716) serve to protect the acid-resistant shell 708 and therapeutic payload (not shown) encased in the differentially permeable (e.g., digestible) capsule system 704 from contact with and action of stomach acid and gastric enzymes; furthermore, both the external dispersible acid barrier 710 and the gas bubbles 720 present within the pores are dispersible by action of bicarbonate in the duodenum and by dissolution in non-acidic intestinal fluids, as described in more detail below. Although the gas bubbles 720 are shown as separate bubbles in this and other figures, it is understood that the gas bubbles 720 may coalesce to occupy some or substantially all of the space within the pores; this coalescence is expected as gas is released from the gas generating material and expands within the pores 712.

[0110] As illustrated diagrammatically in this figure, the acid-resistant shell 708 (e.g., acid-resistant protease digestible membrane) may provide or be formed with an irregular surface (irregular or regularly irregular with grooves, depressions, wrinkles, etc.), with the external dispersive acid barrier 710 itself aligned along the exterior face of the acid-resistant shell 708 in an irregular manner, e.g., more gas bubbles contained in depressions or recesses in the acid-resistant shell 708 surface, thereby resulting in an irregular or uniformly discontinuous exterior surface for the dispersive acid barrier 710 itself. The irregular surface may be formed during residence in the stomach because stomach acid produces gas bubbles that may distort the shape of the matrix that contains or supports them. In embodiments, digestion or deterioration of the acid-resistant shell 708 may result in changes to its surface, which becomes irregular. Regardless of how it is formed, the irregularity of the external dispersive acid barrier interface may increase the hydrophobicity of the external dispersive acid barrier 710 and enhance its ability to repel liquids such as gastric juices. In some embodiments, the acid-resistant shell 708 may be formed with an ordered surface. In such embodiments, the surface configuration may not aid in the formation and maintenance of the external dispersive acid barrier 710, but the protective effect of the internal dispersive acid barrier 716 may be sufficient to insulate the underlying internal erodible layer 714 and the underlying therapeutic agent compartment 702 from attack by gastric acid. In other embodiments, the characteristics of the surface configuration may be selected such that they aid in the formation and maintenance of the external dispersive acid barrier. In some embodiments, the ordered nature of the surface may aid in the formation and maintenance of the external dispersive acid barrier.

[0111] FIG. 8 shows a schematic embodiment illustrating the formation of an internal dispersive acid barrier 816 in more detail. As shown in this figure, an ingestible delivery system 800 includes an acid resistant shell 808 (e.g., an acid resistant protease digestible membrane) and a therapeutic agent compartment 802. There is an internal prosthetic digestible layer 814 disposed inside the acid resistant shell 808. As previously described, the structure of the differentially permeable (e.g., digestible) capsule system including the acid resistant shell 808 can include a single layer structure, a two layer structure, or a multi-layer structure. In the embodiment shown, the acid resistant outer layer 818 of the acid resistant shell 808 is perforated by a system of pores 812. The system of pores 812 is filled with gas, also shown here as individual gas bubbles 820 and aggregated gas bubbles 824. The effect of the gas within the system of pores 812 is to create an internal dispersive acid barrier 816 that prevents the ingress of fluids from the external environment. As previously described, acid-resistant shell 808 may be formed first having a system of pores 812 in which a gas generating material is disposed (not shown); in embodiments, gas generating material 822 may also be disposed within the matrix of outer acid-resistant layer 818 of acid-resistant shell 808 and / or at other locations as shown. In the embodiment shown, portions of system of pores 812 are filled with gas formed by interaction of gas-forming material within the pores with gastric acid. Gas bubbles 820 thus produced may wholly or partially occupy and integrate 824 the pores, producing an internal dispersive acid barrier 816 that prevents further ingress of gastric fluids. Although gas bubbles 820 and integrated gas 824 are shown in this figure as occupying only a portion of system of pores 812, orally ingestible delivery system 800 may be altered to produce a greater or lesser degree of pore filling. Although the figures show a combination of empty pores, pores filled with gas bubbles 820, and integrated gas 824, these illustrations are merely exemplary. The internal dispersive acid barrier 816 may include any combination of fully gas-filled pores, partially gas-filled pores, pores filled with integrated gas bubbles, and pores containing separate gas bubbles; further, the behavior of the gas within the pores may be dynamic depending on the mechanism of bubble formation and passage of the bubbles through the pore system 812.

[0112] Without being bound by theory, it is understood that the gas is retained within the pores 812 as a durable barrier against the ingress of gastric fluids due to the surface tension of the gas itself. In embodiments, the gas content of the pore system may escape through the pores 812 and be released into the stomach surroundings as released gas bubbles 828. In other embodiments, for example as shown in the previous figures, the gas bubbles may be retained on the surface of the acid-resistant shell 808 (e.g., an acid-resistant protease digestible membrane) to form an external dispersive acid barrier (not shown) that works synergistically with the internal dispersive acid barrier 816 shown in this figure. In embodiments, the internal dispersive acid barrier 816 provides the sole or primary protection against the ingress of gastric fluids into the system 800 resulting in the subsequent digestion of the internal erodible membrane 812. In the embodiment shown, the external dispersive acid barrier is absent; in other embodiments, it is optional as an adjunct or alternative to the function of the internal dispersive acid barrier 816. The existence of an external dispersive acid barrier and its relationship to an internal dispersive acid barrier is illustrated in other figures.

[0113] Alternative mechanisms are available for creating dispersive acid barriers, including gaseous mechanical barriers, for use with the orally ingestible delivery systems described herein; non-limiting examples are provided herein to illustrate useful mechanisms. As an example, an emulsion containing a bicarbonate solution can be sprayed or otherwise placed on the surface of an acid-resistant shell (e.g., an acid-resistant protease digestible membrane) during its manufacture under conditions that evaporate the water in the bicarbonate solution, thereby discharging bicarbonate crystals embedded in the emulsion layer onto the surface of the acid-resistant shell. Upon contact with gastric acid, the bicarbonate crystals can then react to form carbon dioxide, which can become present within indentations or irregularities on the acid-resistant shell surface, thereby creating an external dispersive acid barrier. As another example, holes can be punched in the hydrophobic layer by mechanical means (e.g., needles, pins, etc.), resulting in a non-intersecting system of holes, channels, indentations, etc. In embodiments, the pores may have bicarbonate disposed therein, for example, by immersing the layer in a bicarbonate solution and allowing the solvent to dry. Additional mechanisms for forming a gas-dispersible acid barrier may be envisioned by one skilled in the art.

[0114] As previously described, a barrier-forming material, such as a gas forming material 822, may be disposed within, beneath, or on top of another erodible layer 814. The barrier-forming material in such a layer may react upon encounter with gastric or intestinal fluid to form or be added to an internal dispersible acid barrier 816.

[0115] As mentioned above, in embodiments, the barrier-forming material described herein may include a space-occupying solid or fluid instead of or in addition to a gas generating material. FIG. 9 shows an exemplary embodiment. In FIG. 9, an orally ingestible delivery system 900 includes an acid-resistant shell 908 (e.g., an acid-resistant protease digestible membrane) and a therapeutic agent compartment 902. As previously described, the structure for the acid-resistant shell 908 may include a single layer structure, a two-layer structure, or a multi-layer structure. In the embodiment shown, there is an inner erodible layer 914 disposed within the acid-resistant shell 908 and surrounding the therapeutic agent compartment 902, similar to those configurations previously disclosed; if the inner erodible layer 914 is protease digestible, its combination with the acid-resistant shell 908 forms an acid-resistant protease digestible membrane. The acid-resistant shell 908 is perforated by a system of holes 912 within which is a space-occupying fluid, shown generally as individual fluid droplets 920 and as a confluent layer (which may be formed of united fluid droplets) of space-occupying fluid 924 that may block the holes 912. The space-occupying fluid droplets 920 and / or layer 924 within the holes 912 provide a mechanical barrier to the ingress of gastric fluid, thus forming an internal or inner dispersive acid barrier, shown generally as 916. While the embodiment shown lacks a fully formed external dispersive acid barrier, in other embodiments such a barrier may be formed, for example, when there is a confluence of space-occupying fluid on the surface of the external acid-resistant layer 918; such a partial confluence is illustrated generally as 928. In the embodiment shown, the presence of a partially confluent external acid-resistant layer 928 may be sufficient to provide an adequate barrier to the ingress of gastric fluid. In the embodiment shown, the space-occupying fluid only partially fills the holes 912, but is sufficient to block the ingress of gastric fluid. In other embodiments, the space-occupying fluid may fill the holes completely, or to any level sufficient to provide a partial or complete mechanical blockage to the ingress of external gastric fluids. Although the holes 912 in the embodiment shown are shown as convoluted and intersecting, it is understood that the holes 912 may be configured in any arrangement that allows for eventual access of external digestive fluids (whether from the stomach or intestines) to the therapeutic agent compartment 902, as previously described.For example, the pores may be straight, curved, branched, intersecting, networked, lattice-like, or any other shape or configuration, and the pore network may include blind pockets or closed channels that are wholly or partially unconnected with the rest of the network.

[0116] In one embodiment, the pores 912 may be filled, in whole or in part, with a liquid that is resistant to the action of stomach acid, such as a non-polar edible oil. In an embodiment, an optional protective layer (not shown) may be placed on the exterior surface of the orally ingestible delivery system 900, which encases the entire system prior to ingestion and retains the space-occupying fluid within the system of pores 912; the protective layer is intended to be sacrificial, i.e., dissolves in whole or in part upon encounter with stomach fluid. Thus, when the orally ingestible delivery system 900 enters the stomach, the exterior coating may dissolve rapidly, exposing the surface of the acid-resistant shell 908 (e.g., an acid-resistant protease digestible membrane) and the openings of the pores 912 within which the space-occupying fluids 920 and 924 reside. However, within the stomach, the space-occupying fluids 920 and 924 remain substantially within the pores 912 due to surface tension factors and / or polarity differences between the stomach contents and the liquid within the channels. The fluid within the pores provides a barrier preventing the ingress of gastric fluids and their access to any internal erodible layer 914, thus forming an internal dispersive acid barrier, shown diagrammatically as 916. In some embodiments, the space-occupying fluid within the channels may extravasate to form a layer of fluid 928 on the surface of the acid-resistant shell 908. This external fluid extravasation 928 may remain located around the external opening of the pores as shown, or may partially or completely merge to form an external dispersive acid barrier (not shown) that may supplement the protection provided by the internal dispersive acid barrier 916.

[0117] Dispersal of the external dispersive acid barrier (shown in this figure with only a partial confluence 928 overlapping the pores) and the internal dispersive acid barrier 916 occurs when the orally ingestible delivery system 900 enters the duodenum and encounters bile salts and lipases therein. In embodiments, when the space-occupying fluid within the pores 912 (and optionally on the surface 928) encounters bile salts and lipases, the fluid itself may be digested and / or emulsified. An advantageous feature of certain space-occupying fluids is their susceptibility to emulsification and / or digestion by the bile salts and lipases found in the duodenum; these agents may act on the fluid to emulsify it or digest it to form smaller droplets, allowing for the dispersion of the fluid and the resulting dispersive acid barrier that the fluid forms. More specifically, once the orally ingestible delivery system 900 enters the duodenum and is exposed to a more neutral pH environment containing lipases and bile salts, the liquid within the pores 912 is emulsified into droplets and removed from the pores 912. Due to dispersion of the space occupying fluid, the mechanical barrier dissipates and proteases within the duodenal fluid have direct access through the pores to the therapeutic agent compartment 902, either immediately after or after digestion of any internal erodible layer 914. Additionally, duodenal proteases have access to the matrix of the acid resistant shell 908 from the inside of the system of pores 912 and from the outer surface of the acid resistant shell 908. This internal access provides a significantly larger exposed surface area for the action of the internal proteases, thereby facilitating the breakdown of the protease-sensitive acid resistant shell 908 and the subsequent release of the therapeutic agent from the therapeutic agent compartment 902.

[0118] In embodiments, the surfactant may be preloaded into the liquid phase when the internal dispersible acid barrier 916 is prepared. In other embodiments, the liquid surfactant may be spread on top of the internal erodible layer 914 or on the undersurface of the acid resistant shell 908 (e.g., acid resistant protease digestible membrane) or both. The surfactant may be added to either the acid resistant shell or the internal erodible layer as they are shown in this FIG. 9 or other figures, it being understood that the surfactant may improve adhesion between these layers. The surfactant may be used in powder or liquid form. They may be applied in any manner well known to those skilled in the art, for example, by stirring into the molten phase of the layer while the layer is being formed, or by spraying or spreading onto the formed sheet. Advantageously, the surfactants used for these purposes may be pH sensitive, so that they are active at the pH of the duodenum and not at the pH of the stomach, thereby preventing them from contributing to the emulsification of the internal dispersible acid barrier 916 in the stomach.

[0119] Examples of useful surfactants include zwitterionic or amphoteric surfactants, such as betaines, or those with phosphate anions with amines or ammonium, such as the phospholipids phosphatidylserine, phosphatidylcholine, and sphingomyelin. If the surfactants in the internal dispersive acid barrier 916 can be protected from exposure to stomach pH, ​​any surfactant can be used, independent of its pH sensitivity, such as high HLB surfactants that can form water-in-oil emulsions, such as proteins, phospholipids, potassium and sodium salts, alginates, diacetyl tartaric acid esters of monoglycerides, lecithin, ethoxylated monoglycerides, etc. Mixtures or combinations of surfactants can be used advantageously, and different surfactants can be used in different layers. For example, if charged surfactants are used, anionic surfactants can be used in one layer and cationic surfactants can be used in the other layer.

[0120] In embodiments, the space-occupying fluid can be delivered directly to the pores 912 by mechanisms known in the art, such as forming pores in the acid-resistant shell 908 (e.g., an acid-resistant protease digestible membrane) and then immersing the membrane in the space-occupying fluid under sufficient pressure that the fluid enters the pores and replaces whatever the pores previously contained. For example, a less dense fluid can be placed in the pores first, and then this fluid can be replaced with a more dense oil-based fluid, which constitutes the space-occupying fluid in the final system when the therapeutic agent is surrounded by the acid-resistant shell 908. Alternatively, the acid-resistant shell 908 matrix and / or its pores can be loaded with a gas-forming substance, such as sodium bicarbonate, which can be previously removed by exposure to a weak acid, e.g., citric acid or acetic acid; in other embodiments, a salt or sugar can be introduced into the pores and dissolved by water. In these circumstances, the remaining gas or water can be centrifuged away, leaving behind empty channels (i.e., pores 912) through which the oil-based fluid can be delivered. In other embodiments, the space-occupying fluid can be injected into intact acid-resistant shell 908, thereby forming pores 912 and simultaneously introducing the space-occupying fluid.

[0121] An optional sacrificial top coating (not shown) may be placed on the exterior of the acid-resistant shell 908, initially restraining fluid within the pores 912 and protecting the entire system 900 from mechanical trauma. This outermost layer may be any protease-digestible or acid-digestible material that may erode in the stomach so that space-occupying fluid is initially restrained within the pores 912, but then exposed to the environment such that the outermost layer itself becomes sacrificial. In other embodiments, an optional non-sacrificial coating may be placed on the exterior of the acid-resistant shell 908, partially protecting the entire system 900 from exposure to gastric fluids, but which is susceptible to digestion in the duodenum: such a non-sacrificial coating may be pH-sensitive, so that, for example, it retains its integrity in an acidic environment such as the stomach, but is digested or dissolved in the neutral or basic environment of the intestinal tract.

[0122] Space-occupying fluids useful for forming the internal dispersive acid barrier 916 are those that are resistant to gastric fluids (acids and / or proteases in an acidic environment) but are susceptible to the activity of digestive substances found more distally in the intestine (e.g., bile salts, lipases, proteases, all located in a neutral or basic environment) or are pH-sensitive such that their integrity is affected by the pH in the intestinal tract.

[0123] Advantageously, the space-occupying fluid is a non-polar material such as edible oils that can be easily emulsified and separated from stomach acid. By way of example, materials such as triglycerides, fatty acids and esters derived from vegetable oils or vegetable materials are useful as space-occupying fluids. In embodiments, medium chain fatty acids are desirable. Exemplary edible oils that contain medium chain fatty acids include coconut oil, MCT oil, palm kernel oil, bay leaf oil and other oils that contain caproic acid, caprylic acid, capric acid or lauric acid. Useful materials also include triglycerides and esters produced from edible oils, such as caprylic and capric acid ester products, such as CAPTEX® products, NEOBEE® products, MIGLYOL® products, and the like. Other edible oils containing long-chain or short-chain fatty acids, 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, hemp seed oil, Also usable may be used are eel kernel oil, jambu oil, graviola oil, tucuma oil, brazil nut oil, carapa oil, buriti oil, passion fruit oil, prakashi 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 oils from fish such as herring, sardines, tuna, anchovy, mackerel and salmon, for example. In embodiments, the space-occupying fluid may itself contain a therapeutic agent that is released by dispersion of the fluid in the intestine.

[0124] In embodiments, the space-occupying fluid can be introduced into the pores as a liquid, as described above. In other embodiments, the space-occupying fluid is a fat or oil that is heat-sensitive, so that it is liquid when introduced into the pores, but solidifies when the system is cooled; such materials can be solid at room temperature, e.g., can re-liquidize at body temperature, or can solidify when cooled and remain solid at body temperature. Such materials are hybrid space occupants that are liquid at certain temperatures and solid at other temperatures, providing mechanical protection in either case.

[0125] In embodiments, the space-occupying fluid may be introduced into the pores by encapsulation. The fluid, which may be a non-polar material as described above, may be introduced into the pores encapsulated in a microcapsule, the microcapsule being dimensionally adapted to fit within the pore. The microcapsule may be of any size to fit within the pore, for example, ranging in size from about 0.3 microns to about 10 microns in diameter.

[0126] A representative embodiment is shown in Figure 10. As shown in this figure, an orally ingestible delivery system 1000 includes an acid-resistant shell 1008 (e.g., an acid-resistant protease digestible membrane) and a therapeutic agent compartment 1002 similar to those previously described. As previously described, the structure for the acid-resistant shell 1008 can include a single layer structure or a multi-layer structure. In the embodiment shown, there is an optional inner erodible layer 1014 disposed inside the acid-resistant shell 1008 and surrounding the therapeutic agent compartment 1002, similar to those configurations previously disclosed. As shown in the previous figures, if the inner erodible layer 1014 is protease digestible, its combination with the acid-resistant shell 1008 forms an acid-resistant protease digestible membrane. A system of pores 1012 is dispersed throughout the outer acid-resistant layer. As shown in the figure, to the left of the dotted line A-A', the system of pores is loaded with a plurality of microcapsules 1026. This section of the figure shows the state of the dispersive acid barrier of the system when the orally ingestible delivery system 1000 is first ingested. As shown in FIG. 10, the sacrificial coating 1030 covers the exterior surface of the orally ingestible delivery system 1000 to the left of the dotted line A-A'; as shown, the sacrificial coating 1030 may protect the microcapsules 1026 prior to entering the stomach, e.g., during storage conditions, and / or may initially protect the microcapsules 1026 from initial exposure to gastric fluid upon entry into the stomach. As previously described, gastric fluid may erode the sacrificial coating 1030, thereby exposing the microcapsules 1026 to acids and proteases in the stomach. The walls of the microcapsules 1026 may be formed of a material such as gelatin that may be eroded by acids and / or proteases in the stomach, thereby releasing the contents of the microcapsule into the space-occupying fluid 1024 or 1020. This situation is illustrated to the right of dotted line A-A', where when the sacrificial coating is eroded and some of the microcapsules 1026 are ruptured, their fluid contents are released as a combined fluid layer 1024 and / or fluid bubbles 1020 within the pore system.As shown to the right of the dotted line A-A', some of the confluent fluid layer 1024 has extravasated from the pores 1012 and is present on the surface of the orally ingestible delivery system 1000; this extravasated material 1028 may remain disposed over the pore openings or may become confluent itself, thereby forming an external dispersive acid barrier that supplements or replaces the internal dispersive acid barrier formed by the space-occupying fluid. In other embodiments, the sacrificial coating 1030 may be non-sacrificial, as described above, and is intended to remain at least partially intact until the orally ingestible delivery system reaches the intestinal tract. In still other embodiments, the sacrificial coating 1030 is optional; in these cases, the microcapsules 1026 are disposed within the system of pores 1012, so that when the system enters the stomach, they will substantially remain within the pores 1012 and dissolve in the stomach, releasing their contents in the form of gas or liquid within the pores during the passage of the device through the stomach and / or in the intestine. In embodiments, the microcapsules 1026 are packed sufficiently tightly that they form a mechanical barrier themselves: these structures thus act as space-occupying solids until they dissolve and release their fluid contents.

[0127] The microcapsules 1026 illustrated in Figure 10 are one example of a space-occupying solid that can form a mechanical barrier within the pores to prevent the ingress of gastric fluids. Other space-occupying solids can perform the same function, as shown below in Figure 11.

[0128] 11 shows an embodiment of an orally ingestible delivery system 1100 in which a space-occupying solid 1132 (whether of fluid or non-fluid formation) is disposed within the pores, which are shown to replenish a confluent fluid layer 1124 formed from a space-occupying fluid (whether gas or liquid), as described above. The embodiment shown is similar to that previously described, covering a therapeutic agent compartment 1102, having an acid-resistant shell 1118, perforated by a system of pores 1112, and showing an acid-resistant shell 1108 (e.g., an acid-resistant protease digestible membrane), which system of pores may allow passage of fluid from the external environment through the outer acid-resistant layer 1118 to contact any inner erodible layer 1114. As described for the previous figures, if the inner erodible layer 1114 is protease digestible, its combination with the acid-resistant shell 1108 forms an acid-resistant protease digestible membrane. The confluent fluid layer 1124 (whether gas or liquid) and any free floating fluid bubbles 1120 (whether gas or liquid) of sufficient size to occlude the pores may themselves form an internal dispersive acid barrier 1116, as previously described. Additionally, the confluent fluid layer 1124 may escape the pores 1112 to form a further partial or complete external dispersive acid barrier 1128. However, in the embodiment shown, the mechanical protection provided by the confluent fluid layer 1124 and free floating fluid bubbles 1120 may be supplemented or even replaced by a mechanical barrier provided by the space occupying solids 1132. Additionally, an external coating (not shown) around the system 1100 may be either a sacrificial or non-sacrificial coating, providing excess protection to the entire system 1100, including the contents of the pores 1112.

[0129] As shown in this figure, the space-occupying solids 1132 are packed within some or all of the exterior portions of the holes 1112; also shown in this figure, the space-occupying solids 1132 work with the space-occupying fluid within the holes 1112, as represented by the confluent fluid layers 1124 and any occluding fluid bubbles 1120. In other embodiments, the space-occupying solids 1132 may occupy a greater portion or substantially all of the volume within the holes 1112 to provide the majority of the mechanical protection against gastric fluid. In embodiments, the space-occupying solids 1132 simply occupy space, thus deflecting the ingress of gastric fluid. In other embodiments, the space-occupying solids may form a space-occupying fluid (either liquid or gas) when they react with acids or proteases in the gastric fluid. For example, the space-occupying solids 1132 may be bicarbonate particles that produce carbon dioxide gas upon exposure to gastric acid, a phenomenon previously described in detail. Or, as described above with respect to Figure 10, the space-occupying solids 1132 may be microcapsules that contain a space-occupying fluid that is released when the microcapsule wall is digested by stomach fluid. For these space-occupying solids 1132 that react with acids and / or proteases in the stomach or with intestinal enzymes, they may form a two-phase barrier system that includes a first space-occupying fluid and a second space-occupying fluid; in embodiments, the first space-occupying fluid may provide protection during passage through the stomach, while the second space-occupying fluid may provide protection during passage through a portion of the intestinal tract. The composition of this two-phase barrier system may be tailored to optimize the ultimate uptake of the therapeutic agent in the intestinal tract.

[0130] As an example of a space-occupying solid 1132, solid particles may be used in powder form to fully or partially fill the pores, with the selected material being insoluble or minimally soluble in a highly acidic environment, such as the stomach, while being more soluble at neutral or higher pH, such as the 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 a neutral to alkaline pH environment rich in emulsifying bile salts, such as in 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, and docosahexaenoic acid.

[0131] 4. Orally ingestible delivery systems: Method for producing acid-resistant shell structures A variety of manufacturing techniques are available for forming the acid-resistant shells (e.g., acid-resistant protease digestible membranes) described herein. These manufacturing techniques are illustrated with reference to those embodiments that use a gas-generating material as the barrier-forming material, where the gas-generating material forms a gas upon exposure to gastric acid. However, it is understood that many of these manufacturing techniques can be applied to those systems that use space-occupying fluids or solids to create the dispersible acid barriers disclosed herein. The manufacturing techniques described below can be modified by those skilled in the art to include the use of space-occupying fluids and solids with the use of no more than routine experimentation.

[0132] In an exemplary embodiment, an aqueous phase including water, bicarbonate, and xanthan gum can be emulsified in a waxy layer including unrefined beeswax and polyisobutylene, and the emulsion can be used to form a porous acid-resistant shell. The amount of polyisobutylene can be selected to provide the layer with the desired flexibility and integrity, for example, an amount ranging from about 0.5% to about 5%. In one embodiment, the emulsion can include about 1% polyisobutylene. Additives such as fibers can be included in the emulsion to improve its structural strength.

[0133] In particular, in the embodiment in which the gas-generating substance is disposed in the matrix of the membrane, fibrous additives such as xanthan can contribute to the formation of elongated channels in the membrane, and these channels can be sufficiently extended and intertwined to allow the entry of gastric acid; when gastric acid encounters the gas-generating substance disposed in the membrane, it activates these substances to occupy the channel and produce gas that spreads through the channel, as previously described.In the embodiment, edible proteins or hydrocolloids can contribute to the formation of elongated channels.In the embodiment, edible proteins such as whey protein, soy protein, or natural or partially hydrolyzed collagen can contribute to the formation of elongated channels.

[0134] As an alternative approach to chemically forming channels or pores in the presence of a gas generator, dedicated gas formers can be added to the semi-solid matrix so that they produce gas that forms channels through the semi-solid matrix and the channels are integrated in the matrix when it solidifies to form a porous acid-resistant layer; a second set of gas generators can be dispersed through the matrix separately or as part of the same process, where this second set of gas generators is intended to be activated upon contact with gastric acid. The dedicated gas formers that create channels in the semi-solid matrix can operate by chemical reactions or other mechanisms that allow them to produce gas bubbles that are ultimately immobilized within the semi-solid matrix and form channels or pores within the matrix.

[0135] In embodiments, channels or pores can be formed structurally in the acid-resistant matrix, i.e., by designing the arrangement of the matrix itself so that the matrix contains channels or pores. For example, the layer can be formed as a porous lattice of waxy material using techniques for lattice construction well known in the art. As an exemplary approach, channels or pores can be included in the layer when the layer is made as a regular or irregular network structure. The layer can include a pattern of thinner sublayers, for example, overlying each other, each sublayer having matrix material and hollows arranged in a regular or irregular pattern, or, for example, a tangle of protruding solid or semi-solid matrix underlying such that interstitial hollows exist. Other arrangements for creating channels or pores in the layer or designing the layer so that the layer contains channels or pores can be envisioned by those skilled in the art. In embodiments, a monolayer acid-resistant shell can be formed in which a waxy layer intertwines with a gel layer, and a gas-forming substance arranged throughout the layer allows gas to form to permeate the surface and form a dispersive acid barrier.

[0136] When more than one set of gas-forming substances are used, all of them can be dispersed in the acid-resistant shell so that a layer is formed. In an embodiment in which a waxy layer forms the matrix for the acid-resistant shell, an emulsion can be formed in the waxy substance by mixing in a concentrated aqueous solution of bicarbonate; the emulsion (including the waxy phase and the aqueous phase) can then be used to form an acid-resistant shell that is wrapped around or applied to a free form, such as an internal protease digestible layer. In an embodiment, the emulsion can be applied to a gelatin capsule using standard techniques (dipping, spraying, etc.), where the capsule wall serves as an internal erodible layer for the device. Using this technique, the water in the aqueous phase of the emulsion can evaporate, leaving behind bicarbonate crystals as a deposit of gas-forming substances in the matrix. As previously described, these crystals can form carbon dioxide by reacting with hydrochloric acid in the stomach, which enters the waxy matrix and accesses the crystals through a system of channels or pores in the layer.

[0137] In embodiments, the gas generating material or space occupying fluid may be contained in a separate layer beneath the acid resistant shell, which is accessed by gastric acid passing through a system of channels or pores in the acid resistant shell. Such a layer, whether formed as part of the device or as a layer around the therapeutic agent, may include a gas generating material contained within a matrix such as gelatin, sprayed onto the surface of the therapeutic agent, or otherwise disposed between the acid resistant shell and an inner erodible layer. The layer of space occupying fluid beneath the waxy layer may be coated with a sacrificial coating that is eroded by gastric acid or enzymes, releasing the space occupying fluid into the pores to expel gastric acid. Other arrangements of gas generating material, space occupying fluid, or both, may be envisioned by those skilled in the art.

[0138] If the waxy material requires a protective construct, additional polymers can be added to the waxy matrix when the emulsion is formed. For example, a small amount of a rubbery hydrophobic polymer, such as polyisobutylene, can be added to increase structural stability and integrity. Other polymers, such as polyethylene, polyisobutylene, polyvinyl acetate, alone or in combination, can also be added to the waxy matrix to improve its mechanical properties. For example, xanthan gum or other hydrophilic polymers can be added to the waxy material to promote the diffusion of the aqueous phase in the wax, thereby facilitating the formation of a pore system. In embodiments, additives to waxy substances may include cellulose derivatives (e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose) and other hydrocolloids (pectin, pullulan, guar gum, xanthan gum, gum arabic, acacia gum, carrageenan, alginates, chitin, chitosan, starch, soy protein, whey protein, collagen and gelatin), polypeptides, polyvinyl alcohol, polysaccharides and derivatives, hyaluronic acid, poloxamer, PEG, poly(N-vinylpyrrolidone); small molecules such as mono- and oligosaccharides, water soluble salts, glycerol and edible surfactants (e.g., lauric arginate).

[0139] In embodiments, fibers can be added to the acid-resistant shell to improve strength, elasticity, or durability. Any type of fiber can be used, but edible fibers, such as certain plant-derived fibers, are particularly advantageous because the acid-resistant shell and any fibers it contains are ingested and digested. Notwithstanding the above, inorganic fibers can be used if suitable for use in nutritional and / or pharmaceutical products. Suitable plant fibers can include, for example, fibers from the membrane or phloem around the stem of a plant or from the fruit of a plant (e.g., banana fiber, coconut fiber, soybean fiber, etc.) or fibers from leaves or petioles (e.g., wheat, rice, barley, grass, etc.). The fibers can be mixed with a waxy matrix and then an aqueous phase is emulsified therein, or the fibers can be used to build a reinforcing or supporting structure to which the waxy matrix (with or without an included aqueous phase) can be applied. In yet other embodiments, a structure for holes can be patterned with digestible material that is scattered throughout the acid-resistant shell when it is formed, and a membrane is placed on the therapeutic compartment or the therapeutic itself.

[0140] In embodiments, a waxy matrix material may be applied to a preformed lattice, where the lattice is formed from a stiffer wax, polymeric network, or fiber. In embodiments, the lattice may be formed from defibrillated fibers coated with wax, fat, or fatty acid, and the lattice is then coated with a waxy matrix for an acid-resistant shell. Gas-forming substances and / or space-occupying fluids or solids may be included in the waxy matrix applied to the lattice, or such substances may be included in an undercoat to which gastric acid may reach via pores or channels present in the coated lattice.

[0141] In embodiments, the barrier-forming material (whether gas-generating material and / or space-occupying material) can be present in the interstices of the lattice, placed there before the lattice is coated with wax, after the lattice is coated with wax, or both. For example, the lattice can be formed first and then coated with the wax-in-water emulsion described previously, where the aqueous phase of the emulsion contains a concentrated aqueous solution of bicarbonate; when the water evaporates, the bicarbonate remains where the emulsion takes it, for example, in the valleys and hollows of the lattice structure. In other embodiments, the pH-sensitive material, for example, the gas-generating material, can be attached to the fibers in the matrix, so that when the fibers are digested by stomach acid, the acid also contains and activates the gas-generating material, so that gas or fluid fills the pores and reaches the surface of the acid-resistant shell as a dispersive acid barrier. In embodiments, the fibers can be coated with or permeated by the barrier-forming material, for example, the barrier-forming material is attached to or embedded in the fibers. In embodiments, to contain the barrier-forming material in the fibers, the fibers can be co-extruded with the barrier-forming material material. In other embodiments, as discussed above, the barrier-forming material may enter the fibers in solution and then crystallize as the fibers dry.

[0142] In embodiments, the acid-resistant shell may be formed separately, for example using the emulsion techniques described above, and allowed to solidify. A solid or semi-solid layer may then be cast around the inner erodible layer, or it may be cast around a therapeutic agent already enclosed within an erodible layer (e.g., a gel capsule). In a two-layer system, the acid-resistant shell may be formed from a material that is resistant to both acid and proteases, for example, a wax. The inner layer may be formed from a material that is digestible by proteases, for example, a gelatin capsule. The inner layer may be intrinsic to the orally ingestible delivery system itself, for example, as shown in Figures 5 and 6, or the inner layer may be intrinsic to the dosage form of the therapeutic agent present within the therapeutic agent compartment, as described below with respect to Figure 10. It is further understood that in a two-layer or multi-layer system, the gas generating agent may be disposed within both the inner erodible layer and the acid-resistant shell.

[0143] In embodiments, a layer of fibers carrying a barrier-forming substance can be used without a waxy matrix to provide an acid-resistant shell. For example, insoluble fibers such as corn husks or other vegetable materials can be used to form a mesh or web-like layer in which the barrier-forming substance is suspended, attached or otherwise disposed. In such layers, the barrier-forming substance can be disposed within certain fibers that are soluble, so that the barrier-forming substance is released from the fibers when the fibers are dissolved. In embodiments, adhesive materials attach the barrier-forming substance to soluble or insoluble fibers, while in other embodiments; various edible adhesives are available, or materials such as waxes can be used to coat the fibers and trap the barrier-forming substance in their vicinity. These coated fibers can then be used to form an acid-resistant shell, apart from any other waxy matrix. To create mesh or web-like fibers to provide an acid-resistant shell, the fibers can be entangled using any commercially available technique, such as weaving, extrusion, air-laying, spin melting, etc. Advantageously, an outer coating may be applied over the acid-resistant shell to provide structural stability and to initially protect the acid-resistant shell from the influx of gastric fluids. Advantageously, an inner erodible layer may be provided, with or without itself being embedded in a barrier-forming material, to allow fine tuning of therapeutic release.

[0144] For those systems that use space-occupying solids or fluids as barrier-forming materials, similar techniques can be used to disperse the barrier-forming materials within the matrix of the acid-resistant shell, instead of or in addition to dispersing them within the pores. As an example, an internal erodible layer can be formed on top of the therapeutic agent, or can be provided by a third party as an encapsulated therapeutic agent, for example, a gel capsule containing the therapeutic agent. To develop a system of empty pores within the layer, the therapeutic agent-forming element can then be coated with a layer of beeswax and polyisobutylene in which a material that can be removed and may be soluble is suspended. For example, sodium bicarbonate crystals can be suspended within the waxy layer and removed by exposing the layer to acid, which converts the bicarbonate to carbon dioxide. Carbon dioxide bubbles can be expelled from the waxy layer by agitation, leaving behind empty channels or pores. These channels can be filled with space-occupying fluids or solids by dipping, spraying, pouring, or other techniques known in the art. Once the channels are appropriately filled with space-occupying fluids and / or solids, these materials create a barrier that can protect the device from gastric fluids when the device is ingested, as previously described.

[0145] 5. Ingestible Delivery Systems: Coatings and Further Layers As will be appreciated by those skilled in the art, the rate of acid penetration and / or degradation time of the acid-resistant shell (e.g., an acid-resistant protease digestible membrane) can be tailored to suit the desired delivery profile for the therapeutic agent, for example, by increasing the thickness of the outer acid-resistant layer or including additives in the outer acid-resistant layer to improve acid resistance, reduce flaking tendency, or change adhesion to the underlying erodible layer. Additionally, inner layers, such as inner erodible, e.g., protease digestible layers, can be formulated to include agents that retard their digestion when exposed to proteases, thereby protecting and retarding the release of the therapeutic agent contained in the therapeutic agent compartment. For example, if the inner erodible layer is formed of gelatin, a retarding agent can be formulated within the gelatin itself, and the therapeutic agent can be surrounded by such a specially formulated gelatin layer.

[0146] In other embodiments, a layer comprising a barrier-forming material may be provided beneath or within the acid-resistant shell, so that gastric fluid penetrating the acid-resistant shell has access to the barrier-forming material disposed therein. Such a protective layer may be applied to an internal erodible layer, such as a gelatin layer, or may be applied to the underside of the acid-resistant shell as a layer in its own right. In the latter situation, the acid-resistant shell and the protective layer comprising a barrier-forming material may be applied to another gelatin capsule or other forming element provided by a third party, where the other forming element may comprise a therapeutic agent or deliverable therapeutic agent.

[0147] In embodiments, an acid-resistant shell (e.g., an acid-resistant protease digestible membrane) may be constructed to allow passage of gastric fluids, but the fluids encounter a barrier-forming material within a protective layer. An exemplary embodiment is shown in FIG. 12. FIG. 12 shows a cross-section of an embodiment of an ingestible delivery system 1200 showing an acid-resistant shell 1208 penetrated by a system of holes 1212, shown parallel and substantially similar in size, created, for example, by piercing a matrix 1218 of the acid-resistant shell 1208 with multiple collinear microneedles. It is understood that the system of holes 1212 may be straight, curved, serpentine, separated, intersecting, or non-intersecting, as previously described. In the embodiment shown, the system of holes 1212 may be empty or filled with either barrier-forming or non-barrier-forming fluid or solid material. As shown, the holes are of different lengths and they penetrate the matrix 1218 to different depths, although it is understood that the holes can be of similar lengths with similar degrees of matrix penetration. Some or all of the holes can completely penetrate the acid resistant shell. As shown, a plurality of barrier-forming materials 1202 can be disposed beneath the acid resistant shell 1208 such that gastric fluid (not shown) entering the system of holes 1212 can access some or all of the barrier-forming materials 1202 and activate them, e.g., release gas bubbles 1204 that can enter the system of holes 1212 and block the holes to prevent further ingress of gastric fluid. In the embodiment shown, a further optional protective layer 1210 is illustrated on the undersurface of the acid resistant shell 1208, between the acid resistant shell 1208 and the therapeutic agent chamber 1206. As shown, the barrier-forming material 1202 may be disposed on top of and within the protective layer 1210, as shown to the left of dotted line A-A' (section 1); or simply within the protective layer 1210, as shown to the right of dotted line A-A' and to the left of dotted line B-B' (section 2); or underneath the protective layer 1210, as shown to the right of dotted line B-B' and to the left of dotted line C-C' (section 3); or on top of the protective layer 1210, as shown to the right of dotted line C-C' (section 4).If the protective layer 1210 is formed of an internally erodible, e.g., acid hydrolyzable and / or protease digestible material such as gelatin, it may be eroded by gastric fluid reaching it through the system of pores 1212, as shown diagrammatically at 1214. The combination of the acid resistant shell 1208 and the protease digestible protective layer 1210 forms an acid resistant protease digestible membrane. If acid or proteases digest the protective layer 1210 overlying the barrier-forming material 1202, these materials may be released or activated to enter the system of pores 1212 and provide protection against the further effects of gastric fluid that would otherwise enter the system of pores 1212.

[0148] In embodiments, protective layer 1210 is formed of an acid hydrolyzable and / or protease digestible material, such as gelatin. However, protective layer 1210 may be formed of any biocompatible material. For example, in embodiments, protective layer 1210 is an erodible layer that is not necessarily acid hydrolyzable and / or protease digestible, but rather is made of a material or materials selected to optimize release of the therapeutic agent in the appropriate section of the gastrointestinal tract. Although the placement of barrier-forming material 1202 is illustrated in this figure with respect to protective layer 1210, it will be understood that protective layer 1210 is optional. In the absence of protective layer 1210, barrier-forming material 1202 may be disposed beneath acid-resistant shell 1208 (e.g., an acid-resistant protease digestible membrane) as a separate sheet, or barrier-forming material 1202 may be attached to the lower surface of acid-resistant shell matrix 1218, or barrier-forming material 1202 may be attached to therapeutic agent compartment 1206 or integrated with a deliverable therapeutic agent (not shown). In other embodiments, not shown in this figure, a sheet or protective layer comprising a barrier-forming material as described herein may be disposed within the acid-resistant shell matrix at any level: it does not have to be disposed beneath the acid-resistant shell matrix.

[0149] In an exemplary multi-layer design implementing the principles disclosed herein, an acid hydrolyzable and / or protease digestible capsule, such as a gelatin capsule, may encase a deliverable drug, and then the capsule may be coated with a layer of solids. The coating may be a suspension or solution containing solids that is sprayed onto the surface of the capsule, and / or the capsule may also be dipped or rolled into the coating. As previously described, the solids may be included in their own preformed layer, wrapped around the capsule, or fixed to the lower surface of the acid resistant shell, or sandwiched between two layers of the acid resistant shell. However, the solids within the layer that are placed may be gas-producing or non-gas-forming solids. They may be suspended in a liquid or gel vehicle that facilitates their application, such as a volatile liquid that is easily removed during the spraying process or a condensable or hardenable liquid that may solidify over time. A liquid alone may be used to suspend the solids, or other additives may be used to aid in the solidification of the layer, such as gelatin, shellac, corn starch, zein, pectin, etc. In an exemplary embodiment, calcium carbonate can be suspended in gelatin and the suspension is heated. While being heated, the suspension can be sprayed onto an underlying gelatin capsule and allowed to solidify over time, or the gelatin capsule can be immersed in the suspension. By these techniques, the particles of solid material are trapped and solidified within their own layer. Once this layer is applied to the gelatin capsule, a layer of wax can then be applied on top of it to create an acid-resistant shell. This acid-resistant shell can simply be formed of wax and a polymer such as polyisobutylene, which acts as a plasticizer. The wax layer is provided with holes through it, allowing gastric fluids to penetrate the wax layer and reach the layer containing the solids. Several mechanisms have already been described for forming such a wax layer. For example, wax can be sprayed to form a layer, a technique that creates a layer with micron-sized, integrated droplets or "pebbles".In this scenario, the spaces between the pebbles act as fluid permeable channels so that gastric fluids can pass through the channels to access the underlying solid layer. As an alternative mechanism, wax can be applied in a uniform sheet and then holes can be formed in the sheet. Mechanical means such as microneedles can be used to form holes in the sheet. Digestive fibers can be used to form holes, with gastric fluids eroding or interacting with the fibers to create holes or cuts in the wax layer. Other mechanisms for creating a system of holes in the acid resistant shell can be envisioned by those skilled in the art.

[0150] Besides the spraying or dipping techniques as described above, there are other high throughput manufacturing techniques that can be used to develop an ingestible delivery system according to the principles disclosed herein. For example, the entire ingestible delivery system can be formed of previously formed multi-layer sheets, or the ingestible delivery system can be formed of one or more separately formed sheets. For example, the acid hydrolyzable and / or protease digestible layer (e.g., gelatin) can be first formed by blade coating, extrusion, curtain coating, or other techniques well known to those skilled in the art. Blade coating is a process in which a uniformly thin film of liquid is continuously applied onto a surface by the use of a moving flattening device such as a blade that spreads the liquid evenly over the surface. Extrusion (e.g., hot melt extrusion) is a process in which heat and pressure are used to melt a material and force it through a slit or opening in a continuous process, allowing for the formation of products with uniform shape and density in a variety of shapes such as bags, spheres, films, sheets, tubes, fibers, foams, and pipes. Curtain coating creates a continuous sheet of fluid that falls onto a substrate created by a slit or die at the base of a holding tank that distributes the fluid as a sheet. One or more layers of an orally ingestible delivery system can be formed in this manner, and then the layers can be combined to form the entire orally ingestible delivery system. For example, a first acid hydrolyzable and / or protease digestible layer, such as gelatin, can be formed as a flat sheet, and then an acid resistant shell can be formed as another sheet. These two layers can be combined together to form a two-layer composite, with holes formed in the acid resistant shell as described above. Such a two-layer composite, when it includes an acid resistant shell layer and a protease digestible layer, forms an acid resistant protease digestible membrane. A barrier-forming material can be disposed within or under the acid resistant shell, as described above. Any of the techniques for forming such layers can be used for any or all of the layers of an orally ingestible delivery system, as will be understood by those skilled in the art.

[0151] As will be further understood by those skilled in the art, the degradation time of the acid-resistant shell can be further adjusted by adding a coating on top of or below the inner erodible layer, for example, a coating having delayed or extended release properties when exposed to gastric acid and / or proteases. Also, the acid-resistant shell itself can be coated with an additional sacrificial or non-sacrificial coating, for example, having delayed or extended release properties when exposed to gastric acid and / or proteases. Techniques for forming such layers are well known in the art and include the above-mentioned techniques of spraying, dipping, blade coating, extrusion, curtain coating, etc. For example, a conventional enteric coating can be added on top of the inner erodible layer (e.g., on top of a gelatin capsule) before placing an outer acid-resistant layer on top. The conventional enteric coating can be selected and formulated to be sufficiently resistant to conditions in the small intestine, thereby allowing the therapeutic agent enclosed in the therapeutic agent compartment delivered therein to reach the desired location in the small intestine or colon. In embodiments, the therapeutic agent itself may be covered by a coating intended to control release of the therapeutic agent in the intestine, instead of or in addition to other coating layers integrated into the orally ingestible delivery system, as previously described.

[0152] Although a wide range of conventional enteric coating formulations can be used, the orally ingestible delivery system allows for the selection of materials and thicknesses for the additional coating layer (whether added on top of the inner erodible layer or under the inner erodible coating layer) that are less robust than the materials or thicknesses used in conventional enteric coatings. This is because conventional enteric coatings require greater durability so that they can withstand the harsh conditions in the stomach, including acid and protease-induced hydrolysis. In contrast, the dispersible acid barrier of the orally ingestible delivery system disclosed herein protects the inner erodible layer from gastric fluids. Therefore, because of the additional protection provided by the dispersible acid barrier, there are lower performance requirements for the enteric coatings inserted in, on or under the differentially permeable (e.g., digestible) capsule system compared to conventional enteric coatings. Thus, in embodiments, enteric coatings that are considered rather "weak" in resisting acid and protease digestion can be used. In other embodiments, the inserted enteric coating can be specifically designed for the conditions in the intestine. For example, bile secretion releases abundant amounts of lipases and surfactants in addition to proteases. Thus, the modified release layer inserted can be a lipid-based formulation that is lipase digestible at neutral pH at the expected rate. Alternatively, a conventional enteric coating can be used, but thinner than the usual layer.

[0153] Enteric coatings and other specialized coatings may be applied directly to the therapeutic dosage form. Enteric coatings and other specialized coatings may alternatively or additionally be applied to the entire oral ingestible delivery system. Coatings applied to the entire system may be selected to improve the ingestibility of the system or to protect the system from mechanical trauma as it passes through the stomach. For example, confectioner's glaze or pharmaceutical glaze may provide a glossy finish and protective coating around the entire device. Such coatings are well known in the art of formulation. Such coatings may be formed from natural ingredients such as shellac (formed from insect excreta) and carnauba wax.

[0154] 6. Oral Delivery Systems: Therapeutic Modification As previously described, the therapeutic agent itself can be modified or otherwise formulated to cooperate and interact with the orally ingestible delivery system described herein.It is also understood that the therapeutic agent itself can be formulated with gas generating substances and / or space-occupying fluids or solids as part of the dosage form, or can be covered with a layer of such substances.For example, the dosage form in the therapeutic agent compartment can be sprayed with an additional layer of gas generating substances that are available for activation when they encounter stomach acid.

[0155] In embodiments, the therapeutic agent may be formulated as a therapeutic agent dosage form or deliverable therapeutic agent, including an overlying erodible layer, that allows it to be inserted into a differentially permeable (e.g., digestible) capsule system of an ingestible delivery system. This allows the therapeutic agent dosage form to be made by a party different from the manufacturer of the ingestible delivery system, so that the dosage form can be introduced into or coated with a differentially permeable capsule system to produce a complete ingestible delivery system. An embodiment of the configuration is shown in FIG.

[0156] 13, the orally ingestible delivery system 1300 may be formed as a single layer differentially permeable (e.g., digestible) capsule system 1304, here shown generally as including an acid resistant layer 1318 and having an internal dispersive acid barrier 1316, where the dotted lines enclose three representative gas bubbles or fluid droplets, each similar to the single gas bubble or fluid droplet 1320 shown within the hole 1312, representing the fact that the internal dispersive acid barrier 1316 may be formed of a single fluid bubble or droplet or a series of fluid bubbles or droplets or confluent layers of fluids. An optional external dispersive acid barrier 1310 is also shown, where the differentially permeable capsule system 1304 surrounds or encases the deliverable therapeutic agent 1302. Similar to other representations of differentially permeable capsule systems for use with ingestible delivery systems previously disclosed, the acid-resistant shell 1318 shown in this figure includes within its matrix a system of pores 1312 which contain a plurality of gas bubbles 1320 that have been produced by encounter of gastric acid with the gas generating substance. The ingestible delivery system 1300 shown in this figure is exposed to gastric acid during residence in the stomach. As a result, the gas generating substance (not shown) originally dispersed within the system of pores 1312 reacts in whole or in part with the gastric acid to produce gas bubbles 1320 within the system of pores 1312, thereby forming an inner dispersible acid barrier 1316 and, optionally, an outer dispersible acid barrier 1310.

[0157] More specifically, although internal dispersible acid barrier 1316 shows only three non-confluent gas bubbles in making up internal dispersible acid barrier 1316, it is understood that all of the variations of internal dispersible acid barriers, for example those illustrated in and further described in connection with FIG. 8, are encompassed in the schematic representation of internal dispersible acid barrier 1316 shown in this figure. Although gas bubbles 1320 in this figure are shown as separate bubbles, it is understood that gas bubbles 1320 may confluence and occupy some or substantially all of the space within the pores; this confluence is expected when gas is released from the gas generator and spreads within pores 1312. As shown in this figure, some unreacted gas generator 1322 remains within matrix 1324, while those gas generators previously contained within pore system 1312 have been activated by contact with stomach acid and gas bubbles 1320 are released into pores 1312. This figure shows gas bubbles 1320 acting as an internal dispersive acid barrier 1316, however, as previously illustrated, it is understood that space occupying fluids and / or solids may also act as internal dispersive acid barriers.

[0158] As shown in this figure, a differentially permeable (e.g., digestible) encapsulation system 1304 surrounds a deliverable therapeutic agent 1302, which may be provided separately. The differentially permeable encapsulation system 1304 provides an acid resistant layer 1318, as well as a dispersible acid barrier 1316 within the pores 1312 and optionally on the surface 1310. The deliverable therapeutic agent 1302 may then be provided by a third party to be enclosed within the differentially permeable encapsulation system 1304, thereby adapting the differentially permeable encapsulation system 1304 to the needs of the third party manufacturer(s) of the deliverable therapeutic agent 1302.

[0159] In embodiments, the deliverable therapeutic agent 1302 may include an erodible surrounding layer 1306 disposed entirely or partially around the therapeutic agent 1308 itself. While the figure refers to a single therapeutic agent 1308, it is understood that the deliverable therapeutic agent may include one or more of the same or different therapeutic agents. The differentially permeable (e.g., digestible) capsule system 1304 surrounding the deliverable therapeutic agent 1302 is designed to provide a layer of acid resistance by mechanisms described herein, whether by gas production as contemplated in this figure or by dispersion of space-occupying fluids or solids. However, once the protective barrier layer(s) provided by any external dispersive acid barrier 1310 and / or internal dispersive acid barrier 1316 disperse in the small intestine, the deliverable therapeutic agent 1302 contained in the differentially permeable capsule system 1304 may be exposed to attack from the contents of the intestinal fluids, including proteases.

[0160] The deliverable therapeutic agent 1302 may be formulated independently and in any advantageous manner to resist or respond to the effects of intestinal fluids. For example, in embodiments, an initial surrounding layer 1306 may be provided that may modify delivery of the therapeutic agent 1308 to the intestinal tract. In one embodiment, the surrounding layer 1306 may be erodible, e.g., protease digestible, which may result in fairly rapid release of the therapeutic agent 1308 in the small intestine if intestinal enzymes penetrate the overlying acid resistant layer 1318 and then the barrier disperses, as described above. In embodiments, an additional surrounding layer (not shown) for the therapeutic agent 1308 may be provided above or below the initial surrounding layer 1306 to better modify the release of the therapeutic agent 1308 in the small or large intestine. Such additional surrounding layers (not shown) may be added, for example, during formulation of the therapeutic agent 1308, to target delivery of the therapeutic agent 1308 to a specific location or to fine-tune its release profile. In embodiments, the surrounding layer 1306 may be minimal or entirely absent, and the therapeutic agent 1308 may be formulated as a tablet or caplet without another surrounding attached thereto (coated or uncoated). In embodiments, the deliverable therapeutic agent 1302 may include multiple individual therapeutic agent dosage forms that are entirely surrounded by a single surrounding layer 1306, e.g., an erodible surrounding layer such as a gelatin capsule, and the individual dosage forms may each itself be surrounded or covered by one or more coating layers that control their release, protect them from the environment, etc. In other embodiments, the deliverable therapeutic agent 1302 includes a single therapeutic agent dosage form that is optionally packaged with other substances that protect it, support it, modify its release, etc. For example, the deliverable therapeutic agent 1302, including probiotic organisms, may also include substances that support the living organisms, provide nutrients for them, or act synergistically with them as they reach their target destination in the small intestine or colon. In other embodiments, there can be multiple therapeutic agent deposits (not shown) distributed within acid-resistant layer 1318, with the various therapeutic agent deposits containing the same or different deliverable therapeutic agents.

[0161] 13 is suitable for use with a wide range of deliverable therapeutic agents 1302, which may also be provided by a third party for enclosure within the ingestible delivery system 1300. In embodiments, the differentially permeable (e.g., digestible) capsule system 1304 may be made separately from the deliverable therapeutic agent 1302, and the two components are combined together to secondarily form the entire ingestible delivery system 1300 for a particular deliverable agent. In embodiments, the same differentially permeable capsule system 1304 may be used for many deliverable therapeutic agents 1302, where the deliverable agent is manufactured, for example, by a pharmaceutical company, and therefore coated with or encased within the differentially permeable capsule system 1304. In embodiments, the differentially permeable capsule system 1304 is not customized for the deliverable therapeutic agent 1302; instead, customization is provided to the deliverable substance 1302 itself by a pharmaceutical manufacturer who formulates the therapeutic agent 1308 or drug as a dosage form and then coats or encases them within an erodible surrounding layer 1306, such as a gelatin capsule, for insertion into or surrounding by the differentially permeable capsule system 1304. The customization process for the deliverable therapeutic agent 1302 may include specialized formulations, additional layers, separate dosage forms, etc., to control the timing and location for delivery of the therapeutic agent(s) within the small or large intestine, followed by the programmed dissolution of the differentially permeable capsule system 1304.

[0162] In more detail, the deliverable therapeutic agent 1302 may be formed from a liquid, semi-solid, or solid form of therapeutic agent 1308 with an erodible surrounding layer 1306 as shown in FIG. 13. For example, a protease digestible glycerin capsule may be used to coat or encase the therapeutic agent 1308. Other layers may be used above or below the glycerin capsule to impart desired properties, such as coatings to improve strength or modify the timing or duration of release. In embodiments, an additional layer comprising a barrier-forming material may be applied above or below the glycerin capsule to supplement the barrier formation (e.g., gas formation or release of space-occupying fluid) performed within the acid-resistant layer 1318 or to provide a different layer of protection that affects the timing or extent of therapeutic agent release. The acid-resistant shell 1318 of the differentially permeable (e.g., digestible) capsule system 1304 may surround the deliverable therapeutic agent 1302, protecting the deliverable substance from the action of stomach acid, but allowing it to be released to a designated location in the intestine due to the formation of a barrier as described above. In embodiments, the differentially permeable capsule system 1304 and the deliverable therapeutic agent 1302 may be made separately and / or by different manufacturers, and the two components are subsequently brought together by the same manufacturer(s) or by yet another manufacturer that combines the two components to make a complete orally ingestible delivery system.

[0163] Although deliverable therapeutic agents are described above with emphasis on the integration of the active pharmaceutical agent in the delivery agent, it is understood that all variations of therapeutic agents are suitable for use with these systems and methods. The term "therapeutic agent" can include any substance (whether biological or non-biological) used for any therapeutic purpose, including but not limited to pharmaceuticals, nutraceuticals, diagnostic agents and medical devices, as defined and described in more detail below.

[0164] 7. Orally Ingestible Delivery Systems: Applications for Foods and Beverages Orally ingestible delivery systems that contain water-swellable, acid-hydrolyzable and / or protease-digestible phases have particular advantages for oral administration in food or beverages due to their familiarity and palatability. Such systems can be used to deliver therapeutic agents such as APIs, vaccines, probiotics, etc., as components of edible delivery vehicles. As an example, an orally ingestible delivery system can be formulated with a matrix of tapioca starch (water-swellable, acid-hydrolyzable phase) containing gas-forming substances, a mixture of said soluble, water-swellable matrix permeated by a mixed insoluble matrix of food-grade cellulose fibers. The system can be sold in dehydrated form as pellets or powders or other formed articles ready for addition to the edible delivery vehicle of choice, such as edible gels or liquids. Upon hydration, the system swells and becomes suspended in the oral delivery vehicle. As an example, the system can be formatted as "pearls" (or any convenient shape and size) that are dissolved in a flavored beverage, where they become hydrated, suspended, and drinkable with simple stirring. Once ingested, the "pearls" behave similarly to other one-layer, orally ingestible delivery systems described herein with programmed release of their therapeutic content. As will be appreciated by those skilled in the art, food coloring and / or aromas / flavors may be added to the pearls to enhance the consumer appeal of the delivery vehicle. In embodiments, the specialized oral delivery vehicle may be sold in a hydrated form, if more convenient or commercially appropriate.

[0165] In an aspect, disclosed herein is an orally ingestible delivery system for delivering a therapeutic agent to the intestine of a mammal, comprising a hydrophilic matrix and a hydrophobic scaffold disposed therein, wherein the therapeutic agent is contained in the hydrophilic matrix, and the hydrophilic matrix further comprises a plurality of gas former packets comprising a gas forming substance that converts to a gas upon exposure to gastric acid, the hydrophilic matrix being susceptible to digestion by gastric acid or gastric enzymes to form a hydrophilic matrix residue, and digestion of the hydrophilic matrix exposes the gas former packets to gastric acid thereby converting the gas forming substance to a protective gas, which migrates to the surface of the hydrophilic matrix residue forming a dispersible gas barrier thereon, which dispersible gas barrier protects the hydrophilic matrix residue from further digestion by gastric acid or gastric enzymes, and the dispersible gas barrier is dispersible by bicarbonate in the duodenal portion of the intestine, thereby exposing the surface of the hydrophilic residue to intestinal enzymatic activity, which intestinal enzymatic activity further digests the hydrophilic matrix residue releasing the therapeutic agent contained therein, thereby delivering the therapeutic agent to the intestine. In embodiments, the therapeutic agent is placed in a separate packet. In embodiments, the packet is surrounded or coated. In embodiments, the therapeutic agent is combined with a second therapeutic agent contained in a hydrophilic matrix. In embodiments, the therapeutic agent and the second therapeutic agent are contained in separate packets, and in other embodiments, at least one of the therapeutic agent and the second therapeutic agent is contained in the hydrophilic matrix without being placed in a separate packet. In embodiments, the hydrophilic matrix includes a protein or polysaccharide, and the hydrophilic matrix may have hydrocolloid properties. In embodiments, the protein is gelatin. In embodiments, the hydrophobic framework includes a hydrophobic polymer that may be selected from the group consisting of cellulose, fatty acids, waxes, polyolefins, and edible or natural elastomers. In embodiments, the hydrophobic polymer is unrefined beeswax. The hydrophobic framework may further include a second polymer that has advantageous mechanical properties. In embodiments, the second polymer may be a polyisobutylene polymer or a cellulose polymer. In embodiments, the gas-forming substance is a substance that produces carbon dioxide gas, and the gas-forming substance may include carbonate ions.In embodiments, digestion by stomach acid or gastric enzymes exposes portions of the hydrophobic framework as digestion forms hydrophilic matrix remnants, thereby forming exposed hydrophobic frameworks. The protective gas may adhere to or become attached to the exposed hydrophobic framework as it migrates to the surface of the hydrophilic matrix remnants.

[0166] Further disclosed herein is a method of delivering a therapeutic agent to the intestine of a mammal, the method comprising the steps of: providing an ingestible delivery system as described above; administering the ingestible delivery system to a mammal through the mouth; allowing the ingestible delivery system to pass into the stomach of the mammal, where the ingestible delivery system is exposed to gastric acid that digests the ingestible delivery system to form a partially digested residue and interacts with the ingestible delivery system to form a dispersible gas barrier on the surface of the partially digested residue, the dispersible gas barrier protecting the partially digested residue from further digestion in the stomach; and allowing the partially digested residue to pass further into the intestine, where the dispersible gas barrier is dispersed by interaction with bicarbonate secretions in the intestine, and enzyme activity in the intestine erodes the partially digested residue to release the therapeutic agent contained therein, thereby delivering the therapeutic agent to the intestine. In an embodiment, the mammal is a human patient in need of treatment with a therapeutic agent. In embodiments, the human patient is being treated with a therapeutic agent for a condition selected from the group consisting of cancer, metabolic disorders, allergic disorders, hormonal disorders, dermatological disorders, cardiovascular disorders, respiratory disorders, hematological disorders, musculoskeletal disorders, inflammatory disorders, rheumatic disorders, autoimmune disorders, gastrointestinal disorders, urological disorders, sexual and reproductive disorders, neurological disorders, and genetic disorders. In embodiments, the therapeutic agent, which may be a protein or peptide or a living organism, is susceptible to degradation in the stomach.

[0167] As shown in the figures below, certain aspects of the orally ingestible delivery system are particularly advantageous for food and beverage applications.

[0168] 14 shows, in cross-section, an embodiment of an orally ingestible delivery system 1400 including a hydrophilic matrix 1402 through which are dispersed discrete packets (e.g., particles, capsules, vesicles, etc.) of a therapeutic agent 1404, through which are further dispersed a plurality of discrete packets (e.g., particles, capsules, vesicles, etc.) of a gas forming substance 1408, and further including a hydrophobic framework 1410 disposed within the hydrophilic matrix 1402. As used herein, the term "packet" refers to a discrete deposit of the substance of interest, which may be in an uncoated and unenclosed form (naked packet) or may be surrounded and / or coated with another material that wholly or partially covers the deposit of the substance of interest. It is understood that the substance being delivered within the packet may be in any physical state including a solid, liquid, gel, or combinations thereof, as a dispersion or emulsion.

[0169] The system 1400 with hydrophilic matrix 1402, which may be selected for its texture and taste, is dimensionally adapted for digestion to optimize its taste appeal and its mouthfeel. Suitable food grade materials for the matrix may include polysaccharides such as starches (such as tapioca, rice and corn), glycogen, inulin, pectin, xanthan gum, carrageenan, gum arabic, agar, alginates, etc., or protein solutions made with gelatin, wheat gluten, corn zein, soy protein, whey protein and mung bean protein. Other examples of suitable matrix materials may be readily envisioned by those skilled in the art. In embodiments, the matrix may be coated with materials well known to formulation scientists for coating conventional pills to enhance flavor or intake, protect the underlying matrix, provide lubrication, etc. Representative coatings include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, carnauba wax, methacrylic acid copolymers, carboxymethylcellulose polymers, cellulose acetate, polyvinylpyrrolidone, and mixtures of the foregoing coatings.

[0170] In embodiments, the hydrophilic matrix 1402 may be formed from a hydrocolloid, which may be first dehydrated following formation and then rehydrated near the time of ingestion. As an example, a system 1400 having a matrix of tapioca starch may be formed as spheres or "pearls" with a jelly-like consistency. The pearls may then be sold in a dehydrated form ready for addition to a beverage (e.g., orange juice, sports drinks or simply water). Upon hydration, the pearls (any size and shape, from sesame seeds to pea size, e.g., pearls or elongated strings or engineered "gummy" shapes) hydrate and remain suspended in the beverage with simple stirring.

[0171] In other embodiments, the system 1400 is formed into its final shape and then subjected to ingestion without prior dehydration. Any digestible form factor may be used and any consistency suitable for ingestion may be selected. For example, the matrix may be formed into multiple gelatinous spheres that may be swallowed in a liquid such as a syrup or beverage. As another example, the matrix may be formed into an appealing shape for ingestion, such as a gumdrop or gummy bear that may be chewed or swallowed whole. The system 1400 may be adapted for addition to virtually any food item (e.g., yogurt, cold soup, salad, jam, jelly, seasoning paste, condiments, etc.) and virtually any beverage (e.g., iced tea, iced coffee, milkshakes, fruit juice, etc.).

[0172] A support framework 1410 comprising a hydrophobic material is contained within the hydrophilic matrix 1402. The system 1400 is formed as a single structure, which includes two different types of materials, hydrophilic and hydrophobic, each of which is referred to herein as a "phase." The system 1400 itself is therefore understood to be a monolithic three-dimensional object in which two phases are distributed: the hydrophilic matrix 1402 and the hydrophobic framework 1410. This second water-insoluble, acid-resistant phase may be selected from a variety of hydrophobic materials, such as cellulose, fatty acids, waxes, polyolefins, edible / natural elastomers (e.g. natural latex, cuma macrocarpa, tunu, jelutong or chicle), etc. Materials used as pharmaceutical excipients, such as derivatized celluloses (e.g. methyl or hydroxypropyl substituted) or inert cellulosic substances (e.g. cellulose acetate, diacetate and triacetate, etc.), are also suitable for forming the hydrophobic framework 1410. The framework 1410 itself does not require any particular structure: its shape may be organized as a network or intersection of components, or in any other shape based on the properties of the material or materials used for the hydrophobic phase. In embodiments, the framework 1410 may be formed as an integrated unit having a suitable regular or irregular shape suspended or otherwise disposed within the matrix 1402. In other embodiments, the framework 1410 may be constructed or compiled from any arrangement of hydrophobic elements, such as arranged hydrophobic fibers, shards, particles, composites, or other dimensionally suitable shapes, such as networks, meshes, reticulations, squared or squared structures, etc. The framework 1410 may be formed from a single hydrophobic component, or it may include multiple hydrophobic components; the framework 1410 may be continuous or discontinuous throughout the matrix. In embodiments, the hydrophobic framework 1410 may be formed from an active drug component that is itself hydrophobic. Optionally, the gas forming material 1408 may be attached to, embedded in or otherwise integrated with the hydrophilic framework.

[0173] As described herein, various manufacturing techniques are available for forming the matrix 1402 and framework 1410. For example, an aqueous phase including water, bicarbonate, and bovine gelatin can be emulsified within a hydrophobic phase including unrefined beeswax and polyisobutylene, and this emulsion can be used to form the system 1400. In such an emulsion, calcium carbonate gas-forming crystals can be suspended in the aqueous phase as described in more detail below. The amount of polyisobutylene can be selected to provide the device with the desired flexibility and integrity, for example, an amount ranging from about 0.5% to about 5%. In one embodiment, the emulsion can include about 1% polyisobutylene. Additives such as fibers can be included in the emulsion to improve its structural strength. In embodiments, a common hydrocolloid can be used to form the matrix 1402, with the hydrophobic phase embedded or formed therein. In embodiments, edible proteins such as whey protein, soy protein, or natural or partially hydrolyzed collagen can be used to form the matrix 1402. In embodiments, a matrix 1402 and framework 1410 two-phase system may be formed in which the hydrophobic layer is intertwined with the gel layer, and the gas-forming material 1408 and therapeutic agent packets 1404 are disposed within the overall layer. In one embodiment, an emulsion may be formed within the matrix 1402 by mixing in an aqueous solution of concentrated bicarbonate; in embodiments, this emulsion technique may be combined with a process for combining hydrophilic and hydrophobic media as they cooperate to form the hydrophobic framework 1410 within the hydrophilic matrix 1402, so that the gas-forming elements are dispersed throughout the system as it is formed. Using this technique, the water within the aqueous phase of the emulsion may evaporate, leaving behind bicarbonate crystals as a deposit of the gas-generating material 1408 within the matrix 1402.

[0174] In embodiments, a system with asymmetric properties can be formed. For example, using the techniques described above, a matrix 1402 can be formed from a naturally occurring polymer such as gelatin or an engineered polymeric matrix with bicarbonate crystals embedded therein. This hydrophilic matrix 1402 can then be integrated with a hydrophobic framework material in a compartmentalized manner, so that more hydrophobic material is located on the periphery and more hydrophilic material is located in the center. In embodiments, an asymmetric arrangement of phases can be formed using a temperature gradient that creates a gradient of two different constituent hydrophilic and hydrophobic phases. To form this asymmetric arrangement, a mixture containing these two components can be placed between two different temperature boundaries such that the mixture distribution of the component materials is a function of temperature. This causes the two components to be differentially distributed throughout the volume of the system based on their respective responses to the temperature gradient.

[0175] If the hydrophobic framework 1410 requires fortification, additional polymers may be added to the hydrophobic framework as the emulsion is being formed, where such additional polymers are selected to have advantageous mechanical properties, such as to improve the structural stability, integrity, hardness or flexibility of the framework. For example, small amounts of rubbery hydrophobic polymers, such as polyisobutylene, may be added to increase structural stability and integrity. Other polymers, such as polyethylene, polyisobutylene, polyvinyl acetate, etc., may also be added to the hydrophobic framework 1410, alone or in combination, to improve its mechanical properties. For example, xanthan gum or other hydrophilic polymers may be combined with the hydrophobic framework material. In embodiments, additives to the hydrophobic framework may include cellulose derivatives (e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose) and other hydrocolloids (pectin, pullulan, guar gum, xanthan gum, gum arabic, acacia gum, carrageenan, alginates, chitin, chitosan, starch, soy protein, whey protein, collagen and gelatin), polypeptides, polyvinyl alcohol, polysaccharides and derivatives, hyaluronic acid, poloxamer, PEG, poly(N-vinylpyrrolidone); small molecules such as monosaccharides and oligosaccharides, water soluble salts, glycerol and edible surfactants (e.g., lauric arginate).

[0176] In an embodiment, an orally ingestible delivery system 1400 may be formed having a water-swellable, acid hydrolyzable and / or protease digestible hydrophilic phase and a water-resistant and hydrolysis-resistant phase. A therapeutic agent packet 1404 and a gas former packet 1408 as described herein are disposed within the system. In an embodiment, the water-swellable, acid hydrolyzable and / or protease digestible phase may include polysaccharides, proteins or some combination thereof. Polysaccharides well known in the art, such as starches (such as tapioca, rice and corn), glycogen, inulin, pectin, xanthan gum, carrageenan, gum arabic, agar, alginates, etc. may be used in this phase. In an embodiment, polysaccharides with hydrocolloid properties may be selected to exert their ability to swell upon exposure to water. Proteins such as gelatin, wheat gluten, corn zein, soy protein, whey protein and mung bean protein may be used in this phase to form a water-swellable protein solution. The gas generating material 1408 and therapeutic agent packets are dispersed within this layer. The water insoluble, acid resistant phase may be formed from a variety of materials, such as cellulose, fatty acids, waxes, polyolefins, edible / natural elastomers (e.g., natural latex, cuma macrocarpa, tunu, jelutong, or chicle). The water insoluble, acid resistant phase may also include non-digestible food grade materials such as fiber that are intended to improve the strength and durability of this phase.

[0177] In embodiments, fibers (not shown) may be added to the matrix 1402 or hydrophilic framework 1410 to improve strength, elasticity, or durability. Edible fibers, such as fibers from certain plants, such as the covering or phloem around the stem of a plant or from the fruit of a plant (e.g., banana fiber, coconut fiber, soybean fiber, etc.) or fibers from leaves or petioles (e.g., wheat, rice, barley, grass, etc.), are particularly advantageous. The fibers may be mixed with the hydrophobic or aqueous phase, or the fibers may be used to build a reinforcing or support structure to which a hydrophobic material may be applied to create the hydrophobic framework 1410. In embodiments, the hydrophobic material may be applied to a preformed lattice, where the lattice is formed from a stiffer wax, polymeric network, or fiber. In embodiments, the lattice may be formed by defibrillating fibers coated with wax, fat, or fatty acid, and then the lattice is coated with a hydrophobic substrate for an outer acid-resistant layer. The gas-forming substance 1408 may be included within the hydrophobic material applied to the lattice, or the gas-forming substance 108 may be present within the interstices of the lattice that are placed there before the lattice is coated with the hydrophobic material, after the lattice is coated with the hydrophobic material, or both. For example, the lattice may be formed first and then coated with the wax-in-water emulsion previously described, where the aqueous phase of the emulsion contains a concentrated aqueous solution of bicarbonate; as the water evaporates, the bicarbonate remains where it is carried by the emulsion, e.g., in the valleys and hollows of the lattice structure, and it crystallizes as water is lost from the concentrated aqueous solution. In other embodiments, the gas-forming substance 1408 may be attached to the fibers within the matrix 1402, so that as the fibers are digested by stomach acid, the acid also comes into contact with the gas-forming substance and activates them, resulting in the formation of a dispersible gas barrier, as shown below in FIG. 15.

[0178] Two sets of packets are embedded within the matrix: packets of therapeutic agent 1404 and packets of gas-forming material 1408. As used herein, the term "packet" refers to any type of visible or semi-visible structure dimensionally adapted to contain the material of interest, whether therapeutic agent or gas generation. The "packet" may be integrally formed from the material itself, or it may be formed as a capsule, cover or other container in which the material is contained. In embodiments, the packets range in size from about 0.01 micron to about 1 micron, they may be formed regularly or irregularly, and may be formed in any convenient shape, such as, but not limited to, spherical, cubic, trapezoidal, linear, fibrillar, flaky, tangled, elongated, cylindrical, tapered or uniform shapes and combinations thereof. In all embodiments, the packets are substantially smaller in size than the size of the delivery system itself. In embodiments, there may be hundreds or thousands of packets within the matrix for a particular material.

[0179] The size and shape of the packets are such that multiple packets can be suspended in the matrix, allowing for the distribution of materials in the matrix in a random or regular pattern. For example, the packets can be distributed uniformly throughout the matrix, or the packets can be preferentially placed in certain areas. For example, the gas former packets 1408 can be placed closer to the surface of the system 1400, while the therapeutic agent packets 1404 can be more centrally concentrated. Other arrangements of packets can be envisioned by those skilled in the art to achieve the therapeutic goals of the system, as described in more detail below. The gas former packets 1408 include a gas producing material in solid or liquid form that produces a gas when exposed to gastric acid. As used herein, the term "gas former" or "gas former" refers to a material selected to produce a gas when it reacts with acids such as those found in gastric juices. Particularly advantageous are gas formers that produce carbon dioxide upon exposure to hydrochloric acid in the stomach. The gas forming substance (e.g., carbon dioxide formers such as calcium carbonate (including precipitated calcium carbonate (PCC)), sodium bicarbonate, potassium bicarbonate, magnesium carbonate, etc. or hydrogen formers such as, for example, magnesium particles) are present as solid materials or in other physical states that, in embodiments, may be embedded in packets within the matrix to release carbon dioxide when exposed to gastric acid. In one embodiment, the gas forming substance may be embedded within a digestible polymer or small molecule carrier that is disposed within the matrix such that upon contact with gastric acid, the carrier degrades to expose the embedded gas forming substance to react with gastric acid.

[0180] As an example, precipitated calcium carbonate (PCC) generates carbon dioxide when exposed to hydrochloric acid in the stomach. PCC particles disposed within matrix 1402 come into contact with gastric acid as the outer layer of matrix 1402 is hydrolyzed and eroded by the stomach acid. Carbon dioxide is formed when the gastric acid comes into contact with the PCC crystals. Some of the carbon dioxide diffuses freely into the gastric fluid, while other CO2 bubbles arrange themselves on the surface of the eroded matrix and form a protective barrier. This process is shown in more detail in FIG. 16 below.

[0181] The matrix 1402 also includes a number of packets 1404 containing a therapeutic agent. In embodiments, the distribution of the therapeutic agent packets 1404 is preselected such that a desired amount of therapeutic agent is distributed within the matrix 1402 based on the density of the therapeutic agent packets within the matrix 1402. These therapeutic agent packets 1404, like their surrounding matrix 1402, are susceptible to gastric acid hydrolysis. As such, when the matrix 1402 is eroded by contact with gastric acid, some of the therapeutic agent packets 1404 may also be hydrolyzed. However, those therapeutic agent packets 1404 located more internally within the matrix 1402 may be preserved under a layer of carbon dioxide that accumulates on the surface of the system 1400, as shown in more detail in FIG.

[0182] It is understood that, in embodiments, the regular distribution of therapeutic agent packets 1404 in the matrix 1402 may allow for uniform release of the therapeutic agent even if the integrity of the system 1400 is breached, for example, by chewing. When the matrix 1402 is intended to be chewed, it breaks into smaller pieces, each of which contains a certain amount of therapeutic agent packets 1404 and gas former packets 1408, based on the density of these packets within the matrix, and also based on the volume of each chewed piece. Due to the homogenous distribution of the therapeutic agent 1404 and gas former packets 1408 within the matrix, chewing does not simply break up the entire volume of the system 1400 into sub-units, impairing the function of the packets suspended therein; chewing simply breaks up the larger system 1400 into smaller particles, each of which functions similarly to the larger system 1400 upon encounter with stomach acid (as described in more detail below).

[0183] 15 shows a cross-section of an embodiment of an orally ingestible delivery system 1500 including a hydrophilic matrix 1502 in which a therapeutic agent is dissolved or dispersed, with the therapeutic agent 1504 being integrated with the matrix 1502 itself. In this embodiment, the therapeutic agent 1504 is not contained in a separate packet, but rather in the matrix 1502. Also dispersed within the matrix 1502 are multiple separate packets (e.g., particles, capsules, vesicles, etc.) of a gas-forming substance 1508. A hydrophobic framework 1510 is embedded within the matrix. Optionally, the gas-forming substance 1508 may be attached to, embedded in, or otherwise integrated with the hydrophilic framework. The hydrophilic framework 1510 of the embodiment shown is substantially similar in composition and configuration to that described with respect to FIG.

[0184] FIG. 16 shows a cross-section of an embodiment of an ingestible delivery system 1600 shown in FIG. 14 after a period of residence in the stomach following ingestion thereof. As shown in this figure, the ingestible delivery system 1600 includes a hydrophilic matrix 1602 within which are dispersed discrete packets of a therapeutic agent 1604, and throughout which are further dispersed multiple discrete packets (e.g., particles, capsules, vesicles, etc.) of a gas-forming substance 1608. The system 1600 includes a hydrophobic framework 1610 disposed within the hydrophilic matrix 1602. As shown diagrammatically in FIG. 16, the shape of the system 1600 reflects the effect of exposure to hydrochloric acid in the stomach: compared to the ingestible delivery system shown in FIG. 14, the surface 1612 of the system 1600 is irregular and the volume of the matrix is ​​reduced, resulting in erosion of the matrix 1602 upon contact with the stomach acid. The integrity of the system 1600 is maintained by the hydrophobic framework 1610 embedded within the matrix 1602. This framework 1610 provides structural support as it is not affected by stomach acid.

[0185] As further shown in FIG. 16, certain gas former packets 1608 are still present within the matrix 1602 if the stomach acid has not yet arrived. Certain other gas former packets are in contact with the stomach acid and release gas bubbles 1614a and 1614b; for example, with PCC gas formers, the gas bubbles 1614a and 1614b are carbon dioxide gas. Certain gas bubbles 1614a are released into the gastric fluid, while others remain in contact with the surface 1612 of the system 1600. As erosion continues, more gas former packets 1608 come into contact with the stomach acid and release gas bubbles 1614b present on the surface 1612 of the system. These bubbles 1614b merge to form a dispersive gas barrier 1618, which in turn protects the underlying matrix 1602 and the therapeutic agent packets 1604 contained therein. 16, if stomach acid is encountered before the dispersible gas barrier 1618 is formed, some of the more superficial therapeutic agent packets will be hydrolyzed or digested. However, once the dispersible gas barrier 1618 has solidified, the remaining therapeutic agent packets 1604 may be protected.

[0186] As shown in FIG. 16, certain gas former packets 1608 remain within the matrix 1602 and do not come into contact with stomach acid. Thus, in the embodiment shown, their protective effect is lost as their gas forming ability is not activated. In the embodiment, the gas former packets 1608 and the therapeutic agent packets 1604 are distributed substantially uniformly throughout the matrix 1602. This arrangement is advantageous for use with chewable systems, since the gas former packets 1608 and the therapeutic agent packets are distributed proportionally within the smaller volume of the chewed pieces, so that the delivery of the therapeutic agent from each chewed piece is proportionally uniform. However, this uniform distribution, in which the packets are relatively uniformly distributed throughout the matrix 1602, may place a certain percentage of the therapeutic agent packets 1604 on the more superficial surface, making them vulnerable to attack by stomach acid. In such an arrangement, these more superficial therapeutic packets 1604 are sacrificed as the stomach acid erodes the matrix; thus, their contents are destroyed and not delivered to the patient in need. As an alternative, in some embodiments, there may be differential arrangement of the gas former packets 1608 and the therapeutic packets 1604, so that the gas former packets 1608 are more superficial, while the therapeutic packets 1604 are buried deeper. With this arrangement, the more superficially located gas former packets encounter the stomach acid first and form a dispersive gas barrier 1618 before the matrix 1602 is sufficiently eroded to expose the therapeutic packets 1604 to the harmful effects of stomach acid. In other embodiments, the matrix 1602 may be perforated with a plurality of pores or channels (not shown) that may allow stomach acid to penetrate the matrix through the pores or channels and react with the gas formers 1608 located within the matrix. In yet other embodiments, system 1600 may include fibers or other conduits that carry gastric acid to matrix 1602 so that internal gas formers 1608 may be activated.

[0187] The dispersible gas barrier 1618 formed on the surface 1612 of the system 1600 protects the matrix 1602 and the remainder of the therapeutic packet 1604 dispersed therein from stomach acid and the digestive enzymes of the stomach. However, for the therapeutic agent to be released from the system, the dispersible gas barrier 1618 must be dispersed. This occurs in the duodenum as described below. Carbon dioxide is particularly advantageous as the primary component of the dispersible gas barrier 1618 because it dissolves in the neutral secretions of the intestine and reacts with bicarbonate released in the pancreatic secretions. This feature allows the carbon dioxide gas barrier formed in the stomach by the action of gas-producing substances to rapidly disperse in the duodenum, allowing various pancreatic enzymes to gain access to the acid-resistant protease digestible membrane, as described in more detail below.

[0188] As shown in FIG. 16, the exterior surface of the matrix 1602 of the orally ingestible delivery system 1600 is eroded due to acid digestion, resulting in loss of matrix material and loss of some of the therapeutic agent 1604. To control the loss of the therapeutic agent 1604 in the stomach, the system 1600 can be engineered to reduce the erosion of the surface layer of the matrix 1602. As described above, the system 1600 can be designed with a differential distribution of hydrophobic and hydrophilic components or gas formers 1608 so that more hydrophobic material and / or more gas formers 1608 are located on the periphery to resist acid hydrolysis. Also, as described above, the therapeutic agent 1604 can be located more centrally so that it is not as accessible to digestion as the periphery of the matrix 1602 is digested. In embodiments, additives can be integrated throughout the matrix 1602 or on the exterior of the matrix 1602 to improve its acid resistance. In embodiments, the matrix may include an agent that prevents its digestibility when exposed to proteases, thereby protecting the therapeutic agent contained therein 1604. For example, if the matrix 1602 is formed of gelatin, a retardant material may be incorporated into the gelatin itself.

[0189] As will be further understood by those skilled in the art, the degradation time of the matrix 1602 can be further tailored by adding a coating on top of it, for example, a coating that has delayed or extended release properties when exposed to gastric acid and / or proteases. Techniques for forming such layers are well known in the art. In some embodiments, an enteric coating can be applied to the therapeutic agent packets 1604 to protect them from conditions in the small intestine, thereby allowing the therapeutic agent 1604 to reach a desired location distal to the duodenum, for example, the jejunum, ileum or colon. Although a wide range of conventional enteric coating formulations can be used, it is envisioned that a protective coating for the therapeutic agent packet 1604 can be selected that is less robust than those materials or thicknesses used for conventional enteric coatings. This is because conventional enteric coatings require greater durability so that they can withstand the harsh conditions in the stomach, including acid and protease-induced hydrolysis. In contrast, the gas barrier 1618 formed in the stomach protects the system 1600 from hydrolysis. Therefore, there are lower performance requirements for the enteric coating applied to the therapeutic agent packet 1604 compared to conventional enteric coatings. Thus, in embodiments, enteric coatings that are considered rather "weak" in their resistance to acid and protease degradation may be used. In other embodiments, the enteric coating for the therapeutic agent 1604 may be specifically designed for the conditions in the intestine. For example, bile secretions release abundant amounts of lipases and surfactants in addition to proteases. Thus, the modified release layer may be a lipid-based formulation that is degradable by lipases at neutral pH at a predicted rate. Alternatively, conventional enteric coatings may be used, albeit as thinner than normal layers.

[0190] In embodiments, the coating applied to the entire system can be selected to improve the intake of the system, improve its palatability, or 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 field of formulation.Such coatings can be formed from natural ingredients such as shellac (formed from insect excreta) and carnauba wax.

[0191] FIG. 17 shows a cross-section of an embodiment of an ingestible delivery system 1700 shown in FIG. 15 after a period of residence in the stomach following ingestion thereof. As shown in this figure, the ingestible delivery system 1700 includes a hydrophilic matrix 1702 having a plurality of separate packets (e.g., particles, capsules, vesicles, etc.) of a gas-forming substance 1708 dispersed therethrough. A therapeutic agent is dissolved or dispersed within the hydrophilic matrix. The system 1700 further includes a hydrophobic framework 1710 disposed within the hydrophilic matrix 1702. As shown diagrammatically in FIG. 17, the shape of the system 1700 reflects the effects of exposure to hydrochloric acid in the stomach: compared to the ingestible delivery system shown in FIG. 16, the surface 1712 of the system 1700 is irregular and the volume of the matrix is ​​reduced, reflecting erosion of the matrix 1702 upon contact with stomach acid. The integrity of the system 1700 is maintained by the hydrophobic framework 1710 embedded within the matrix 1702. This framework 1710 is not affected by stomach acid and therefore provides structural support.

[0192] As further shown in FIG. 17, certain gas former packets 1708 are still present within the matrix 1702 if the stomach acid has not yet arrived. Certain other gas former packets are in contact with the stomach acid and release gas bubbles 1714a and 1714b; for example, with PCC gas formers, the gas bubbles 1714a and 1714b are carbon dioxide gas. Certain gas bubbles 1714a are released into the gastric fluid while others remain in contact with the surface 1712 of the system 1700. As erosion continues, more gas former packets 1708 come into contact with the stomach acid and gas bubbles 1714b present on the surface 1712 of the system are released. These bubbles 1714b combine to form a dispersible gas barrier 1718, which in turn protects the underlying matrix 1702 and the therapeutic agent dispersed within the matrix 1702. After acid erosion as shown in FIG. 17, the more superficial regions of matrix 1702 may be hydrolyzed or digested if they encounter stomach acid before dispersible gas barrier 1718 is formed; if matrix 1702 erodes, the therapeutic agent contained therein may also be destroyed. However, due to solidification of dispersible gas barrier 1718, the remaining matrix 1702 and the therapeutic agent dispersed therein may be protected. In embodiments, the therapeutic agent within matrix 1702 is uniformly distributed, such that erosion of the superficial matrix 1702 results in a comparable loss of therapeutic agent. In other embodiments, there is a differential localization of therapeutic agent within matrix 1702, e.g., a higher concentration of therapeutic agent is more central and less or no therapeutic agent is contained within the more superficial matrix 1702. In this arrangement, digestion or hydrolysis of the surface matrix 1702 has less impact on the overall concentration of therapeutic agent within the system 1700 following exposure to gastric acid: the portion of the matrix 1702 that is eroded by gastric acid contains relatively less therapeutic agent than the portion of the matrix 1702 that is protected so that it remains undigested.

[0193] As described with respect to FIG. 16, in some embodiments, there may be a differential placement of the gas former packets 1708 such that more of the gas former packets 1708 are disposed more superficially within the matrix 1702. In embodiments, this differential placement of the gas former packets 1708 may be combined with a differential localization of the therapeutic agent within the matrix 1702 as previously described, such that, for example, there is a higher concentration of the therapeutic agent more centrally of the matrix 1702. When the gas former packets 1708 are disposed more superficially, they will encounter gas acid first and form a dispersive gas barrier 1718, which then protects the remainder of the matrix 1702 and the therapeutic agent disposed therein. When the superficial location of the gas former packets 1708 is combined with a differential, more central location of the therapeutic agent in the matrix 1702, this provides additional protection to the therapeutic agent, preventing more of its loss to gastric acid erosion, as compared to a uniform distribution of the therapeutic agent in the matrix 1702. In embodiments, matrix 1702 may be perforated with a plurality of pores or channels (not shown) that may allow gastric acid to penetrate the matrix through the pores or channels and react with gas formers 1708 disposed within the matrix. In yet other embodiments, system 1700 may include fibers or other conduits that carry gastric acid to matrix 1702 so that gas formers 1708 therein may be activated.

[0194] The dispersible gas barrier 1718 formed on the surface 1712 of the system 1700 protects the matrix 1702 and the remainder of the therapeutic agent dispersed therein from gastric acid and the digestive enzymes of the stomach. As described with respect to Figure 16, carbon dioxide is particularly advantageous as the primary component of the dispersible gas barrier 1718 because it dissolves in the neutral secretions of the intestine and reacts with bicarbonate released in the pancreatic secretions. This feature allows the carbon dioxide gas barrier formed in the stomach by the action of gas-forming substances to disperse rapidly in the duodenum, allowing various pancreatic enzymes to gain access to the acid-resistant protease digestible membrane, as described in more detail below.

[0195] The diagram above shows an embodiment of an ingestible delivery system that is presumed to be orally ingested in a relatively intact form (acceptable for chewing or dissolution in the mouth). Upon encounter of the system with stomach acid, exposure of the gas formers in the matrix to stomach acid digests the matrix and they form gas bubbles that coalesce on the surface of the system to provide a dispersible gas barrier. However, in embodiments, the ingestible delivery system may encounter an acidic environment prior to its ingestion and respond to the exposure similar to how it responds to stomach acid. For example, the ingestible delivery system may be provided to an acidic environment for ingestion or it may be swallowed with an acidic liquid, gel or solid. Contact with acid prior to the stomach, whether in the stomach or before it reaches the stomach, initiates the mechanism for producing a dispersible gas barrier. It is understood that if the ingestible delivery system is exposed to acid prior to reaching the stomach, further contact with stomach acid may continue the reaction with the gas formers in the matrix, resulting in a dispersible gas barrier.

[0196] In embodiments, the delivery system can be tailored to optimize the precise administration of one or more therapeutic agents. It is understood that there is some erosion of the outside of the matrix in which the therapeutic agent is dissolved or dispersed. If some of the therapeutic agent is present on the outer surface of the matrix (dissolved within the therapeutic agent packet or matrix), it will be subject to degradation (e.g., digestion, denaturation, inactivation, loss of therapeutic efficacy, instability or other adverse effects) when it encounters gastric acid or enzymes. As previously described, differential placement of the therapeutic agent and / or gas former packet can help protect the therapeutic agent within the device. In embodiments, the therapeutic agent can be more centrally placed within the matrix, so that the outer portion of the matrix is ​​digested, but the therapeutic agent escapes encounter with gastric fluids. In other embodiments, there can be a predominance of gas former packets in the outer portion of the matrix, so that they are activated by gastric acid to form a dispersible gas barrier, which then protects the therapeutic agent within the matrix.

[0197] In yet other embodiments, calculation of the delivered dose of therapeutic agent may include a correction for the amount of therapeutic agent originally contained in the matrix that is lost upon encounter with gastric fluid. In embodiments, the amount of matrix to be digested may be pre-calculated, and the loading of therapeutic agent may be adjusted so that the desired dose is administered after accounting for some losses during matrix digestion. Certain mathematical models allow for approximation of matrix losses; empirical methods may also be used to provide more accurate information.

[0198] In embodiments, different doses of therapeutic agent can be administered by adjusting the size or shape of the delivery system itself.For example, the matrix can be shaped as a flat ribbon or elongated strand or hollow cylinder in which the therapeutic agent is dispersed or dissolved in a uniform manner.Then, the ribbon / strand / cylinder can be cut to a specific length to provide the appropriate dose of therapeutic agent.For example, in a 5 cm long dosage form that contains 100 mg of therapeutic agent evenly distributed in the matrix, a 1 cm long piece contains 20 mg of therapeutic agent.

[0199] In another embodiment, the delivery system can be shaped into a symmetrical three-dimensional object, such as a sphere or ellipse, where the amount of therapeutic agent in a particular object varies with the volume of the object. For example, a sphere with a radius of 5 mm has a volume of approximately 0.52 cm. 3 has a volume of 1 cm 3 If the agent has a concentration of 100 mg per cm, this sphere contains approximately 52 mg. A sphere of this size may be suitable for swallowing whole, or it may be chewed. If chewing is avoided, the spheres may be made smaller and the same dose may be achieved by swallowing more of the smaller spheres. In this case, if the agent is 1 cm 3 When present in a matrix at a concentration of 100 mg per unit area, a sphere with a radius of 2 mm has a size of approximately 0.033 cm 3and contains about 3.3 mg of therapeutic agent. Approximately sixteen 2 mm radius spheres would need to be ingested to provide the same dose of therapeutic agent as a single 0.5 cm radius sphere. However, multiple 2 mm radius spheres may be quite suitable for swallowing whole, for example suspended in a liquid or easily swallowed food substance. Smaller spheres, ovals, rods, etc. may lend themselves to even easier ingestion. For illustrative purposes, symmetrical three-dimensional objects are described above, but the three-dimensional delivery systems may be constructed asymmetrically or molded into attractive shapes or otherwise fabricated using techniques well known to pharmaceutical manufacturers, confectioners, and the like.

[0200] In embodiments, the delivery system may be coated with a slippery and / or palatable coating (e.g., confectioner's glaze, carnauba wax, gelatin, mucilage, etc.) that makes it easier to consume. In embodiments, the delivery system may be ingested with a liquid, gel, or solid to facilitate its swallowing. For those delivery systems dimensionally adapted for swallowing whole, it may still be necessary to make further adjustments for erosion in the stomach that reduces the delivered dose of therapeutic agent. An additional challenge for delivery systems intended for chewing is the fragmentation of a single dosage form into multiple chewed pieces. After chewing, each of the pieces contains a portion of the original administered dose based on the volume of the piece, but the therapeutic agent present in each piece may be attacked differently by stomach acid and enzymes depending, for example, on the surface area or composition of the piece. Therefore, chewable delivery systems are particularly suitable for therapeutic agents that do not require precise dosing. For chewable delivery systems containing therapeutic agents requiring more precise dosing, the administered dose requires empirical study or mathematical modeling to ensure that an appropriate amount of the administered therapeutic agent is available to the patient after passage of the chewed pieces through the stomach.

[0201] B. Methods of Treatment Using Orally Ingestible Delivery Systems 1. Definitions and Overview As used herein, the terms "treatment," "treating," "therapy," "therapeutic," and the like, may refer to an intervention intended to cure, heal, mitigate, improve, correct, diagnose, or otherwise beneficially affect a disorder or condition affecting the well-being of a human or animal. A disorder is any condition that alters the homeostatic well-being of a human or animal, including, but not limited to, an acute or chronic disease, or a pathological condition that predisposes a mammal to an acute or chronic disease. Non-limiting examples of disorders include cancer, metabolic disorders (e.g., diabetes), allergic disorders (e.g., asthma), hormonal disorders, dermatological disorders, cardiovascular disorders, respiratory disorders, hematological disorders, musculoskeletal disorders, inflammatory or rheumatic disorders, autoimmune disorders, gastrointestinal disorders, urinary disorders, sexual and reproductive disorders, neurological disorders, genetic disorders, and the like. As used herein, the term "condition" includes disorders and non-pathological conditions that are nevertheless characterized by susceptibility to a particular disease or condition. The term "condition" also includes a state of health in a human that can be improved, enhanced, or otherwise favorably altered to the subjective benefit of the human. As used herein, the term "patient" is any human or animal afflicted with a disorder; the term "patient", in context, can refer to any mammal, including humans, domestic animals, pets, farm animals, sports animals, working animals, and the like. Patients can be of any age, such as prenatal mammals. Patients in need of treatment include both those already with a particular disorder or condition, whether symptomatic or not, and those in which prevention of the disorder is desired.

[0202] As used herein, the terms "treatment", "treating", "treatment", "therapeutic", and the like may refer to an intervention intended to diagnose a disorder or condition or otherwise assess the status of a disorder or condition in a patient. Such diagnosis or evaluation may include any type of intervention, procedure, or process of gathering information to detail the state or condition of a disorder or condition. For example, diagnosis or evaluation may be performed using biological, chemical, or physical methods. Exemplary and non-limiting biological methods for diagnosis or evaluation include techniques such as performing a biopsy of an area, recovering exfoliated cells from an area, testing the response of tissue to a particular stimulus, and the like. Exemplary and non-limiting chemical methods for diagnosis or evaluation include measuring chemical parameters in bodily fluids or biological samples, and the like. Exemplary and non-limiting physical methods include visual inspection by direct visualization or image capture, diagnostic imaging by scanning, ultrasound, x-ray, and the like.

[0203] Under appropriate circumstances, the terms "treatment", "treating", "treatment", "therapeutic", and the like may refer to an intervention intended to promote health or other desired physical or physiological conditions in a human or non-human subject, such that "treatment", "treatment", and the like may refer to an intervention having a satisfying, mind-affecting or other non-medical, holistic or recreational effect. Examples of such "treatment", "treatment", and the like may include various functional foods or health supplements intended to enhance a subject's sense of well-being and health. Other examples of such "treatment", "treatment", and the like may include substances taken for recreational, hedonistic or sensual purposes, such as cannabis, cannabis-derived substances, certain cannabinoids, and the like. While medical cannabis, synthetic cannabinoid products such as dronabinol (Marinol® sold by Unimed) or the cannabidiol (CBD) preparation Epidiolex® (sold by GW Research Ltd.) and generic cannabidiol, which are “over-the-counter” preparations, have utility in treating diseases or disorders, whole plant cannabis or preparations such as the psychoactive cannabinoid delta-9-tetrahydrocannabinol (THC) may be used for non-medical, recreational or health / well-being inducing purposes. Such substances, whether they achieve a medical or non-medical effect, are considered to be “treatments,” “treatments,” etc. for purposes of this disclosure.

[0204] In embodiments, treatment involves providing a therapeutically effective amount of a therapeutic agent to a patient in need thereof. A "therapeutically effective amount" is at least the minimum concentration of a therapeutic agent administered to a human or animal in need thereof to effect treatment of an existing disorder or prevention of an anticipated disorder (either such treatment or such prevention is a "therapeutic intervention").

[0205] A wide range of therapeutic agents are suitable for placement in the orally ingestible delivery system described herein. One or more therapeutic agents may be included in the orally ingestible delivery system using formulation methods well known to those skilled in the art. In embodiments, the therapeutic agent is a pharmaceutical, nutraceutical (i.e., a pharmaceutical substitute that claims a physiological benefit), or diagnostic agent that is formulated for delivery in liquid, semi-solid, or solid form, or any combination thereof. Solid forms may include powders, pellets, crystals, and the like. Semi-solid forms may include slurries, pastes, gels, gums, and the like. Formulations of therapeutic agents that include excipients designed to enhance the physical properties of the therapeutic agents, their uptake rate, their delayed or controlled release, and the like, may be made using techniques well known in the art. The therapeutic agents may be surrounded by other membranes or layers intended to encapsulate them, protect them from dissolution, prolong their release, or other indications well known to those skilled in the art.

[0206] More specifically, the therapeutic agent for placement in the orally ingestible delivery system described herein can be formulated as a dosage form for immediate release or modified release. As used herein, the term "dosage form" refers to any form of formulation that contains a sufficient amount of therapeutic agent to achieve a therapeutic effect with a single administration. The dosage form can be tailored to provide immediate release of active pharmaceutical ingredient or modified release of active pharmaceutical ingredient or a combination of release patterns.

[0207] As used herein, the term "immediate release" refers to a dosage form or delivery system in which an active pharmaceutical ingredient (API) is released from the dosage form with a fast dissolution profile that is achieved quickly after administration. The term "immediate release" often simply refers to a highly soluble API, although an equivalent immediate release profile can be achieved with a less soluble therapeutic agent when excipients such as surfactants are added to the formulation to facilitate drug dissolution. Therapeutic agents delivered by orally ingestible delivery systems and intended for immediate release are released over a significantly shorter period of time (T max At its highest plasma level (C maxImmediate release dosage forms can cross the intestinal mucosal barrier by mechanisms such as passive diffusion or active transport to reach the intestinal mucosal barrier (referred to as "instant release"). Immediate release dosage forms typically release the therapeutic agent in a single action following a first-order kinetic profile in which the rate of the process is proportional to the concentration of the therapeutic agent.

[0208] To counteract the disadvantages of immediate release dosage forms or to achieve different therapeutic results, dosage forms can be designed to modify the release profile of therapeutic agents.As used herein, the term "modified release" for formulations or compositions refers to any dosage form that delivers therapeutic agents at a rate different from the immediate release described above.Modified release dosage forms have drug release characteristics that differ from immediate release dosage forms in terms of time or release location.Modified dosage forms can be further classified as "delayed release", where drug is released at a time and / or location different from the time and location of initial administration, and "extended release", where drug release is extended over time compared to immediate release forms.

[0209] In an embodiment, the therapeutic agent used by the orally ingestible delivery system described herein can be further coated (e.g., with an enteric coating) to delay the release of the therapeutic agent even after the therapeutic agent is released from the delivery system. The delayed release modification can allow the therapeutic 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 the release of the pharmaceutical agent until the formulation passes through the stomach or until the drug passes through the gastrointestinal tract to the colon. Typically, an extended release dosage form is formulated in such a manner that the therapeutic agent is available for an extended period of time after administration. An extended release dosage form can be further characterized as sustained release or controlled release. An extended release system maintains the rate of drug release for an extended period of time. An extended release dosage form can release the therapeutic agent gradually, for example, along the entire small intestine, resulting in an extended period of absorption and a resulting extended interval of drug concentration in the therapeutic range. Sustained release dosage forms generally use various polymers that coat granules or tablets or form a matrix in which the drug is dissolved or dispersed. Controlled release systems are engineered to provide a sustained release profile but provide a predictable constant plasma concentration of the therapeutic agent that is independent of the biological environment of application. Although the various approaches for modified release dosage forms are not interchangeable, they all generally have a tendency to prolong the time that the drug is in the therapeutic range after a single administration, while reducing the possibility for peaks and valleys in plasma levels that increase toxicity or reduce therapeutic efficacy. Other approaches for the delivery of therapeutic agents can be used to achieve the desired plasma levels of one or more agents. For example, two therapeutic agent doses can be combined into one dosage form, with each dose formulated to achieve different timing for delivery, or two different therapeutic agents can be combined into a dosage form. By adjusting the release profile of the doses (either with the same agent or different agents), the temporal distribution of 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 in the formulation. The dosage form can be formulated with an enteric coating to control the sustained release. Coating materials well known in the art include polymers with pH-dependent solubility (i.e. pH controlled release), polymers with slow or pH-dependent swelling, dissolution or erosion rates (i.e. time controlled release), polymers that are degraded by enzymes (i.e. enzyme controlled release) and polymers that form a solid layer that is broken down by increasing 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 colon include enteric coating systems based on methacrylic acid copolymers, such as poly(methacrylic acid, methyl methacrylate), which are soluble only at pH 6 or higher, so that the polymer only begins to dissolve upon release from the orally ingestible delivery system into the small intestine. The site at which such polymeric formulations disintegrate depends on the rate of small intestinal passage and the amount of polymer present. For example, a relatively thick polymer coating may be used for colonic delivery, while a thinner layer is appropriate if faster dissolution of the coating is desired. Polymers that can provide site-specific colonic delivery may also be used, where the polymer relies on the bacterial flora of the large intestine to provide enzymatic degradation of the polymer coating and thereby release of the drug. For example, azopolymers, glycosides, and various naturally available modified polysaccharides may be used in such formulations. Using the orally ingestible delivery system described herein, multiple therapeutic agents may be delivered as deliverable therapeutic agents. In embodiments, multiple therapeutic agents may be bound together, enclosed within a single matrix or cover layer, or otherwise integrated into a single structure that may then be enclosed within a therapeutic agent compartment of the delivery system. In other embodiments, several different dosage forms may be enclosed within a single therapeutic agent compartment, each with its own enclosure and its own delivery characteristics.Without limitation, the deliverable therapeutic agents may be provided in single or multiple dosage forms, optionally formulated for delayed or extended release, and then enclosed by the orally ingestible delivery system described herein, where such agents are either mixed together or completely or partially isolated from each other, for example, by placing each agent in its own compartment inside the therapeutic agent compartment or by encasing each agent in its own membrane with specific parameters for dissolution and drug release. The single agent or agents within the deliverable therapeutic agent may be formulated as pellets contained within a capsule or other enclosing medium. In embodiments, one therapeutic agent may be coated on the surface of the second therapeutic agent, either as a single forming element or multiple bilayer coated capsules, and the bilayer pharmaceutical structure(s) contains the deliverable therapeutic agent as it is placed within the therapeutic agent compartment. The combination of two therapeutic agents within one forming element may achieve bimodal pharmacokinetic release of the two agents, if required by the patient's treatment plan. Alternatively or additionally, an external enteric coating that dissolves more distally in the intestine may be provided to allow delayed release. In embodiments, combinations of therapeutic agents can be combined as deliverable therapeutic agents for delivery by oral ingestible delivery system, where the combination of therapeutic agents is complementary or synergistic.For example, combinations of therapeutic agents, such as peptides such as incretins (e.g., exenatide) and small molecules such as biguanide compounds (e.g., metformin), can be provided to treat diabetes and other glucose control disorders.In embodiments, small molecule therapeutic agents can be dissolved in the matrix, while insoluble or larger therapeutic agents are dispersed throughout the matrix in the packet.The dosage preparations of the two agents can be titrated to achieve appropriate blood levels and therapeutic efficacy.

[0210] As another example, a combination of live organisms and nutritional substances, such as probiotic bacteria and prebiotic substances, which are synergistic or complementary to each other, can be included in a single oral delivery system as a deliverable therapeutic agent (whether intended for pharmaceutical or functional food use).As the term is used herein, prebiotic substances 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 that are present or become present in the intestinal tract, and more broadly, can include substances that are selectively used by microorganisms to confer health benefits to the host.Prebiotic substances can include materials such as non-digestible fibers (e.g., galacto-oligosaccharides, fructo-oligosaccharides, oligofructose, chicory fiber, inulin, etc.) that can provide a supportive environment for the probiotic organisms introduced.Other prebiotic substances can include natural or partially hydrolyzed collagen and other proteins that can act as a supportive environment for probiotic organisms and / or have independent functional food effects.

[0211] Both probiotic organisms and prebiotic substances can benefit from the stomach-to-intestinal tract transfer provided by the ingestible delivery system; the properties of the ingestible delivery system and the packaging of the therapeutic agent that it contains can be further optimized to deliver the prebiotic substances and probiotic organisms to a preselected destination in the large intestine or small intestine.In an embodiment, a single ingestible delivery system can contain an optimized combination of prebiotic substances and probiotic organisms designed to facilitate biome growth and maintenance while minimizing side effects; a combination of prebiotic substances and probiotic organisms can be delivered together in the therapeutic agent compartment of the ingestible delivery system.The combination of prebiotics and probiotics administered together can also act as a "synbiotic", understood as a product that combines prebiotic substances and probiotic organisms, so that they interact synergistically to enhance the survival and embedding of live microorganisms in the gastrointestinal tract by selectively stimulating their growth and / or metabolism. Probiotic strains used in synbiotic formulations may include Lactobacillus spp., Bifidobacterium spp., S. boulardii, B. coagulans, etc., while the primary prebiotics used include oligosaccharides such as fructooligosaccharides, galacto-oligosaccharides, xylose oligosaccharides, inulin, prebiotics derived from natural sources such as chicory and yacon root, etc.

[0212] The physical proximity of the prebiotic substance and the probiotic organisms can be tailored within the oral delivery system to maximize the downstream interaction of the two therapeutic agents.In an embodiment, the probiotic organisms and the prebiotic substance can be delivered separately using separate oral delivery systems, for example, one system adapted to deliver the probiotic organisms and another system adapted to deliver the prebiotic substance; in this example, the two delivery systems can be administered simultaneously or sequentially based on the clinical needs of the patient.In yet another embodiment, the probiotic organisms can be formulated in combination with other substances other than the prebiotic component to enhance the viability of the probiotic organisms or increase their therapeutic effect, and these combinations can be delivered as a deliverable therapeutic agent within the oral delivery system.Preparations using live organisms such as probiotic bacteria can be formulated, for example, in pellet form, with any enteric coating that regulates their delivery to preselected regions of the intestine using conventional methods; in another embodiment, preparations containing freeze-dried live bacteria can be pelleted and enveloped in an enteric coating material to facilitate their delivery to designated target sites in the intestine. As will be appreciated by those skilled in the art, other formulations using multiple pellets containing probiotic organisms can be envisioned, such as a formulation process in which the probiotic-loaded pellets are mixed with a cushioning agent (microcrystalline cellulose, lactose monohydrate, corn starch, porous calcium, etc.) and the mixture is compressed into a tablet that can then be included within the therapeutic compartment of the orally ingestible delivery system.

[0213] Therapeutic agents can be specially formulated to optimize their pharmacokinetic aspects when they are released from the orally ingestible delivery system described herein.Using an orally ingestible delivery system, certain therapeutic agents can be delivered in intact or active or activatable form into the small intestine, for example, from where they must be absorbed through the intestinal mucosa so that they can reach the systemic circulation and exert their desired effects.In one embodiment, this can be achieved by formulating one or more therapeutic agents into a liquid or gel matrix, so that they can be absorbed by endocytosis (including but not limited to phagocytosis, pinocytosis and potocytosis), and thereby transported within vesicles throughout the cells of the intestinal villi to enter the circulation.After uptake of the therapeutic agent by endocytosis, it travels across the intestinal cells for excretion into the extracellular fluid in the intestinal wall, from where it can enter the lymphatics and / or the systemic circulation.

[0214] For the formulation of a particular therapeutic agent, the therapeutic agent itself may first be dissolved in an aqueous medium, such as a water-soluble protein in a hydrophilic environment, such as a viscous matrix loaded with oligosaccharides to minimize the water content of the solution. The aqueous medium may be pH buffered and may contain one or more oligosaccharides, such as inulin, trehalose, dextran, etc., as well as other protective excipients as found in the formulation of proteins for parenteral administration. The aqueous medium may then be mixed into an oil phase to form an oil-in-water emulsion, in which the aqueous droplets are suspended within the oil matrix. The oil phase may contain edible oils and fats well known in the art, such as coconut oil, palm oil, olive oil, omega-3 and -6 containing fish oils, etc., and / or their corresponding monoglycerides or long chain fatty acids (or mixtures thereof). Using known techniques in pharmaceutical formulation and remodeling, such as ultrasonic vibration and homogenization, the aqueous and oily phases can be combined so that the oily phase contains ultrafine nanodroplets (e.g., tens to hundreds of nanometers in diameter) of the aqueous phase as the starting oily phase. Edible surfactants, such as lecithin and phospholipids, can be used to stabilize the emulsion. Upon release of this therapeutic formulation from the orally ingestible delivery system, the oily material containing the aqueous nanodroplets can be taken up into the small intestine by transcytosis; furthermore, while the oily phase is susceptible to the action of lipases in the small intestine, it protects the therapeutic agent within the nanodroplets from the enzymatic action of intestinal proteases in the intestine. As a result, the aqueous nanodroplets within the oily matrix can be absorbed by the small intestine and delivered through the mucosa to the extracellular fluid for further absorption into the systemic circulation.

[0215] The oil-based vehicle may transport other types of therapeutic agents without including them in the aqueous nanodroplets. For example, freeze-dried protein particles may be permanently suspended in the oil matrix and may be carried along in the oil upon absorption in the small intestine and subsequent release from the oral delivery system. Similarly, live organisms may be suspended alone in the oil matrix or may be included in a viscous aqueous matrix that is then emulsified by the oil matrix to form an oil-in-water emulsion that includes aqueous nanodroplets with live organisms therein, which are suspended in the oil matrix. In some embodiments, the aqueous nanodroplets may also include nutrients to preserve and protect the living cells; in other embodiments, the aqueous nanodroplets may include other organisms, such as virus particles, freeze-dried cells, etc., instead of living cells.

[0216] Other combinations for treatment can be easily envisioned by those skilled in the art for conditions such as cancer treatment or HIV treatment, where the treatment requires multiple drugs with different pharmacokinetic properties and different doses. Packaging drug combinations with different properties (e.g., solid, semi-solid, gelling, emulsion, single-phase aqueous vehicle, oil vehicle, etc.) within an ingestible delivery system allows them to bypass the stomach and its effects on different therapeutic agents and be delivered to designated target areas, allowing for more focused, specific and / or predictable absorption distal to the stomach.

[0217] The therapeutic systems and methods as disclosed herein are suitable for a wide range of diseases, disorders, and conditions. For those therapeutic agents that would otherwise require parenteral administration due to their susceptibility to degradation in the stomach, it is particularly advantageous to deliver the therapeutic agent by the orally ingestible delivery system described herein. For example, certain small molecules undergo hydrolysis when exposed to acid in the stomach. If they are used in conventional oral formulations, they require special preparations or even modification of their chemical structure to enable them to resist the effects of stomach acid. As another example, molecules characterized by one or more peptide bonds, such as peptides, proteins, and related structures, are susceptible to enzymatic attack in the stomach by their proteases; therapeutic formulations containing these molecules typically require parenteral administration. As yet another example, preparations containing beneficial bacteria ("probiotics") or other live organisms reduce the number of live bacterial cells or other living cells (if applicable) that are vulnerable to damage in the stomach and ultimately reach the colon or other intestinal targets. For example, although various coating strategies and tablet preparations are under investigation to protect probiotics when administered orally, preparations containing live bacterial cells are typically delivered by enema to ensure that they reach the colon in a healthy state. The systems and methods described herein provide an alternative delivery route and / or a better environment to bring live cells to their intestinal destination for these fragile but important therapeutic agents.

[0218] As an added benefit, the orally ingestible delivery system protects the stomach from therapeutic agents that may be harmful to the stomach. Certain classes of drugs, such as corticosteroids or nonsteroidal anti-inflammatory drugs, have well-recognized damage to 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.

[0219] A wide range of therapeutic agents are suitable for administration using the orally ingestible delivery system described herein, including, but not limited to, certain of these therapeutic agents are currently available in oral dosage forms, such as various antibiotics, antivirals, antiparasitics, immunosuppressants, etc. The use of the orally ingestible delivery system disclosed herein may provide other advantages, such as improving pharmacokinetics and preventing stomach-related side effects. Other therapeutic agents not currently available for oral administration, particularly peptides and proteins susceptible to degradation in the stomach, may be advantageously delivered orally using the orally ingestible delivery system disclosed herein. Further description of therapeutic uses of the orally ingestible delivery system is provided below, along with specific examples of its use with therapeutic agents currently available for oral ingestion and therapeutic agents not currently available for oral ingestion and currently delivered parenterally or rectally. The orally ingestible delivery system disclosed herein is suitable for replacing current delivery mechanisms for, but not limited to, orally ingested, parenterally delivered, and rectally delivered therapeutic agents.

[0220] 2. Orally Ingested Therapeutic Agents Suitable for Delivery via an Ingestable Delivery System a. Active pharmaceutical ingredients Certain therapeutic agents (e.g., active pharmaceutical ingredients or "APIs") are currently formulated for oral ingestion. In embodiments, these APIs can be small molecules rather than macromolecules such as peptides and proteins. Without specific formulation to control gastric absorption, APIs can be altered or modified in the stomach, for example by hydrolysis or by changes in their ionization state, with effects on their absorption profile: for example, drugs that are weakly acidic (e.g., aspirin) will be present in the stomach primarily in their non-ionic form, allowing them to be absorbed in the stomach, while drugs that are weakly basic will be in their ionic form and will not be absorbed in the stomach. Furthermore, certain of these APIs can damage the stomach itself. For both of these reasons (to control absorption in the stomach and to avoid contact of the drug with the stomach that would cause damage), it is desirable to allow certain APIs to pass through the stomach without encountering its environment or its tissues.

[0221] Currently, some APIs are formulated to resist exposure to gastric acid, with variable results. As an example, certain antibiotics, such as macrolide antibiotics (e.g., erythromycin), are unstable under the low pH conditions in the stomach. Bypassing the stomach may improve bioavailability if these drugs can be delivered to the small intestine for uptake without being damaged by gastric pH. As another example, certain drugs are known to have adverse effects but can be delivered orally. For these drugs (e.g., NSAIDs, COX inhibitors, corticosteroids, bisphosphonates, clopidogrel, potassium supplements, and various cytotoxic agents used in cancer chemotherapy), both local and systemic factors have been identified that produce their adverse effects on the gastric mucosa. Bypassing the gastric mucosa may reduce local adverse effects, potentially reducing morbidity associated with their use.

[0222] b. Health products In other instances, certain therapeutic agents are intended to achieve non-medical benefits, such as enhancing health, improving a sense of well-being, or providing recreational or hedonistic benefits. An example of a group of therapeutic agents that provides both medical and non-medical benefits is the cannabinoid family. Oral administration of cannabinoids through whole plant or cannabis-infused foods (so-called "edibles") is well known. However, the bioavailability of bioactive cannabinoids via oral ingestion is variable. Although oral preparations are desirable for various social, economic, and hedonistic reasons, consistent and reproducible bioavailability is also desirable. Delivery systems such as the orally ingestible delivery systems provided herein can produce more predictable absorption, bioavailability, and physiological effects.

[0223] Probiotic treatment represents a hybrid treatment modality, with both oral and rectal administration currently in use. The systems and methods disclosed herein provide an alternative to both delivery routes. The documented beneficial effects of probiotics include prevention or treatment of diarrhea, constipation, alteration of bile salt conjugation, increased antibacterial activity, and anti-inflammatory effects. Various diarrheal conditions (e.g., acute infantile diarrhea, antibiotic-associated diarrhea, and traveler's diarrhea) have been successfully treated with probiotics, including mechanisms such as stimulation of the immune system, competition for binding sites on intestinal epithelial cells, and secretion of bactericidin. Irritable bowel syndrome (IBS), a chronic condition characterized by recurrent attacks of abdominal discomfort, bloating, and abnormal bowel habits, has been effectively treated with probiotic organisms in several trials. Administration of probiotic organisms also holds promise for treating inflammatory bowel disorder (IBD), a chronic, recurrent, multifactorial disorder that causes inflammation of the intestinal tract, resulting in severe diarrhea and abdominal pain; IBD occurs in the intestinal tract and includes diagnoses of ulcerative colitis (affecting the colon and rectum) and Crohn's disease (affecting any part of the gastrointestinal tract). Mechanisms for the efficacy of probiotic administration in these conditions include their competitive interactions with pathogenic flora and their effects on the immune system. IBS and IBD have also been treated with certain prebiotic substances (e.g., hydrolyzed guar gum), raising the possibility that a synbiotic approach may produce even better therapeutic responses. Probiotics have also been used to treat non-gastrointestinal conditions, such as allergies, cancer, AIDS, respiratory and urinary tract infections, cardiovascular disease and hypercholesterolemia, metabolic diseases, etc. Rectal delivery of probiotic organisms is typically reserved for the treatment of severe diseases, as described in more detail below, while oral administration is used for the treatment of milder diseases and to achieve health benefits.

[0224] The use of the orally ingestible delivery system described herein can protect live organisms as they pass through the stomach and proximal intestine en route to their target destination. Thus, the oral route of administration can be used for serious diseases, where delivery of live organisms in sufficient quantities and to a designated anatomical location can be important. The oral route can also be used for health purposes, where more precise doses of live organisms are delivered and their viability is more stable. One example described in more detail herein is the delivery of probiotic bacteria using these systems and methods. Probiotic bacteria can be delivered by commercially available food products, but foods such as cheese, yogurt, milk, etc. do not deliver many live bacteria to their targets because the bacteria they contain cannot survive the physiological conditions in the stomach and intestine. Conventional pharmaceutical products use delivery systems such as beads, capsules, and tablets in an attempt to deliver live functional bacteria to their targets in sufficient numbers to achieve the desired health benefits. However, typically more than 10% of the bacteria are required to exert the desired health-related effects. 8 ~10 9 A dose of healthy bacteria must reach the intestine, but tests have shown that up to 60% of live bacteria orally administered by conventional formulations can be killed in the stomach. The orally ingestible delivery system disclosed herein provides an oral delivery route for probiotic bacteria that protects them from the conditions in the stomach, allowing them to reach their target areas in the large or small intestine alive and in sufficient numbers to provide their intended beneficial effects.

[0225] In embodiments, probiotic bacteria can be advantageously combined with prebiotic substances or other agents that can enhance the viability or efficacy of live organisms. As previously described, probiotic organisms can be combined with prebiotic substances to enhance their viability and / or therapeutic efficacy, delivered together in a single ingestible delivery system or delivered separately in another delivery system. The synergistic effect of the combination of probiotic organisms and prebiotic substances (e.g., in a synbiotic formulation) can provide therapeutic benefits. In embodiments, probiotic organisms can be combined with other agents that enhance their viability and / or therapeutic efficacy, and the combination is ...

Claims

1. 1. An orally ingestible delivery formulation for releasing a therapeutic agent in the intestine of a mammal, comprising a therapeutic agent and a differentially permeable capsule system containing the therapeutic agent in a therapeutic agent compartment, The differentially permeable capsule system exhibits different permeabilities in the stomach and in the intestine; the differentially permeable capsule system is dimensionally adapted for oral ingestion and passage into the stomach and then the intestine of a mammal; The differentially permeable capsule system comprises an acid resistant shell and a dispersible acid barrier; a dispersible acid barrier is disposed at a location selected from the group consisting of an exterior surface of the acid-resistant shell, an interior surface within the acid-resistant shell, and an underlying region beneath the acid-resistant shell, said dispersible acid barrier inhibiting contact between the acid-resistant shell and gastric fluids within the stomach; A dispersive acid barrier is formed when the formulation is in the stomach; The dispersible acid barrier disperses in the intestine, allowing enzymes in the intestine to reach the therapeutic compartment, thereby releasing the therapeutic in the intestine. Formulations for oral delivery.

2. 2. The formulation of claim 1, wherein the acid-resistant shell is an acid-resistant protease-digestible membrane.

3. 10. The formulation of claim 1, wherein the acid-resistant shell comprises a waxy material.

4. 10. The formulation of claim 1, wherein the acid-resistant shell comprises fibers.

5. 5. The formulation of claim 4, wherein the fiber is digestible or hydrolyzable.

6. 4. The formulation of claim 3, wherein the acid-resistant shell consists essentially of a waxy material.

7. 2. The formulation of claim 1, wherein the dispersible acid barrier is a gas barrier.

8. 8. The formulation of claim 7, wherein the gas barrier is formed by reaction of gastric acid with a gas generating substance, the gas generating substance being disposed on at least one of an exterior surface of the acid-resistant shell, an interior surface within the acid-resistant shell, and a lower region beneath the acid-resistant shell.

9. 9. The formulation of claim 8, wherein the acid-resistant shell is perforated by a system of pores containing a deposit of the gas generating substance.

10. 8. The formulation of claim 7, wherein the gas barrier comprises carbon dioxide.

11. 11. The formulation of claim 10, wherein the gas barrier is dispersed by interaction of carbon dioxide and bicarbonate in the intestine.

12. The formulation of claim 1 , wherein the acid-resistant shell comprises a space-occupying fluid or a space-occupying solid.

13. 13. The formulation of claim 12, wherein the space-occupying fluid or solid is disposed within the system of pores.

14. 13. The formulation of claim 12, wherein the space-occupying fluid is a non-polar liquid.

15. 13. The formulation of claim 12, wherein the space-occupying solid reacts with gastric fluids to produce a second space-occupying fluid comprising a liquid or a gas.

16. 16. The formulation of claim 15, wherein the space-occupying solid comprises a solid bicarbonate and the gas comprises carbon dioxide.

17. 10. The formulation of claim 1, further comprising a protective layer disposed on the exterior of the exterior surface of the acid-resistant shell.

18. 18. The formulation of claim 17, wherein the protective layer is a sacrificial protective layer.

19. A formulation according to any one of claims 1 to 18 for use in intestinal delivery of a therapeutic agent, comprising: After oral administration, the formulation is exposed to gastric acid which interacts with the formulation to form a dispersive acid barrier; After passage into the intestine, the dispersible acid barrier is dispersed by interaction with intestinal fluid, which penetrates the acid resistant shell after the dispersible acid barrier is dispersed, releasing the therapeutic agent from the therapeutic agent compartment.

20. 20. The formulation of claim 19, wherein intestinal fluid compromises the integrity of the acid-resistant shell, thereby facilitating release of the therapeutic agent from the therapeutic agent compartment.

21. 20. The formulation of claim 19, wherein the therapeutic agent is susceptible to degradation in the stomach.

22. 22. The formulation of claim 21, wherein the therapeutic agent is a protein or peptide.

23. 22. The formulation of claim 21, wherein the therapeutic agent is a living organism.

24. 1. A formulation for orally ingestible delivery comprising an acid resistant shell surrounding a therapeutic agent compartment, further comprising a space occupying fluid or space occupying solid disposed at a location selected from the group consisting of an exterior surface of the acid resistant shell, an interior surface within the acid resistant shell, and an underlying region beneath the acid resistant shell, A formulation in which the space-occupying fluid or solid provides a mechanical obstacle to penetration of the acid-resistant shell by gastric acid.

25. 25. The formulation of claim 24, wherein the acid-resistant shell is perforated by a system of pores.

26. 26. The formulation of claim 25, wherein at least a portion of the space-occupying fluid or solid is within the pore system.

27. 25. The formulation of claim 24, wherein the therapeutic agent compartment is dimensionally adapted to contain a deliverable therapeutic agent.

28. 28. The formulation of claim 27, wherein the therapeutic agent compartment is hollow.

29. 30. The formulation of claim 28, wherein the therapeutic agent compartment comprises a deliverable therapeutic agent.

30. 30. The formulation of claim 29, wherein the deliverable therapeutic agent comprises at least one therapeutic agent.

31. 25. The formulation of claim 24, wherein the space-occupying fluid or solid is an acid-reactive material.

32. 32. The formulation of claim 31, wherein the acid-reactive material comprises a gas-forming material that produces or releases gas upon contact with hydrochloric acid in the stomach, the gas providing a mechanical obstacle to penetration of the acid-resistant shell by gastric acid.

33. 33. The formulation of claim 32, wherein the gas is carbon dioxide.

34. 1. A formulation for orally ingestible delivery comprising a digestible capsule system surrounding a therapeutic agent compartment, The digestible capsule system comprises an acid resistant shell and a dispersible acid barrier; a dispersive acid barrier is disposed at a location selected from the group consisting of an exterior surface of the acid-resistant shell, an interior surface within the acid-resistant shell, and a lower region beneath the acid-resistant shell; a dispersible acid barrier prevents at least one of acids and enzymes from reaching the therapeutic compartment and compromising the integrity of the therapeutic compartment; A formulation in which the dispersible acid barrier, once formed, is dispersible upon exposure to components of the duodenal fluid; and the therapeutic agent compartment comprises a deliverable therapeutic agent.

35. 35. The formulation of claim 34, wherein the dispersible acid barrier comprises a space-occupying solid or a space-occupying fluid.

36. 36. The formulation of claim 35, wherein the space-occupying fluid is a gas.

37. 36. The formulation of claim 35, wherein the space-occupying solid or space-occupying fluid comprises an acid-reactive substance.

38. 37. The formulation of claim 36, wherein the space-occupying solid or space-occupying fluid generates a second space-occupying material upon contact with acid in the stomach, and the second space-occupying material forms, in whole or in part, a dispersible acid barrier.

39. 40. The formulation of claim 38, wherein the second space-occupying material is a gas.

40. 35. The formulation of claim 34, wherein the integrity of the therapeutic compartment is compromised by enzymatic activity following dispersion of the dispersible acid barrier.

41. 35. The formulation of claim 34, wherein the component of the duodenal fluid is a bicarbonate or a bile salt.

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