阅读说明：本技术 用于将治疗剂递送到胃壁中的装置、系统和方法 (Devices, systems, and methods for delivering therapeutic agents into the stomach wall ) 是由 米尔·伊姆兰 于 2020-02-28 设计创作，主要内容包括：本发明的实施例提供了用于在GI道内和具体地向窦壁(AW)递送药物和其它治疗剂(TA)的可吞咽装置、制剂和方法。特定实施例提供了一种用于将药物或其它TA递送到AW的可吞咽装置(SD),如胶囊。所述SD可以容纳压敏组件或组合件,所述压敏组件或组合件响应于外部压力,如因窦收缩而施加到所述可吞咽胶囊或其它SD的压力而触发将包括至少一种TA的治疗剂制剂(TAP)释放和插入到所述AW中。所述SD的特定实施例可以成形为使得其在窦内自对齐以在所述TAP插入到所述AW中之前恰当地定向。本发明的实施例特别可用于口服递送在所述GI道内降解并且需要肠胃外注射的药物或其它TA。(Embodiments of the present invention provide swallowable devices, formulations and methods for the delivery of drugs and other Therapeutic Agents (TA) within the GI tract and specifically to the sinus wall (AW). Particular embodiments provide a Swallowable Device (SD), such as a capsule, for delivering drugs or other TAs to an AW. The SD may house a pressure sensitive component or assembly that triggers the release and insertion of a therapeutic agent formulation (TAP) comprising at least one TA into the AW in response to external pressure, such as pressure applied to the swallowable capsule or other SD due to sinus constriction. Particular embodiments of the SD can be shaped such that they self-align within the sinus to properly orient before the TAP is inserted into the AW. Embodiments of the invention are particularly useful for oral delivery of drugs or other TAs that degrade within the GI tract and require parenteral injection.)

1. A swallowable device for delivering a therapeutic agent formulation into a sinus wall of a patient's stomach, the device comprising:

a swallowable capsule having a capsule wall, wherein the therapeutic agent formulation is retained inside the capsule;

a driver within the capsule configured to advance the therapeutic agent formulation through the capsule wall and into the sinus wall;

a sensor operatively coupled to the capsule wall, the sensor sensing when the capsule wall is being squeezed by peristaltic contractions of the sinuses; and

a trigger operatively coupled to the sensor and the driver, wherein the trigger causes the driver to advance the therapeutic agent formulation through the capsule wall and into the sinus wall when the sensor senses that the capsule is being squeezed due to the peristaltic contraction of the sinuses, and wherein the therapeutic agent formulation is advanced through the capsule wall when at least a portion of the capsule is being squeezed due to the peristaltic contraction of the sinuses.

2. The device of claim 1, wherein the swallowable capsule wall comprises a cylindrical shell.

3. The device of claim 1, wherein at least a portion of the capsule wall is degradable in the patient's intestinal tract.

4. The device of claim 3, wherein the at least a portion of the capsule wall degrades at a pH equal to or greater than about 6.5.

5. The device of claim 1, wherein at least a portion of the capsule wall is not degradable in the gastrointestinal tract of the patient.

6. The device of claim 1, wherein the driver comprises a propellant.

7. The device of claim 6, wherein the propellant comprises nitrocellulose.

8. The device of claim 1, wherein the driver comprises a balloon.

9. The device of claim 1, wherein the driver comprises a compression spring.

10. The device of claim 1, comprising at least two drivers configured to drive the therapeutic agent formulation in at least two directions.

11. The device of claim 10, wherein at least two drivers configured to drive the therapeutic agent formulation in at least two diametrically opposed directions.

12. The apparatus of claim 1, wherein the sensor comprises an electronic transducer that generates a pressure signal representative of an external pressure on the capsule wall.

13. The apparatus of claim 12, wherein the trigger comprises electronic circuitry that receives the pressure signal from the sensor and generates a trigger signal when the pressure exceeds a predetermined threshold.

14. The device of claim 13, wherein the predetermined threshold ranges from about 300 to 1100 dynes/cm²。

15. The device of claim 14, wherein the predetermined threshold ranges from about 300 to 900 dynes/cm²。

16. The apparatus of claim 14, wherein the predetermined threshold ranges from about 835 to 1086 dynes/cm²。

17. The device of claim 1, wherein the sensor comprises a mechanical or fluidic sensor element that changes state in response to a change in external pressure on the capsule wall exceeding a threshold.

18. The device of claim 17, wherein the trigger comprises a mechanical or fluidic trigger element that responds to a change in state of a mechanical or fluidic sensor and mechanically releases the driver to advance the therapeutic agent formulation through the capsule wall and into the sinus wall.

19. The device of claim 17, wherein the threshold ranges from about 300 to 1100 dynes/cm²。

20. The device of claim 1, wherein the therapeutic agent formulation comprises a solid dosage form configured to be advanced into the sinus wall by the driver.

21. The device of claim 20, wherein the solid dosage form comprises a therapeutic agent formed or mixed with at least one of an excipient or a binder into an elongate member having a tapered, sharp, or pointed tip.

22. The device of claim 1, wherein the therapeutic agent comprises a liquid dosage form that is advanced by the driver through the hollow needle into the intestinal wall.

23. A method for delivering a therapeutic agent into a sinus wall of a stomach of a patient, the method comprising:

providing a swallowable capsule having a therapeutic agent formulation comprising the therapeutic agent retained therein;

wherein the patient ingests the swallowable capsule;

wherein the capsule passes through the patient's stomach and into the patient's antrum while maintaining a therapeutic agent formulation therein;

wherein the capsule senses pressure externally applied to an outer surface of the capsule due to constriction of the sinuses; and is

Wherein the capsule injects the therapeutic agent formulation into the sinus wall when the sensed pressure exceeds a predetermined threshold.

24. The method of claim 23, wherein the predetermined threshold is selected based on a peak pressure applied by the sinus wall.

25. The method of claim 24 wherein the predetermined threshold is about 50-95% of the peak pressure applied by the sinus wall.

26. The method of claim 23 wherein the capsule is elongated and has an axis that is substantially aligned with a luminal direction of the antrum of the patient as the capsule passes from the stomach into the antrum, wherein the therapeutic agent formulation is injected from the capsule into the antrum wall in a lateral direction.

27. The method of claim 23, wherein the pressure is sensed by an electronic pressure transducer incorporated into a wall of the swallowable capsule.

28. The method of claim 27, wherein the electronic transducer is coupled to a means for triggering a propellant to advance the therapeutic agent formulation into the sinus wall when the sensed pressure exceeds the predetermined threshold.

29. The method of claim 23, wherein the pressure is sensed by a mechanical or fluid pressure transducer incorporated into the swallowable capsule.

30. The method of claim 29, wherein the mechanical or fluid transducer is coupled to trigger a balloon or compression spring to advance the therapeutic agent formulation into the sinus wall when the sensed pressure exceeds the predetermined threshold.

31. The method of claim 23, wherein the therapeutic agent formulation is injected from the capsule in at least two different directions.

32. The method according to claim 31, wherein said therapeutic agent formulation is injected from said capsule in at least two diametrically opposed directions.

33. The method of claim 23, the predetermined threshold ranging from about 300 to 1100 dynes/cm²。

34. A swallowable device for delivering a therapeutic agent formulation into a sinus wall of a patient's stomach, the device comprising:

a capsule sized to pass through the patient's gastrointestinal tract, the capsule having a wall including opposing sides and opposing ends, the capsule having an elongated shape configured to be longitudinally oriented within a sinus of the stomach during peristaltic contraction of the sinus such that a side of the capsule wall is adjacent the wall of the sinus;

a therapeutic formulation in the capsule, the therapeutic formulation including a therapeutic agent and being shaped as a tissue penetrating member;

a sensor disposed in a sidewall portion of the capsule wall, the sensor configured to sense a force applied to the capsule by the sinus wall corresponding to peristaltic contractions of the sinuses and to generate an output; and

an ejection member operatively coupled to the tissue-penetrating component and the sensor, the ejection member configured to eject the tissue-penetrating component from the capsule into sinus wall tissue in response to the output from the sensor.

35. The swallowable device of claim 34, wherein the ejection means comprises mechanical ejection means.

36. The swallowable device of claim 35, wherein the mechanical ejection means comprises an energy storage mechanism or a spring.

37. The swallowable device of claim 34, wherein the ejection member comprises a chemical ejection member.

38. The swallowable device of claim 37, wherein the chemical ejection means comprises a chemical reactant, a chemical reactant impregnated fiber or membrane, a nitrate impregnated fiber or membrane, or nitrocellulose.

39. The swallowable device of claim 34, wherein the sensor is a pressure sensor or a mechanical pressure sensor.

40. An ingestible device for delivering a therapeutic agent formulation into the wall of a patient's stomach, the device comprising:

a capsule sized to pass through an intestinal tract, the capsule having a wall with opposing sides and opposing ends, the capsule having an elongated shape configured to be longitudinally oriented within a sinus of the stomach during peristaltic contraction of the stomach such that a side of the capsule wall is adjacent to the wall of the sinus;

a therapeutic formulation in the capsule, the formulation including a therapeutic agent and being shaped as a tissue penetrating member;

a sensor disposed in a sidewall portion of the capsule wall, the sensor configured to sense a force applied to the capsule by the sinus wall and to generate an electrical output;

a logic component configured to analyze the electrical output from the sensor and generate a trigger signal upon detection of a peristaltic contraction in the sinus; and

an ejection member operatively coupled to the tissue-penetrating component and the logic member, the ejection member configured to eject the tissue-penetrating component from the capsule into stomach wall tissue in response to the trigger signal, and wherein the tissue-penetrating component is ejected from the capsule when the sinuses are in a peristaltic contraction state.

41. The device of claim 40, wherein the logic means comprises a processor or an analog device.

42. The device of claim 40, wherein the spray member comprises a mechanical spray member.

43. The device of claim 42, wherein the mechanical spray member comprises an energy storage mechanism, a spring, a coil spring, or a leaf spring.

44. The device of claim 43, wherein the ejection member further comprises a trigger configured to be triggered by the trigger signal.

45. The device of claim 44, wherein the trigger comprises an electromechanical trigger or a solenoid.

46. The apparatus of claim 40, wherein the spray member comprises a chemical spray member.

47. The device of claim 46, wherein the chemical injection member comprises a chemical reactant, a chemical reactant impregnated fiber or membrane, a nitrate impregnated fiber or membrane, or nitrocellulose.

48. The device of claim 47, wherein the ejection member further comprises a trigger configured to be triggered by the trigger signal.

49. The device of claim 48, wherein the trigger comprises an igniter.

50. The device of claim 40, wherein the ejection member comprises an electromechanical mechanism.

51. A swallowable device for delivering a therapeutic agent formulation into a wall of a Gastrointestinal (GI) tract of a patient, the device comprising:

a swallowable capsule having a capsule wall, wherein the therapeutic agent formulation is retained inside the capsule;

a driver within the capsule configured to advance a therapeutic agent through the capsule wall and into the GI wall;

a sensor operatively coupled to the capsule wall, the sensor sensing when the capsule is being squeezed by peristaltic contraction of the GI wall; and

a trigger operatively coupled to the sensor and the driver, wherein the trigger causes the driver to advance a therapeutic agent through the capsule wall and into the GI wall when the sensor senses that the capsule is being squeezed due to the peristaltic contraction of the GI wall, and wherein the therapeutic agent formulation is advanced through the capsule wall when at least a portion of the capsule is being squeezed due to the peristaltic contraction of the GI wall.

Technical FieldEmbodiments of the present invention relate to swallowable drug delivery devices. More particularly, the present invention relates to swallowable drug delivery devices for delivering therapeutic agents into the antrum or other portions of the stomach wall.

Although the development of new drugs for the treatment of various diseases has increased in recent years, many drugs including proteins, antibodies, peptides and other labile agents are limited in use because they cannot be administered orally and thus generally require intravenous administration or other forms of parenteral administration (e.g., intramuscular, etc.) to avoid degradation. The inability to deliver drugs orally may be due to any one of a number of reasons including: poor oral tolerance with complications including gastric irritation and bleeding; drug compounds are decomposed/degraded in the stomach; and poor, slow or unstable drug absorption.

Conventional alternative drug delivery methods, such as intravenous and intramuscular delivery, have a number of disadvantages, including: pain and infection risk from needle sticks; the use of aseptic techniques is required; and the requirement to maintain an intravenous line (IV line) in the patient for an extended period of time and its associated risks. While other drug delivery methods, such as implantable drug delivery pumps, have been employed, these methods require semi-permanent implantation of the device and may still have many of the limitations of IV delivery.

Accordingly, there is a need for additional, alternative, and improved methods, devices, and articles of manufacture for oral delivery of drugs and other therapeutic agents. In particular, it is desirable to provide delivery vehicles and configurations that allow for oral administration of a drug and subsequent injection or other delivery of the drug into the walls of the patient's antrum and other target regions of the patient's Gastrointestinal (GI) tract.

US2017/0265598 describes an implantable system that injects drugs into the sinuses of a patient to induce contractions as part of obesity treatment. Patents and published patent applications having co-inventors and/or common ownership with the present application describing swallowable capsules for injection of a medicament into the intestinal or other wall in the GI tract include US9,149,617; US 2011/0208270; and US 20120010590. Published PCT application WO2018/213582 describes a capsule having a spring-loaded medicament structure for injecting a medicament into the stomach wall.

Background

Disclosure of Invention

Various embodiments of the present invention provide devices, systems, articles of manufacture, formulations, kits and methods for delivering drugs or other therapeutic agents into the wall of a patient's stomach, including the antral wall or other wall of the patient's GI tract. In many embodiments, the present invention provides swallowable capsules and other swallowable devices suitable for the delivery of drugs and other labile therapeutic agents that are poorly absorbed, poorly tolerated, and/or degraded in the Gastrointestinal (GI) tract, such as proteins, polypeptides, and antibodies. While particularly useful for injecting such labile therapeutic agents into the walls of the antrum of the stomach, embodiments of the present invention will also find use with other agents and be introduced to other locations in the GI tract, such as the small intestine wall, large intestine wall, buccal surface in the oral cavity and other parts of the patient's body.

In many embodiments, the present invention provides a swallowable drug delivery device (also described herein as a swallowable device) that may incorporate a sensor such as a pressure sensor or other mechanism or sensing member that may detect when the swallowable device has entered the antrum of the stomach. Particular embodiments include swallowable devices, such as capsules, for delivering drugs and other therapeutic agents into the walls of the gastric antrum of a patient. For example, the device may be a swallowable capsule configured to detect or respond to pressure exerted on the exterior of the device by the constriction of the sinuses, and to inject or otherwise deliver a therapeutic agent while the capsule is in the sinuses. Such swallowable capsules and other devices are typically further configured to self-align when in the antrum such that the drug or other therapeutic agent is injected from the capsule into the adjacent wall of the antrum in a predetermined direction. Preferably, the direction is substantially perpendicular to the wall of the antrum or other wall portion of the stomach or GI tract. However, other orientations are contemplated, such as at a 45 angle. In particular embodiments, the range of directions may be about 45 ° across either side of the longitudinal axis of the sinus wall.

Embodiments of the present invention are particularly useful for delivering drugs and other therapeutic agents in solid dosage forms, particularly those that would otherwise be degraded or otherwise lose their biological activity by exposure to the digestive fluids of the GI tract without being delivered into the GI wall tissue. Other embodiments may be used to deliver liquids, gels, powders, and other conventional pharmaceutical agent/drug forms, particularly those that would otherwise be degraded or otherwise lose their biological activity by exposure to the digestive fluids of the GI tract without delivery into the GI wall tissue. Exemplary solid dosage forms will generally be self-penetrating, e.g., having a sharp, pointed, tapered, or other shaped distal tip to facilitate penetration of the surface of the antrum (antrum) or other lumen wall of the GI tract. Hereinafter, such self-penetrating solid dosage forms are sometimes referred to herein as Tissue Penetrating Members (TPMs). Many embodiments of the present invention will enable rapid release of drugs into the bloodstream by oral delivery with minimal or no degradation due to passage through any part of the GI tract.

In a first particular aspect, embodiments of the invention include a swallowable device for delivering a therapeutic agent formulation into a wall of the GI tract, such as the antral wall of the stomach (also known as antrum wall), of a patient. The device may include a swallowable capsule or other housing having a capsule wall, with the therapeutic agent formulation held within the capsule or other housing. A driver is also housed within the capsule and configured to advance the therapeutic agent through the capsule wall and into the sinus wall or other GI wall upon detection of a selected condition surrounding the capsule, such as proximity of the capsule to the sinus wall and/or amount of pressure or force exerted by the sinus wall onto the capsule wall, particularly an amount of pressure or force indicative of peristaltic contraction of the sinus wall surrounding the capsule. Sensors on or within the swallowable device sense when the capsule wall is adjacent to the sinus (or other GI) wall, such as occurs when the sinus wall contracts (e.g., squeezes a portion of the capsule) around a portion of the capsule due to peristaltic contraction. The driver is configured to advance the therapeutic agent through the capsule wall and into the stomach wall when the sensor senses that the capsule wall is adjacent to a antral wall or other GI wall. In particular embodiments, the proximity of the capsule to the sinus wall, e.g., due to peristaltic contraction around a portion of the capsule, may be determined by the amount of force applied by the sinus wall to the capsule wall ranging from about 200 to 3100 dynes, with a narrower range described in more detail herein. In many embodiments, the driver and the sensor are configured to respond quickly enough (e.g., within tenths of a second or less) to advance the therapeutic agent into the sinus wall while the sinus (or other GI wall) is contracting (e.g., squeezing) around or otherwise in contact with at least a portion of the capsule wall.

In particular aspects and embodiments, the swallowable capsule wall may comprise a cylindrical shell, wherein the capsule may or may not be degradable in all or part of the GI tract of the patient. In exemplary embodiments herein, for example, the capsule wall may be made in whole or in part of a material that degrades in specific regions of the GI tract, including, for example, enteric materials that degrade at a pH equal to or greater than about 6.5 but remain intact in the stomach, particularly the antrum where the pharmaceutical other therapeutic agent disposed or carried by the capsule will typically be released.

An exemplary driver according to the present invention may include a mechanical, chemical, or other component capable of selectively delivering drugs or other therapeutic agents into the sinus wall (or other wall of the GI tract) in response to a trigger from the sensor. For example, according to one or more embodiments, the driver can be a compression spring, can be a balloon, or can be another mechanical component capable of storing and/or generating energy as needed to propel the therapeutic agent. Alternatively, in disclosed embodiments, the driver may comprise a chemical propellant material that can release sufficient energy to drive a mechanical element to advance the therapeutic agent through the capsule wall. In certain embodiments described in more detail below, the actuator includes nitrocellulose or other chemical propellant that can be ignited by an electrical or other ignition or ignition source.

In various embodiments, the swallowable device of the present invention may comprise two or more drivers configured to drive the therapeutic agent in at least two directions, optionally three drivers, four drivers, or more drivers that may direct the therapeutic agent in three, four, or more directions. The at least two drivers may be further configured to drive the therapeutic agent in at least two diametrically opposed directions. Similarly, when three or more drivers are used, the drivers may direct the therapeutic agent in a symmetrical or asymmetrical pattern.

Suitable sensors according to the present invention may include electronic sensors that may generate a signal indicative of proximity, such as external pressure on a wall or other external region of the swallowable capsule. The electronic sensor may comprise a solid state pressure transducer, such as a piezoelectric transducer, or other transducer that may be miniaturized to fit in or through the capsule wall. Other sensors that may be used to detect proximity include one or more of capacitive, resistive (electrical) or optical based sensors.

When electronic sensors such as piezoelectric or other pressure/force transducers are employed, the swallowable device will typically further include a controller or other electronic circuitry (analog or digital) that receives pressure/force or other sensor signals from the sensors and generates trigger signals when the swallowable capsule is adjacent the sinus (or other section of the GI wall). For example, the proximity status may be determined when a pressure sensor detects a pressure that exceeds a predetermined threshold. Such thresholds for the application force encountered when the swallowable capsule is located in the sinus of a patient will typically range from about 200 to 3100 dynes, will typically range from 200 to 750 dynes, and will often range from about 400 to 750 dynes of the application force. For the widest range of forces, it may correspond to about 300 to 1100 dynes/cm²The pressure of (a). Such threshold forces may be of particular concern when the capsule is ingested in the fed versus the fasted state. In the eating state, the trigger threshold may range from about 570 to 750 dynes of applied force (corresponding to about 835 to 1086 dynes/cm)²Pressure) corresponding to a range of about 200 to 610 dynes of applied force (corresponding to about 300 to 900 dynes/cm) in the fasted state²Pressure of). One or more of the above-mentioned forces may be converted into a pressure using equations and computational methods known in the art of medical sensors. Further description of forces and pressures in the GI tract can be found in the following papers: laulichta et al, entitled "Understanding gastric strength by high resolution pill tracking" (acquired and calculated from high-resolution pill tracking) ", journal of the national academy of sciences (PNAS), 2010, 5/4, 107, 18, 8201-8206, which is incorporated herein by reference in its entirety for all purposes.

In other embodiments, the pressure or other proximity sensor may comprise a mechanical fluidic element that changes state in response to proximity or a change in external pressure on a wall or other external region of the swallowable capsule. In such cases, the trigger would include a mechanical or fluidic trigger element that responds to a change in state of a mechanical or fluidic sensor and mechanically releases the driver to advance the therapeutic agent formulation through the capsule wall and into the sinus wall or other GI wall. In a preferred embodiment, the trigger and the driver are configured to sense and respond quickly enough to advance the therapeutic agent through the capsule wall and into the sinus wall while the capsule wall is still proximate to the sinus wall (or other wall of the GI tract). Such mechanical or fluid sensor elements will typically be configured to respond to the same pressure/force ranges set forth above that are characteristic of the sinuses. However, other forces are also contemplated.

In many cases, the therapeutic agent delivered by the swallowable device will comprise a solid dosage form having a tissue penetrating end that is advanced by the driver into the intestinal wall. Such solid dosage forms typically include an active agent compressed or otherwise formed with at least one of an excipient or binder into an elongate member having a tapered, sharp, or pointed tip at one end thereof, which may be straight or curved. However, other shapes are also contemplated. In other cases, the therapeutic agent may comprise a liquid dosage form or other non-solid form that is advanced into the intestinal wall by the drive or associated device through a hollow needle or other syringe. Also, in one or more instances, the therapeutic agent may include a biomolecule or biological substance (e.g., a cell) that would otherwise be chemically degraded by digestive fluids (e.g., intestinal fluids) in the GI tract if not delivered to the sinus wall or other lumen wall of the GI tract. Such biomolecules may comprise various biological agents comprising one or more of proteins, antibodies, polypeptides, and other molecules produced by a cell or other biological process.

In a second particular aspect, embodiments of the invention provide a method for delivering a therapeutic agent into a sinus wall of a patient's intestinal tract, the method comprising providing a swallowable capsule having a therapeutic agent formulation retained therein. The patient ingests the swallowable capsule and the capsule passes through the patient's stomach and into the patient's antrum. When in the stomach, the therapeutic agent remains inside the swallowable capsule, and upon entering the antrum, the capsule senses pressure externally applied to an outer surface of the capsule due to constriction of the antrum. The capsule is configured such that when the sensed pressure exceeds a predetermined threshold and/or contraction frequency, it injects the therapeutic agent into the sinus wall. In a particular embodiment, the capsule is configured to sense peristaltic contractions with a particular application force/pressure and contraction frequency.

The predetermined threshold will typically be selected based on the peak pressure exerted by the sinus wall, although other pressures and physiological events are also contemplated. The peak pressure may be an average of a population or, in other cases, may be determined for a particular patient. In either case, the threshold value selected to trigger release of the therapeutic agent will typically range from about 50% to 95% of the peak pressure expected to be exerted by the sinus wall, will often be from 60% to 90% of the peak pressure, will often be from 75% to 85% of the peak pressure, and will often be about 80% of the peak pressure. As described above, the trigger threshold or event may include a contraction frequency in addition to the sensed peak pressure. In one or more embodiments, the triggered contraction frequency may correspond to a range of 3 to 6 contractions per second, more preferably 3 to 4 contractions per second, and still more preferably about 3 contractions per second, corresponding to a contraction motion of the sinuses that tightly constrict around the food in an abrasive motion that is part of the sinus pump function described herein. In certain embodiments, the capsule will remain in the sinus in an undeployed state until the necessary number of contractions has been sensed to determine the frequency of the contractions (e.g., by the processor or other logic means), at which time the capsule will eject the therapeutic agent into the sinus wall. In a related embodiment, the capsule remains in the sinus until the necessary number of contractions is sensed, having a peak or% (e.g., 50% to 95% etc.) of the peak pressure described herein. According to some embodiments, the patient may first swallow a test capsule or capsule mimic that does not necessarily contain a trigger and a therapeutic agent, but rather its primary function is to record the pressures exerted on the capsule by multiple sinus peristaltic contractions and then calculate and transmit to an external device various information related to those contractions, including one or more of average peak peristaltic pressure, frequency and period of contractions. This information may then be downloaded from an external device to a processor or other control module incorporated into the capsule, and then used to trigger or otherwise control the release of the therapeutic agent into the sinus wall.

The swallowable capsule will typically be configured such that it self-aligns when present in the sinuses, particularly when the sinuses undergo contraction, such as from peristaltic contractions. For example, the capsule may be elongate, such as cylindrical with rounded distal and proximal ends, and have an axis that aligns with the direction of the lumen of the patient's antrum as the capsule passes from the stomach into the antrum. By orienting the capsule in this manner, the therapeutic agent can be injected in a lateral or other preselected direction (e.g., at an acute angle, such as 45 °) relative to the longitudinal axis of the capsule, resulting in greater accuracy in the entry of the therapeutic agent into a given location on the sinus wall.

The force/pressure resulting from the sinus wall contracting around the capsule may be sensed in various ways. For example, according to one embodiment, the swallowable capsule may include an electronic pressure transducer, such as a solid state piezoelectric transducer, incorporated into a wall of the swallowable capsule. In such cases, the electronic transducer may be coupled to a device or other means for triggering a propellant to propel the therapeutic agent formulation into the sinus wall when the sensed pressure exceeds a predetermined threshold. In some embodiments, the electronic transducer may be directly or otherwise operatively coupled to the propellant to trigger the propellant to propel the therapeutic agent into the sinus wall.

In other cases, the pressure may be sensed by a mechanical or fluid pressure transducer incorporated into the swallowable capsule, for example, into the capsule wall. Such mechanical or fluid transducers may be coupled to a device or other means for triggering a balloon, compression spring, or other such mechanical element to advance a therapeutic agent into the sinus wall when the sensed pressure exceeds a predetermined value. In some embodiments, the mechanical or fluid pressure transducer may be directly or otherwise operatively coupled to a balloon, compression spring, or other such mechanical element to trigger the balloon, compression spring, or other such mechanical element to advance the therapeutic agent into the sinus wall.

In still other cases, the therapeutic agent may be injected from the capsule in at least two directions. For example, the therapeutic agent may be injected from the capsule in two diametrically opposite directions, such that the forces acting on the capsule when injecting the agent balance each other. In use, such embodiments improve the reliability of the drug entering the sinus wall (or other location in the GI tract) by counteracting any forces (e.g., recoil forces) that tend to push the capsule away from the sinus surface when a solid drug dose is ejected from the capsule by a driver such as nitrocellulose or other combustible chemical propellant, in addition to delivering an increased amount of the drug.

In all such methods, the therapeutic agent may be in various forms, including, for example, solid dosage forms, liquid dosage forms, or other forms such as powders, gels, and the like, as well as combinations of any of the forms mentioned above. In preferred cases, the therapeutic agent will be in a solid dosage form having a self-penetrating distal tip to facilitate advancement to the sinus wall or other wall portion of the GI tract. However, other embodiments contemplate the form of a solid therapeutic agent without a self-penetrating distal tip. For solid dosage forms of the therapeutic agent, the size and shape of the solid dosage form may be adjusted to the particular targeted delivery area in the GI tract, e.g., the sinus wall.

In yet another aspect of the present invention, a swallowable device for delivering a therapeutic agent formulation into a wall of a patient's stomach (e.g., a sinus wall) or other portion of the GI tract includes a capsule, a therapeutic agent, a sensor, and a spray member. The capsule is sized to pass through the gastrointestinal tract of a patient and has a wall with opposing sides and opposing ends. Preferably, the capsule has an elongated shape configured to be longitudinally oriented within a antrum of the stomach during peristaltic contractions of the stomach such that a side of the capsule wall is adjacent to a wall of the antrum. The capsule carries a therapeutic agent, typically including a therapeutic agent shaped as a Tissue Penetrating Member (TPM). Disposed in a side wall portion of the capsule wall is a sensor configured to sense force/pressure applied by the sinus wall to the capsule wall (or other exterior region of the capsule) due to peristaltic contraction of the sinuses and generate an output corresponding to the pressure/force otherwise containing information about the sensed pressure/force. A jet member is operatively coupled to the sensor and the tissue-piercing member. When a sensor senses a selected amount of force/pressure applied from the sinus wall (or other GI wall portion) to the capsule wall (or other capsule exterior region), the sensor generates an output that causes the injection member to desirably inject the tissue penetrating member through the capsule wall and into the sinus wall (or other wall of the GI tract or surrounding tissue) while the capsule wall is still proximate to the sinus wall (or other wall of the GI tract). In this way, the ejector member may eject the tissue penetrating member from the capsule into sinus wall tissue in response to the output of the sensor. The amount of pressure/force to trigger the ejection member is desirably selected to improve or enhance delivery of the tissue-penetrating component into the sinus wall (or other GI wall), for example, by ensuring that the sinus wall is in close proximity and/or that the capsule is being squeezed with sufficient force to cause the tissue-penetrating component to enter the sinus wall (or other GI wall).

The spray member may comprise any energy storage mechanism, such as a spring, a compressed air spring, a chemical reservoir, or the like. In particular embodiments, the injection member includes a chemical, such as a combustible propellant or other reactant that can be ignited to release energy to drive the tissue-piercing member into the tissue. For example, the sparging member can comprise one or more of a chemical reactant, a chemical reactant-impregnated fiber, a chemical reactant-impregnated membrane, a nitrate-impregnated fiber or membrane, nitrocellulose, and the like.

In various embodiments, the pressure sensor may be an electronic pressure sensor, a mechanical pressure sensor, or a combination thereof. In an exemplary embodiment, the pressure sensor comprises a solid state piezoelectric sensor calibrated to detect pressure within the ranges set forth above. Also, according to some embodiments, the patient may first take a test or measurement capsule that is separately configured to measure the pressure/force applied to the capsule wall due to sinus constriction (e.g., it does not contain a therapeutic agent, driver, ejection member, etc.) and then transmit the data to an external device. In particular embodiments, the pressure sensor and/or other proximity sensor may be positioned in close proximity (e.g., about 1 to 5mm) to where the solid drug dose (e.g., in the form of a tissue penetrating member) is away from the capsule, such that the accuracy with which the sinus wall does come into contact with the capsule surface when the driver is triggered to eject the solid drug dose into the sinus wall is improved. In this manner, the reliability of the solid drug dose being delivered to the sinus wall or other desired location in the GI tract is increased. In still other embodiments, the ejection member may comprise, for example, a bellows (or similar structure) having opposing surfaces for advancing a pair of tissue-piercing members in opposite directions.

In yet another embodiment, a swallowable capsule for delivering a therapeutic agent formulation into a wall of a stomach of a patient includes a capsule, a therapeutic formulation, a sensor, a logic member, and an ejection member. The capsule, the therapeutic agent, the sensor and the ejection member may be as just described. The logic means is configured to analyze the electrical output from the pressure sensor and generate a trigger signal upon detection of a peristaltic condition in the antrum (or stomach or other portion of the GI tract). According to various embodiments, the logic means may correspond to a microprocessor or other digital processor or analog device.

In some embodiments, the TPM contains a drug or other therapeutic agent and is configured to be inserted into a sinus wall or other intestinal wall by inflation of a driving component such as a pushing element, delivery balloon, or other inflatable delivery member. The TPM typically comprises a shaft containing a proximal portion detachably coupled to a delivery device, a tissue penetrating distal portion, and optionally a retention feature for retaining the tissue penetrating member within a sinus or other region of the intestinal wall. The tissue penetrating end is generally tapered, chamfered or otherwise formed or sharpened to enhance tissue penetration when driven into tissue. The tissue retention features may be hooks, barbs, prongs, etc. that allow advancement into tissue but resist retraction from tissue. In various embodiments, the TPM need not contain retention features, but may be shaped or otherwise configured to be retained in the stomach or intestinal wall without retention features.

The TPM will typically be formed, at least in part, from a therapeutic agent formulation that includes a drug or other therapeutic agent configured to dissolve or otherwise be absorbed within the intestinal wall to deliver the therapeutic agent formulation to the bloodstream of a patient. The therapeutic agent formulation may also include one or more pharmaceutical excipients known in the art, such as disintegrants, binders and the like. Desirably, the TPM is configured to penetrate a selected distance into the stomach, intestinal wall, or surrounding tissue of either to deliver a therapeutic agent to a particular tissue layer of the intestinal wall, such as a mucosal layer, submucosa, or the like. This may be accomplished by using a stop positioned on the TPM shaft and/or configuring the TPM shaft to bend or even shear once it penetrates a selected distance in the intestinal wall.

Typically, the drug or other therapeutic agent delivered by the TPM may be mixed with a biodegradable polymer such as PEO (polyethylene oxide), PGLA and/or a sugar such as maltose. In such embodiments, the TPM may comprise a substantially heterogeneous mixture of a drug and a biodegradable polymer. Alternatively, the penetrating member may comprise a portion formed substantially of a biodegradable polymer and a separate section or compartment formed of or containing the drug or other therapeutic agent. For example, in one embodiment, the TPM may comprise a shell of biodegradable material having a hollow core that is fitted with a small portion (e.g., cylindrical in shape) of a therapeutic agent. The tip or tissue penetrating portion of the TPM may comprise a relatively hard material such as sugar or a metal (e.g., magnesium) to enable easy penetration of tissue, including, for example, tissue in the sinus wall or other wall of the intestinal tract (e.g., the wall of the small intestine). Once placed in the stomach wall (e.g., sinus wall) or other wall of the GI tract, the tissue-penetrating component is degraded by interstitial fluid within the wall tissue, and the drug dissolves in that fluid and is absorbed into the blood stream through capillaries in or around the stomach, intestine, or other GI wall tissue (e.g., peritoneum). The TPM may also contain one or more tissue retention features, such as barbs or hooks, to retain the penetrating member within tissue of the stomach wall or other wall of the GI tract (e.g., intestinal wall) after advancement. The retention features may be arranged in various patterns to enhance tissue retention, such as two or more barbs symmetrically distributed about the component axis. However, the TPM may also be held in the stomach wall or other GI tract wall by other means, such as by an inverted cone or other shape. The reverse taper may also be combined with one or more retention features to further enhance retention.

The drug or other therapeutic agent may be in solid form and then formed into the shape of the tissue-penetrating member using molding or other similar methods, or may be in solid or liquid form and then added to the biodegradable polymer in liquid form, and the mixture then formed into the Tm using molding or other forming methods known in the polymer art. Desirably, embodiments of tissue-penetrating components comprising a drug and a degradable polymer are formed (e.g., cured) at temperatures that do not produce any significant thermal degradation of the drug, including drugs such as various peptides and proteins. This can be achieved by using room temperature curing polymers and room temperature molding and solvent evaporation techniques known in the art. In particular embodiments, the amount of thermally degraded drug within the tissue penetrating member is desirably less than about 10% by weight, more preferably less than 5%, and still more preferably less than 1%. The thermal degradation temperature of a particular drug is known or can be determined using methods known in the art, and such temperatures can then be used to select and adjust a particular polymer processing method (e.g., molding, curing, solvent evaporation, etc.).

In other aspects, the invention provides therapeutic agent formulations for delivery into the wall of the small intestine (or other wall of a lumen in the GI tract) using embodiments of the swallowable devices described herein. The formulations include a therapeutically effective dose of at least one therapeutic agent (e.g., insulin, incretins, anti-epileptic compounds, NSAIDs, antibiotics, etc.). The formulations may include solids, liquids, gels, and combinations thereof, and may contain one or more pharmaceutical excipients. The formulation has a shape and material consistency to be contained in a swallowable capsule, delivered from the capsule into the lumen wall, and degraded within the lumen wall to release a dose of the therapeutic agent. Typically, such shape and material consistency is achieved by placing or forming the formulation into one or more embodiments of the tissue-piercing member described herein. The formulation may also have a selectable surface area to volume ratio to enhance or otherwise control the rate of degradation of the formulation in the wall of the small intestine or other body cavity. The dose of the drug or other therapeutic agent in the formulation can be titrated down from the dose required for conventional oral delivery methods so that potential side effects of the drug can be reduced.

In another aspect, the present invention provides methods for delivering drugs and therapeutic agents into the walls of the patient's antrum and other regions of the GI tract using embodiments of the swallowable drug delivery device. Such methods can be used to deliver therapeutically effective amounts of a variety of drugs and other therapeutic agents. These include many macromolecular peptides and proteins that would otherwise require injection due to chemical breakdown in the stomach, such as growth hormone, parathyroid hormone, insulin, interferon (for treatment of MS and other conditions), and other similar compounds. Suitable drugs and other therapeutic agents that can be delivered by embodiments of the invention include various antibodies (e.g., HER 2 antibodies), chemotherapeutic agents (e.g., interferon), insulin and related compounds used to treat diabetes, glucagon-like peptides (e.g., GLP-1, exenatide), parathyroid hormone, growth hormones (e.g., IFG and other growth factors), immunosuppressive agents (e.g., cyclosporine, cortisone, etc.), vaccines, and antiparasitic agents such as various antimalarial agents. In particular embodiments, embodiments of the swallowable capsule may be used to deliver a therapeutically effective amount of the monoclonal antibody adalimumab (adalimumab) for the treatment of various autoimmune-related conditions, such as rheumatoid arthritis. The dose of this or a particular therapeutic agent may be titrated against the patient's weight, age, condition, or other parameter.

In various method embodiments of the invention, embodiments of the swallowable drug delivery device may be used to deliver multiple drugs (e.g., a mixture of protease inhibitors for the treatment of HIV AID) for the treatment of multiple conditions or for the treatment of a single condition, particularly those conditions that require or benefit from the delivery of multiple drugs. In use, such embodiments allow a patient to forgo the necessity of having to take multiple drugs for one or more particular conditions. Moreover, it provides a means to facilitate delivery and absorption of two or more drugs by a regimen into the small intestine and thus into the bloodstream at about the same time. Due to differences in chemical composition, molecular weight, etc., drugs can be absorbed through the intestinal wall at different rates, resulting in different pharmacokinetic profiles. Embodiments of the present invention address this problem by injecting the desired drug mixture at about the same time. This in turn improves the pharmacokinetics and, therefore, the efficacy of the selected drug mixture.

Further details of these and other embodiments and aspects of the invention are described more fully below with reference to the accompanying drawings.

Drawings

FIG. 1A illustrates a region of the Gastrointestinal (GI) tract and particularly the stomach of a patient associated with the devices and methods of the present invention.

FIG. 1B illustrates an anatomical region of a patient's stomach.

FIG. 1C illustrates the functional area of the patient's stomach.

Fig. 2A illustrates the major components of a swallowable drug delivery device constructed in accordance with the principles of the present invention.

Fig. 2B illustrates a test capsule for measuring pressure in the GI tract of a patient.

Fig. 3 illustrates the major components of a particular embodiment of a swallowable drug delivery device constructed in accordance with the principles of the present invention.

Fig. 4 is a graph illustrating a typical pressure profile in the antrum of a patient during normal digestive processing of food.

Figures 5A-1 to 5F-2 illustrate the treatment of a swallowable capsule in the antrum of a patient, as shown in figures 5D-1 and 5D-2, which results in the injection of a therapeutic agent into the antral wall.

Detailed Description

Embodiments of the present invention provide devices, systems and methods for delivering drugs, substances, drugs, etc. into the sinus wall or other locations in the body. As used herein, the terms "therapeutic agent," "medicament," "drug" and "drug" are used interchangeably and refer to any pharmaceutical formulation intended for therapeutic, diagnostic or other bioactive purposes in any form, which may contain a drug or other therapeutic agent and one or more pharmaceutical excipients. Many embodiments of the present invention provide a swallowable device for delivering a drug within the GA or other regions of the GI tract. Certain embodiments provide an ingestible device, such as a capsule, for delivering a pharmaceutical product into a wall of a sinus in response to pressure exerted on the capsule by the constriction of the sinus.

The devices, systems and methods of the present invention are particularly useful for delivering drugs to specific regions within the GI tract, including, for example, portions of the stomach wall, such as the sinus wall. Further, the devices, systems, and methods are also suitable for delivering drugs into the sinus wall even when partially digested food is present in the stomach. After the digestive process begins in the stomach, partially digested food enters the fundus or body and then penetrates into the antrum. In the antrum GA (also referred to as antrum a), the devices and methods of the present invention will preferably deliver a therapeutic agent into the wall of the antrum. After delivery of the therapeutic agent, the device will pass through the pyloric sphincter PS and into the duodenum D, from where the intact, partially degraded, or fully degraded device passes through the large intestine and is expelled from the body.

Because many embodiments of the present invention contemplate the delivery of drugs and other therapeutic agents to the wall of the GI tract, including the wall of the antrum of the stomach, a brief description of the anatomy and function of the GI tract, including the stomach, will now be provided. As shown in FIG. 1A, the GI tract begins in the esophagus E and enters the stomach S at the cardia C. Food thus enters the stomach through the esophagus after passing through the cardia. As shown in fig. 1B, the major anatomical regions of the stomach include the fundus F, the body B, the antrum (a), and the pylorus P. Although the walls of the floor are thin, the walls of the sinuses are much thicker (due to the muscle layer), thereby readily allowing delivery of the solid drug dose embodiments described herein. However, the functional area of the stomach does not correspond to an anatomical area. As shown in fig. 1C, functionally, the stomach may be divided into a stomach reservoir GR and a stomach pump GP. The gastric reservoir comprises a base F and a body B. The gastric pump is represented by the region where the peristaltic wave appears: the region includes a distal portion of the body and a sinus. Due to the different properties of smooth muscle cells, the gastric reservoir is characterized by tonic activity, and the gastric pump is characterized by phasic activity called peristaltic waves. The main feature of gastric pumps is the peristaltic wave. The peristaltic wave originates in the proximal stomach and propagates to the pylorus. The peristaltic wave is based on an electric wave originating in the stomach wall. In the walls of both the stomach and the small intestine, there is a network of stromal cells, known as Cajal stromal cells (ICC). These mesenchymal cells produce electrical pacing potentials due to oscillations in their membrane potential. The pacing potential of the ICC drives electrical events in the smooth muscle cells at which slow waves are reflected. The frequency of the pacing potentials and the resulting peristaltic contractions occur approximately three times per minute or about 20 seconds. The pacing potential determines the maximum frequency and propagation speed of the peristaltic wave. In the region of the stomach body, the peristaltic wave is shallow; they represent the pump of the gastric reservoir as mentioned above. When the peristaltic wave reaches the sinus (a), the sinus's circular constriction becomes deeper, causing the sinus to develop into a tubular shape in which forces are applied to the sinus's contents. The evacuation mechanism of the sinus pump can be divided into three phases: 1) a propulsion phase, 2) an evacuation and mixing phase, and 3) a retreat and grinding phase. A brief explanation of the three stages will now be provided. As the peristaltic wave moves over the proximal sinus, the previously contracted distal sinus relaxes. This results in chyme and other gastric contents being advanced into the distal (or distal) middle antrum, which corresponds to the phase of advancement. When the peristaltic wave moves over the middle of the antrum, the pylorus opens and duodenal constriction is inhibited; thus, a small amount of stomach chyme is delivered across the pylorus into the duodenum. During this emptying and mixing phase, the peristaltic wave is relatively far away from the pylorus, i.e. gastric chyme is not pressed into the duodenum by pressure, but is swept into the small intestine by the peristaltic wave. This mechanism of sinus pump is associated with the sieving effect. In particular, the sinuses become tubular in shape, allowing liquid and small particles to flow from the pylorus into the duodenum, while more solid matter, including embodiments of the swallowable capsule 10, remains in the sinuses as a result of being blocked by the relatively small opening of the pylorus. When so held during this sinus contraction phase, the forces that contract the sinuses are applied to the surface of the capsule where they can be sensed using pressure or other sensors 12 described below.

In accordance with one or more embodiments, a swallowable capsule or other swallowable device 10 for delivering a therapeutic agent into the lumen wall of the GI tract may contain a pressure or other proximity sensor 12, an actuator 14, and a drug dose 16 to be delivered, as shown in fig. 2A. The nature of these particular components can vary widely depending on the mode of drug delivery and the targeted drug delivery area within the GI tract. For example, the pressure or other proximity sensor 12 may be mechanical, electrical, or a combination thereof, depending on whether the device 10 is intended for delivery in the stomach or small intestine. The sensor 12 will typically be capable of sensing the force/pressure externally applied to the swallowable capsule 10, and in particular will be capable of sensing when pressure is being applied to the exterior of the capsule due to the constriction of the sinuses. It will be appreciated that the pressure exerted by the sinuses is unique within the GI tract, and may be relied upon to sense that the pressure exceeds a minimum threshold to indicate that the swallowable capsule 10 has reached the interior of the sinuses.

The driver 14 may also have any of a variety of forms. Furthermore, it may rely on mechanical, electrical, chemical or other stored energy to initiate release of the therapeutic agent from the capsule, as indicated by the dashed arrows shown in fig. 2A. The driver 14 will be coupled to the pressure or other proximity sensor 12 such that the driver will be actuated in response to the pressure sensor sensing a pressure above a predetermined threshold, indicating that the swallowable capsule 10 has reached the interior of the sinus of the patient. In some cases, the sensor and the driver may be configured to convert pressure applied due to a constriction of the antrum into a force that drives the drug into the wall of the antrum.

Referring now to fig. 3, a particular embodiment of an ingestible capsule 24 having the operative components of the present invention is shown in greater detail. A solid state pressure sensor 26, such as a solid state piezoelectric element, is typically mounted in the outer wall of the capsule. According to a particular embodiment, the pressure sensor 26 or other proximity sensor 12 may be positioned very close (1 to 5mm) to where the solid drug dose 40 (e.g., the problem penetration component TPM) exits the capsule 24 (e.g., where the cylinder 36 is positioned in the capsule), such that the accuracy with which the sinus wall does come into contact with the capsule surface when the driver 14 is triggered to inject the solid drug dose into the sinus wall is improved. In this manner, the reliability of the solid drug dose 40 being delivered into the sinus wall or other desired location in the stomach or other portion of the GI tract is improved. The pressure sensor 26 is connected to a control module 28 (also referred to herein as a controller 28) in the interior of the capsule. The control module 28 will typically include or contain a microprocessor (and associated software executable on the processor) configured to control all (or part) of the operation of the swallowable capsule 24 as described in more detail below. In an alternative or additional embodiment, the control module 28 may also correspond to a simulation device. In some embodiments, the swallowable capsule 24 will also have a fluid or other sensor 30 for confirming when the swallowable capsule has been swallowed and is in the stomach in order to turn on the capsule power to begin sensing pressure by the pressure sensor. In accordance with one or more embodiments, the fluid sensor 30 may correspond to electrodes disposed on the surface of the capsule or other locations on the capsule that sense a conductive bridge between the electrodes through the digestive juices in the stomach to confirm when the capsule has entered the stomach. In use, the fluid sensor 30 serves to conserve power of the battery or other power source 48 so that the capsule begins consuming power to sense pressure applied to the capsule through the surface only after the capsule has been swallowed.

The swallowable capsule 24 is surrounded by a capsule wall 32 that encloses an interior holding a pair of drug delivery modules 34. Each drug delivery module 34 contains a cylinder 36 having a reciprocating piston 38 therein. As shown in fig. 3, the piston 38 is initially retracted so that there is space near the bottom of the associated cylinder 36. The space may be filled with a chemical propellant 44 and may have a coil or other igniter 46 therein. In this manner, the control module 28 may electrically ignite the propellant 44, thereby driving the solid dose medicament 40 in the direction shown in phantom in fig. 3. The swallowable capsule 24 will also typically carry a chemical storage battery (e.g., a lithium battery) or other power source 48 to power the control module 28, the igniter 46, and other components. In some embodiments, the power supply 48 may correspond to a capacitor. In particular embodiments where the driver corresponds to nitrocellulose or other ignitable chemical propellant being ignited by the igniter, the igniter may have its own dedicated power supply 48', which typically corresponds to a capacitor configured to provide sufficient current and voltage to ignite the igniter 46.

The drug dose 16 may have various forms including solid, liquid, powder, gel, and combinations thereof. In many embodiments, at least a portion of the dose 16 will be in solid form and/or carried by a solid carrier. Typically, the solid form of the medicament dose 16 and/or its carrier is self-penetrating, typically having a sharp, sharp or other tissue penetrating tip. In many embodiments, such self-penetrating forms of dose 16 and/or its carrier are in the form of tissue penetrating members 40. Details of the tissue-penetrating member 40 and other such solid dosage forms 16 of therapeutic agents are provided in greater detail below.

According to particular embodiments, pressure sensor 26 and control module 28 may be configured and programmed to sense changes in external pressure/force applied to the capsule wall due to the peristaltic motion of the sinus wall known as sinus peristalsis. Sinus peristalsis typically involves a series of pressure waves, as shown in FIG. 4, with peak pressure P_p. A particular peak pressure value may be determined for a population of patients and/or for a particular patient, and a pressure value less than the peak pressure may be selected at which to initiate delivery of the therapeutic agent from the swallowable capsule 24. For example, the trigger pressure may be 80% of the peak pressure value, as shown by P in FIG. 4_0.8. It is contemplated that other trigger pressure values (e.g., peak pressure P) may be selected_p70%, 85%, 90%, etc.). As described in accordance with some embodiments, the peak pressure may be determined by configuring the capsule to remain in the sinus for several peristaltic contractions of the sinus and configuring the controller 28 and or control module to record the sinus pressure applied through several cycles of the peristaltic contractions, and then calculate the average peak pressure and other information related to the sinus peristaltic contractions, including the average contraction frequency and contraction period. According to some embodiments, the patient may first swallow a test capsule or capsule mimic 24 '(fig. 2B) that does not necessarily house the driver 14 and therapeutic agent 40, but rather whose primary function is to record the pressures applied to the capsule by the multiple sinus peristaltic contractions 24' (or peristaltic contractions in other locations of the GI tract) and then calculate and transmit to an external device (e.g., a cell phone or tablet) various information related to those contractions, including one or more of average peak peristaltic pressure, contraction frequency, and contraction period, among others. Typically, the test capsule 24 'will have a pressure or related sensor 25 positioned on or operatively coupled to its outer surface for measuring such pressure data and internal circuitry (not shown) for recording and/or transmitting observed pressure data as the test capsule 24' travels through the GI tract. The acquired data or information may then be input from an external device to a control module 28 (e.g., a processor or other logic component) incorporated into or otherwise associated with the capsule 24, and then used to trigger, modify, or otherwise control the release of the therapeutic agent into the sinus wall. In these and related embodiments, control module 28 may contain or otherwise be operatively coupled to memory means (e.g., ram, dram, volatile memory, etc.) for storing acquired data in the operation of the device and/or application software executable on the controller/processor, as well as transmission means such as RF transmission devices as are known in the art. In particular embodiments, the RF transmitter/transceiver device may be configured to use a bluetooth communication protocol for communicating with external devices such as cell phones, tablets, and the like.

Referring now to fig. 5A-1 through 5F-2, the delivery of a swallowable capsule 10 to the sinus wall in accordance with the principles of the present invention will be described. Initially, the antrum GA is empty, while the sinus wall AW is undergoing peristaltic contraction and thus contracting, as shown in FIGS. 5B-1 and 5B-2. The patient then ingests the swallowable capsule 10, and the capsule eventually approaches the antrum GA, as shown in fig. 5C-1 and 5C-2. When the swallowable capsule 10 enters the antrum GA, the stomach wall will contract outside the capsule, as shown in fig. 5D-1 and 5D-2. The pressure/force exerted by the sinus wall AW on the exterior of the capsule 24 is then sensed by the pressure/force sensor 26, causing (e.g., by using the control module 28) the solid dosage form 40 to be released through the wall of the capsule and into the sinus wall AW, as shown in fig. 5D-1 and 5D-2.

In particular embodiments, control module 28 or other circuitry may be configured to measure and store pressure/force versus time curves of several peristaltic contractions from the sinus wall in order to develop a database of pressure/force curves of sinus contractions of an individual patient, particularly occurring during one or more stages of the sinus pump described above. As further described below, various information including parameters such as the peak peristaltic pressure/force applied to the capsule (or a selected peak pressure, e.g., 80%) and the frequency and/or period of peristaltic contractions of the sinuses may be derived from the pressure/force curve by control module 28 or logic means. In various embodiments, one or a combination of two of these or other parameters may be used by control module 28 to trigger release of tissue-penetrating member 40 into the sinus wall. In particular methods, control module 28 may be configured to trigger release of tissue-piercing member 40 using both a selected percentage of peak systolic pressure and a selected systolic period. When using one or more of these methods, the capsule is better able to sense when peristaltic waves/peristaltic contractions of the sinuses (or other GI walls) occur, which results in a desired amount of contraction and/or contact of the sinuses on the capsule 10. In this manner, the reliability of delivery of the tissue penetrating member 40 (or other form of the drug dose 16) into the sinus wall (or other portion of the stomach or GI tract) is significantly improved.

In various embodiments, the size and shape of the capsule 24 may be desirably set or the capsule may be otherwise configured to remain in the sinuses during several phases of peristaltic contractions of the sinus pump, such that the capsule may sense and record multiple peristaltic contractions of the sinuses in order to derive information of sinus contractions specific to a particular patient, including average peak sinus peristaltic pressure applied to the capsule and the frequency and/or period of the sinus peristaltic contractions. This can be achieved by various methods. For example, according to one approach, the diameter of the capsule 24 may be sized such that it is slightly larger than the diameter of the pyloric sphincter that is only partially open. In additional or alternative embodiments, the capsule 24 may be configured to remain in the antrum during peristaltic contractions that might otherwise press the capsule out of the antrum a or sphincter PS by using various surface coatings or surface features to enhance or improve the sinus grip or retention on the wall 32 of the capsule 24 during contractions of the antrum or other portions of the stomach or GI wall around at least a portion of the capsule. The coating may comprise a pressure activated bioadhesive coating comprising a pressure activated bioadhesive with weak adhesion as known in the art. Such surface features may include various textured surfaces known in the art, including knurled surfaces, which increase the coefficient of friction between the sinus surface and the capsule surface when the capsule is grasped by the sinuses, thereby increasing the amount of force required to press the capsule distally out of the sinuses and/or reducing movement of the capsule within the sinuses during peristaltic or other contractions of the sinuses or other GI walls. In use, such surface coatings or features improve the reliability of advancing the tissue-penetrating member 40 (or other carrier or form of the drug dose 16) into the sinus wall during peristaltic contractions.

The sinus wall will continue to undergo peristalsis, eventually releasing swallowable capsule 10, as shown in fig. 5E-1 and 5E-2. If the capsule 10 has not completely degraded, it will pass through the pyloric sphincter PS (also described as the pyloric valve PS) and into the duodenum D, as shown in FIGS. 5F-1 and 5F-2. After passing through the pyloric sphincter PS and into the duodenum D, the capsule 10 is eventually expelled from the patient.

Referring back to fig. 3, in various embodiments, the swallowable capsule 24 containing the tissue penetrating member 40 may be configured for delivery of a liquid, semi-liquid, or fixed form of a drug or a combination of all three forms of a drug. Regardless of the form, the drug product desirably has a material consistency that allows the drug product to be pushed out of the swallowable capsule 24, into a target location on a sinus or other GI wall (e.g., small intestine), and then to degrade within the wall to release the drug or other therapeutic agent into the wall and/or surrounding tissue and further into the patient's bloodstream. The material consistency of the pharmaceutical product may comprise one or more of the hardness, porosity and solubility of the formulation (in body fluids). The material and dimensions of the tissue penetrating member or other drug dosage 40 may also be optimized for a particular target location in the GI tract. For example, to deliver a longer tissue-penetrating member into the sinus wall, a stiffer tissue-penetrating member may be used so as to penetrate through more of the muscle of the sinus wall. Material consistency may be achieved by selecting and using one or more of the following: i) compaction force for preparing the formulation; ii) using one or more pharmaceutical disintegrants known in the art; iii) use of other pharmaceutical excipients; iv) particle size and distribution of the formulation (e.g., micronized particles); and v) using micronization and other particle formation methods known in the art.

The swallowable capsule 24 is sized to be swallowed through the GI tract and across it at least to the sinuses. However, in certain embodiments, the diameter of the capsule may be sized such that the capsule remains in the antrum when the pyloric sphincter is only partially open. The size may also be adjusted depending on the amount of drug to be delivered as well as the weight of the patient and the adult and pediatric applications. In additional or alternative methods, the capsule may further comprise a surface coating and features described herein to help retain the capsule in the antrum when the pyloric sphincter is only partially open. Typically, the capsule will have a tubular shape similar to the curved ends of the vitamin. In these and related embodiments, the capsule length may range from 0.5 to 2 inches and the diameter may range from 0.1 to 0.5 inches, and other dimensions are contemplated. The swallowable capsule 24 includes a capsule wall 32 having an outer surface and an inner surface defining an interior space or volume. In some embodiments, the capsule wall may contain one or more apertures sized for outward advancement of the tissue-piercing member 40.

The swallowable capsule 24 will typically, but not necessarily, be made of a biodegradable material such as gelatin as is known in the pharmaceutical art, and may contain an enteric coating configured to protect the capsule from degradation in the stomach and antrum (due to acids, etc.) and then subsequently in the higher pH found in the small intestine or other regions of the intestinal tract. In various embodiments, the swallowable capsule 24 may be formed of multiple portions or segments (e.g., two halves), one or more of which may be biodegradable.

As discussed above, one or more portions of capsule 24 may be made from various biocompatible polymers known in the art, including various biodegradable polymers, which may include cellulose, gelatin materials, PGLA (polylactic-co-glycolic acid) in preferred embodiments. Other suitable biodegradable materials include the various enteric materials described herein as well as lactide, glycolide, lactic acid, glycolic acid, p-dioxanone, caprolactone, trimethylene carbonate, caprolactone, blends and copolymers thereof.

The use of biodegradable materials for the swallowable capsule 24, including biodegradable enteric materials, allows the capsule to be fully or partially degraded to facilitate passage through the GI system before, during, or after drug delivery. As described in further detail herein, in various embodiments, the swallowable capsule 24 may contain a seam 22 of biodegradable material so as to controllably degrade into smaller pieces 23 that more readily pass through the intestinal tract.

In various embodiments, the swallowable capsule 24 may contain various radiopaque, echogenic, or other materials for positioning the device using medical imaging modalities such as fluoroscopy, ultrasound, MRI, and the like. In particular embodiments, all or a portion of the capsule may contain a radiopaque/echogenic coating. Materials suitable for radiopaque markers include barium sulfate, compounds, titanium dioxide, and compounds thereof. In use, such materials allow for positioning of the swallowable capsule 24 and its deployed state in the GI tract (e.g., unique markers may be positioned on each end on the wall 32 and optionally elsewhere), allowing for visual confirmation that the swallowable capsule 24 has been properly aligned in the sinus prior to release of the therapeutic agent. Such materials may also be used to allow determination of the transit time of the device through the GI tract. Such information may be used to titrate a medication dose for a particular patient and, for example, in the case of taking insulin for the treatment of diabetes, provide information on when the particular patient should take a particular medication after an event such as ingestion of a meal.

Tissue-penetrating member 40 may be made of various drugs and other therapeutic agents, one or more pharmaceutical excipients (e.g., disintegrants, stabilizers, etc.), and one or more biodegradable materials (e.g., PEO) that may be used to form the primary structural component of a TPM containing a shaft with a tip, as discussed below and described in detail in the following documents: U.S. patent No. 9,757,548; 8,562,589 No; 8,809,269 No; 8,969,293 No; 8,809,271 No; 8,980,822 No; 9,861,683 No; 9,259,386 No; 9,284,367 No; 9,149,617 No; 8,734,429 No; 9,283,179 No; 8,764,733 No; 9,402,806 No; 9,629,799 No; 9,415,004 No; 9,402,807 No; 8,846,040 No; 10,098,931 No; and No. 10,220,003; and U.S. application serial No. 15/144,733; 15/150,379, respectively; 15/260,260, respectively; 15/928,606, respectively; 16/183,573, respectively; and co-pending provisional application No. 62/786,831, having co-inventors with the present application, the entire disclosure of which is incorporated herein by reference for all purposes.

The particular material may be selected to impart desired structural and material properties to the penetrating member (e.g., breaking strength for insertion into the stomach or intestinal wall, or porosity and hydrophilicity to control disintegration of the penetrating member and thus release of the drug). In many embodiments, the penetrating member 40 may be formed with a shaft and a needle tip or other pointed tip to easily penetrate tissue of the sinus or other intestinal wall, as shown, for example, in FIGS. 5D-1 and 5D-2. In an exemplary embodiment, the tip has a trocar and may include various degradable materials such as sucrose, maltose or other sugars (within the body of the tip or as a coating) that increase the hardness and tissue penetration characteristics of the tip. Once placed in the intestinal wall, the penetrating member 40 is degraded by interstitial fluid within the wall tissue, such that the drug or other therapeutic agent dissolves in those fluids and is absorbed into the blood stream. One or more of the size, shape, and chemical composition of tissue-penetrating component 40 may be selected to allow for dissolution and absorption of the incorporated drug within seconds, minutes, or even hours. The dissolution rate can be controlled by using various disintegrants known in the pharmaceutical art. Examples of disintegrants include, but are not limited to, various starches such as sodium starch glycolate and various cross-linked polymers such as carboxymethyl cellulose. The choice of disintegrant may be specifically adjusted according to the environment within the wall of the small intestine, e.g. blood flow, average number of peristaltic contractions, etc.

The tissue-piercing member 40 may also generally include one or more tissue retention features, such as barbs or hooks, to retain the piercing member within tissue of the sinus or other region of the intestinal wall after advancement. The retention features may be arranged in various patterns to enhance tissue retention, such as two or more barbs that are symmetrical or otherwise distributed about or along the component axis. Additionally, in many embodiments, the penetration component may also include a recess or other mating feature for attachment to a coupling assembly on the delivery mechanism. Such features are described in more detail in U.S. patent No. 8,734,429, previously incorporated herein by reference.

The tissue-penetrating member 40 is desirably configured to be detachably coupled to the piston 38 such that the tissue-penetrating member is separated from the piston after the tissue-penetrating member 40 is advanced into the sinus wall. Detachability may be implemented in a variety of ways, including: i) the closeness or fit between the openings in the piston; ii) the configuration and placement of tissue retaining features on the tissue-piercing member 40 that anchor the tissue retaining features of the tissue-piercing member are tissue for facilitating separation from the piston; and iii) the depth of penetration of the tissue-penetrating member into the intestinal wall. Using one or more of these factors, the tissue-penetrating member 40 may be configured to separate when the piston is retracted from or otherwise pulled back away from the sinus wall and/or by the force of peristaltic or other contractions of the sinus on the swallowable capsule 24.

As described above, in various embodiments, tissue-penetrating members 40 may be made from a variety of drugs and other therapeutic agents. Moreover, according to one or more embodiments, the tissue-penetrating component may be made entirely of a drug, or may also have other constituent components, such as various pharmaceutical excipients (e.g., binders, preservatives, disintegrants, etc.), polymers that impart desired mechanical properties, and the like. Further, in various embodiments, one or more of the tissue-penetrating members 40 may carry a drug (or other therapeutic agent) that is the same as or different from the drug (or other therapeutic agent) carried by the other tissue-penetrating members. The former configuration allows for the delivery of a greater amount of a particular drug, while the latter configuration allows for the delivery of two or more different drugs into the sinus wall at about the same time to facilitate drug treatment regimens that require the delivery of multiple drugs in large amounts at the same time.

Typically, the drug or other therapeutic agent carried by the tissue-penetrating member 40 will be mixed with the biodegradable material to form the tissue-penetrating member 40. The biodegradable material may comprise one or more biodegradable polymers such as PEO (polyethylene oxide), PGLA, cellulose, and the like, as well as sugars such as maltose or other biodegradable materials described herein or known in the art. In such embodiments, the penetrating member 40 may include a substantially heterogeneous mixture of the drug and the biodegradable material. Alternatively, the tissue-penetrating member 40 may comprise a portion substantially formed of a biodegradable material and a separate segment substantially formed of or containing a drug, described herein as a drug segment. Such individual drug segments may include shaped segments that may be pre-formed into individual segments that are then inserted into cavities in tissue-piercing member 40 to allow for modular manufacturing. Alternatively, the drug and/or drug formulation may be introduced into the cavity in the tissue penetrating member 40, for example, by combining the drug and/or drug formulation into a powder, liquid, or gel that is poured or injected into the cavity, hole, hollow interior, or other container in the tissue penetrating member 40. The shaped sections 42s may be formed from the drug itself or a pharmaceutical formulation containing the drug and one or more binders, preservatives, disintegrants, and other excipients.

In various embodiments, the weight of tissue-penetrating members 40 may range between about 10 and 15mg, with larger and smaller weights contemplated. For embodiments of the tissue-penetrating member 40 made of maltose, the weight may range from about 11 to 14mg, while for PEO, the weight of the tissue-penetrating member may range from 10 to 15 mg. In various embodiments, the weight percentage of the drug in the component 40 may range from about 0.1% to about 15%, depending on the drug and desired delivered dose. The weight percentage of the drug in the component 40 may be adjusted depending on the desired dosage and according to the structural and stoichiometric stability of the drug provided and also according to achieving a desired drug elution profile. Table 1 lists the dosage and weight percent ranges of various drugs that may be delivered by tissue-penetrating component 40.

TABLE 1

Medicine	Dosage through capsules	Weight% of the drug in the needle
			Insulin	5-30 units	2-15％
Exenatide	10ug	<1％
			Liraglutide (Liraglutide)	0.6mg	3-6％
Pramlintide (Pramlintide)	15-120ug	0.1-1％
			Growth hormone	0.2-1mg	2-10％
Somatostatin	50-600ug	0.3-8％
			GnRH and analogues	0.3-1.5mg	2-15％
Vasopressin	2-10 units	<1％
			PTH/Teriparatide (Terispatide)	20ug	1-2％
Interferon and analogs
			1. For multiple sclerosis	0.03-0.25mg	0.1-3％
2. For hepatitis B and hepatitis C	6-20ug	0.05-0.2％
			Adalimumab	2-4 mg/day	8-12％
Infliximab (Infliximab)	5 mg/day	8-12％
			Etanercept (Etanercept)	3 mg/day	8-12％
Natalizumab (Natalizumab)	3 mg/day	8-12％

Tissue-penetrating members 40 may be formed using one or more polymers and pharmaceutical techniques known in the art. For example, the drug (with or without the biodegradable material) may be in solid form and then formed into the shape of the tissue-penetrating member 40 using molding, compaction, or other similar methods and the addition of one or more adhesives. Alternatively, the drug and/or drug formulation may be in solid or liquid form and then added to the biodegradable material in liquid form, and then the mixture formed into the penetrating member 40 using molding or other forming methods known in the polymer art.

Desirably, embodiments of tissue-penetrating component 40 that include a drug or other therapeutic agent and a degradable material are formed at temperatures that do not produce any significant thermal degradation of the drug (or other therapeutic agent) including drugs such as various peptides and proteins. This can be achieved by using room temperature curing polymers and room temperature molding and solvent evaporation techniques known in the art. In particular embodiments, the amount of thermally degraded drug or other therapeutic agent within the tissue penetrating member is desirably less than about 10% by weight, and more preferably less than 5%, and still more preferably less than 1%. The thermal degradation temperature of a particular drug is known or can be determined using methods known in the art, and such temperatures can then be used to select and adjust a particular polymer processing method (e.g., molding, curing, solvent evaporation methods, etc.) to minimize the temperature and associated level of thermal degradation of the drug.

Following drug delivery, the swallowable capsule 24 (containing some or all of the pressure sensor 26, control module 28, and drug delivery module 34) may be passed from the sinuses through the intestinal tract, including the small and large intestines, and eventually expelled. For embodiments of the capsule 24 having a biodegradable seam or other biodegradable portion, the capsule degrades into smaller pieces in the intestinal tract to facilitate passage through the intestinal tract and expulsion from the intestinal tract. In certain embodiments having a biodegradable tissue penetrating needle/member 40, if the needle is stuck in the stomach wall, intestinal wall (small or other large) or other location in the GI tract, the needle will biodegrade, releasing the capsule 24 from the stomach or intestinal wall.

One or more embodiments of the above-described methods can be used to deliver formulations containing therapeutically effective amounts of various drugs and other therapeutic agents to treat various diseases and conditions. These include many macromolecular peptides and proteins that would otherwise need to be injected due to chemical degradation and/or inactivation in the stomach or intestine, including, for example, antibodies, including various monoclonal antibodies such as tnf alpha antibodies, growth hormone, parathyroid hormone, insulin, interferon, and other similar compounds. Suitable drugs and other therapeutic agents that can be delivered by embodiments of the invention include various immunochemical agents (e.g., interferons), antibiotics, antiviral agents, insulin and related compounds, glucagon-like peptides (e.g., GLP-1, exenatide), parathyroid hormone, growth hormones (e.g., IFG and other growth factors), antiepileptics (e.g., Furosemide), antimigraine (sumatriptan), immunosuppressive agents (e.g., cyclosporine), and antiparasitic agents such as various antimalarial agents. The dosage of a particular drug may be titrated against the weight, age, or other parameter of the patient. Moreover, if the drug has been delivered by conventional oral delivery, the amount of drug to achieve the desired or therapeutic effect (e.g., insulin for blood glucose regulation, furosemide for anti-epileptic) may be less than the amount needed (e.g., a swallowable pill that is digested in the stomach and absorbed through the wall of the small intestine). This is due to the fact that the drug is not degraded by acids and other digestive fluids in the stomach and the fact that all but only a portion of the drug is delivered into the wall of the small intestine (or other lumen in the gastrointestinal tract, e.g., large intestine, stomach, etc.). Depending on the drug, the dose delivered in the formulation may range from 5% to 100% of the dose delivered by conventional oral delivery means to achieve the desired therapeutic effect (e.g., blood glucose regulation, epilepsy regulation, etc.), and even lower amounts are contemplated. The specific dose reduction may be titrated based on the specific drug, the condition to be treated, and the weight, age, and condition of the patient. For some drugs, whose degradation level in the intestinal tract is known, standard dose reductions (e.g., 10% to 20%) can be used. For drugs that are more susceptible to degradation and malabsorption, a larger dose reduction may be used. In this manner, the potential toxicity and other side effects (e.g., stomach cramps, irritable bowel, bleeding, etc.) of the particular drug or drugs delivered by the swallowable capsule 24 may be reduced because the dose ingested is reduced. This in turn improves patient compliance, as the severity and incidence of side effects in the patient are reduced. Additional benefits of embodiments employing drug dose reduction include a reduced likelihood of the patient developing resistance to the drug (higher doses are required), and in the case of antibiotics, a likelihood of the patient developing resistant strains. Moreover, other levels of dose reduction may be achieved for patients who have undergone gastric bypass surgery and other procedures where a segment of the small intestine has been removed or its working (e.g., digestion) length effectively shortened.

In addition to the delivery of a single drug, embodiments of swallowable drug delivery swallowable capsule 24 and methods of use thereof may be used to deliver multiple drugs for treating multiple conditions or for treating a particular condition (e.g., protease inhibitors for treating HIV AID) into the sinus wall or other locations in the GI tract. In use, such embodiments allow a patient to forgo the necessity of having to take multiple drugs for one or more particular conditions. Moreover, it provides a means to facilitate delivery and absorption of two or more drugs by a regimen into the small intestine (or surrounding tissue) and thus into the bloodstream at about the same time. Due to differences in chemical composition, molecular weight, etc., drugs can be absorbed through the intestinal wall at different rates, resulting in different pharmacokinetic profiles. Embodiments of the present invention address this problem by injecting the desired drug mixture substantially simultaneously. This in turn improves the pharmacokinetics and thus the efficacy of the selected drug mixture. Additionally, eliminating the need to take multiple medications is particularly beneficial for patients with one or more long-term chronic conditions, including those with impaired cognitive or physical abilities.

In various applications, embodiments of the above-described methods may be used to deliver formulations comprising drugs and other therapeutic agents to provide treatment for a variety of medical conditions and diseases. Medical conditions and diseases that may be treated with embodiments of the present invention may include, but are not limited to: cancer, hormonal conditions (e.g., hypothyroidism/hyperthyroidism, growth hormone conditions), osteoporosis, hypertension, elevated cholesterol and triglycerides, diabetes and other glucose regulating disorders, infections (focal infections or sepsis), epilepsy and other epilepsy, osteoporosis, coronary heart disease arrhythmias (both atrial and ventricular), coronary ischemic anemia, or other similar conditions. Still other conditions and diseases are also contemplated, such as various autoimmune disorders, including multiple sclerosis, guillian barre syndrome, ankylosing spondylitis, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, lupus and other similar conditions. The therapeutic agent for the latter condition may comprise IgG and rituximab (rituximab).

In many embodiments, treatment of a particular disease or condition may be performed without the need for injection of a drug or other therapeutic agent (or other non-oral form of delivery, such as a suppository) but relying solely on the therapeutic agent delivered into the walls of the sinus, small intestine, or other portion of the GI tract. For example, diabetes or another glucose regulating condition can be treated (e.g., by controlling blood glucose levels) solely by using insulin delivered into the walls of the sinuses, small intestine, without requiring the patient to inject insulin. Similarly, the patient need not take a conventional oral form of medication or other therapeutic agent, but again relies solely on delivery into the sinus or wall of the small intestine using embodiments of the swallowable capsule. In other embodiments, the therapeutic agent delivered into the wall of the small intestine may be delivered in conjunction with an injected dose of the agent. For example, a patient may use an embodiment of a swallowable capsule to take a daily dose of insulin or a compound for blood glucose regulation, but only need to take an injected dose every few days or when the patient's condition requires (e.g., hyperglycemia). The same is true for therapeutic agents that are traditionally delivered in oral form (e.g., patients may take swallowable capsules as well as conventional oral forms of medication as needed). The dose delivered in such embodiments (e.g., swallowed dose and injected dose) can be titrated as needed (e.g., using a standard dose-response curve, and other pharmacokinetic methods can be used to determine the appropriate dose). Moreover, for embodiments using therapeutic agents that can be delivered by conventional oral means, the dose delivered using embodiments of the swallowable capsule can be titrated to a lower dose than would normally be administered for oral delivery of the agent, as the agent undergoes little or no degradation in other parts of the stomach or intestinal tract (standard dose response curves and other pharmacokinetic methods can also be applied here).

Various sets of embodiments of formulations containing one or more drugs or other therapeutic agents for the treatment of various diseases and conditions will now be described with reference to dosages. It is to be understood that these embodiments containing particular therapeutic agents and corresponding dosages are exemplary, and that the formulation may include a variety of other therapeutic agents (as well as those known in the art) described herein configured for delivery into the lumen wall (e.g., small intestine wall) in the intestinal tract using various embodiments of swallowable capsule 24. The dosages can be greater or less than those described, and can be adjusted using one or more of the methods described herein or known in the art. In one set of embodiments, the therapeutic agent formulation can include a therapeutically effective dose of insulin for the treatment of diabetes and other glucose regulating conditions. As known in the art, insulin may be of human or synthetic origin. In one embodiment, the formulation may contain a therapeutically effective amount of insulin (one unit being the biological equivalent of about 45.5 μ g pure crystalline insulin) in the range of about 1-10 units, specifically in the range of 2-4 units, 3-9 units, 4-9 units, 5-8 units, or 6-7 units. The amount of insulin in the formulation can be titrated based on one or more of the following factors (referred to herein as "glucose control titration factors"): i) a condition in the patient (e.g., type 1 diabetes versus type II diabetes); ii) a previous global glycemic control level of the patient; iii) the weight of the patient; iv) the age of the patient; v) frequency of administration (e.g., once a day versus multiple times a day); vi) time of day (e.g., morning and night); vii) specific meals (breakfast versus dinner); viii) content/glycemic index of a particular meal (e.g., a meal with high fat/lipid and sugar content (which tends to lead to a rapid rise in blood glucose and thus a higher glycemic index) versus a meal with low fat and sugar content (which does not lead to a rapid rise in blood glucose and thus a lower glycemic index)); and ix) the content of the patient's overall diet (e.g., the amount of sugar and other carbohydrates, lipids, and proteins consumed daily).

In another set of embodiments, the therapeutic agent formulation can include a therapeutically effective dose of one or more incretins for the treatment of diabetes and other glucose regulating conditions. Such incretins may include glucagon-like peptide 1(GLP-1) and analogs thereof, as well as Gastric Inhibitory Peptide (GIP). Suitable GLP-1 analogs include exenatide, liraglutide, albiglutide, and tasoglutide, as well as analogs, derivatives, and other functional equivalents thereof. In one embodiment, the formulation may contain a therapeutically effective amount of exenatide in the range of about 1-10 μ g, specifically in the range of 2-4 μ g, 4-6 μ g, 4-8 μ g, and 8-10 μ g, respectively. In another example, the formulation may contain a therapeutically effective amount of liraglutide in the range of about 1-2mg (milligrams), specifically in the ranges of 1.0 to 1.4mg, 1.2 to 1.6mg, and 1.2 to 1.8mg, respectively. One or more of the glucose control titration factors may be used to titrate a dosage range of exenatide, liraglutide, or other GLP-1 analogs, or incretins.

In yet another set of embodiments, the therapeutic agent formulation may include a combination of therapeutic agents for the treatment of diabetes and other glucose regulating conditions. Embodiments of such combinations may comprise therapeutically effective doses of an incretin and a biguanide compound. The incretins can include one or more GLP-1 analogs described herein, such as exenatide, and the biguanides can include metformin (e.g., metformin available under the trademark GLUCOPHAGE manufactured by Merck Sant s.a.s.) and analogs, derivatives, and other functional equivalents thereof. In one embodiment, the formulation may include a combination of a therapeutically effective amount of exenatide in the range of about 1-10 μ g and a therapeutically effective amount of metformin in the range of about 1-3 grams. Smaller and larger ranges of one or more of the glucose control titration factors used to titrate the respective doses of exenatide (or other incretins) and metformin or other biguanides are also contemplated. In addition, the dosages of exenatide or other incretin and metformin or other biguanide may be matched to increase the patient's glycemic control level (e.g., maintain blood glucose within normal physiological levels and/or reduce the incidence and severity of instances of hyperglycemia and/or hypoglycemia) over an extended period of time, ranging from hours (e.g., 12 hours) to days, and longer periods of time are contemplated. Matching of doses may be achieved by monitoring the patient's blood glucose levels over an extended period of time using glucose control regulators and by using glycated hemoglobin (known as hemoglobin A1c, HbA1c, A1C, or Hb1c) and other bioanalytics and measurements related to long-term mean blood glucose levels.

In yet another set of embodiments, the therapeutic agent formulation may include a therapeutically effective dose of growth hormone for the treatment of one or more growth disorders and wound healing. In one embodiment, the formulation may contain a therapeutically effective amount of growth hormone in the range of about 0.1-4mg, with specific ranges of 0.1-1mg, 1-4mg, 1-2mg, and 2-4mg, respectively, and still larger ranges are contemplated. A particular dose may be titrated based on one or more of the following: i) the particular condition to be treated and its severity (e.g., stunted growth versus wound healing); ii) the weight of the patient; iii) the age of the patient; and iv) frequency of administration (e.g., once per day versus twice per day).

In yet another set of embodiments, the therapeutic agent formulation may include a therapeutically effective dose of parathyroid hormone for the treatment and/or prevention of osteoporosis or thyroid disease. In one embodiment, the formulation may contain a therapeutically effective amount of parathyroid hormone in the range of about 1-40 μ g, with specific ranges being 10-20 μ g, 20-30 μ g, 30-40 μ g and 10-40 μ g, respectively, and still larger ranges are contemplated. A particular dose may be titrated based on one or more of the following: i) the particular condition to be treated and its severity (e.g., the degree of osteoporosis as determined by bone density measurements); ii) the weight of the patient; iii) the age of the patient; and iv) frequency of administration (e.g., once per day versus twice per day). Particular embodiments contemplate delivering (e.g., daily) a prophylactic dose of PTH to prevent osteoporosis in middle-aged (e.g., over 50 years) or elderly patients, including preventing osteoporosis in postmenopausal women. Such prophylactic doses may be in the lower range, e.g. 5-20 μ g, in order to reduce the risk of osteosarcoma during long term administration of the drug.

As used herein, the singular terms "a" and "the" may include plural referents unless the context clearly dictates otherwise. Reference to an object in the singular is not intended to mean "one and only one" unless explicitly so stated, but rather "one or more.

As used herein, the term "set" is a collection of one or more objects. Thus, for example, a set of objects may contain a single object or multiple objects.

As used herein, the terms "substantially" and "about" are used to describe and explain minor variations. When used in conjunction with an event or circumstance, the terms may refer to the exact instance in which the event or circumstance occurs, as well as the instance in which the event or circumstance occurs in close proximity. When used in conjunction with numerical values, the term can refer to a range of variation of less than or equal to ± 10% of the stated numerical value, such as less than or equal to ± 5%, less than or equal to ± 4%, less than or equal to ± 3%, less than or equal to ± 2%, less than or equal to ± 1%, less than or equal to ± 0.5%, less than or equal to ± 0.1%, or less than or equal to ± 0.05%. For example, "substantially" aligned can refer to a range of angular variation of less than or equal to ± 10 °, such as less than or equal to ± 5 °, less than or equal to ± 4 °, less than or equal to ± 3 °, less than or equal to ± 2 °, less than or equal to ± 1 °, less than or equal to ± 0.5 °, less than or equal to ± 0.1 °, or less than or equal to ± 0.05 °.

Additionally, amounts, ratios, and other numerical values are sometimes presented herein in a range format. It is to be understood that such range format is used for convenience and brevity, and should be interpreted flexibly to include the numerical values explicitly recited as the limits of the range, as well as to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a ratio in the range of about 1 to about 200 should be understood to encompass the explicitly recited limits of about 1 and about 200, but also individual ratios such as about 2, about 3, and about 4, and sub-ranges such as about 10 to about 50, about 20 to about 100, etc.

The foregoing description of various embodiments of the invention has been presented for the purposes of illustration and description. The foregoing description is not intended to limit the invention to the precise form disclosed. Many modifications, variations and improvements will be apparent to those skilled in the art. For example, embodiments of the device may be sized and otherwise adapted for various pediatric and neonatal applications as well as various veterinary applications. Moreover, those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific devices and methods described herein. Such equivalents are considered to be within the scope of the invention and are covered by the following claims.

Elements, characteristics or acts from one embodiment may be readily recombined with or substituted for one or more elements, characteristics or acts from other embodiments to form many additional embodiments within the scope of the present invention. Furthermore, elements shown or described as combined with other elements may, in various embodiments, exist as separate elements. Further, embodiments of the present invention specifically contemplate the exclusion of elements, values, characteristics, components, features, acts, steps, etc. for any positive recitation of elements, characteristics, components, characteristics, acts, steps, etc. The scope of the invention is therefore not limited to the details of the described embodiments, but only by the appended claims.