Patent Description:
<CIT> discloses an ingestible capsule for delivery of medicaments.

The invention provides a capsule according to claim <NUM>. For better understanding of the invention this disclosure provides also further examples and describes a capsule, such as an ingestible capsule, configured for insertion into a mammalian body to release a substance in that body. The capsule generally includes a payload compartment, or reservoir, that contains the substance. An opening is formed in the capsule to provide an egress through which the substance can exit the capsule, and a threshold valve is provided in the opening. The threshold valve retains the substance in the reservoir until a pressure in the reservoir reaches a threshold pressure, at which time the threshold valve opens to release some or all of the substance through the opening. According to the invention, the threshold valve is a single use valve whereas in other non-claimed examples it is a re-sealable valve that allows for iterative opening and closing, to control an amount and/or timing of release of the substance. A gas generating unit is provided in the capsule, to generate a gas that provides an internal pressure in the capsule, which eventually creates the threshold pressure that expels the substance through the threshold valve.

<FIG> illustrates a capsule <NUM> according to one embodiment of this disclosure. The capsule <NUM> generally includes a housing <NUM> shaped for placement in a mammalian body through an orifice in that body. For example, the capsule may be sized and shaped to be swallowed by a mammal. In other implementations, the capsule may be designed for insertion into a different body orifice. For example, the capsule may be intended for insertion into a woman's vaginal canal or uterus. In such an embodiment, the capsule may longer and/or thinner than the capsule illustrated. Moreover, a capsule for insertion may also be formed on or otherwise attached to a carrier structure that facilitates insertion of the capsule. In still other implementation, the capsule may be constructed as an implant, and placed subcutaneously. Because the capsule is intended for placement in a mammalian body, the capsule preferably is formed of a non-degrading, biocompatible material. By way of non-limiting example, the capsule may be formed from a biocompatible plastic or stainless steel.

As illustrated in <FIG>, the housing <NUM> includes a substantially cylindrical sidewall <NUM> and a rounded end <NUM>. An opening <NUM> is formed at an axial end of the sidewall <NUM>, opposite the rounded end <NUM>. The shape of the housing is not limited to the illustrated configuration; the housing may take any configuration that allows for insertion into the mammalian body.

In the embodiment illustrated in <FIG>, the opening <NUM> is sealed with a threshold valve <NUM>. As will be described in more detail below, the threshold valve <NUM> preferably seals the opening <NUM> until the pressure inside the capsule reaches a threshold pressure that opens the threshold valve, thereby allowing contents of the capsule to exit through the opening. In the illustrated embodiment, the threshold valve <NUM> is a disc-shaped member that creates a seal with an inner surface of the sidewall <NUM>, proximate the opening <NUM>. In some embodiments, the threshold valve <NUM> may be a sealing gasket that seals the opening <NUM>, forming a closed end of the capsule <NUM>. In other embodiments, the threshold valve <NUM> may comprise more than one piece, such as a relatively hard disc surrounded by an O-ring or similar sealing structure.

A reservoir <NUM> is disposed in the housing, in fluid communication with the opening <NUM>, for storing the contents to be released from the capsule. In the illustrated embodiment, the reservoir <NUM> is a sealed space, bounded by the threshold valve <NUM> and a deformable membrane <NUM>. The membrane <NUM> may be fixed to an inner wall of the housing <NUM>, proximate the opening <NUM>. In other embodiments, a portion of the sidewall <NUM> may also define at least a portion of the reservoir <NUM>. As will be appreciated, in the illustration of <FIG>, removing, or opening, the threshold valve <NUM> will allow for the contents of the reservoir to exit the capsule through the opening <NUM>.

Also illustrated schematically in <FIG>, the capsule <NUM> includes electronics <NUM> and a gas generating unit <NUM>. The electronics <NUM> and the gas generating unit <NUM> preferably are retained in the capsule such that they do not come into contact with the substance contained in the reservoir. In <FIG> the substance to be administered is sealed in the reservoir <NUM>, and thus sealed relative to the electronics <NUM> and the gas generating unit <NUM>. The electronics <NUM> and the gas generating unit <NUM> may also be sealed relative to each other.

The electronics <NUM> may be any number of electronic components that contribute to the operation and functionality of the capsule <NUM>. For example, the electronics <NUM> may include a power source such as a battery, logic circuitry, one or more sensors, an antenna, a receiver, a transmitter, a transceiver, control electronics, and/or the like. The electronics <NUM> may vary depending upon the design of the capsule, as will be appreciated from this disclosure.

The gas generating unit <NUM> is a mechanism that selectively generates and/or releases a gas. In some embodiments, the generating unit <NUM> is of a type including an electrolytic cell filled with an aqueous solution and that has at least two electrodes. When a voltage is applied across the electrodes, hydrogen and oxygen gas are generated, which gasses are, in turn, released from the gas generating unit <NUM>.

In operation, as the gas generating unit <NUM> generates a gas <NUM>, the gas <NUM> expands in the capsule <NUM>. Continued gas generation leads to an increased pressure inside the capsule <NUM>, which pressure eventually becomes sufficient that it acts on the deformable membrane <NUM>. In <FIG>, the gas <NUM> is illustrated as filling a space between the gas generating unit and the membrane <NUM>, to press the membrane <NUM> toward the opening <NUM>. In some embodiments, a separate chamber may be provided in which the gas is generated, while in others the gas is free to expand anywhere in the capsule. Continued pressure on the deformable membrane <NUM> applies a pressure to the reservoir <NUM>, which increasing pressure, in turn, applies a pressure on the threshold valve <NUM>. When the increasing internal pressure in the reservoir reaches a threshold pressure, the threshold valve opens, releasing the contents of the reservoir <NUM> through the opening <NUM>.

<FIG> illustrates the capsule <NUM> of <FIG> after enough of the gas <NUM> has been generated that the threshold pressure has been reached, and the threshold valve <NUM> has been opened. In this embodiment, the threshold pressure opens the threshold valve <NUM> by completely dislodging the valve <NUM> from the housing <NUM>. More specifically, the valve <NUM> was retained in place by a frictional or interference fit with the sidewall <NUM>, and the force maintaining that seal was overcome, thus dislodging the valve <NUM>. Choice of materials used for the valve <NUM> and the sidewall <NUM> will dictate the threshold pressure in these embodiments,.

Also in <FIG>, a portion of the deformable membrane <NUM> has been pushed through the opening <NUM>. More specifically, the deformable membrane <NUM> is still attached to the sidewall <NUM> in <FIG>, but has been turned "inside-out" from its original position. In other embodiments the deformable membrane may not extend through the opening in this manner, but such a construction may result in a more complete release of the substance contained in the reservoir, i.e., because the substance is actively pushed out of the capsule, into the surrounding environment. Moreover, when the inner surface of the reservoir is exposed to the environment, as in <FIG>, constituents in the environment, e.g., gastro-intestinal fluid, may assist in removing the contents from that surface.

Although the threshold valve <NUM> is shown as being completely removed from the housing <NUM> in <FIG>, in other embodiments the threshold valve <NUM> may remain attached to the housing <NUM> after the valve becomes dislodged from the housing. For example, the threshold valve <NUM> may be hinged or tethered, e.g., to the sidewall <NUM>, of the housing <NUM>. Such arrangements may promote easier recovery of the complete capsule.

<FIG> illustrates another example embodiment of a capsule <NUM>. In <FIG>, the capsule <NUM> includes a housing <NUM> having a cylindrical sidewall <NUM> terminating at two rounded ends <NUM>. An opening <NUM> is formed through one of the ends <NUM>. The opening <NUM> provides a fluid passageway between a reservoir <NUM> and the exterior of the housing <NUM>.

Like in the embodiments described above, a threshold valve <NUM> is disposed in the opening <NUM>. Unlike the embodiments described above, however, the threshold valve <NUM> does not become dislodged from the housing <NUM>. Instead the threshold valve is a one-way, re-sealing valve. In some implementations, the threshold valve <NUM> behaves like a check-, bleed-, or release-valve.

In operation, as in the embodiments described in connection with <FIG>, the gas generating unit <NUM> of <FIG> generates the gas <NUM> that expands and presses on the deformable membrane <NUM>. As the membrane deforms, the pressure inside the reservoir increases, eventually to a threshold pressure sufficient to open the threshold valve <NUM>, allowing the contents of the reservoir <NUM> to leave the capsule <NUM>, through the opening <NUM>. Unlike in the previous embodiments, however, as the contents of the reservoir <NUM> exit and the pressure inside the reservoir decreases, the pressure will eventually drop below a re-sealing pressure, and the threshold valve <NUM> will re-seal. The re-sealing pressure may be the same as or lower than the threshold pressure, depending upon the design of the threshold valve <NUM>. Moreover, once the threshold valve is re-sealed, with continued gas generation, the pressure may again increase to the threshold pressure, to again discharge contents from the reservoir. As will be appreciated, the capsule <NUM> illustrated in <FIG> provides a one-time, or bolus, release of the contents of the reservoir, whereas the embodiment of <FIG> may allow for the contents to be released all at once, or in several, smaller releases.

In one implementation of the capsule <NUM>, the gas <NUM> may be continuously generated. In this implementation, the threshold valve <NUM> opens each time the pressure in the capsule builds to the threshold pressure, and then closes as the substance is released and the pressure drops back to the re-sealing pressure. Because the gas continues to be generated, the pressure will again build to the threshold pressure, and the process of releasing and re-sealing will repeat. As will be appreciated, design and construction of the threshold valve <NUM> and the gas generating unit <NUM> will dictate how much substance is released, and how frequently it is released. Thus, a release profile may be varied, depending upon the gas generation unit and/or the threshold valve used.

In other implementations of the capsule <NUM>, release of the gas <NUM> may be controlled, e.g., selectively started and stopped, to provide a desired release profile of the substance. For example, in some embodiments, the gas generation may be stopped when the threshold valve <NUM> opens, such that the valve closes upon a reduction in pressure to the re-sealing pressure, and remains closed until the gas generation is re-started, and the gas again reaches the threshold pressure. In one embodiment, once the threshold valve opens, or shortly thereafter, application of the voltage across the electrodes in the gas generating unit is stopped, and thus gas generation is stopped. At a later time, the voltage may be reapplied across the electrodes, to again begin gas generation, eventually resulting in another dispensing of the contents of the reservoir.

Another embodiment of a capsule <NUM> is illustrated in <FIG>. The capsule <NUM> is similar in most aspects to the capsule <NUM> illustrated in <FIG>, but the capsule <NUM> includes a plurality of gas generating units <NUM>. Although four gas generating units <NUM> are illustrated, more or fewer may alternatively be provided. In some uses of the capsule <NUM>, each of the gas generating units <NUM> may be capable of releasing a gas <NUM> sufficient to open the threshold valve <NUM>. Thus, some amount of the substance contained in the reservoir <NUM> will be released each time one of the gas generating units <NUM> is triggered. For example, one of the gas generating units <NUM> may be triggered, such that a pressure reaches the threshold pressure and the contents are expelled. Such expulsion will cause a decrease in the internal pressure of the capsule, until the threshold valve <NUM> re-seals. Then, at an appropriate, perhaps pre-determined time, another of the gas generating units <NUM> may be triggered, resulting in a release of additional contents from the reservoir.

In the embodiment of <FIG>, the amount of content released from the reservoir when each of the gas generating units <NUM> is triggered will be dictated in part by the amount of gas released by each unit <NUM> and in part by the specifics of the threshold valve <NUM>. Moreover, the speed at which each of the gas generating units <NUM> generates the gas <NUM> will impact how quickly the contents are expelled from the capsule, i.e., relative to the time at which the respective gas generating unit <NUM> is triggered.

Although in the implementation of <FIG> the triggering of each of the gas generating units <NUM> will result in expulsion of some amount of the contents of the reservoir <NUM>, in another embodiment, each gas generating unit may be associated with a separate reservoir. An example of such an embodiment is illustrated in <FIG>.

In <FIG>, a capsule <NUM> includes an internal partition <NUM> that helps to define a plurality of internal compartments 404a, 404b. In some embodiments, the compartments 404a, 404b are sealed relative to each other. Although two compartments 404a, 404b are illustrated in <FIG>, more compartments may be formed inside the capsule.

Each compartment 404a, 404b includes an opening 406a, 406b, and as illustrated, each opening is sealed with a threshold valve 408a, 408b. In the illustrated embodiment the threshold valves 408a, 408b are similar in construction to the threshold valve <NUM> of the embodiment of <FIG>, although the threshold valves may instead be similar in construction to the threshold valve <NUM> illustrated in <FIG> and <FIG>. Each of the compartments 404a, 404b has a respective reservoir 410a, 410b disposed therein. As in previously-described embodiments, the reservoirs 410a, 410b, may include a deformable membrane 412a, 412b.

Gas generating units 414a, 414b also are provided in the capsule <NUM>, one corresponding to each reservoir 410a, 410b. As with previous embodiments, the gas generating units 414a, 414b, when activated, produce a gas 416a, 416b. The generated gas 416a, 416b, deforms the respective membranes 412a, 412b, applying a pressure to the respective threshold valves 408a, 408b. As in the embodiment of <FIG>, as the pressure in the respective compartments reaches and exceeds a threshold pressure, the threshold valves 408a, 408b open, allowing the contents of the reservoirs 410a, 410b to be released from the capsule <NUM>.

The embodiment of <FIG> may provide for a multiple release arrangement that is more easily controlled than the use of the threshold valve <NUM> that opens and re-seals. Moreover, the capsule <NUM> may allow for administration of more than one substance, i.e., by containing a different substance in each of the reservoirs 410a, 410b.

Another capsule <NUM> is illustrated in <FIG>. The capsule <NUM> is similar in construction to the capsule <NUM> described above and illustrated in <FIG>, but the capsule <NUM> includes a platen <NUM> movable axially in the capsule <NUM>. In the illustrated embodiment, the platen <NUM> serves to define a portion of a reservoir <NUM> containing a substance for dispensing. The platen <NUM> is illustrated schematically as being movable relative to and along the sidewall <NUM>. In some embodiments, the platen <NUM> and/or the inner surface of the sidewall <NUM> may include features that assist or otherwise guide this movement. For example, the platen may have features on its periphery that key the platen <NUM> to the sidewall <NUM>. Such features may prevent rotation of the platen <NUM> relative to the sidewall <NUM>. In another embodiment, a shaft may be provided in the capsule, arranged parallel to a longitudinal axis of the capsule, and the platen includes a cutout sized to receive the shaft. In such an embodiment, the platen <NUM> rides along the shaft. The platen <NUM> may be keyed to the shaft, to prevent rotation of the platen relative to the capsule.

In the capsule <NUM>, the reservoir <NUM> is preferably sealed, such that contents of the reservoir <NUM> remain in the reservoir until being released through the opening <NUM>. To seal the reservoir <NUM>, the platen <NUM> may be sealed relative to the sidewall <NUM>. For example, a wiper seal or the like may be provided on the periphery of the platen <NUM> for contacting the sidewall <NUM>. Other seals are also known, and may be used to seal the reservoir <NUM>. Other methods may also be used to seal the reservoir. For example, a deformable membrane such as one of those illustrated in previous embodiments may also be used in the embodiment of <FIG>. In such an arrangement, the generated gas <NUM> moves the platen <NUM>, which acts on the deformable membrane to increase the pressure in the reservoir. It may be beneficial that in this embodiment the platen need not be sealed relative to the sidewall.

As described throughout this disclosure, operation of each of the example capsules is preferably controlled and/or performed using the electronics <NUM>, which are illustrated schematically in each of the Figures.

In embodiments of this disclosure, the electronics <NUM> preferably are constructed such that they control the generation of gas by the gas generating unit(s) and thus the delivery of the substance(s) contained in the capsule. The electronics <NUM> may be pre-programmed, i.e., programmed before swallowing or insertion. For example, in the embodiment illustrated in <FIG>, the control electronics <NUM> may be pre-programmed to time the release of each of the reservoirs 410a, 410b. The pre-programming may include an instruction to trigger gas release at a certain time, e.g., measured from the time of swallowing or an activation of the capsule, or when a certain condition is met, such as a sensed condition in the body, such as a pH-level, a temperature, or the like. To this end, the control electronics <NUM> may include one or more sensors, such as a pH sensor and/or a thermometer. Other or different sensors may also be included.

The functioning of the capsules may also be partly or completely dictated from outside the body to which the capsule has been administered. For example, the control electronics <NUM> may include a receiver that receives instructions, such as from outside the body or from a sensor associated with the capsule. For instance, an administrator may track the position of the capsule in the mammal, such as through a global positioning or other positioning sensor included in the electronics <NUM> and instruct gas generation, as appropriate, for example, via a wireless transmission.

As should be appreciated, the electronics <NUM> may enable capsules according to embodiments of this disclosure to provide targeted administration of substances, for example, at a specific location and/or a specific time. Such a targeted administration is useful in clinical studies, e.g., to determine efficacy of a drug-in-test at various locations along the GI tract, and in administration, e.g., to ensure a drug is administered where and/or when it will be most effective.

Embodiments of the disclosure may also be well suited for administering different types of products. For example, the embodiments illustrated in <FIG>, and <FIG>, in which the threshold valve is a single-use valve, may be better suited for delivering solid, granular, or powdered substances, whereas the valves illustrated in <FIG>, <FIG>, and <FIG> may be better suited for delivery of liquid or suspended-formulations. In addition, as noted above in the discussion of <FIG>, the capsule <NUM> that has a plurality of reservoirs 410a, 410b, may be used to administer several different drugs via the same capsule. Of course, use of disclosed embodiments is not intended to be limited to delivering any formulation.

The illustrated embodiments are provided as examples, and modifications to the embodiments may be appreciated by those having ordinary skill in the art with the benefit of this disclosure. By way of non-limiting example, different types of threshold valves may be used than those illustrated specifically in the Figures. For example, the multi-use threshold valve of <FIG> may be used in conjunction with some or all of the multiple reservoirs shown in <FIG>.

Moreover, although <FIG> illustrates multiple reservoirs, each containing an amount of a substance to be dispensed into the mammalian body, one reservoir may contain multiple substances. For example, a single reservoir may be filled with a plurality of different types of substances, e.g., drugs, to be dispensed to the mammal. Alternatively, a single reservoir may contain multiple compartments. The compartments may be maintained by a partition or the like, which may be a membrane disposed or otherwise formed in the reservoir. In some embodiments each partitioned compartment is in fluid communication with the opening, such that all compartments are evacuated through the opening. In other embodiments, the partition may be rupturable, such that the multiple partitions mix or otherwise come into fluid communication with each other, before the contents of the reservoir are dispensed. The rupturable membrane may be chosen to rupture at a pressure below the threshold pressure, while in other embodiments the membrane may be mechanically ruptured by a rupturing member disposed in the reservoir.

In each of the illustrated embodiments, the capsule is a complete capsule, i.e., in that it includes both the payload element (including the reservoir) and the drive element (including the gas generating unit). According to the invention, the payload element and the drive element may be formed separately, and joined at a later time, for example, at the time of administration. In this manner, different payload elements, i.e., having different contents or amounts, may be used, as necessary for each patient. The payload element and the drive element may be formed as separate halves of a complete capsule, for example, that are mated together to form the complete capsule. They may be mated together, for example, using a threaded engagement, a snap-fit engagement, or the like.

Claim 1:
A capsule (<NUM>) configured for insertion into a mammalian body to release a substance in that body comprising:
a housing (<NUM>);
a gas generating unit (<NUM>) for generating gas in the housing;
a compressible reservoir (<NUM>) sealed relative to the gas generating unit and configured to obtain a substance to be dispensed from the capsule;
an opening (<NUM>) in the housing providing an outlet for the substance contained in the reservoir; and a single use threshold valve (<NUM>) configured for sealing the opening until a pressure in the capsule exceeds a threshold pressure; wherein the valve (<NUM>) is configured to be retained in place by a frictional or interference fit forming a seal until the threshold pressure is reached and, the threshold valve (<NUM>) is configured to be completely dislodged from the housing (<NUM>) when the threshold pressure is reached;
wherein the capsule is formed of a payload element and a drive element and the payload element comprises the compressible reservoir (<NUM>) and the drive element comprises the gas generating unit (<NUM>); and the payload and drive elements are formed separately and are joinable to each other.