Patent Publication Number: US-2021161805-A1

Title: Delivery Capsule with Threshold Release

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     The present application is an International Application claiming priority to U.S. Provisional Patent Application No. 61/882,965 filed Sep. 26, 2013, the entire disclosure of which is hereby expressly incorporated by reference. 
    
    
     BACKGROUND 
     Electronic capsules have been proposed for controlling the delivery of a substance in a mammal&#39;s body. In one use, a swallowable capsule carries the substance in a sealed reservoir and includes an electro-mechanical drive mechanism that forces the drug from the reservoir, through an opening in the capsule, and into the surrounding gastrointestinal tract. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The detailed description is described with reference to the accompanying figures. In the figures, the left-most digit(s) of a reference number identifies the figure in which the reference number first appears. The use of the same reference numbers in different figures indicates similar or identical components or features. 
         FIG. 1A  illustrates, in cross-section, a capsule including a payload compartment including a deformable portion and a gas generating unit according to one implementation of this disclosure. 
         FIG. 1B  illustrates the capsule of  FIG. 1A  after the contents of the payload compartment have been released from the capsule. 
         FIG. 2  illustrates, in cross-section, a capsule including a payload compartment and a gas-generating unit according to another implementation of this disclosure. 
         FIG. 3  illustrates, in cross-section, a capsule including a payload compartment and a plurality of gas-generating units according to another implementation of this disclosure. 
         FIG. 4  illustrates, in cross-section, a capsule including a plurality of reservoirs, each having a corresponding threshold release valve and gas generating unit. 
         FIG. 5  illustrates, in cross-section, a capsule including a payload compartment and a platen acted upon by gas generated by a gas generating unit to dispense the contents of the payload compartment. 
     
    
    
     DETAILED DESCRIPTION 
     This disclosure 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. In some implementations, the threshold valve is a single use valve whereas in other embodiments 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. 1  illustrates a capsule  100  according to one embodiment of this disclosure. The capsule  100  generally includes a housing  102  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&#39;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. 1A , the housing  102  includes a substantially cylindrical sidewall  104  and a rounded end  106 . An opening  108  is formed at an axial end of the sidewall  104 , opposite the rounded end  106 . 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. 1A , the opening  108  is sealed with a threshold valve  110 . As will be described in more detail below, the threshold valve  110  preferably seals the opening  108  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  110  is a disc-shaped member that creates a seal with an inner surface of the sidewall  104 , proximate the opening  108 . In some embodiments, the threshold valve  110  may be a sealing gasket that seals the opening  108 , forming a closed end of the capsule  100 . In other embodiments, the threshold valve  110  may comprise more than one piece, such as a relatively hard disc surrounded by an O-ring or similar sealing structure. 
     A reservoir  112  is disposed in the housing, in fluid communication with the opening  108 , for storing the contents to be released from the capsule. In the illustrated embodiment, the reservoir  112  is a sealed space, bounded by the threshold valve  110  and a deformable membrane  114 . The membrane  114  may be fixed to an inner wall of the housing  102 , proximate the opening  108 . In other embodiments, a portion of the sidewall  104  may also define at least a portion of the reservoir  112 . As will be appreciated, in the illustration of  FIG. 1A , removing, or opening, the threshold valve  110  will allow for the contents of the reservoir to exit the capsule through the opening  108 . 
     Also illustrated schematically in  FIG. 1A , the capsule  100  includes electronics  116  and a gas generating unit  118 . The electronics  116  and the gas generating unit  118  preferably are retained in the capsule such that they do not come into contact with the substance contained in the reservoir. In  FIG. 1A  the substance to be administered is sealed in the reservoir  112 , and thus sealed relative to the electronics  116  and the gas generating unit  118 . The electronics  116  and the gas generating unit  118  may also be sealed relative to each other. 
     The electronics  116  may be any number of electronic components that contribute to the operation and functionality of the capsule  100 . For example, the electronics  116  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  116  may vary depending upon the design of the capsule, as will be appreciated from this disclosure. 
     The gas generating unit  118  is a mechanism that selectively generates and/or releases a gas. In some embodiments, the generating unit  118  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  118 . 
     In operation, as the gas generating unit  118  generates a gas  120 , the gas  120  expands in the capsule  100 . Continued gas generation leads to an increased pressure inside the capsule  100 , which pressure eventually becomes sufficient that it acts on the deformable membrane  114 . In  FIG. 1A , the gas  120  is illustrated as filling a space between the gas generating unit and the membrane  114 , to press the membrane  114  toward the opening  108 . 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  114  applies a pressure to the reservoir  112 , which increasing pressure, in turn, applies a pressure on the threshold valve  110 . When the increasing internal pressure in the reservoir reaches a threshold pressure, the threshold valve opens, releasing the contents of the reservoir  112  through the opening  108 . 
       FIG. 1B  illustrates the capsule  100  of  FIG. 1A  after enough of the gas  120  has been generated that the threshold pressure has been reached, and the threshold valve  120  has been opened. In this embodiment, the threshold pressure opens the threshold valve  110  by completely dislodging the valve  110  from the housing  102 . More specifically, the valve  110  was retained in place by a frictional or interference fit with the sidewall  104 , and the force maintaining that seal was overcome, thus dislodging the valve  110 . Choice of materials used for the valve  110  and the sidewall  104  will dictate the threshold pressure in these embodiments. 
     Also in  FIG. 1B , a portion of the deformable membrane  114  has been pushed through the opening  108 . More specifically, the deformable membrane  114  is still attached to the sidewall  104  in  FIG. 1B , 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. 1B , constituents in the environment, e.g., gastro-intestinal fluid, may assist in removing the contents from that surface. 
     Although the threshold valve  110  is shown as being completely removed from the housing  102  in  FIG. 1B , in other embodiments the threshold valve  110  may remain attached to the housing  102  after the valve becomes dislodged from the housing. For example, the threshold valve  110  may be hinged or tethered, e.g., to the sidewall  104 , of the housing  102 . Such arrangements may promote easier recovery of the complete capsule. 
       FIG. 2  illustrates another example embodiment of a capsule  200 . In  FIG. 2 , the capsule  200  includes a housing  202  having a cylindrical sidewall  204  terminating at two rounded ends  206 . An opening  208  is formed through one of the ends  206 . The opening  208  provides a fluid passageway between a reservoir  212  and the exterior of the housing  202 . 
     Like in the embodiments described above, a threshold valve  210  is disposed in the opening  208 . Unlike the embodiments described above, however, the threshold valve  210  does not become dislodged from the housing  202 . Instead the threshold valve is a one-way, re-sealing valve. In some implementations, the threshold valve  210  behaves like a check-, bleed-, or release-valve. 
     In operation, as in the embodiments described in connection with  FIGS. 1A and 1B , the gas generating unit  118  of  FIG. 2  generates the gas  120  that expands and presses on the deformable membrane  114 . As the membrane deforms, the pressure inside the reservoir increases, eventually to a threshold pressure sufficient to open the threshold valve  210 , allowing the contents of the reservoir  212  to leave the capsule  200 , through the opening  208 . Unlike in the previous embodiments, however, as the contents of the reservoir  212  exit and the pressure inside the reservoir decreases, the pressure will eventually drop below a re-sealing pressure, and the threshold valve  210  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  210 . 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  100  illustrated in  FIGS. 1A and 1B  provides a one-time, or bolus, release of the contents of the reservoir, whereas the embodiment of  FIG. 2  may allow for the contents to be released all at once, or in several, smaller releases. 
     In one implementation of the capsule  200 , the gas  120  may be continuously generated. In this implementation, the threshold valve  210  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  210  and the gas generating unit  118  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  200 , release of the gas  120  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  210  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  300  is illustrated in  FIG. 3 . The capsule  300  is similar in most aspects to the capsule  200  illustrated in  FIG. 2 , but the capsule  300  includes a plurality of gas generating units  302 . Although four gas generating units  302  are illustrated, more or fewer may alternatively be provided. In some uses of the capsule  300 , each of the gas generating units  302  may be capable of releasing a gas  304  sufficient to open the threshold valve  210 . Thus, some amount of the substance contained in the reservoir  212  will be released each time one of the gas generating units  302  is triggered. For example, one of the gas generating units  302  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  210  re-seals. Then, at an appropriate, perhaps pre-determined time, another of the gas generating units  302  may be triggered, resulting in a release of additional contents from the reservoir. 
     In the embodiment of  FIG. 3 , the amount of content released from the reservoir when each of the gas generating units  302  is triggered will be dictated in part by the amount of gas released by each unit  302  and in part by the specifics of the threshold valve  210 . Moreover, the speed at which each of the gas generating units  302  generates the gas  304  will impact how quickly the contents are expelled from the capsule, i.e., relative to the time at which the respective gas generating unit  302  is triggered. 
     Although in the implementation of  FIG. 3  the triggering of each of the gas generating units  302  will result in expulsion of some amount of the contents of the reservoir  212 , in another embodiment, each gas generating unit may be associated with a separate reservoir. An example of such an embodiment is illustrated in  FIG. 4 . 
     In  FIG. 4 , a capsule  400  includes an internal partition  402  that helps to define a plurality of internal compartments  404   a ,  404   b . In some embodiments, the compartments  404   a ,  404   b  are sealed relative to each other. Although two compartments  404   a ,  404   b  are illustrated in  FIG. 4 , more compartments may be formed inside the capsule. 
     Each compartment  404   a ,  404   b  includes an opening  406   a ,  406   b , and as illustrated, each opening is sealed with a threshold valve  408   a ,  408   b . In the illustrated embodiment the threshold valves  408   a ,  408   b  are similar in construction to the threshold valve  110  of the embodiment of  FIG. 1A , although the threshold valves may instead be similar in construction to the threshold valve  210  illustrated in  FIGS. 2 and 3 . Each of the compartments  404   a ,  404   b  has a respective reservoir  410   a ,  410   b  disposed therein. As in previously-described embodiments, the reservoirs  410   a ,  410   b , may include a deformable membrane  412   a ,  412   b.    
     Gas generating units  414   a ,  414   b  also are provided in the capsule  400 , one corresponding to each reservoir  410   a ,  410   b . As with previous embodiments, the gas generating units  414   a ,  414   b , when activated, produce a gas  416   a ,  416   b . The generated gas  416   a ,  416   b , deforms the respective membranes  412   a ,  412   b , applying a pressure to the respective threshold valves  408   a ,  408   b . As in the embodiment of  FIGS. 1A and 1B , as the pressure in the respective compartments reaches and exceeds a threshold pressure, the threshold valves  408   a ,  408   b  open, allowing the contents of the reservoirs  410   a ,  410   b  to be released from the capsule  400 . 
     The embodiment of  FIG. 4  may provide for a multiple release arrangement that is more easily controlled than the use of the threshold valve  210  that opens and re-seals. Moreover, the capsule  400  may allow for administration of more than one substance, i.e., by containing a different substance in each of the reservoirs  410   a ,  410   b.    
     Another capsule  500  is illustrated in  FIG. 5 . The capsule  500  is similar in construction to the capsule  200  described above and illustrated in  FIG. 2 , but the capsule  500  includes a platen  502  movable axially in the capsule  500 . In the illustrated embodiment, the platen  502  serves to define a portion of a reservoir  504  containing a substance for dispensing. The platen  502  is illustrated schematically as being movable relative to and along the sidewall  204 . In some embodiments, the platen  502  and/or the inner surface of the sidewall  204  may include features that assist or otherwise guide this movement. For example, the platen may have features on its periphery that key the platen  502  to the sidewall  204 . Such features may prevent rotation of the platen  502  relative to the sidewall  204 . 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  502  rides along the shaft. The platen  502  may be keyed to the shaft, to prevent rotation of the platen relative to the capsule. 
     In the capsule  500 , the reservoir  504  is preferably sealed, such that contents of the reservoir  504  remain in the reservoir until being released through the opening  208 . To seal the reservoir  504 , the platen  502  may be sealed relative to the sidewall  204 . For example, a wiper seal or the like may be provided on the periphery of the platen  502  for contacting the sidewall  204 . Other seals are also known, and may be used to seal the reservoir  504 . 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. 5 . In such an arrangement, the generated gas  120  moves the platen  502 , 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  116 , which are illustrated schematically in each of the Figures. 
     In embodiments of this disclosure, the electronics  116  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  116  may be pre-programmed, i.e., programmed before swallowing or insertion. For example, in the embodiment illustrated in  FIG. 4 , the control electronics  116  may be pre-programmed to time the release of each of the reservoirs  410   a ,  410   b . 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  116  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  116  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  116  and instruct gas generation, as appropriate, for example, via a wireless transmission. 
     As should be appreciated, the electronics  116  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  FIGS. 1A, 1B, and 4 , 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  FIGS. 2, 3, and 5  may be better suited for delivery of liquid or suspended-formulations. In addition, as noted above in the discussion of  FIG. 4 , the capsule  400  that has a plurality of reservoirs  410   a ,  410   b , 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. 2  may be used in conjunction with some or all of the multiple reservoirs shown in  FIG. 4 . 
     Moreover, although  FIG. 4  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). In some embodiments, 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. 
     Although the subject matter has been described in language specific to structural features, it is to be understood that the subject matter defined in the appended claims is not necessarily limited to the specific features described. Rather, the specific features are disclosed as illustrative forms of implementing the claims.