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WO2016155671A1 - 可吞咽式装置 - Google Patents

可吞咽式装置 Download PDF

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Publication number
WO2016155671A1
WO2016155671A1 PCT/CN2016/078405 CN2016078405W WO2016155671A1 WO 2016155671 A1 WO2016155671 A1 WO 2016155671A1 CN 2016078405 W CN2016078405 W CN 2016078405W WO 2016155671 A1 WO2016155671 A1 WO 2016155671A1
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WO
WIPO (PCT)
Prior art keywords
needle
swallowable device
outer casing
attachment member
capsule
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2016/078405
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English (en)
French (fr)
Inventor
傅君志
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
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Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of WO2016155671A1 publication Critical patent/WO2016155671A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
    • A61M31/002—Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/07—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of capsules or similar small containers for oral use
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body

Definitions

  • the present invention relates to a swallowable device. More specifically, the present invention relates to a swallowable drug delivery device.
  • a swallowable device that can be used to deliver a drug in the gastrointestinal tract.
  • a swallowable device such as a swallowable capsule, is provided for delivering a drug into a tissue, such as the wall of the stomach, the wall of the small intestine, the wall of the large intestine, or the wall of other gastrointestinal organs.
  • the apparatus, system, kit and square of the present invention The method can be used to deliver any drug suitable for delivery to the wall of the stomach, the wall of the small intestine, the wall of the large intestine or other gastrointestinal organs.
  • the devices, systems, kits and methods of the invention are useful for delivery in the gastrointestinal tract that are difficult to absorb, poorly tolerated, and/or subject to biological/chemical degradation (eg, by digestive enzymes in the gastrointestinal tract and/or Or acid decomposition) of the drug.
  • the devices, systems, kits and methods of the invention can be used to deliver drugs that were previously only or preferably administered by parenteral administration, such as intravenous or intramuscular injection.
  • the devices, systems, kits and methods of the invention can be used to achieve rapid release of a drug into the bloodstream by oral delivery.
  • a swallowable device for delivering a drug into a tissue.
  • the device includes a housing sized for swallowing, an attachment member, a drug, a penetrating member, and an actuation member, wherein the drug, the first configured penetration member and the actuation member are located inside the housing, and the attachment member is located on the outer surface of the housing.
  • a swallowable device comprising:
  • An attachment member on an outer surface of the outer casing adapted to attach the swallowable device to an external tissue
  • An actuating member located inside the outer casing having third and fourth configurations respectively adapted to the first and second configurations of the penetrating member, wherein the actuating member is from the third configuration
  • the penetrating member is driven to change from the first configuration to the second configuration when the fourth configuration is changed, and the drug is driven to be output via the penetrating member.
  • the attachment member is overcoated with a degradable coating.
  • At least one through hole is provided on the outer casing adjacent the actuating member, and the through hole is optionally shielded with a degradable shielding layer.
  • the coating layer degrades faster than the degradation rate of the masking layer.
  • the penetrating member includes a needle-shaped body that supports the needle-shaped body, the needle-shaped body is adjacent to the attachment member and the needle tip direction is toward the swallowable device On the outside, the needle-shaped body contains a drug; the actuating member is located between the support and a side of the outer casing opposite the attachment member.
  • the needle is provided with a barb.
  • the actuation component comprises an expandable element.
  • the actuation component includes an elastomer and a degradable stop component coupled to the outer casing and/or the support such that the elastomer is in a compressed state.
  • the outer periphery of the support is coupled to a skirt, the outer edge of the skirt abutting the inner surface of the outer casing.
  • the outer casing includes an internal volume and can be made from a variety of biocompatible polymers known in the art, such as various biodegradable polymers.
  • the outer shell can be controllably degraded into smaller pieces to facilitate passage of the swallowable device through the gastrointestinal tract and excretion and/or absorption.
  • the outer shell may comprise a suture of biodegradable material that is controllably degraded to produce an outer size piece of optional size and shape to facilitate its passage through the gastrointestinal tract.
  • the suture can be pre-stressed, perforated, or otherwise treated to accelerate degradation.
  • the outer casing is integrally formed of a biodegradable material and has grooves or depressions on the inner or outer surface of the outer casing such that the outer casing first degrades at the grooves or depressions, resulting in an optional The outer size of the size and shape of the piece to facilitate the swallowable device through the gastrointestinal tract.
  • the outer casing further includes one or more openings.
  • Part or all of the penetrating member of the swallowable device can extend out of the housing through the opening and into the tissue.
  • the opening has a degradable coating.
  • the cladding layer can be configured to degrade in various ways in response to various conditions.
  • the coating may be made of a biodegradable material configured to be degraded in whole or substantially all by body fluid in response to higher pH or other conditions within the small intestine.
  • the coating may completely enclose the opening such that the digestive juice cannot enter the interior of the housing until the swallowable device has reached a predetermined position.
  • the outer casing is integral with the portion adjacent the penetrating member. As the penetrating member of the swallowable device changes from the first configuration to the second configuration, the penetrating member penetrates the outer casing, thereby partially or fully extending out of the outer casing and into the tissue.
  • the attachment component of the swallowable device is located on the outer surface of the outer casing for attaching the swallowable device to a tissue surface, such as the surface of the gastrointestinal tract.
  • the attachment component can be attached to the tissue surface in a variety of ways.
  • the attachment component is an adhesive layer, such as various bioadhesives known in the art, to bond the swallowable device to the tissue surface.
  • the swallowable device can be bonded to different tissues by adjusting the composition of the adhesive.
  • the adhesive can be an adhesive that has strong adhesion only under acidic conditions, thereby allowing the swallowable device to adhere to the stomach tissue.
  • the adhesive may be an adhesive that has strong adhesion only under alkaline conditions, thereby allowing the swallowable device to adhere to the intestinal tissue.
  • the adhesive loses adhesion or is decomposed after bonding to the tissue surface for a period of time, thereby allowing the swallowable device to detach from the tissue surface.
  • the adhesive is configured to lose adhesion or be decomposed in response to the location of the swallowable device, such as due to hydration or loss of adhesion or decomposition upon exposure to pH or other chemical conditions within the gastrointestinal tract.
  • the attachment member comprises a hook.
  • the hooks may be one or more that extend upright on the outer surface of the outer casing away from the outer casing.
  • the hook has a stem connected to the outer casing and a head connected to the stem.
  • the projection of the head on the surface of the outer casing at least partially extends beyond the stem, for example in the form of a hook, an arrow or a mushroom.
  • the hook portions of adjacent hooks may protrude in the same or different directions.
  • Each of the adjacent hooks may have a flat surface that faces each other in a face to face relationship.
  • the hook forms a hook-and-loop fastening system with the outer tissue to attach the swallowable device to the outer tissue.
  • the attachment member further includes a substrate between the hook and the outer casing.
  • the attachment components of the swallowable device can be made of a degradable material such as PGLA, cellulose, and the like.
  • the attachment member is located adjacent the end of the penetrating member and is located on the outer surface of the respective outer casing.
  • the attachment member can be located around the opening when the swallowable device has an opening in the housing through which the penetrating member passes.
  • the swallowable device after adhering to the tissue, penetrates the end of the component proximate to the tissue such that the penetrating member can penetrate into the tissue after extending out of the outer shell. In this way, the drug in the swallowable device can enter all or substantially all of the tissue, resulting in a stable and controllable delivery effect.
  • the surface of the attachment member has a coating.
  • the cover layer covers all or substantially all of the attachment members such that the attachment members do not have an attachment function in the initial state.
  • the coating may be made of a degradable material and degraded after the swallowable device is swallowed.
  • the degradation rate of the coating is higher than other portions of the swallowable device, such as substantially degraded before the swallowable device reaches the desired location or is about to reach the desired location, such that the swallowable device It can be attached to the surface of the tissue and deliver the drug.
  • the penetrating member of the swallowable device can include a needle or other similar structure having a lumen or other compartment and a needle for penetration into a selectable depth in the wall of the gastrointestinal tract.
  • the device of the present invention can include one or more penetrating members, including, for example, a second penetrating member, a third penetrating member, and a greater number of penetrating members.
  • Each penetrating member can be used to deliver the same or different drugs.
  • each worn The transmissive members may be distributed in different directions with respect to the long or short axis of the outer casing, or the penetrating members may be concentrated in one direction.
  • the penetrating member includes a needle and a support that are integrally connected, the needle of the needle being adjacent to the attachment member and having a tip direction toward the outside of the swallowable device.
  • the needle is hollow with a conduit connected to at least one opening in the support.
  • the swallowable device of the present invention further includes a sachet adjacent the needle and the support, the bladder being sealingly coupled to the support and in fluid communication with a conduit in the needle.
  • the penetrating member of the swallowable device has a first configuration and a second configuration.
  • the penetrating member When the penetrating member is in the first configuration, it is in a normal sense or in an initial state, in which case all or substantially all of the penetrating member is located inside the casing.
  • the penetrating member When the penetrating member is in the second configuration, it is in a normal sense of use, when the swallowable device has been swallowed into the body and all or part of the penetrating member is located outside the casing and penetrates into the target tissue . By penetrating the component, the drug in the swallowable device enters the tissue.
  • the actuation member is coupled to at least one of the penetration member and the medicament.
  • the actuation member is configured to drive the penetration member to change from the first configuration to the second configuration such that it partially or fully enters the interior of the tissue, such as the gastrointestinal wall.
  • the actuation component is configured to drive the drug through the penetrating component to deliver the drug into the tissue, such as the gastrointestinal wall.
  • the actuation member is configured to withdraw the penetrating member from the tissue after pushing the drug through the penetrating member into the tissue.
  • the actuating member is configured to retain the penetrating member within the tissue.
  • the actuation component of the swallowable device has a third configuration and a fourth configuration.
  • the actuating member When the penetrating member of the swallowable device is in the first configuration, the actuating member has a third configuration that is adapted thereto.
  • the actuation member changes from the third configuration to the fourth configuration, the drive penetration member changes from the first configuration to the second configuration, and the drug is driven through the penetration The component is output to the outside of the casing.
  • the stop member is coupled to the outer casing and/or the support such that the elastomer is in a compressed state. Degradation of the stop member causes the elastomer to be released, thereby driving the penetrating member to change from the first configuration to the second configuration and driving the drug out of the outer casing via the penetrating member.
  • the outer periphery of the support is coupled to a skirt, the outer edge of the skirt abutting the inner surface of the outer casing such that the elastomer is in a compressed state. Degradation of the skirt causes the elastomer to be released, thereby driving the penetrating member to change from the first configuration to the second configuration and driving the drug out of the housing via the penetrating member.
  • the actuating member is located between the support and the side of the housing opposite the attachment member.
  • the actuating member comprises an expandable member.
  • the expandable element is, for example, an expandable material, a balloon or other expandable element.
  • An expandable element is provided inside the outer casing, which is optionally coupled to the penetrating member.
  • the expandable member is located inside the outer casing and the outer casing has a through hole adjacent the expandable member. Body fluid can enter the swallowable through the through hole Inside the device, in contact with the expandable element.
  • at least a portion of the surface of the outer shell comprising the through holes is desirably coated with a masking layer, such as an enteric polymer layer. The masking layer can be degraded in response to various conditions such as pH conditions.
  • the shielding layer provides a protective seal over the through hole such that the digestive fluid cannot enter the interior of the outer casing such that the expandable member expands until the swallowable device has reached a predetermined position.
  • a degradable masking layer on the aperture provide the primary means and means of ensuring that the swallowable device does not extend and/or deploy its penetrating member prior to reaching the target tissue. .
  • the expansion of the expandable member pushes the penetrating member into the tissue.
  • the expansion of the expandable member also pushes the drug into the tissue.
  • the maximum expanded volume of the expandable member can be configured to exceed the volume of the outer casing such that after expansion, the outer casing is ultimately expanded into one or more pieces to facilitate passage through the intestine.
  • the swellable material comprises a swellable polymer that is variable in volume under specific conditions, such as a superabsorbent polymer (SAP).
  • SAP superabsorbent polymer
  • Superabsorbent polymers are a class of macromolecules containing hydrophilic groups and crosslinked structures, including starches (grafts, carboxymethylates, etc.), celluloses (carboxymethylation, grafts, etc.). And synthetic polymers (polyacrylic, polyvinyl alcohol, polyoxyethylene, etc.) and other types. Before the water absorption, the chains of the superabsorbent polymer are entangled with each other and crosslinked into a network structure, thereby achieving an overall compactness and a small volume.
  • the expandable member includes a bladder and a degradable valve that divides the bladder into two first and second chambers that are isolated from one another.
  • the bladder In the first configuration, the bladder is typically located within the outer casing in an at least partially non-expanded state.
  • the capsules can be made from a variety of biocompatible polymers known in the art. Desirably, the bladder has a thin wall, such as less than about 0.01 centimeters.
  • the first chamber and the second chamber store the first reactant and the second reactant, respectively.
  • an acid such as citric acid and a base such as sodium carbonate may have a suitable ratio, for example, about 2:1.
  • the reactants may also include other acids such as acetic acid and bases.
  • the first reactant and the second reactant may each independently comprise a plurality of different components.
  • the first reactant and the second reactant mix and cause the volume of the bladder to expand, such as by generating a gas such as carbon dioxide.
  • the volume expansion produced by the first reactant and the second reactant can be configured to be greater than the maximum volume of the bladder such that upon expansion, the bladder is ultimately expanded into one or more pieces, To make it easier to pass through the intestines.
  • the valve can be configured to open in various ways in response to various conditions.
  • the valve can be configured to open by degrading one or more portions in response to higher pH or other conditions within the small intestine.
  • the valve will be placed in the center of the bladder, but it can be placed in other locations.
  • the valve can have a beam-like structure that is placed within the outer casing to compress the portion of the bladder between the first chamber and the second chamber.
  • the beam can be attached to the inner surface of the outer casing at one or both ends.
  • the beam is attached to the radial side of the outer casing using an interference fit such that the beam can be snapped into place using pick and place methods and other similar methods known in the art of fabrication.
  • valve may include one or more hooping features, such as ridges that engage grooves or other mating features on the inner surface of the outer casing to apply additional to the balloon wall under the hoop feature. Force and apply a redundancy to the seal.
  • the valve can include a constricted section of the expandable element having a cover hoop made of a biodegradable material. This ring keeps the valve closed and opens the valve when it degrades.
  • the valve can be located in multiple locations within or on the housing for exposure to body fluids and degradation by body fluids. At least a portion of the valve can be exposed to the surface of the outer casing. Alternatively, the valve may also be located inside the housing, and the housing has a through hole near the valve where the valve is exposed to body fluid entering through the through hole. In one aspect of the invention, at least a portion of the surface of the outer shell comprising the through-holes is desirably coated with a masking layer, such as an enteric polymer layer, which can be degraded in response to various conditions, such as pH conditions. The shielding layer provides a protective seal over the through hole to prevent the digestive fluid from entering the interior of the housing to begin the degradation valve until the swallowable device has reached the predetermined position.
  • a masking layer such as an enteric polymer layer
  • embodiments employing a degradable protective layer on the holes and on the degradable valve provide for ensuring swallowing
  • the pharyngeal device does not extend and unfold its primary means and aids to penetrate the component prior to reaching the target tissue.
  • the valve can also be configured to open in response to a compressive force applied by peristaltic contraction within the small intestine.
  • the valve may be a time delay release valve that is configured to open after a certain period of time after an activation step initiated by the patient, such as peeling off a label or pressing a button.
  • the bladder or other expandable member can generally also include a retraction valve for contracting the expandable member after it has expanded.
  • the retraction valve can comprise a biodegradable material configured to degrade upon exposure to fluid in the small intestine and/or liquid within one of the balloon chambers to form an opening or passage for gas selection within the balloon .
  • the contraction valve can include a biodegradable portion at the end of the balloon to connect the opposite ends of the balloon wall together. In one aspect of the invention, when the degradable segment degrades due to exposure to a liquid, the balloon wall tears or otherwise breaks, thereby ensuring a high degree of rapid contraction.
  • the outer shell can be split into two or more pieces by configuring the expanded balloon to expose the large balloon segment directly to the degrading fluid in the small intestine. In order to promote the degradation of the valve. This can be accomplished by making the outer casing from separate parts, such as the two halves that are mechanically joined together, and/or by using the sutures described herein.
  • one or more piercing elements can be attached to the inner surface of the outer casing wall to be contacted and pierced by the piercing element when the bladder is fully retracted.
  • one or more tissue penetrating members can be coupled directly to the balloon and configured to be torn from the balloon when they are disengaged, thereby tearing the balloon wall during the process.
  • the activation component can include a film or peg that retains the penetrating component within the outer casing.
  • the tissue penetrating member is coupled to the spring loaded actuation member such that when the activation member is sufficiently degraded, it releases the penetrating member, which in turn pops out of the housing to penetrate into the tissue.
  • the shape of the activation member can function as a latch that holds the penetrating member in place.
  • the activation component can be located external or internal to the housing. In embodiments located inside the outer casing, the outer casing is configured to allow bodily fluids to enter the interior of the outer casing to allow degradation of the activation components.
  • the senor can include a strain gauge or other pressure/force sensor for detecting the number of peristaltic contractions experienced by the outer casing at a particular location within the intestinal tract.
  • the outer casing is sized such that it can be clamped by the small intestine during peristaltic contraction.
  • the small intestine has a contraction between 12 and 9 times per minute, which frequency gradually decreases along the length of the intestine.
  • the detection of the number of peristaltic contractions can be used to determine the relative position of the outer casing within the gastrointestinal tract.
  • a user of the swallowable device can externally activate the actuation member to deliver the drug via an RF device, a magnetic device, or other wireless signaling device known in the art.
  • a user may use a handheld device (eg, a handheld RF device) that includes not only signaling devices, but also for when the swallowable device is in the small intestine or gastrointestinal The device that notifies the user when other locations in the track.
  • a handheld device eg, a handheld RF device
  • the device that notifies the user when other locations in the track.
  • the same handheld device can also be configured to alert the user when the actuation member has been activated and one or more selected medications have been delivered. In this way, the user is confirmed that the drug has been delivered. This allows the user to take other appropriate medications and make other relevant decisions (eg, whether the diabetic has eaten and what food should be consumed).
  • the handheld device can also be configured to send a signal to the swallowable device to manipulate the actuation member and thereby prevent, delay or accelerate drug delivery. In use, such embodiments allow the user to intervene to prevent, delay, or accelerate drug delivery based on other symptoms and/or patient behavior (eg, eating, sleeping, exercising, etc.).
  • the user can also activate the actuation member from the outside for a selected period of time after swallowing the housing.
  • This period of time may be related to the typical transit time or passage time range through which the food moves through the gastrointestinal tract of the user to a particular location within the gastrointestinal tract.
  • the medicament of the swallowable device can be configured in the form of a liquid, semi-liquid or solid or any combination thereof.
  • the solid form of the drug may include a powder or a pill.
  • the semi-liquid may include a slurry, a paste, a gel, or the like.
  • the medicament of the swallowable device can be contained directly in the cavity of the outer casing.
  • the medicament can be contained within a closed medicament container.
  • the swallowable device can include more than one drug, for example, including a first drug, a second drug, a third drug, or more. These drugs may be included separately or collectively in a cavity within the outer casing, or each separately or collectively contained in a separate reservoir within the outer casing body.
  • a swallowable device can be used to deliver a variety of therapeutically effective amounts of the drug.
  • these drugs include various macromolecular peptides and proteins that would otherwise require injection due to their chemical breakdown in the stomach/gastrointestinal tract, for example, growth hormone, parathyroid hormone, insulin, interferon and others. A similar compound.
  • Suitable drugs that can be delivered by swallowable devices include various chemotherapeutic agents (eg, interferons), antibiotics, antivirals, insulin and related compounds, glucagon-like peptides (eg, GLP-1, Exenatide) , parathyroid hormone, growth hormone (eg, IFG and other growth factors), anti-epileptic agents, immunosuppressive agents, and various anti-like agents An anti-parasitic agent such as a malaria agent.
  • chemotherapeutic agents eg, interferons
  • antibiotics eg, antivirals, insulin and related compounds
  • glucagon-like peptides eg, GLP-1, Exenatide
  • parathyroid hormone eg, growth hormone (eg, IFG and other growth factors)
  • anti-epileptic agents eg, IFG and other growth factors
  • immunosuppressive agents e.g, anti-parasitic agent
  • An anti-parasitic agent such as a malaria agent.
  • the pharmaceutical composition can be incorporated into the swallowable device of the present invention for delivery to a user.
  • the drug can be incorporated into a pharmaceutical composition suitable for administration to a user with the device of the present invention.
  • these pharmaceutical compositions include pharmaceutically active ingredients, as well as a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier includes any solvent that is physiologically compatible, dispersion media, bactericidal and fungicidal agents, isotonic and absorption delaying agents, and the like.
  • pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffer, dextrose, glycerol, ethanol, and the like, and combinations thereof.
  • isotonic agents for example, sugars, polyols (such as mannitol, sorbitol) or sodium chloride, may be included in the compositions.
  • the pharmaceutically acceptable carrier may also include minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers which enhance the shelf life or effectiveness of the drug.
  • compositions for use in the methods and compositions of the present invention may be adapted to a variety of different forms for administration by the devices of the present invention, including, for example, liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions.
  • liquid solutions e.g., injectable and infusible solutions
  • dispersions or suspensions e.g., dispersions, dispersions or suspensions.
  • compositions typically must be sterilized and stable under the conditions of manufacture and storage.
  • the compositions may be formulated as solutions, microemulsions, dispersions, liposomes or other ordered structures suitable for high drug concentrations.
  • the sterilized injection solution can be prepared by incorporating the required amount of the pharmaceutically active ingredient into a suitable solvent, which contains one of the above-listed components or a combination thereof as needed, followed by filter sterilization.
  • dispersions are prepared by incorporating the active compound into a sterilized carrier liquid containing the base dispersion medium and the additional ingredients enumerated above.
  • the preferred preparation methods are vacuum drying and lyophilization, yielding a powder from the active component of the pre-filter sterilized solution and any desired component.
  • the proper fluidity of the solution can be maintained, for example, by the use of a coating such as lecithin, by the required particle size in the case of dispersion, and by the use of surfactants.
  • Prolonged absorption of the injectable compositions can be brought about by the inclusion in the compositions in the compositions, such as,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,
  • a variety of drugs can be delivered using a swallowable device to treat various conditions or conditions.
  • a swallowable device can be used to deliver multiple protease inhibitors to treat Treat AIDS. This allows the patient to take multiple medications for a condition or condition, but only once using the device of the present invention.
  • the swallowable device solves this problem by controlling the timing of delivery of various drugs.
  • two or more drugs of one treatment regimen are delivered and absorbed into the bloodstream or target tissue at specific time intervals or simultaneously. method. This improves the pharmacokinetics of the various target drugs and thus improves their efficacy.
  • the various portions of the swallowable device can each be independently fabricated from a suitable material, such as from the same or different biodegradable materials.
  • portions of the swallowable device can be independently made of the same or different materials that are not biodegradable but are not harmful to the user.
  • biodegradable material generally refers to a material whose chemical structure can be altered by a conventional environment, such as substances in the physiological environment of a human body, such as enzymes, pH, and natural compounds, to produce a simple element or chemical structure. So harmless. Biodegradable materials can also be bioerodible.
  • bioerodible means that the material is biodegradable, digestible or erosive in the environment, or is soluble or degradable into a reduced size material, for example, by chemical, biological (eg enzymatic), physical decomposition, Or solubilization, so that the material is eliminated from the environment without major harm.
  • biodegradable as used herein also encompasses the term “bioabsorbable”, which generally describes a material whose decomposition products that decompose under physiological conditions can enter a host subject to undergo biological activity. Absorption, for example, a metabolite of the biochemical system that becomes the host object.
  • biodegradable materials may include gelatin, sodium alginate, cellulose esters (such as hydroxypropylmethylcellulose, etc.), plant polysaccharides (such as pullulan, fucoidan, carrageenan, agar, etc.) and starch. And its derivatives (such as modified starch, etc.).
  • Degradation of the various components caused by one or more conditions in the gastrointestinal tract can be achieved by selecting the ingredients of the materials used in the various components of the swallowable device, the degree of crosslinking of these components, the thickness, and other conditions. Similarly, the order of degradation of each component can be controlled thereby, thereby appropriately functioning the various parts. The function of the piece reaches the intended purpose of the swallowable device. For example, less cross-linking and/or thinner gauges can increase the rate of degradation and vice versa.
  • copolymerization or otherwise mixing one or more polymers can result in a number of specific material properties in addition to biodegradation, such properties including, but not limited to, stiffness, strength, flexibility, and hardness.
  • the coating of the clad attachment member degrades faster than the degradation layer of the obscuring through-hole.
  • the attachment member is exposed in the gastrointestinal tract cavity, and the through hole is also shielded by the shielding layer, so that the swallowable device can be attached to the surface of the gastrointestinal tissue, and the actuating member is
  • the penetrating members are still wholly or substantially entirely inside the casing.
  • the shielding layer is degraded, and the body fluid enters the outer casing of the swallowable device through the through hole, so that the actuating member is changed from the third configuration to the fourth configuration, and the driving and penetrating member is changed from the first configuration to the second configuration, and the driving device is driven
  • the drug is output into the gastrointestinal tissue via the penetrating member.
  • the drug in the swallowable device can be all or substantially all exported to the gastrointestinal tissue via the penetrating member.
  • the rate of degradation of the attachment member, outer shell, bladder, and the like of the swallowable device is lower than the rate of degradation of the cover layer and the masking layer.
  • the penetrating member of the swallowable device can also be configured to degrade after the drug in the swallowable device is exported to the gastrointestinal tissue, for example, at intervals of two administrations, such that the previously administered swallowable The device does not affect the administration of the subsequent swallowable device.
  • the penetrating member of the swallowable device can be configured to have a higher stiffness for better penetration into tissue.
  • Materials having higher hardness and methods for their preparation are well known in the art, such as polymers having a relatively high degree of crosslinking.
  • Figure 1 is a schematic view of the swallowable capsule 100 in the intestine
  • Figure 2 shows a perspective view of the appearance of a capsule 200 of one embodiment
  • Figure 3 shows a perspective view of the appearance of a capsule 300 of one embodiment
  • Figure 4A shows the outer casing 402 in one embodiment, and Figure 4B shows the degraded outer casing piece;
  • Figure 5A shows a cross-sectional view of a capsule 500 of one embodiment
  • Figure 5B shows a cross-sectional view of a capsule 500' of one embodiment
  • Figure 6 shows a schematic cross-sectional view of a capsule 600 of one embodiment
  • Figure 7 shows a cross-sectional view of a capsule 700 of one embodiment
  • Figure 8 shows a schematic cross-sectional view of a capsule 800 of one embodiment
  • Figure 9A shows a schematic cross-sectional view of a capsule 900 of one embodiment
  • Figure 9B shows a schematic cross-sectional view of a capsule 900' of one embodiment
  • Figure 10 shows a schematic cross-sectional view of a capsule 1000 of one embodiment
  • Figure 11 shows a schematic cross-sectional view of a capsule 1100 of one embodiment
  • Figure 12 shows a schematic cross-sectional view of a capsule 1200 of one embodiment.
  • Figure 1 is a schematic illustration of the capsule 100 positioned within the intestinal tract.
  • the capsule 100 can be swallowed through the mouth and can be moved to the stomach or intestine via the digestive tract.
  • Hooks 108 are provided on the outer surface of one side of the capsule 100, and these hooks 108 serve as attachment members for attaching the capsule to the stomach wall or the intestinal wall.
  • FIG. 2 shows a perspective view of the appearance of a capsule 200 of one embodiment.
  • the appearance of the capsule generally appears as an oblong or olive shape.
  • An attachment member 210 composed of a plurality of hooks 208 is disposed on one side of the outer surface of the capsule.
  • the hook 208 engages the tissue of the stomach wall or the intestinal wall to effectively attach the capsule 200 to the stomach wall or the intestinal wall.
  • the hooks 208 in this example are arranged in a neat array.
  • the bending directions of the hooks 208 are not uniform. For example, the hooks 208 having the same bending direction in each of the two columns constitute one unit, and the hooks 208 of the adjacent two units are opposed to each other in the bending direction.
  • attachment members that employ other combinations of hooks and/or bend directions are also possible.
  • the stomach environment is acidic and the intestinal environment is alkaline.
  • a coating layer may be disposed on the outer side of the attachment member or wrapped around the attachment member, and before the coating layer is degraded, the capsule may be To advance smoothly along the digestive tract (esophagus, stomach, intestines, etc.).
  • the coating may be enteric, which does not degrade in the stomach and degrades in the intestine to ensure that the attachment components are exposed in the intestinal tract, thereby allowing the capsule to effectively adhere to the intestinal wall.
  • the coating may be gastric soluble, which degrades in the stomach to ensure that the attachment components are exposed in the stomach, thereby allowing the capsule to effectively adhere to the stomach wall.
  • FIG. 3 shows a perspective view of the appearance of a capsule 300 of one embodiment.
  • the appearance of the capsule 300 generally appears as an oblong or olive shape.
  • the attachment member 310 composed of the viscous body 308 is disposed on one side of the outer surface of the capsule.
  • the viscous body 308 adheres to the tissue of the stomach wall or the intestinal wall to effectively attach the capsule 300 to the stomach wall or the intestinal wall.
  • a coating layer may also be disposed outside the attachment member 310, and the capsule 300 can smoothly advance along the digestive tract (esophagus, stomach, intestine, etc.) before the coating is degraded.
  • the coating may be enteric to ensure that the attachment member 310 is exposed in the intestine such that the capsule 300 is effectively attached to the intestinal wall.
  • the coating may be gastric soluble, which degrades in the stomach to ensure that the attachment member 310 is exposed in the stomach, thereby allowing the capsule 300 to effectively adhere to the stomach wall.
  • the appearance of the capsule is generally spherical.
  • the outer shell of the capsule can be made from a variety of biocompatible polymers known in the art, such as various biodegradable polymers.
  • 4A illustrates an outer casing 402 in one embodiment of the present invention that is integrally formed of a biodegradable material and has grooves or depressions 404 on its outer surface such that the outer shell first degrades in the grooves or depressions.
  • An outer panel 403 of optional size and shape as shown in Figure 4B is created to facilitate passage of the capsule through the gastrointestinal tract and to reduce the likelihood of the capsule being stuck within the gastrointestinal tract.
  • FIG. 5A shows a schematic cross-sectional view of a capsule 500 of one embodiment.
  • the outer casing 502 generally assumes an oblong or olive shape.
  • An attachment member 510 composed of a plurality of hooks 508 is disposed on one side of the outer surface of the outer casing 502.
  • the hook 508 can engage the tissue of the stomach wall or the intestinal wall to effectively attach the capsule 500 to the stomach wall or the intestinal wall.
  • a needle 520, a support 524, and a sachet 528 are disposed on a side close to the attachment member 510, and an expansion member 530 is disposed on a side away from the attachment member 510.
  • the needle 520 and the support 524 are integrally connected, generally located adjacent to the attachment member 510 with the needle tip facing the outside of the capsule 500.
  • the needle 520 is hollow with an infusion line 521 in communication with a conduit 525 in the holder 524.
  • a drug such as a liquid is stored in the sachet 528.
  • the sachet 528 is sealingly coupled to the support 524 and exposes the end opening 526 of the conduit 525 inside the sachet such that the chamber within the sachet is in fluid communication with the infusion conduit 521.
  • the sachet 528 is relatively soft and easily deformed, and the needle 520 and the support 524 are relatively strong and are not easily deformed.
  • the outer casing 502 is provided with at least one opening 506 on one side of the expansion element 530.
  • the expansion member 530 contacts the body fluid through the opening 506 in the stomach or intestine to cause volume expansion.
  • the material contained in the expansion element 530 is, for example but not limited to, a superabsorbent polymer (SAP), such as the BASF Corporation. Series SAP. Due to the limitations of the outer casing 502, the expansion element 530 will squeeze the needle 520, the support 524 and the sachet 528 toward the attachment member 510 side. The needle 520 thus penetrates the outer casing 502 and penetrates the stomach wall or intestinal wall tissue to which the attachment element 510 is attached. The sachet 528 is deformed by extrusion so that the stored drug solution is injected into the stomach wall or the intestinal wall tissue via the infusion tube 521.
  • a coating layer 512 may be disposed outside the attachment member 510 or enclosing the attachment member 510, and the capsule 500 may smoothly advance along the digestive tract (esophagus, stomach, intestine, etc.) before the coating layer 512 is degraded.
  • the opening 506 can be obscured by the obscuring layer 516 such that the expansion element 530 does not contact body fluids in the stomach or intestine until the capsule 500 reaches the desired site of administration.
  • the coating layer 512 and the shielding layer 516 may both be enteric, and the degradation speed of the coating layer 512 is faster than the degradation speed of the shielding layer 516; after the coating layer 512 degrades and exposes the attachment member 510 and adheres to the intestinal wall, The obscuring layer 516 at the opening 506 degrades and exposes the expansion element 530.
  • the coating layer 512 and the shielding layer 516 may both be gastric-soluble, and the degradation speed of the coating layer 512 is faster than the degradation speed of the shielding layer 516; after the coating layer 512 degrades and exposes the attachment member 510 and adheres to the stomach wall, the opening 506 The obscuring layer 516 at the site degrades and exposes the expansion element 530.
  • Fig. 5B is a cross-sectional view showing the capsule 500' of a variation of the embodiment shown in Fig. 5A.
  • the difference from the capsule 500 includes that at least one conduit 525' is provided with a plurality of openings 526' on the support 524', which helps to reduce the deformed sachet 528' blocking the opening 526' and causing the remaining liquid medicine The risk of injecting into the stomach wall or intestinal wall tissue through the conduit 525' and the infusion conduit 521' cannot continue.
  • Figure 6 shows a schematic cross-sectional view of a capsule 600 of one embodiment.
  • the outer casing 602 generally assumes an oblong or olive shape.
  • An attachment member 610 composed of a plurality of hooks 608 is disposed on one side of the outer surface of the outer casing 602.
  • the hook 608 can engage the tissue of the stomach wall or the intestinal wall to effectively attach the capsule 600 to the stomach wall or the intestinal wall.
  • a needle 620, a support 624, and a sachet 628 are disposed on a side close to the attachment member 610, and a side away from the attachment member 610 is provided.
  • An expansion element 630 is placed.
  • the needle 520 and the support 524 are integrally connected, generally located adjacent to the attachment member 610 with the needle tip facing the outside of the capsule 600.
  • the needle 620 is hollow, with the infusion conduit 621 communicating with the conduit 625 in the holder 624.
  • a drug such as a liquid is stored in the sachet 628.
  • the sachet 628 is sealingly coupled to the holder 624 and exposes the end opening 626 of the conduit 625 inside the sachet such that the chamber within the sachet is in fluid communication with the infusion conduit 621.
  • the sachet 628 is relatively soft and easily deformed, and the needle 620 and the support 624 are relatively strong and are not easily deformed.
  • the outer casing 602 is provided with at least one opening 606 on one side of the expansion element 630.
  • the expansion element 630 includes a bladder 632 and a valve 634.
  • valve 634 clamps the middle of bladder 632 to form two first chambers 635 and a second chamber 637 that are isolated from one another, storing first reactants and second reactants, respectively.
  • the valve 634 is degraded by contact with the body fluid through the opening 606, and the first chamber 635 and the second chamber 637 are in communication with each other, and the first reactant and the second reactant are mutually connected to each other. Mixing occurs chemically and/or physically to cause volume expansion.
  • the first reactant and the second reactant are mixed to produce carbon dioxide, resulting in volume expansion. Due to the limitations of the outer casing 602, the expanded bladder 632 will squeeze the needle 620, the support 624, and the sachet 628 toward the side of the attachment member 610. The needle 620 thus penetrates the outer casing 602 and penetrates the stomach wall or intestinal wall tissue to which the attachment element 610 is attached. The sachet 628 is deformed by extrusion so that the stored medical solution is injected into the stomach wall or intestinal wall tissue via the infusion conduit 621.
  • the expanded bladder 632 will squeeze the needle 620, the support 624, and the sachet 628 toward the side of the attachment member 610.
  • the needle 620 thus penetrates the outer casing 602 and penetrates the stomach wall or intestinal wall tissue to which the attachment element 610 is attached.
  • the sachet 628 is deformed by extrusion so that the stored medical solution is injected into the stomach wall or intestinal wall tissue via the infusion conduit 621.
  • a coating layer may be disposed outside the attachment member 610 or enclosing the attachment member 610, and the capsule 600 may smoothly advance along the digestive tract (esophagus, stomach, intestine, etc.) before the coating is degraded.
  • the opening 606 can be obscured by the obscuring layer such that the valve 634 does not contact body fluids in the stomach or intestine until the capsule 600 reaches the desired site of administration.
  • the coating layer and the shielding layer may both be enteric, and the degradation rate of the coating layer is faster than the degradation speed of the shielding layer; after the coating layer degrades and exposes the attachment member 610 and adheres to the intestinal wall, the opening 606
  • the masking layer degrades and exposes valve 634.
  • the coating layer and the shielding layer may both be gastric-soluble, and the degradation rate of the coating layer is faster than the degradation rate of the shielding layer; when the coating layer degrades and exposes the attachment member 610 and adheres to the stomach wall, the shielding layer at the opening 606 Degradation and exposure of valve 634.
  • FIG. 7 shows a cross-sectional view of a capsule 700 of one embodiment.
  • the outer casing 702 generally assumes an oblong or olive shape.
  • An attachment member 710 composed of a plurality of hooks 708 is disposed on one side of the outer surface of the outer casing 702.
  • the hook 708 can bite the tissue of the stomach wall or the intestinal wall to effectively attach the capsule 700 to the stomach wall or the intestinal wall.
  • a needle-shaped body 720 and a support 724 are provided on a side close to the attachment member 710, and an expansion member 730 is provided on a side away from the attachment member 710.
  • the support 724 holds the needle 720, generally adjacent to the attachment member 710, with the needle tip 720 facing the outside of the capsule 700.
  • a coating may also be provided on the outside of the attachment member 710 or wrapped around the attachment member 710, and the capsule 700 may smoothly advance along the digestive tract (esophagus, stomach, intestine, etc.) before the coating is degraded.
  • the opening 706 can be obscured by the obscuring layer such that the expansion element 730 does not contact body fluids in the stomach or intestine until the capsule 700 reaches the desired site of administration.
  • the coating layer and the shielding layer may both be enteric, and the degradation rate of the coating layer is faster than the degradation speed of the shielding layer; when the coating layer degrades and exposes the attachment member 710 and adheres to the intestinal wall, the opening 706 The masking layer degrades and exposes the expansion element 730.
  • the coating layer and the shielding layer may both be gastric-soluble, and the degradation rate of the coating layer is faster than the degradation rate of the shielding layer; when the coating layer degrades and exposes the attachment member 710 and adheres to the stomach wall, the shielding layer at the opening 706 The expansion element 730 is degraded and exposed.
  • FIG. 8 shows a schematic cross-sectional view of a capsule 800 of one embodiment.
  • the outer casing 802 generally assumes an oblong or olive shape.
  • An attachment member 810 including a viscous body is disposed on one side of the outer surface of the outer casing 802.
  • the capsule 800 can be effectively attached to the stomach wall or the intestinal wall by stickiness.
  • a needle-like body 820 and a support 824 are provided on a side close to the attachment member 810, and an expansion member 830 is provided on a side away from the attachment member 810.
  • the support 824 holds the needle 820, generally adjacent to the attachment member 810, with the needle tip 820 facing the outside of the capsule 800.
  • the needle 820 contains a solid drug and is provided with a barb 821.
  • the outer casing 802 is provided with at least one opening 806 on one side of the expansion element 830.
  • the expansion element 830 includes a bladder 832 and a valve 834. For example but not Limited to the valve 834 clamping the middle of the bladder 832, forming two first chambers 835 and a second chamber 837 that are isolated from one another, storing the first reactant and the second reactant, respectively.
  • the valve 834 When the capsule 800 is attached to the stomach or intestine by the attachment member 810, the valve 834 is degraded by contact with the body fluid through the opening 806, and the first chamber 835 and the second chamber 837 are in communication with each other, the first reactant and the second reactant are mutually connected to each other. Mixing occurs chemically and/or physically to cause volume expansion.
  • the first reactant and the second reactant such as but not limited to, acetic acid and sodium bicarbonate, respectively, are mixed to produce carbon dioxide, resulting in volume expansion. Due to the limitations of the outer casing 802, the expanded bladder 832 will squeeze the support 824 and the needle 820 toward the side of the attachment member 810.
  • the needle 820 thus penetrates the outer casing 802 and penetrates the stomach wall or intestinal wall tissue to which the attachment element 810 is attached, and the barb 821 causes the needle 820 to remain inside the tissue. Thereafter, the needle 820 is degraded inside the tissue to complete the administration.
  • a coating layer may also be disposed on the outside of the attachment member 810, and the capsule 800 can smoothly advance along the digestive tract (esophagus, stomach, intestine, etc.) before the coating is degraded.
  • the opening 806 can be obscured by the obscuring layer such that the valve 834 does not contact body fluids in the stomach or intestine until the capsule 800 reaches the desired site of administration.
  • the coating layer and the shielding layer may both be enteric, and the degradation rate of the coating layer is faster than the degradation speed of the shielding layer; when the coating layer degrades and exposes the attachment member 810 and adheres to the intestinal wall, the opening 806 The masking layer degrades and exposes valve 834.
  • the coating layer and the shielding layer may both be gastric-soluble, and the degradation rate of the coating layer is faster than the degradation rate of the shielding layer; when the coating layer degrades and exposes the attachment member 810 and adheres to the stomach wall, the shielding layer at the opening 806 Degrading and exposing valve 834.
  • the support 924 holds the needle 920 substantially in the immediate vicinity of the attachment member 910 with the needle tip 920 facing the outside of the capsule 900.
  • the needle 920 contains a solid drug and is provided with a barb 921.
  • Each of the actuating members 930 includes an elastic member (e.g., a spring) 933 and a limit member 935 between the respective holder 924 and the other side of the outer casing 902. In the initial state, the limiting member 935 will support the attachment member 924 with the housing 902 and the attachment member 910. The opposite side is joined together such that the spring 933 is in a compressed state. At least one opening 906 is provided on the outer casing 902 adjacent to the limiting member 935.
  • a coating layer 912 may also be disposed outside the attachment member 910 or enclosing the attachment member 910.
  • the capsule 900 may smoothly advance along the digestive tract (esophagus, stomach, intestines, etc.) before the coating 912 degrades.
  • the opening 906 can be obscured by the obscuring layer 916 such that the stop element 935 does not contact body fluids in the stomach or intestine until the capsule 900 reaches the desired site of administration.
  • the coating layer 912 and the shielding layer 916 may both be enteric, and the degradation speed of the coating layer 912 is faster than the degradation speed of the shielding layer 916; after the coating layer 912 degrades and exposes the attachment member 910 and adheres to the intestinal wall, The obscuring layer 916 at the opening 906 degrades and exposes the stop element 935.
  • the coating layer 912 and the shielding layer 916 may both be gastric-soluble, and the degradation speed of the coating layer 912 is faster than the degradation speed of the shielding layer 916; after the coating layer 912 degrades and exposes the attachment member 910 and adheres to the stomach wall, the opening 906 The obscuring layer 916 at the location degrades and exposes the stop element 935.
  • the coating layer 912, the shielding layer 916, and the limiting element 935 comprise materials such as, but not limited to, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), acrylic resin, polyvinylpyrrolidone (PVP). , methacrylic acid-ethyl acrylate copolymer or a mixture thereof.
  • HPMC hydroxypropyl methylcellulose
  • HPC hydroxypropyl methylcellulose
  • HPC hydroxypropyl cellulose
  • acrylic resin acrylic resin
  • PVP polyvinylpyrrolidone
  • methacrylic acid-ethyl acrylate copolymer or a mixture thereof.
  • Figure 9B shows a schematic cross-sectional view of a capsule 900' of one embodiment.
  • the main difference of the capsule 900' compared to the capsule 900 includes that the stop member 935' is located between the holder 924' and the outer casing on the side of the attachment member 910'. In the initial state, the stopper member 935' supports the holder 924' such that the spring 933' is in a compressed state. At least one opening 906' is provided on the outer casing 902' adjacent to the limiting member 935'.
  • the body fluid entering the housing 902' through the opening 906' causes the stop member 935' to degrade, the support 924' and the needle 920' will be at the spring 933'
  • the restoring force urges the lower attachment member 910' to be pressed.
  • the needle 920' thus penetrates the outer casing 902' and penetrates the stomach wall or intestinal wall tissue to which the attachment member 910' is attached, the barb 921'
  • the needle 920' remains inside the tissue. Thereafter, the needle 920' is degraded inside the tissue to complete the administration.
  • the coating layer 912', the shielding layer 916', and the limiting element 935' comprise materials such as, but not limited to, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), acrylic resin, polyvinylpyrrolidone. (PVP), methacrylic acid-ethyl acrylate copolymer or a mixture thereof.
  • HPMC hydroxypropyl methylcellulose
  • HPC hydroxypropyl methylcellulose
  • HPC hydroxypropyl cellulose
  • acrylic resin acrylic resin
  • PVP polyvinylpyrrolidone.
  • methacrylic acid-ethyl acrylate copolymer or a mixture thereof.
  • the outer edge of the skirt 1027 abuts the inner surface of the outer casing 1002.
  • An elastic member (spring) 1033 and a stopper member 1035 are disposed between the holder 1024 and the side of the outer casing 1002 away from the attachment member 1010. In the initial state, the limiting member 1035 will support the attached component of the housing 1024 and the housing 1002. The opposite sides of 1010 are joined together such that spring 1033 is in a compressed state. At least one opening 1006 is provided on the outer casing 1002 near the limiting member 1035.
  • the body fluid entering the outer casing 1002 through the opening 1006 causes the stopper member 1035 to degrade, and the spring 1033 presses the needle 1020 toward the attachment member 1010 under the restoring force. 1024 and sachet 1028.
  • the needle 1020 thus penetrates the outer casing 1002 and penetrates the stomach wall or intestinal wall tissue to which the attachment element 1010 is attached.
  • the sachet 1028 is deformed by extrusion such that the stored medical fluid is injected into the stomach wall or intestinal wall tissue via the infusion conduit 1021.
  • the coating layer 1012 and the shielding layer 1016 may both be enteric, and the degradation rate of the coating layer 1012 is faster than the degradation rate of the shielding layer 1016; after the coating layer 1012 degrades and exposes the attachment member 1010 and adheres to the intestinal wall, The masking layer 1016 at the opening 1006 degrades and exposes the stop element 1035.
  • the coating layer 1012 and the shielding layer 1016 may all be gastric-soluble, and the degradation speed of the coating layer 1012 is faster than the degradation speed of the shielding layer 1016; after the coating layer 1012 degrades and exposes the attachment member 1010 and adheres to the stomach wall, the opening 1006
  • the obscuring layer 1016 at the site degrades and exposes the expansion element 1030.
  • a needle 1120, a support 1124, a sachet 1128 are disposed on a side close to the attachment member 1110, and a needle 1170, a support 1174, a sachet 1178, and a support 1124 and 1174 are disposed on a side close to the attachment member 1160.
  • An expansion element 1130 is provided therebetween.
  • the needle 1120 and the support 1124 are integrally connected, generally adjacent to the attachment member 1110, with the tip direction facing the outside of the capsule 1100.
  • the needle 1120 is hollow, with the infusion conduit 1121 communicating with the conduit 1125 in the holder 1124.
  • a drug such as a liquid is stored in the sachet 1128.
  • the sachet 1128 is sealingly coupled to the support 1124 and exposes the end opening 1126 of the conduit 1125 inside the sachet such that the chamber within the sachet is in fluid communication with the infusion conduit 1121.
  • the sachet 1128 is relatively soft and easily deformed, and the needle 1120 and the support 1124 are relatively strong and not easily deformable.
  • the needle 1170, the support 1174, and the sachet 1178 are generally disposed similarly to the needle 1120, the support 1124, and the sachet 1128. At least one opening is provided on the outer casing 1102 proximate the expansion element 1130.
  • the expansion element 1130 contacts the body fluid through the opening in the stomach or intestine to cause volume expansion.
  • the material contained in the expansion element 1130 is, for example but not limited to, a superabsorbent polymer (SAP), such as the BASF Corporation. Series SAP.
  • SAP superabsorbent polymer
  • the expansion element 1130 will press the needle 1120, the holder 1124, and the sachet 1128 toward the attachment member 1110 side, and press the needle 1170, the holder 1174, and the sachet 1178 toward the attachment member 1160 side.
  • the needles 1120, 1170 thus penetrate the outer casing 1102 and penetrate the stomach wall or intestinal wall tissue to which the attachment elements 1110, 1160 are attached.
  • the sachets 1128, 1178 are deformed by extrusion such that the stored medical fluid is injected into the stomach wall or intestinal wall tissue via the infusion conduits 1121, 1171.
  • the coating layers 1112 and 1162 may also be disposed outside the attachment members 1110 and 1160, or around the attachment members 1110 and 1160, and the capsule 1100 may smoothly follow the digestive tract (esophagus, stomach, etc.) before the coating layers 1112 and 1162 are degraded. Intestines, etc.) Advance.
  • the opening adjacent the expansion element 1130 can be obscured by the obscuring layer such that the expansion element 1130 does not contact body fluids in the stomach or intestine until the capsule 1100 reaches the desired site of administration.
  • the cladding layers 1112, 1162 and the shielding layer may both be enteric, and the degradation speed of the coating layers 1112 and 1162 is faster than the degradation speed of the shielding layer; when the coating layers 1112, 1162 are degraded to expose the adhesion members 1110, 1160 and adhered After the intestinal wall, the obscuring layer at the opening degrades and exposes the expansion element 1130.
  • the cladding layers 1112, 1162 and the shielding layer may all be gastric-soluble, and the degradation speed of the coating layers 1112 and 1162 is faster than the degradation speed of the shielding layer; when the coating layers 1112 and 1162 degrade and expose the adhesion members 1110 and 1160 and adhere thereto After the stomach wall, the masking layer at the opening degrades and exposes the expansion element 1130.
  • a needle-like body 1220 and a support 1224 are disposed on a side close to the attachment member 1210, and a needle-like body 1270 and a support 1274 are disposed on a side close to the attachment member 1260, and a support is provided between the holders 1224 and 1274.
  • the support 1224 holds the needle 1220 substantially in the immediate vicinity of the attachment member 1210 with the needle tip 1220 facing the outside of the capsule 1200.
  • the support 1274 holds the needle 1270 substantially in the immediate vicinity of the attachment member 1260 with the needle tip 1270 facing the outside of the capsule 1200.
  • the needles 1220, 1270 contain solid drugs and are provided with barbs 1221, 1271, respectively.
  • At least one opening 1206 is provided on the outer casing 1202 adjacent the expansion element 1230.
  • the expansion element 1230 contacts the body fluid through the opening 1206 in the stomach or intestine causing volume expansion.
  • the expansion member 1230 presses the needle body 1220 and the holder 1224 toward the attachment member 1110 side, and presses the needle body 1270 and the holder 1274 toward the attachment member 1260 side.
  • the material contained in the expansion element 1230 is, for example but not limited to, a superabsorbent polymer (SAP), such as the BASF Corporation. Series SAP.
  • the needles 1220, 1270 thus penetrate the outer casing 1202 and penetrate the stomach wall or intestinal wall tissue to which the attachment elements 1210, 1260 are attached, and the barbs 1221, 1271 maintain the needles 1220, 1270 inside the tissue. Thereafter, the needles 1220, 1270 are degraded inside the tissue to complete the administration.
  • Cladding layers 1212, 1262 may also be provided on the outside of the attachment members 1210, 1260 or around the attachment members 1210, 1260. Prior to degradation of the coating 1212, 1262, the capsule 1200 can smoothly advance along the digestive tract (esophagus, stomach, intestines, etc.). The opening 1206 can be obscured by the obscuring layer 1216 such that the expansion element 1230 does not contact body fluids in the stomach or intestine until the capsule 1200 reaches the desired site of administration.
  • the cladding layers 1212, 1262 and the shielding layer 1216 may all be enteric, and the degradation speed of the coating layers 1212, 1262 is faster than the degradation speed of the shielding layer 1216; when the coating layers 1212, 1262 degrade the exposed components 1210, 1260 After being attached to the intestinal wall, the obscuring layer 1216 at the opening 1206 degrades and exposes the expansion element 1230.
  • the coating layers 1212, 1262 and the shielding layer 1216 may all be gastric-soluble, and the degradation speed of the coating layers 1212, 1262 is faster than the degradation speed of the shielding layer 1216; when the coating layers 1212, 1262 are degraded to expose the attachment members 1210, 1260 After being attached to the stomach wall, the shielding layer 1216 at the opening 1206 degrades and exposes the swelling element.
  • the coatings 1212, 1262 and the shielding layer 1216 comprise materials such as, but not limited to, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), acrylic resin, polyvinylpyrrolidone (PVP), methyl Acrylic acid-ethyl acrylate copolymer or a mixture thereof.

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Abstract

一种可吞咽式装置（100，200，300，500，500'，600，700，800，900，900'，1000，1100，1200），其包括外壳（402，502，602，702，802，902，902'，1002，1102，1202）；一个或多个穿透部件（520，620，720，820，920，920'，1020，1120，1170，1220，1270）；致动部件（530，630，730，830，930，933'，1030，1130，1230）；位于所述外壳（402，502，602，702，802，902，902'，1002，1102，1202）外表面上的附着部件（108，210，310，510，610，710，810，910，910'，1010，1110，1160，1210，1260）；以及位于所述外壳（402，502，602，702，802，902，902'，1002，1102，1202）内部的药物。

Description

可吞咽式装置
本申请要求了2015年4月2日提交的、申请号为201510155518.7、发明名称为“可吞咽式装置”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及可吞咽式装置。更具体地说，本发明涉及可吞咽式药物递送装置。
背景技术
虽然近年来用于治疗各种疾病的新药日益发展，但是许多药物由于它们不能口服而使得其应用受到限制。药物不能口服可归因于很多原因，例如：药物可引起包括胃刺激和出血在内的并发症；药物在胃肠道内的分解/降解；以及不良、缓慢或不稳定的口服药物吸收。静脉内注射和肌内注射等常规的替代药物递送方法具有很多缺点，例如：疼痛、需要专业人员操作、来自针具的感染风险以及对长时间在患者身上维持注射装置的需求和相关风险。虽然已有诸如可植入式药物输送泵之类其他药物递送途径，但是这些途径需要装置的半永久性植入，仍然具有常规注射的许多限制，并且可能引发其它的风险，例如抗移植物的免疫反应。
因此，需要改进的装置和方法来递送药物和其他治疗剂。
发明内容
本发明的一个目的在于提供用于将药物递送到体内的装置、系统、套件和方法。
在本发明的一个方面，提供了一种可吞咽式装置，其可用于在胃肠道内递送药物。在本发明的一个方面，提供了可吞咽式装置，例如可吞咽式胶囊，用于将药物递送到组织中，例如胃壁、小肠壁、大肠壁或其它胃肠道器官的壁中。在本发明的一个方面，本发明的装置、系统、套件和方 法可用于递送任何适合递送到胃壁、小肠壁、大肠壁或其它胃肠道器官的壁中的药物。在本发明的另一个方面，本发明的装置、系统、套件和方法可用于递送在胃肠道内难以吸收、耐受性差和/或会经历生物/化学降解(例如被胃肠道内消化酶和/或酸分解)的药物。在本发明的另一个方面，本发明的装置、系统、套件和方法可用于递送那些以前只能或者优选通过胃肠外施用(例如静脉内或肌肉内注射)而递送的药物。另外，在本发明的一个方面，本发明的装置、系统、套件和方法可用于通过口服递送实现药物快速释放进入血流。
在一个方面，提供了用于将药物递送到组织中的可吞咽式装置。该装置包括尺寸适合吞咽的外壳、附着部件、药物、穿透部件和致动部件，其中药物、第一配置的穿透部件和致动部件位于外壳内部，而附着部件位于外壳的外表面上。
在一个方面，提供了一种可吞咽式装置，包括：
外壳；
位于所述外壳外表面上的附着部件，其适于将所述可吞咽式装置附着于外部组织；
位于所述外壳内部的药物；
一个或多个穿透部件，其在第一配置时位于所述外壳内部，其在第二配置时至少部分地穿透到所述外壳的外部；
位于所述外壳内部的致动部件，其具有分别与所述穿透部件的第一配置和第二配置相适应的第三配置和第四配置，当所述致动部件从所述第三配置向所述第四配置变化时驱动所述穿透部件从所述第一配置变化到所述第二配置，并驱动所述药物经由所述穿透部件输出。
在一个方面，所述附着部件外包覆有可降解的包覆层。
在一个方面，所述外壳上靠近所述致动部件处设有至少一个通孔，所述通孔上任选遮蔽有可降解的遮蔽层。
在一个方面，所述包覆层的降解速度快于所述遮蔽层的降解速度。
在一个方面，所述附着部件包括一个或多个钩状体，或包括粘性体。
在一个方面，所述多个钩状体的弯曲方向并非一致。
在一个方面，所述穿透部件包括连接为一体的针和承托，所述针的针头靠近所述附着部件且针尖方向朝向所述可吞咽式装置外侧；所述针中空，其中的管道连通到所述承托上的至少一个开口；所述可吞咽式装置在所述针和承托附近还包括药囊，所述药囊封闭地接合于所述承托且与所述针中的管道流体连通；所述致动部件位于所述承托和与所述附着部件相对的所述外壳一侧之间。
在一个方面，所述穿透部件包括针状体、承托，所述承托夹持着所述针状体，所述针状体靠近所述附着部件且针尖方向朝向所述可吞咽式装置外侧，所述针状体包含药物；所述致动部件位于所述承托和所述外壳的与所述附着部件相反的一侧之间。
在一个方面，所述针状体上设有倒勾。
在一个方面，所述致动部件包括可膨胀元件。
在一个方面，所述可膨胀元件包括囊和可降解的阀，所述阀将所述囊分隔为两个彼此隔离的第一腔室和第二腔室，所述第一腔室和第二腔室分别储存了第一反应物和第二反应物，所述第一反应物和第二反应物混合后能够使得所述囊的体积膨胀。
在一个方面，所述致动部件包括弹性体以及可降解的限位部件，所述限位部件与所述外壳和/或承托耦合以使得所述弹性体处于压缩状态。
在一个方面，所述承托的外周连接有裙边，所述裙边的外缘抵触着所述外壳的内表面。
外壳
外壳包括内部容积，并且可以由本领域中已知的各种生物相容性聚合物制成，例如各种可生物降解的聚合物。在本发明的一个方面，外壳可以可控地降解为更小的片块，从而促进可吞咽式装置通过胃肠道并排泄和/或吸收。在本发明的一个实施方案中，外壳可以包括可生物降解材料的缝合线，该缝合线可控地降解以产生可选尺寸和形状的外壳片块以促进其通过胃肠道。可以对缝合线进行预应力、穿孔或其他处理以加速降解。使用可生物降解缝合线使得可吞咽式装置在胃肠道内可控降解，以促进其通过 胃肠道以及降低装置卡在胃肠道内的可能性。在本发明的另一个实施方案中，外壳由可生物降解材料整体构成，并且在外壳的内表面或外表面上具有沟槽或凹陷，从而使得外壳首先在沟槽或凹陷处降解，产生可选尺寸和形状的外壳片块，以促进可吞咽式装置通过胃肠道。
在本发明的一个方面，外壳还包括一个或多个开口。可吞咽式装置的穿透部件的部分或全部可通过所述开口伸出外壳，并进入组织中。在本发明的一个方面，所述开口上具有可降解的包覆层。包覆层可被配置为响应于各种条件并以各种方式降解。例如，包覆层可由生物可降解材料制成，被配置成响应于小肠内较高的pH或其它条件而被体液全部或基本全部降解。在本发明的一个方面，所述包覆层可完全封闭所述开口，以使消化液不能进入外壳内部，直至可吞咽式装置已到达预定位置。在本发明的另一个方面，外壳在靠近穿透部件的部分为一个整体。在可吞咽式装置的穿透部件从所述第一配置变化到所述第二配置时，穿透部件穿透外壳，从而部分或全部伸出外壳并进入组织中。
附着部件
在本发明的一个方面，可吞咽式装置的附着部件位于外壳的外表面，用于将可吞咽式装置附着在组织表面，例如胃肠道的表面。附着部件可通过各种方式附着至组织表面。在本发明的一个方面，附着部件是粘合剂层，例如本领域中已知的各种生物粘合剂，从而将可吞咽式装置粘合至组织表面。可以通过调整粘合剂的成分，使得可吞咽式装置粘合至不同的组织。例如，粘合剂可为仅仅在酸性条件下具有强粘合力的粘合剂，从而使得可吞咽式装置粘合至胃组织。或者，粘合剂可为仅仅在碱性条件下具有强粘合力的粘合剂，从而使得可吞咽式装置粘合至肠组织。在本发明的一个方面，粘合剂在粘合至组织表面一段时间后失去粘合力或被分解，从而使得可吞咽式装置从组织表面脱离。粘合剂被配置为响应于可吞咽式装置所处的位置而失去粘合力或被分解，例如由于水合或在暴露于胃肠道内的pH或其他化学条件时失去粘合力或被分解。
在本发明的一个方面，附着部件包括钩状体。所述钩状体可为一个或多个，其直立在外壳外表面向远离外壳方向延伸。所述钩状体具有连接到外壳的茎部和与茎部相连的头部。所述头部在外壳表面上的投影至少部分超出茎部，例如为钩状、箭头状或蘑菇状。相邻钩状体的钩头部分可沿着相同或不同方向突出。所述相邻的钩状体各自可都具有平坦表面，所述平坦表面以面对面的关系彼此相对。
所述钩状体与外部组织形成钩-环固紧系统，从而将可吞咽式装置附着在外部组织上。在本发明的一个方面，附着部件还包括位于钩状体和外壳之间的衬底。可吞咽式装置的附着部件可由可降解材料制成，例如PGLA、纤维素等。
在本发明的一个方面，附着部件的位置靠近穿透部件的末端，位于相应的外壳外表面。当可吞咽式装置在外壳上具有供穿透部件通过的开口时，附着部件可位于开口的周围。在一个实施方案中，可吞咽式装置在附着至组织后，其穿透部件末端靠近组织，从而穿透部件在伸展出外壳后即可穿透进入组织。这样，可吞咽式装置中的药物可全部或基本全部进入组织中，从而获得稳定可控的递送效果。
在本发明的一个方面，附着部件的表面具有包覆层。包覆层覆盖附着部件的全部或基本全部，使得附着部件在初始状态时不具有附着功能。包覆层可由可降解材料制成，并且在可吞咽式装置被吞咽后降解。在一个实施方案中，包覆层的降解速度高于可吞咽式装置的其它部分，例如在可吞咽式装置在到达预期位置之前或在即将到达预期位置时就基本降解完毕，使得可吞咽式装置可附着至组织表面并递送药物。
穿透部件
在本发明的一个方面，可吞咽式装置的穿透部件可包括针或其它类似的结构，其具有内腔或其它隔室以及用于穿透到胃肠道壁中可选深度的针头。在一个方面，本发明的装置可以包括一个或多个穿透部件，例如包括第二穿透部件、第三穿透部件和更多数目的穿透部件。每个穿透部件可以用于递送相同或不同的药物。在具有多个穿透部件的实施方案中，各穿 透部件可以相对于外壳的长轴或短轴分布在不同的方向上，或者各穿透部件可以集中朝一个方向分布。各穿透部件还可以朝向外壳的同一侧或不同侧分布。在本发明的一个方面，穿透部件可包含药物，例如所属穿透部件或穿透部件的一部分(例如针头)可以由药物本身制成。在这些实施方案中，药物可具有针状或镖状结构，并且任选具有倒钩，其被配置成穿透组织壁并滞留在组织内。穿透部件可以由各种可生物降解材料制成，以便在胃肠道内降解，并有助于保护胃肠道壁。这还可以提供故障安全机制，在穿透部件滞留于胃肠道壁中的情况下有助于可吞咽式装置从胃肠道壁脱离。
在本发明的一个方面，穿透部件包括连接为一体的针和承托，所述针的针头靠近所述附着部件且针尖方向朝向所述可吞咽式装置外侧。所述针是中空的，其中的管道连通到所述承托上的至少一个开口。本发明的可吞咽式装置在所述针和承托附近还包括药囊，所述药囊封闭地接合于所述承托且与所述针中的管道流体连通。
在本发明的一个方面，可吞咽式装置的穿透部件具有第一配置和第二配置。当穿透部件处于第一配置时，其为通常意义上的待使用状态或初始状态，此时穿透部件的全部或基本全部位于外壳内部。当穿透部件处于第二配置时，其为通常意义上的使用状态，此时可吞咽式装置已被吞咽至体内，并且穿透部件的全部或部分位于外壳外部，并穿透进入目标组织内。通过穿透部件，可吞咽式装置内的药物进入组织。
致动部件
在本发明的一个方面，致动部件耦合到穿透部件和药物中的至少一个。在本发明的一个方面，致动部件被配置为驱动穿透部件从第一配置变化至第二配置，从而使其部分或全部进入组织内部，例如胃肠道壁。在本发明的另一个方面，致动部件被配置为驱动药物通过穿透部件递送药物进入组织，例如胃肠道壁。在本发明的另一个方面，致动部件被配置成在推送送药物通过穿透部件进入组织中后将穿透部件从组织中撤回。在本发明的一个方面，当穿透部件本身就是药物时，致动部件被配置成将穿透部件留在组织内。
在本发明的一个方面，可吞咽式装置的致动部件具有第三配置和第四配置。当可吞咽式装置的穿透部件处于第一配置时，致动部件具有与之相适应的第三配置。当可吞咽式装置被吞咽时，致动部件从第三配置向第四配置变化，驱动穿透部件从所述第一配置变化到所述第二配置，并驱动所述药物经由所述穿透部件而输出到所述外壳之外。
在本发明的一个方面，致动部件包括弹性体，例如预载弹簧部件，该预载弹簧部件被配置成通过限位部件的降解来释放。合适的弹簧可以包括盘簧(包括锥形弹簧)和板簧，还可以包括其它弹簧结构。在特定实施方案中，弹簧可以是锥形，以便减小弹簧在压缩状态中的长度，甚至使弹簧的压缩长度达到几个线圈(例如两个或三个线圈)或者仅一个线圈厚度的程度。
在本发明的一个方面，所述限位部件与所述外壳和/或承托耦合以使得所述弹性体处于压缩状态。限位部件的降解导致弹性体释放，从而驱动穿透部件从所述第一配置变化到所述第二配置，并驱动所述药物经由所述穿透部件而输出到所述外壳之外。在本发明的另一个方面，承托的外周连接有裙边，所述裙边的外缘抵触着所述外壳的内表面，使得所述弹性体处于压缩状态。裙边的降解导致弹性体释放，从而驱动穿透部件从所述第一配置变化到所述第二配置，并驱动所述药物经由所述穿透部件而输出到所述外壳之外。
在本发明的一个方面，致动部件位于所述承托和与所述附着部件相对的所述外壳一侧之间。
在本发明的一个方面，致动部件还包括机电部件，例如螺线管或压电器件。在本发明的一个方面，压电器件可以包括具有非展开状态和展开状态的成形压电部件。该部件可被配置成在施加电压的情况下进入展开状态，并继而在除去电压的情况下返回到非展开状态。这允许致动部件往复运动以便推送穿透部件并继而将其撤回。
在本发明的一个方面，致动部件包括可膨胀元件。可膨胀元件例如为可膨胀材料、球囊或其它可膨胀元件。可膨胀元件设在外壳的内部，其任选地耦合到穿透部件。在本发明的一个方面，可膨胀元件位于外壳内部，并且外壳在靠近可膨胀元件的位置具有通孔。体液可通过通孔进入可吞咽 式装置内部，与可膨胀元件接触。在本发明的一个方面，包括含有通孔的外壳表面的至少一部分期望地涂有遮蔽层，例如肠溶聚合物层。该遮蔽层可响应于各种条件例如pH条件而降解。遮蔽层在所述通孔上可提供保护性密封，以使消化液不能进入外壳内部而使得可膨胀元件膨胀，直至可吞咽式装置已到达预定位置。在可吞咽式装置的使用中，在孔上采用可降解遮蔽层的实施方案提供了确保可吞咽式装置在到达目标组织之前不会伸出和/或展开其穿透部件的主要手段和辅助手段。在本发明的一个方面，可膨胀元件的膨胀将穿透部件推送到组织中。在本发明的一个方面，可膨胀元件的膨胀还将药物推送到组织中。
在本发明的一个方面，可膨胀元件的最大膨胀体积可被配置为超过外壳的体积，从而在膨胀后最终将外壳胀开分成一个或多个片块，以使其更容易地通过肠道。
在本发明的一个方面，可膨胀材料包括在特定条件下体积可变化的可膨胀聚合物，例如超吸收聚合物(SAP)。超吸收聚合物是一类含有亲水基团和交联结构的大分子，包括有淀粉类(接枝物、羧甲基化物等)、纤维素类(羧甲基化、接枝物等)、合成聚合物类(聚丙烯酸系、聚乙烯醇系、聚氧乙烯系等)等类型。吸水前，超吸收聚合物的链相互靠拢缠在一起，彼此交联成网状结构，从而达到整体上的紧密，体积小。与水或含水液体接触时，水分子通过毛细作用及扩散作用渗透到聚合物中，链上的电离基团在水中电离，由于链上同离子之间的静电斥力而使链伸展溶胀，从而体积增大。由于电中性要求，反离子不能迁移到树脂外部，聚合物内外部溶液间的离子浓度差形成反渗透压。水在反渗透压的作用下进一步进入树脂中，形成水凝胶。同时，树脂本身的交联网状结构及氢键作用，又限制了凝胶的无限膨胀。
在本发明的另一个方面，可膨胀元件包括囊和可降解的阀，所述阀将所述囊分隔为两个彼此隔离的第一腔室和第二腔室。在处于第一配置时，囊通常以至少部分地非膨胀状态而位于外壳内。囊可以由本领域中已知的各种生物相容性聚合物制成。期望地，囊具有薄壁，例如小于约0.01厘米。所述第一腔室和第二腔室分别储存了第一反应物和第二反应物。反应物例 如为酸(如柠檬酸)和碱(如碳酸钠)，其可具有合适的比例，例如约2∶1。反应物还可以包括其它的酸(例如醋酸)和碱。或者，第一反应物和第二反应物可独立各自包括多种不同的成分。当阀或其它分隔装置打开时，第一反应物和第二反应物混合并使得所述囊的体积膨胀，例如通过产生如二氧化碳等气体。在本发明的一个方面，第一反应物和第二反应物产生的体积膨胀可被配置为大于所述囊的最大体积，从而在膨胀后，囊最终被胀开分成一个或多个片块，以使其更容易地通过肠道。
阀可被配置为响应于各种条件并以各种方式打开。例如，阀可被配置成通过响应于小肠内较高的pH或其它条件让一个或多个部分降解而打开。另外，通常情况下，阀将会放置在囊的中心部分，但也可以放置在其它位置。在本发明的一个方面，阀可以具有梁状结构，该梁状结构放置在外壳内用以压缩在第一腔室与第二腔室之间的囊部分。该梁可以在一端或全部两端附接到外壳的内表面。在一个实施方案中，梁使用过盈配合而附接到外壳的径向侧，从而可以使用拾取与放置方法以及制造领域中已知的其它类似方法将梁扣合到位。当该梁降解时，压缩力得到释放。阀的这些实施方案和其它实施方案可以包括一个或多个箍压特征，诸如接合外壳内表面上的凹槽或其它配合特征的凸脊，以在箍压特征下的球囊壁上施加额外的力，并向密封施加冗余量。在另一实施方案中，阀可以包括可膨胀元件的收缩分段，该收缩分段具有由可生物降解材料制成的覆盖箍压环。该环可以使阀保持关闭并在降解时将阀打开。
阀可以位于外壳内或外壳上的多个位置，以便暴露于体液并被体液降解。阀的至少一部分可以暴露于外壳表面。或者，阀也可位于外壳内部，并且外壳在靠近阀的位置具有通孔，在此阀暴露于通过通孔进入的体液。在本发明的一个方面，包括含有通孔的外壳表面的至少一部分期望地涂有遮蔽层，例如肠溶聚合物层，该遮蔽层可响应于各种条件例如pH条件而降解。遮蔽层在所述通孔上提供了保护性密封，以使消化液不能进入外壳内部开始降解阀，直至可吞咽式装置已到达预定位置。在可吞咽式装置的使用中，在孔上和可降解阀上采用可降解保护层的实施方案提供了确保可吞 咽式装置在到达目标组织之前不会伸出和展开其穿透部件的主要手段和辅助手段。
在本发明的一个方面，也可以将阀配置成响应于小肠内的蠕动性收缩所施加的压缩力而打开。在另一方法中，阀可以是延时释放阀，其被配置成在由患者开始的激活步骤(诸如揭下标签或按动按钮)后的特定时间段后打开。
除用于打开的阀之外，囊或其它可膨胀元件通常还可包括收缩阀，收缩阀用来在可膨胀元件膨胀之后使其收缩。该收缩阀可以包含可生物降解材料，其被配置成在暴露于小肠中的流体和/或球囊腔室之一内的液体时降解，以便形成用于球囊内气体选出的开口或通道。在一个实施方案中，收缩阀可以包含位于球囊端部的可生物降解部分，以便将球囊壁的相对两端连接在一起。在本发明的一个方面，当可降解的分段由于暴露于液体而降解时，球囊壁撕裂或以其它方式破碎，从而高度确保快速收缩。可以将多个可降解分段期望地放置在球囊壁的固体反应物部分中，以提供甚至更高程度的收缩可靠性。对于其中收缩阀被小肠内的流体所降解的实施方案，可以通过配置膨胀的球囊将外壳分裂成两个或更多个片块从而使大的球囊分段直接暴露于小肠内的降解液中，来促进阀的降解。这可以通过由单独的部分(例如机械地拼合到一起的两个半部)制造外壳和/或通过使用本文所述的缝合线来实现。
此外，作为确保收缩的进一步补充，可以将一个或多个穿刺元件附接到外壳壁的内表面，以在囊充分收缩时被穿刺元件接触和刺穿。在本发明的另一个方面，一个或多个组织穿透部件可以直接耦合到囊，并且被配置成当它们脱离时从囊上被撕去，从而在此过程中撕裂球囊壁。
在本发明的一个方面，可吞咽式装置的致动部件还包括启动部件。例如，启动部件可耦合到位于外壳内的弹簧，以便保持弹簧处于压缩状态。启动部件的降解将弹簧释放，以启动致动部件。在本发明的一个方面，启动部件包含被配置成在暴露于小肠或大肠中的化学条件(如pH)时会降解的材料。例如，可将启动部件配置成在暴露于小肠内选定pH时降解，例如7.0、7.1、7.2、7.3、7.4、8.0或更高。然而，还可以将其配置成响应于小肠 内的其它条件而降解。在本发明的一个方面，可以将启动部件配置成响应于胃肠道中的特定条件而发生降解，例如在进食之后出现的条件，例如存在高脂肪或高蛋白食物时。
在本发明的一个方面，启动部件可以包括薄膜或栓，该薄膜或栓将穿透部件保持在外壳内。组织穿透部件耦合到弹簧加载式致动部件，使得当启动部件充分降解时，其释放出穿透部件，而穿透部件继而弹出到外壳之外以穿透到组织中。在其它实施方案中，启动部件的形状可以起到将穿透部件保持在适当位置的闩锁的功能。启动部件可以位于外壳的外部或内部。在位于外壳内部的实施方案中，外壳被配置成允许体液进入外壳内部以允许启动部件的降解。
在本发明的一个方面，启动部件包括传感器。所述传感器诸如为pH传感器或其它化学传感器，这些传感器检测外壳在胃肠道中的存在并且发送信号到致动部件，或发送至耦合到致动部件的电子控制器以启动致动部件。pH传感器的实施方案可以包括基于电极的传感器，或者它可以是基于机械的传感器，诸如在暴露于胃肠道内的pH或其他化学条件时会收缩或扩张的聚合物。在相关实施方案中，可扩张/可收缩式传感器还可以通过使用源于传感器扩张或收缩的机械运动而使自身包含致动部件。
在本发明的一个方面，传感器可以包含应变计或其它压力/力传感器，用来检测外壳在肠道内特定位置所经历的蠕动性收缩的数目。在这些实施方案中，外壳的尺寸使得其可在蠕动性收缩期间被小肠紧夹。胃肠道内不同位置具有不同数目的蠕动性收缩。小肠具有介于每分钟12次至9次之间的收缩，该频率沿肠的长度而逐渐降低。因此，在本发明的一个方面，对蠕动性收缩的数目的检测可以用于确定外壳在胃肠道内的相对位置。
在本发明的一个方面，可吞咽式装置的使用者可以通过RF装置、磁装置或者本领域中已知的其它无线信令装置而从外部启动致动部件以递送药物。在这些实施方案以及相关的实施方式中，使用者可以使用手持式设备(例如，手持式RF设备)，其不仅包括信令装置，而且还包括用于当可吞咽式装置处于小肠内或胃肠道中其它位置时通知使用者的装置。通过在可吞咽式装置上包含RF发射器以在该装置处于小肠中或胃肠道中的其它位 置时向使用者发出信号(例如，通过发送来自传感器的输入)，可以实现后一实施方案。相同的手持式设备还可被配置成当致动部件已被激活并且一种或多种选定的药物已被递送时提醒使用者。以这种方式，向使用者确认药物已经被递送。这样允许使用者采用其它适当的药物，以及做出其它的相关决定(例如，糖尿病患者是否进食和应当食用什么食物)。手持设备还可以被配置成向可吞咽式装置发送信号以操纵致动部件，并以此来阻止、延迟或加速药物递送。在使用中，此类实施方案允许使用者基于其它症状和/或患者的行为(例如，进食、睡眠、锻炼等)而进行干预以阻止、延迟或加速药物递送。
使用者还可以在吞咽外壳后的选定时间段从外部启动致动部件。该时间段可以与食物移动通过使用者的胃肠道到达胃肠道内特定位置的典型通过时间或通过时间范围相关。
药物
在本发明的一个方面，可吞咽式装置的药物可以被配置成液体、半液体或固体的形式或者其任何组合。固体形式的药物可以包括粉剂或丸剂。半液体可以包括浆、糊、凝胶等。在本发明的一个发明，可吞咽式装置的药物可以直接包含在外壳的空腔中。在本发明的另一个方面，药物可被包含在封闭的药物容器内。在本发明的一个方面，可吞咽式装置可包括超过一种药物，例如包括第一药物、第二药物、第三药物或者更多的药物。这些药物可以独立或共同包含在外壳内的空腔中，或者各自独立或共同包含在外壳主体内单独的储器中。
在本发明的一个方面，可吞咽式装置可以用于递送各种治疗有效量的药物。在本发明的一个方面，这些药物包括由于其在胃/胃肠道内的化学分解而本来需要注射的各种大分子肽和蛋白质，例如，生长激素、甲状旁腺激素、胰岛素、干扰素和其它类似的化合物。可通过可吞咽式装置递送的合适药物包括各种化疗剂(例如干扰素)、抗生素、抗病毒药、胰岛素和相关化合物、胰高血糖素样肽(例如，GLP-1，艾塞那肽)、甲状旁腺激素、生长激素(例如，IFG和其它生长因子)、抗癫痫剂、免疫抑制剂和诸如各种抗 疟疾剂等抗寄生虫剂。本领域技术人员可容易地根据现有技术和本发明的精神来确定可用于可吞咽式装置的药物。可吞咽式装置中药物的剂量可以根据患者的体重、年龄或其它参数来滴定测量。
可以将药物组合物装入本发明的可吞咽式装置中用来递送给使用者。在一项实施方案中，可以将药物掺入到适合用本发明的装置向使用者施用的药物组合物中。通常，这些药物组合物包括药物活性成分，以及一种药学上可接受的载体。本文所用的术语“药学上可接受的载体”包括生理上相容的任何溶剂、分散介质、杀菌和杀真菌剂、等渗剂和吸收延迟剂等。药学上可接受的载体的实例包括水、盐水、磷酸盐缓冲液、葡萄糖、甘油、乙醇等中的一种或几种，以及它们的组合物。例如，在组合物中可包含等渗剂，例如糖、多元醇(如甘露醇、山梨醇)或氯化钠。药学上可接受的载体还可以包括少量的辅助物质，例如提高药物的储存寿命或效力的润湿或乳化剂、防腐剂或缓冲剂。
用在本发明方法和组合物中的组合物可以是适应由本发明的装置施用的多种不同形式，包括例如液体溶液(如可注射和输注的溶液)、分散体或悬浮液。
药物组合物通常必须灭菌，并且在制造和储存条件下稳定。组合物可以被配制成溶液、微乳液、分散体、脂质体或其它适合高药物浓度的有序结构。灭菌的注射溶液可以通过将所需数量的药物活性成分掺入到合适的溶剂中制备，溶剂中根据需要含有以上列举的一种组分或其组合，随后过滤灭菌。通常，分散体通过将活性化合物掺入灭菌的载液中制备，载液中含有基础分散介质和所需要的上面列举的其它组分。在用于配制无菌注射溶液的无菌粉末的情形，优选的制备方法是真空干燥和冷冻干燥，得到来自其预先过滤灭菌的溶液的活性组分与任何所要的组分的粉末。溶液的合适流动性可以通过例如使用涂层如卵磷酯，在分散体的情形保持所需要的颗粒大小，以及使用表面活性剂来保持。通过在组合物中包含一种延缓吸收的试剂，例如单硬脂酸酯和明胶，可以实现注射组合物的延长吸收。
在本发明的一个方面，可以使用可吞咽式装置递送多种药物以治疗各种病症或病症。例如，可使用可吞咽式装置递送多种蛋白酶抑制剂以治 疗AIDS。这样允许患者无需针对病症或病症而摄取多种药物，而只是使用本发明的装置一次。
此外，现有技术中由于各种药物的化学组成、分子量等的不同，药物可能以不同的速率被吸收，从而导致不同的药代动力学分布曲线，并因此在不同的时间到达靶组织。可吞咽式装置通过控制递送各种药物的时间而解决了这个问题。因此，在本发明的一个方面，通过使用可吞咽式装置，还提供了使一个治疗方案的两种或更多种药物以特定的时间间隔或同时被递送和吸收到血流或靶组织中的方法。这改善了各种目标药物的药代动力学并因此改善了其疗效。
材料
在本发明的一个方面，可吞咽式装置的各个部分可各自独立地由合适的材料制成，例如由相同或不同的生物可降解材料制成。或者，可吞咽式装置的各部分可独立地由相同或不同的不可生物降解但对使用者无害的材料制成。本文所述的“生物可降解材料”一般指这样的材料：其化学结构可以被常规环境如人体生理环境中的物质，例如酶、pH和天然化合物，改变，从而产生简单的元素或化学结构，从而无害化。可生物降解材料也可以是可生物侵蚀的。术语“可生物侵蚀”表示材料在环境中可生物降解、可消化或可侵蚀，或者可溶解或可降解成为材料尺寸减小的形式，例如，通过化学、生物(例如酶促)、物理分解、或增溶，从而使材料从环境中消除，而没有重大害处。在一些实施方案中，本申请所使用的术语“可生物降解”还涵盖术语“可生物吸收”，其一般描述这样的材料：其在生理条件条件下分解的分解产物可进入宿主对象中经历生物吸收，例如成为宿主对象的生化系统的代谢物。“生物可降解材料”的例子可以包括明胶、海藻酸钠、纤维素酯(如羟丙甲基纤维素等)、植物多糖(如普鲁兰糖、褐藻糖、卡拉胶和琼脂等)和淀粉及其衍生物(如改性淀粉等)。
可通过选择用于可吞咽式装置各部件的材料的成分、这些成分的交联度、厚度和其它条件，可以实现由胃肠道内一种或多种条件而引起各部件的降解。类似地，可由此控制各部件降解的顺序，从而适合地发挥各部 件的功能，达到可吞咽式装置预期的目的。例如，较少的交联量和/或较薄的尺度可以增加降解速率，反之亦然。此外，将一种或多种聚合物共聚或者以其它方式相混合可获得除生物降解之外的许多特定的材料性质，此类性质可以包括但不限于刚度、强度、柔性和硬度。
在本发明的一个方面，包覆附着部件的包覆层的降解速度快于遮蔽通孔的遮蔽层的降解速度。这样，包覆层降解后遮蔽层降解前，附着部件暴露在胃肠道腔内，而通孔还被遮蔽层遮蔽，使得可吞咽式装置可附着于胃肠道组织表面，而致动部件处于第三配置，穿透部件仍全部或基本全部位于外壳内部。随后，遮蔽层降解，体液通过通孔进入可吞咽式装置的外壳内，使得致动部件从第三配置变化为第四配置，驱动穿透部件从第一配置变化为第二配置，并驱动所述药物经由所述穿透部件输出到胃肠道组织中。这样，可吞咽式装置中的药物可全部或基本全部经由述穿透部件输出到胃肠道组织中。
在本发明的另一个方面，可吞咽式装置的附着部件、外壳和囊等的降解速度低于包覆层和遮蔽层的降解速度。这样，在可吞咽式装置中的药物输出到胃肠道组织中后，附着部件、外壳和囊等降解，导致可吞咽式装置从胃肠道组织脱离和崩解，有助于可吞咽式装置从胃肠道排除，达到保护胃肠道的效果。可吞咽式装置的穿透部件也可被配置为在可吞咽式装置中的药物输出到胃肠道组织中后降解，例如在两次给药的间隔时间内降解，使得在先给予的可吞咽式装置不影响在后的可吞咽式装置的给予。
在本发明的一个方面，可吞咽式装置的穿透部件可被配置为具有较高的硬度，从而可更好的穿透进入组织。具有较高硬度的材料及其制备方法是本领域中公知的，例如具有相对较高交联度的聚合物。
附图说明
通过参照附图阅读以下所作的对非限制性实施例的详细描述，本发明的其它特征、目的和优点将会变得更明显。各附图仅仅意在表现相应实施例中各部件的相对位置关系，而非意在表现各部件的精确尺寸。
图1为可吞咽胶囊100位于肠道内的示意图；
图2示出了一个实施例的胶囊200的外观立体示意图；
图3示出了一个实施例的胶囊300的外观立体示意图；
图4A示出了一个实施例中的外壳402，图4B示出了降解的外壳片块；
图5A示出了一个实施例的胶囊500的剖面示意图，图5B示出了一个实施例的胶囊500’的剖面示意图；
图6示出了一个实施例的胶囊600的剖面示意图；
图7示出了一个实施例的胶囊700的剖面示意图；
图8示出了一个实施例的胶囊800的剖面示意图；
图9A示出了一个实施例的胶囊900的剖面示意图；
图9B示出了一个实施例的胶囊900’的剖面示意图；
图10示出了一个实施例的胶囊1000的剖面示意图；
图11示出了一个实施例的胶囊1100的剖面示意图；
图12示出了一个实施例的胶囊1200的剖面示意图。
具体实施方式
图1为胶囊100位于肠道内的示意图。胶囊100可通过口腔吞咽，并可经由消化道而运动到胃部或肠道。在胶囊100一侧的外表面上设置有钩状体108，这些钩状体108作为附着部件将胶囊附着在胃壁或肠道壁上。
图2示出了一个实施例的胶囊200的外观立体示意图。在该实施例中，胶囊的外观大体上呈现为长圆形或橄榄形。多个钩状体208组成的附着部件210设置于胶囊外表面的一侧。钩状体208咬合胃壁或肠道壁的组织，以有效地将胶囊200附着于胃壁或肠道壁。该示例中的钩状体208排列成整齐的阵列。钩状体208的弯曲方向并非一致的，例如，每两列相邻的弯曲方向一致的钩状体208组成一个单元，相邻两个单元的钩状体208的弯曲方向相对。本领域技术人员应能理解，采用其他钩状体排列和/或弯曲方向组合的附着部件也是可行的。
如所知的，胃部环境呈酸性，肠道环境呈碱性。在附着部件外侧、或者包裹着附着部件还可以设置一包覆层，在该包覆层降解之前，胶囊可 以顺利地沿着消化道(食道、胃、肠道等)前进。该包覆层可以是肠溶性的，其在胃部不降解而在肠道中降解，以确保在肠道中曝露出附着部件，从而使得胶囊有效地附着于肠道壁。该包覆层可以是胃溶性的，其在胃部降解以确保在胃中曝露出附着部件，从而使得胶囊有效地附着于胃壁。
图3示出了一个实施例的胶囊300的外观立体示意图。在该实施例中，胶囊300的外观大体上呈现为长圆形或橄榄形。粘性体308组成的附着部件310设置于胶囊外表面的一侧。粘性体308粘附于胃壁或肠道壁的组织，以有效地将胶囊300附着于胃壁或肠道壁。在附着部件310外侧还可以设置一包覆层，在该包覆层降解之前，胶囊300可以顺利地沿着消化道(食道、胃、肠道等)前进。该包覆层可以是肠溶性的，以确保在肠道中曝露出附着部件310，从而使得胶囊300有效地附着于肠道壁。该包覆层可以是胃溶性的，其在胃部降解以确保在胃中曝露出附着部件310，从而使得胶囊300有效地附着于胃壁。
在其他一些实施例中，胶囊的外观大体上呈现球形。
在本发明的一些实施例中，胶囊的外壳可以由本领域中已知的各种生物相容性聚合物制成，例如各种可生物降解的聚合物。图4A示出了本发明的一个实施例中的外壳402，该外壳由可生物降解材料整体构成，并且在其外表面上具有沟槽或凹陷404，从而使得外壳首先在沟槽或凹陷处降解，产生如图4B所示的可选尺寸和形状的外壳片块403，以促进胶囊通过胃肠道以及降低胶囊卡在胃肠道内的可能性。
图5A示出了一个实施例的胶囊500的剖面示意图。如图所示，外壳502大体上呈现为长圆形或橄榄形。多个钩状体508组成的附着部件510设置于外壳502外表面的一侧。钩状体508可以咬合胃壁或肠道壁的组织，以有效地将胶囊500附着于胃壁或肠道壁。外壳502中，靠近附着部件510的一侧设置有针头520、承托524、药囊528，远离附着部件510的一侧设置有膨胀元件530。针头520和承托524连接为一体，大体上位于紧邻着附着部件510，针尖方向朝向胶囊500外侧。针头520中空，其中的输液管道521与承托524中的管道525连通。药囊528中储存有例如液态的药物。药囊528封闭地接合于承托524，并在药囊内侧曝露出管道525的端部开口 526，使得药囊内的腔室与输液管道521流体连通。药囊528较为柔软而易于变形，针头520和承托524较为坚固而不易变形。外壳502在膨胀元件530一侧设有至少一个开口506。当胶囊500通过附着元件510附着于胃部或肠道，膨胀元件530在胃部或肠道内通过开口506接触到体液而导致体积膨胀。膨胀元件530所包含的材料例如但不限于超吸收聚合物(SAP)，例如BASF公司的
Figure PCTCN2016078405-appb-000001
系列SAP。由于外壳502的限制，膨胀元件530将向附着部件510一侧挤压针头520、承托524和药囊528。针头520因而穿透外壳502并刺入附着元件510所附着的胃壁或肠道壁组织。药囊528受挤压变形从而使得所储存的药液经由输液管道521而注射到胃壁或肠道壁组织。
在附着部件510外侧、或者包裹着附着部件510还可以设置一包覆层512，在该包覆层512降解之前，胶囊500可以顺利地沿着消化道(食道、胃、肠道等)前进。开口506可以由遮蔽层516所遮蔽，使得膨胀元件530在胶囊500到达期望的给药部位之前不会接触到胃部或肠道内的体液。包覆层512和遮蔽层516可以都是肠溶性的，包覆层512的降解速度快于遮蔽层516的降解速度；当包覆层512降解曝露出附着部件510并附着于肠道壁之后，开口506处的遮蔽层516降解并曝露出膨胀元件530。包覆层512和遮蔽层516可以都是胃溶性的，包覆层512的降解速度快于遮蔽层516的降解速度；当包覆层512降解曝露出附着部件510并附着于胃壁之后，开口506处的遮蔽层516降解并曝露出膨胀元件530。
图5B示出了图5A所示实施例的一个变化例的胶囊500’的剖面示意图。与胶囊500的不同之处包括：至少一条管道525’在承托524’上设有多个开口526’，这有助于降低变形的药囊528’堵住开口526’而导致剩余的药液无法继续通过管道525’、输液管道521’注射到胃壁或肠道壁组织的风险。
图6示出了一个实施例的胶囊600的剖面示意图。如图所示，外壳602大体上呈现为长圆形或橄榄形。多个钩状体608组成的附着部件610设置于外壳602外表面的一侧。钩状体608可以咬合胃壁或肠道壁的组织，以有效地将胶囊600附着于胃壁或肠道壁。外壳602中，靠近附着部件610的一侧设置有针头620、承托624、药囊628，远离附着部件610的一侧设 置有膨胀元件630。针头520和承托524连接为一体，大体上位于紧邻着附着部件610，针尖方向朝向胶囊600外侧。针头620中空，其中的输液管道621与承托624中的管道625连通。药囊628中储存有例如液态的药物。药囊628封闭地接合于承托624，并在药囊内侧曝露出管道625的端部开口626，使得药囊内的腔室与输液管道621流体连通。药囊628较为柔软而易于变形，针头620和承托624较为坚固而不易变形。外壳602在膨胀元件630一侧设有至少一个开口606。膨胀元件630包括囊632和阀634。例如但不限于，阀634夹紧囊632的中部，形成两个彼此隔离的第一腔室635和第二腔室637，分别储存了第一反应物和第二反应物。当胶囊600通过附着元件610附着于胃部或肠道，阀634通过开口606接触到体液而降解，第一腔室635和第二腔室637彼此连通，第一反应物和第二反应物彼此混合发生化学和/或物理变化从而导致体积膨胀。第一反应物和第二反应物例如但不限于分别为乙酸和碳酸氢钠，其混合产生二氧化碳，从而导致体积膨胀。由于外壳602的限制，膨胀的囊632将向附着部件610一侧挤压针头620、承托624和药囊628。针头620因而穿透外壳602并刺入附着元件610所附着的胃壁或肠道壁组织。药囊628受挤压变形从而使得所储存的药液经由输液管道621而注射到胃壁或肠道壁组织。
在附着部件610外侧、或者包裹着附着部件610还可以设置一包覆层，在该包覆层降解之前，胶囊600可以顺利地沿着消化道(食道、胃、肠道等)前进。开口606可以由遮蔽层所遮蔽，使得阀634在胶囊600到达期望的给药部位之前不会接触到胃部或肠道内的体液。该包覆层和遮蔽层可以都是肠溶性的，包覆层的降解速度快于遮蔽层的降解速度；当包覆层降解曝露出附着部件610并附着于肠道壁之后，开口606处的遮蔽层降解并曝露出阀634。该包覆层和遮蔽层可以都是胃溶性的，包覆层的降解速度快于遮蔽层的降解速度；当包覆层降解曝露出附着部件610并附着于胃壁之后，开口606处的遮蔽层降解并曝露出阀634。
图7示出了一个实施例的胶囊700的剖面示意图。如图所示，外壳702大体上呈现为长圆形或橄榄形。多个钩状体708组成的附着部件710设置于外壳702外表面的一侧。钩状体708可以咬合胃壁或肠道壁的组织， 以有效地将胶囊700附着于胃壁或肠道壁。外壳702中，靠近附着部件710的一侧设置有针状体720、承托724，远离附着部件710的一侧设置有膨胀元件730。承托724夹持着针状体720，大体上位于紧邻着附着部件710，针状体720的针尖方向朝向胶囊700外侧。针状体720包含固态的药物、且设有倒勾721。外壳702在膨胀元件730一侧设有至少一个开口706。当胶囊700通过附着元件710附着于胃部或肠道，膨胀元件730在胃部或肠道内通过开口706接触到体液而导致体积膨胀。膨胀元件730所包含的材料例如但不限于超吸收聚合物(SAP)，例如BASF公司的
Figure PCTCN2016078405-appb-000002
系列SAP。由于外壳702的限制，膨胀元件730将向附着部件710一侧挤压承托724和针状体720。针状体720因而穿透外壳702并刺入附着元件710所附着的胃壁或肠道壁组织，倒勾721使得针状体720保持在组织内部。之后，针状体720在组织内部降解从而完成给药。
在附着部件710外侧、或者包裹着附着部件710还可以设置一包覆层，在该包覆层降解之前，胶囊700可以顺利地沿着消化道(食道、胃、肠道等)前进。开口706可以由遮蔽层所遮蔽，使得膨胀元件730在胶囊700到达期望的给药部位之前不会接触到胃部或肠道内的体液。该包覆层和遮蔽层可以都是肠溶性的，包覆层的降解速度快于遮蔽层的降解速度；当包覆层降解曝露出附着部件710并附着于肠道壁之后，开口706处的遮蔽层降解并曝露出膨胀元件730。该包覆层和遮蔽层可以都是胃溶性的，包覆层的降解速度快于遮蔽层的降解速度；当包覆层降解曝露出附着部件710并附着于胃壁之后，开口706处的遮蔽层降解并曝露出膨胀元件730。
图8示出了一个实施例的胶囊800的剖面示意图。如图所示，外壳802大体上呈现为长圆形或橄榄形。包含粘性体的附着部件810设置于外壳802外表面的一侧。通过粘性可以有效地将胶囊800附着于胃壁或肠道壁。外壳802中，靠近附着部件810的一侧设置有针状体820和承托824，远离附着部件810的一侧设置有膨胀元件830。承托824夹持着针状体820，大体上位于紧邻着附着部件810，针状体820的针尖方向朝向胶囊800外侧。针状体820包含固态的药物、且设有倒勾821。外壳802在膨胀元件830一侧设有至少一个开口806。膨胀元件830包括囊832和阀834。例如但不 限于，阀834夹紧囊832的中部，形成两个彼此隔离的第一腔室835和第二腔室837，分别储存了第一反应物和第二反应物。当胶囊800通过附着元件810附着于胃部或肠道，阀834通过开口806接触到体液而降解，第一腔室835和第二腔室837彼此连通，第一反应物和第二反应物彼此混合发生化学和/或物理变化从而导致体积膨胀。第一反应物和第二反应物例如但不限于分别为乙酸和碳酸氢钠，其混合产生二氧化碳，从而导致体积膨胀。由于外壳802的限制，膨胀的囊832将向附着部件810一侧挤压承托824和针状体820。针状体820因而穿透外壳802并刺入附着元件810所附着的胃壁或肠道壁组织，倒勾821使得针状体820保持在组织内部。之后，针状体820在组织内部降解从而完成给药。
在附着部件810外侧还可以设置一包覆层，在该包覆层降解之前，胶囊800可以顺利地沿着消化道(食道、胃、肠道等)前进。开口806可以由遮蔽层所遮蔽，使得阀834在胶囊800到达期望的给药部位之前不会接触到胃部或肠道内的体液。该包覆层和遮蔽层可以都是肠溶性的，包覆层的降解速度快于遮蔽层的降解速度；当包覆层降解曝露出附着部件810并附着于肠道壁之后，开口806处的遮蔽层降解并曝露出阀834。该包覆层和遮蔽层可以都是胃溶性的，包覆层的降解速度快于遮蔽层的降解速度；当包覆层降解曝露出附着部件810并附着于胃壁之后，开口806处的遮蔽层降解并曝露出阀834。
图9A示出了一个实施例的胶囊900的剖面示意图。如图所示，外壳902大体上呈现为长圆形或橄榄形。多个钩状体908组成的附着部件910设置于外壳902外表面的一侧。钩状体908可以咬合胃壁或肠道壁的组织，以有效地将胶囊900附着于胃壁或肠道壁。外壳902中，靠近附着部件910的一侧设置有多个针状体920、承托924，远离附着部件910的一侧与多个承托924相配合设置有多个致动部件930。承托924夹持着针状体920，大体上位于紧邻着附着部件910，针状体920的针尖方向朝向胶囊900外侧。针状体920包含固态的药物、且设有倒勾921。每一致动部件930包括位于相应承托924和外壳902另一侧之间的弹性部件(例如弹簧)933和限位部件935。初始状态下，限位部件935将承托924与外壳902的与附着部件910 相反的一侧连接在一起，从而使得弹簧933处于压缩状态。外壳902上靠近限位部件935处设有至少一个开口906。当胶囊900通过附着元件910附着于胃部或肠道，通过开口906进入外壳902的体液导致限位部件935降解，承托924和针状体920将在弹簧933的回复力驱使下向附着部件910一侧挤压。针状体920因而穿透外壳902并刺入附着元件910所附着的胃壁或肠道壁组织，倒勾921使得针状体920保持在组织内部。之后，针状体920在组织内部降解从而完成给药。
在附着部件910外侧、或者包裹着附着部件910还可以设置一包覆层912，在该包覆层912降解之前，胶囊900可以顺利地沿着消化道(食道、胃、肠道等)前进。开口906可以由遮蔽层916所遮蔽，使得限位元件935在胶囊900到达期望的给药部位之前不会接触到胃部或肠道内的体液。包覆层912和遮蔽层916可以都是肠溶性的，包覆层912的降解速度快于遮蔽层916的降解速度；当包覆层912降解曝露出附着部件910并附着于肠道壁之后，开口906处的遮蔽层916降解并曝露出限位元件935。包覆层912和遮蔽层916可以都是胃溶性的，包覆层912的降解速度快于遮蔽层916的降解速度；当包覆层912降解曝露出附着部件910并附着于胃壁之后，开口906处的遮蔽层916降解并曝露出限位元件935。包覆层912、遮蔽层916、限位元件935所包含的材料例如但不限于羟丙基甲基纤维素(HPMC)、羟丙基纤维素(HPC)、丙烯酸树脂、聚乙烯吡咯烷酮(PVP)、甲基丙烯酸-丙烯酸乙酯共聚物或其混合物。
图9B示出了一个实施例的胶囊900’的剖面示意图。胶囊900’相比于胶囊900的主要区别包括：限位部件935’位于承托924’和附着部件910’一侧的外壳之间。初始状态下，限位部件935’支撑住承托924’，从而使得弹簧933’处于压缩状态。外壳902’上靠近限位部件935’处设有至少一个开口906’。当胶囊900’通过附着元件910’附着于胃部或肠道，通过开口906’进入外壳902’的体液导致限位部件935’降解，承托924’和针状体920’将在弹簧933’的回复力驱使下向附着部件910’一侧挤压。针状体920’因而穿透外壳902’并刺入附着元件910’所附着的胃壁或肠道壁组织，倒勾921’使得 针状体920’保持在组织内部。之后，针状体920’在组织内部降解从而完成给药。
在附着部件910’外侧、或者包裹着附着部件910’还可以设置一包覆层，在该包覆层降解之前，胶囊900’可以顺利地沿着消化道(食道、胃、肠道等)前进。开口906’可以由遮蔽层所遮蔽，使得限位元件935’在胶囊900’到达期望的给药部位之前不会接触到胃部或肠道内的体液。该包覆层和遮蔽层可以都是肠溶性的，包覆层的降解速度快于遮蔽层的降解速度；当包覆层降解曝露出附着部件910’并附着于肠道壁之后，开口906’处的遮蔽层降解并曝露出限位元件935’。该包覆层和遮蔽层可以都是胃溶性的，包覆层的降解速度快于遮蔽层的降解速度；当包覆层降解曝露出附着部件910’并附着于胃壁之后，开口906’处的遮蔽层降解并曝露出限位元件935’。包覆层912’、遮蔽层916’、限位元件935’所包含的材料例如但不限于羟丙基甲基纤维素(HPMC)、羟丙基纤维素(HPC)、丙烯酸树脂、聚乙烯吡咯烷酮(PVP)、甲基丙烯酸-丙烯酸乙酯共聚物或其混合物。
图10示出了一个实施例的胶囊1000的剖面示意图。如图所示，外壳1002大体上呈现为长圆形或橄榄形。多个钩状体1008组成的附着部件1010设置于外壳1002外表面的一侧。钩状体1008可以咬合胃壁或肠道壁的组织，以有效地将胶囊1000附着于胃壁或肠道壁。外壳1002中，靠近附着部件1010的一侧设置有针头1020、承托1024、药囊1028。针头1020和承托1024连接为一体，大体上位于紧邻着附着部件1010，针尖方向朝向胶囊1000外侧。针头1020中空，其中的输液管道1021与承托1024中的管道1025连通。药囊1028中储存有例如液态的药物。药囊1028封闭地接合于承托1024，并在药囊内侧曝露出管道1025的端部开口1026，使得药囊内的腔室与输液管道1021流体连通。药囊1028较为柔软而易于变形，针头1020和承托1024较为坚固而不易变形。承托1024的外周连接着较为柔软而易于变形的裙边1027。药囊1028相比于裙边1027更加柔软且易于变形。裙边1027的外缘抵触着外壳1002的内表面。在承托1024和外壳1002远离附着部件1010的一侧之间设置有弹性元件(弹簧)1033和限位部件1035。初始状态下，限位部件1035将承托1024与外壳1002的与附着部件 1010相反的一侧连接在一起，从而使得弹簧1033处于压缩状态。外壳1002上靠近限位部件1035处设有至少一个开口1006。当胶囊1000通过附着元件1010附着于胃部或肠道，通过开口1006进入外壳1002的体液导致限位部件1035降解，弹簧1033在回复力作用下向附着部件1010一侧挤压针头1020、承托1024和药囊1028。针头1020因而穿透外壳1002并刺入附着元件1010所附着的胃壁或肠道壁组织。药囊1028受挤压变形从而使得所储存的药液经由输液管道1021而注射到胃壁或肠道壁组织。
在附着部件1010外侧、或者包裹着附着部件1010还可以设置一包覆层1012，在该包覆层1012降解之前，胶囊1000可以顺利地沿着消化道(食道、胃、肠道等)前进。开口1006可以由遮蔽层1016所遮蔽，使得限位部件1035在胶囊1000到达期望的给药部位之前不会接触到胃部或肠道内的体液。包覆层1012和遮蔽层1016可以都是肠溶性的，包覆层1012的降解速度快于遮蔽层1016的降解速度；当包覆层1012降解曝露出附着部件1010并附着于肠道壁之后，开口1006处的遮蔽层1016降解并曝露出限位元件1035。包覆层1012和遮蔽层1016可以都是胃溶性的，包覆层1012的降解速度快于遮蔽层1016的降解速度；当包覆层1012降解曝露出附着部件1010并附着于胃壁之后，开口1006处的遮蔽层1016降解并曝露出膨胀元件1030。包覆层1012、遮蔽层1016、限位元件1035所包含的材料例如但不限于羟丙基甲基纤维素(HPMC)、羟丙基纤维素(HPC)、丙烯酸树脂、聚乙烯吡咯烷酮(PVP)、甲基丙烯酸-丙烯酸乙酯共聚物或其混合物。
图11示出了一个实施例的胶囊1100的剖面示意图。如图所示，外壳1102大体上呈现为长圆形或橄榄形。多个钩状体1108组成的附着部件1110设置于外壳1102外表面的一侧，多个钩状体1158组成的附着部件1160设置于外壳1102外表面上与附着部件1110相对的另一侧。钩状体1108、1158可以咬合胃壁或肠道壁的组织，以有效地将胶囊1100附着于胃壁或肠道壁。外壳1102中，靠近附着部件1110的一侧设置有针头1120、承托1124、药囊1128；靠近附着部件1160的一侧设置有针头1170、承托1174、药囊1178；承托1124和1174之间设置有膨胀元1130。针头1120和承托1124连接为一体，大体上位于紧邻着附着部件1110，针尖方向朝向胶囊1100 外侧。针头1120中空，其中的输液管道1121与承托1124中的管道1125连通。药囊1128中储存有例如液态的药物。药囊1128封闭地接合于承托1124，并在药囊内侧曝露出管道1125的端部开口1126，使得药囊内的腔室与输液管道1121流体连通。药囊1128较为柔软而易于变形，针头1120和承托1124较为坚固而不易变形。针头1170、承托1174、药囊1178的设置大体上与针头1120、承托1124、药囊1128类同。外壳1102上在靠近膨胀元件1130处设有至少一个开口。当胶囊1100通过附着元件1110、1160附着于胃部或肠道，膨胀元件1130在胃部或肠道内通过开口接触到体液而导致体积膨胀。膨胀元件1130所包含的材料例如但不限于超吸收聚合物(SAP)，例如BASF公司的
Figure PCTCN2016078405-appb-000003
系列SAP。膨胀元件1130将向附着部件1110一侧挤压针头1120、承托1124和药囊1128，且向附着部件1160一侧挤压针头1170、承托1174和药囊1178。针头1120、1170因而穿透外壳1102并刺入附着元件1110、1160所附着的胃壁或肠道壁组织。药囊1128、1178受挤压变形从而使得所储存的药液经由输液管道1121、1171而注射到胃壁或肠道壁组织。
在附着部件1110和1160外侧、或者包裹着附着部件1110和1160还可以设置包覆层1112和1162，在包覆层1112和1162降解之前，胶囊1100可以顺利地沿着消化道(食道、胃、肠道等)前进。靠近膨胀元件1130的开口可以由遮蔽层所遮蔽，使得膨胀元件1130在胶囊1100到达期望的给药部位之前不会接触到胃部或肠道内的体液。包覆层1112、1162和遮蔽层可以都是肠溶性的，包覆层1112和1162的降解速度快于遮蔽层的降解速度；当包覆层1112、1162降解曝露出附着部件1110、1160并附着于肠道壁之后，开口处的遮蔽层降解并曝露出膨胀元件1130。包覆层1112、1162和遮蔽层可以都是胃溶性的，包覆层1112和1162的降解速度快于遮蔽层的降解速度；当包覆层1112和1162降解曝露出附着部件1110和1160并附着于胃壁之后，开口处的遮蔽层降解并曝露出膨胀元件1130。
图12示出了一个实施例的胶囊1200的剖面示意图。如图所示，外壳1202大体上呈现为长圆形或橄榄形。多个钩状体1208组成的附着部件1210设置于外壳1202外表面的一侧，多个钩状体1258组成的附着部件1260 设置于外壳1202外表面上与附着部件1210相对的另一侧。钩状体1208、1258可以咬合胃壁或肠道壁的组织，以有效地将胶囊1200附着于胃壁或肠道壁。外壳1202中，靠近附着部件1210的一侧设置有针状体1220、承托1224，靠近附着部件1260的一侧设置有针状体1270、承托1274，在承托1224和1274之间设置有膨胀元件1230。承托1224夹持着针状体1220，大体上位于紧邻着附着部件1210，针状体1220的针尖方向朝向胶囊1200外侧。承托1274夹持着针状体1270，大体上位于紧邻着附着部件1260，针状体1270的针尖方向朝向胶囊1200外侧。针状体1220、1270包含固态的药物，且分别设有倒勾1221、1271。外壳1202上靠近膨胀元件1230处设有至少一个开口1206。当胶囊1200通过附着元件1210、1260附着于胃部或肠道，膨胀元件1230在胃部或肠道内通过开口1206接触到体液而导致体积膨胀。膨胀元件1230将向附着部件1110一侧挤压针状体1220和承托1224，且向附着部件1260一侧挤压针状体1270和承托1274。膨胀元件1230所包含的材料例如但不限于超吸收聚合物(SAP)，例如BASF公司的
Figure PCTCN2016078405-appb-000004
系列SAP。针状体1220、1270因而穿透外壳1202并刺入附着元件1210、1260所附着的胃壁或肠道壁组织，倒勾1221、1271使得针状体1220、1270保持在组织内部。之后，针状体1220、1270在组织内部降解从而完成给药。
在附着部件1210、1260外侧、或者包裹着附着部件1210、1260还可以设置包覆层1212、1262。在包覆层1212、1262降解之前，胶囊1200可以顺利地沿着消化道(食道、胃、肠道等)前进。开口1206可以由遮蔽层1216所遮蔽，使得膨胀元件1230在胶囊1200到达期望的给药部位之前不会接触到胃部或肠道内的体液。包覆层1212、1262和遮蔽层1216可以都是肠溶性的，包覆层1212、1262的降解速度快于遮蔽层1216的降解速度；当包覆层1212、1262降解曝露出附着部件1210、1260并附着于肠道壁之后，开口1206处的遮蔽层1216降解并曝露出膨胀元件1230。包覆层1212、1262和遮蔽层1216可以都是胃溶性的，包覆层1212、1262的降解速度快于遮蔽层1216的降解速度；当包覆层1212、1262降解曝露出附着部件1210、1260并附着于胃壁之后，开口1206处的遮蔽层1216降解并曝露出膨胀元 件1230。包覆层1212、1262和遮蔽层1216所包含的材料例如但不限于羟丙基甲基纤维素(HPMC)、羟丙基纤维素(HPC)、丙烯酸树脂、聚乙烯吡咯烷酮(PVP)、甲基丙烯酸-丙烯酸乙酯共聚物或其混合物。
本领域技术人员应能理解，上述实施例均是示例性而非限制性的。本领域技术人员在研究附图、说明书及权利要求书的基础上，应能理解并实现所揭示的实施例的其他变化的实施例。在权利要求书中，术语“包括”并不排除其他装置或步骤；不定冠词“一个”不排除多个；术语“第一”、“第二”用于标示名称而非用于表示任何特定的顺序。权利要求中的任何附图标记均不应被理解为对保护范围的限制。某些技术特征出现在不同的实施例或从属权利要求中并不意味着不能将这些技术特征进行组合以取得有益效果。

Claims (14)

  1. 一种可吞咽式装置，包括：
    外壳；
    位于所述外壳外表面上的附着部件，其适于将所述可吞咽式装置附着于外部组织；
    位于所述外壳内部的药物；
    一个或多个穿透部件，其在第一配置时位于所述外壳内部，其在第二配置时至少部分地穿透到所述外壳的外部；
    位于所述外壳内部的致动部件，其具有分别与所述穿透部件的第一配置和第二配置相适应的第三配置和第四配置，当所述致动部件从所述第三配置向所述第四配置变化时驱动所述穿透部件从所述第一配置变化到所述第二配置，并驱动所述药物经由所述穿透部件输出。
  2. 如权利要求1所述的可吞咽式装置，其中所述附着部件外包覆有可降解的包覆层。
  3. 如权利要求2所述的可吞咽式装置，其中所述外壳上靠近所述致动部件处设有至少一个通孔，所述通孔上任选遮蔽有可降解的遮蔽层。
  4. 如权利要求3所述的可吞咽式装置，其中所述包覆层的降解速度快于所述遮蔽层的降解速度。
  5. 如权利要求1-4中任一项所述的可吞咽式装置，其中所述附着部件包括一个或多个钩状体，或包括粘性体。
  6. 如权利要求5所述的可吞咽式装置，其中所述多个钩状体的弯曲方向并非一致。
  7. 如权利要求1-6中任一项所述的可吞咽式装置，其中，
    所述穿透部件包括连接为一体的针和承托，所述针的针头靠近所述附着部件且针尖方向朝向所述可吞咽式装置外侧，
    所述针中空，其中的管道连通到所述承托上的至少一个开口，
    所述可吞咽式装置在所述针和承托附近还包括药囊，所述药囊封闭地接合于所述承托且与所述针中的管道流体连通，
    所述致动部件位于所述承托和与所述附着部件相对的所述外壳一侧之间。
  8. 如权利要求1-6中任一项所述的可吞咽式装置，其中，
    所述穿透部件包括针状体、承托，所述承托夹持着所述针状体，所述针状体靠近所述附着部件且针尖方向朝向所述可吞咽式装置外侧，所述针状体包含药物，
    所述致动部件位于所述承托和所述外壳的与所述附着部件相反的一侧之间。
  9. 如权利要求8所述的可吞咽式装置，其中所述针状体上设有倒勾。
  10. 如权利要求7-9中任一项所述的可吞咽式装置，其中所述致动部件包括可膨胀元件。
  11. 如权利要求10中所述的可吞咽式装置，其中所述可膨胀元件为可膨胀材料。
  12. 如权利要求10中所述的可吞咽式装置，其中所述可膨胀元件包括囊和可降解的阀，所述阀将所述囊分隔为两个彼此隔离的第一腔室和第二腔室，所述第一腔室和第二腔室分别储存了第一反应物和第二反应物，所述第一反应物和第二反应物混合后能够使得所述囊的体积膨胀。
  13. 如权利要求7-9中任一项所述的可吞咽式装置，其中所述致动部件包括弹性体以及可降解的限位部件，所述限位部件与所述外壳和/或承托耦合以使得所述弹性体处于压缩状态。
  14. 如权利要求7-9中任一项所述的可吞咽式装置，其中所述承托的外周连接有裙边，所述裙边的外缘抵触着所述外壳的内表面。
PCT/CN2016/078405 2015-04-02 2016-04-01 可吞咽式装置 Ceased WO2016155671A1 (zh)

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