Pharmaceutical dosage form for in vivo retention

Abstract

An oral pharmaceutical dosage form, which is intended to provide the desired retention in an individual on the basis of geometric differences between dosage form states before and after administration. The oral pharmaceutical dosage form comprises swellable and expandable material (5). The material (5), upon swelling or expansion, drives the overall size of the oral pharmaceutical dosage form to expand, thereby allowing the oral pharmaceutical dosage form to remain in the stomach for a desired period of time.

Description

Drug dosage forms for retention in the body CROSS-REFERENCE TO RELATED APPLICATIONS The priority claimed by this application is PCT / CN2024 / 081848 filed on March 15, 2024, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0001] In some aspects, the present disclosure is directed to pharmaceutical dosage forms, and is intended to provide required residence time in an individual based on the geometric difference between dosage form states before and after administration. In some aspects, the oral pharmaceutical dosage form provided includes a swellable material, which, when swollen or expanded, drives the expansion of the overall size of the oral pharmaceutical dosage form so that the oral pharmaceutical dosage form is retained in the stomach for a period of time required. In some other aspects, the present disclosure is directed to the material of oral pharmaceutical dosage forms as described herein. In some other aspects, the present disclosure is directed to design methods, dosage form manufacturing methods, such as, relating to three-dimensional (3D) printing, injection molding, ultrasonic welding or any combination thereof, and by drug delivery to a method comprising administering an individual of oral pharmaceutical dosage forms as described herein. Background Art

[0002] Conventional oral pharmaceutical dosage forms, when administered to an individual, are subject to natural forces, such as the natural flow of liquids, semisolids, and solids through the individual's gastrointestinal system, and / or forces applied by the individual. As with oral administration, this natural flow can vary between administrations to a particular individual and between populations of individuals, depending on fluctuations relative to the time of administration, such as the timing of meals and / or beverages and the size of the contents of the meals and / or beverages, as well as the current gastric phase and remaining duration. These circumstances can cause variability, for example, in the location of drug delivery, bioavailability, safety profile, and efficacy of pharmaceutical dosage forms (e.g., oral pharmaceutical dosage forms) that remain in the stomach for a period of time.

[0003] All references cited herein, including patent applications and publications, are hereby incorporated by reference in their entirety. Summary of the Invention

[0004] In certain aspects, a drug dosage form comprises: a main body structure forming an expandable material chamber; wherein the expandable material chamber contains expandable material; an arm operably connected to the main body; the arm rotates about the main body of the drug dosage form by a force provided by the expandable material; and a drug; wherein the drug dosage form is configured to have a pre-dose state having a compact form and a post-dose state having an expanded form that provides gastric retention, and the expanded form of the post-dose state of the drug dosage form is due, at least in part, to expansion of the expandable material in the presence of gastrointestinal fluid.

[0005] A drug dosage form, comprising: a body extending in the Z-axis direction, the body including an internal chamber and an expandable structure housed in the internal chamber, the internal chamber including a fluid inlet; an arm rotatable around the body; and a drug; wherein the drug dosage form is configured to have a first state extending in the Z-axis direction and a second state extending simultaneously in the XY and Z-axis directions; the second state occurs at least in part due to expansion of the expandable structure; and the extension in the XY axis direction occurs due to rotation of the arm around the body.

[0006] A pharmaceutical dosage form is configured to have a compact pre-dose state and an expanded post-dose state, the pharmaceutical dosage form comprising: an arm and a main body connected to the arm, the arm being rotatable about the main body, the main body comprising a pushing device, the pushing device being triggered by external conditions and pushing the arm to rotate about the main body to form an expanded post-dose state; the pharmaceutical dosage form comprising an outer surface and an inner portion opposite to the outer surface when configured to have a compact pre-dose state; a drug component, the drug component being carried in the interior of the pharmaceutical dosage form, the drug being at least partially exposed in the expanded post-dose state of the pharmaceutical dosage form.

[0007] In some embodiments, the Z axis can be considered as the central axis of the pharmaceutical dosage form, and the X axis and the Y axis are axes perpendicular to the Z axis. The plane formed by the XY axes is a plane perpendicular to the Z axis.

[0008] In some embodiments, the urging device comprises an expandable material.

[0009] In some embodiments, the pushing device comprises a gas-generating material.

[0010] In some embodiments, the fluid inlet may be a through hole on the main body that connects the inside and outside of the main body when the arm is extended from the main body. In some embodiments, the fluid inlet may be a water inlet hole located separately on the main body. In some embodiments, the pushing device further includes a moving member.

[0011] In some embodiments, the drug component is loaded on the arm, and / or loaded on the body.

[0012] In some embodiments, the body of the pharmaceutical dosage form is a monolithic structure.

[0013] In some embodiments, the drug dosage form includes a first compartment housing an expandable member, and a second compartment in communication with the first compartment.

[0014] In some embodiments, the main structure of the pharmaceutical dosage form further includes a movable member that can move from the first compartment to the second compartment. The pharmaceutical dosage form is configured such that in a compact pre-administration state, the movable member is located in the first compartment, and in an expanded post-administration state, the movable member is at least partially contained in the second compartment.

[0015] In some embodiments, the main structure of the pharmaceutical dosage form further comprises a fluid inlet in communication with the first compartment or the second compartment.

[0016] In some embodiments, the body of the pharmaceutical dosage form comprises a lid and a base. In some embodiments, the inner wall of the base forms a first compartment, and the inner wall of the lid forms a second compartment. In some embodiments, the body of the oral dosage form comprises one or more bases and one or more lids. In some embodiments, the lids comprise a first lid and a second lid.

[0017] In some embodiments, the body of the pharmaceutical dosage form comprises a partially or fully semipermeable membrane that allows liquid to enter. In some embodiments, the body of the pharmaceutical dosage form is a semipermeable membrane. In some embodiments, the body of the pharmaceutical dosage form has pores / orifices that allow liquid to enter.

[0018] In some embodiments, the base of the pharmaceutical dosage form is composed of a semipermeable material or semipermeable membrane that partially or completely allows liquid to enter. In some embodiments, the base of the pharmaceutical dosage form body is a semipermeable membrane. In some embodiments, the base of the pharmaceutical dosage form has pores / orifices that allow liquid to enter. In some embodiments, the receiving cavity formed by the semipermeable membrane contains a swellable material. In some embodiments, the receiving cavity formed by the semipermeable membrane also contains a drug and an osmotic pressure regulator, and the drug is released from the semipermeable membrane under the action of the osmotic pressure regulator. In some embodiments, the osmotic pressure regulator can be a non-ionic osmotic pressure regulator or an ionic osmotic pressure regulator, and can be selected from one or more of the following materials: glucose, mannitol, sorbitol, glycerol, lactose, fructose, ammonium sulfate, betaine, sodium chloride, potassium chloride, calcium chloride, and potassium bromide.

[0019] In some embodiments, the base and the cover of the drug dosage form body are coupled to each other by snap fastening, threading, mortise and tenon joints, gluing, riveting, ultrasonic welding, or hot stamping.

[0020] In some embodiments, the body of the pharmaceutical dosage form comprises two or more materials.

[0021] In some embodiments, the base of the dosage form body comprises an opening at the top, the opening being connected to the lid. In some embodiments, the opening of the oral dosage form base is configured to be circular, oval, rectangular, or polygonal, such as triangular, quadrilateral, hexagonal, or octagonal. In some embodiments, the opening of the oral dosage form base has a diameter of 4 mm to 8 mm.

[0022] In some embodiments, the base of the pharmaceutical dosage form body comprises a bottom portion, wherein the bottom portion of the base portion is a curved surface. In some embodiments, the bottom portion of the oral dosage form base portion comprises a material that allows liquid to flow in. In some embodiments, the bottom portion of the oral dosage form base portion has pores / orifices that allow liquid to enter.

[0023] In some embodiments, the diameter of the orifice of the dosage form body or base is 0.1 mm to 2 mm. In some embodiments, the orifice of the dosage form body or base is one or more, specifically 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 15, 18, 20, or 30.

[0024] In some embodiments, the channel formed by the bottom of the pharmaceutical dosage form base and the opening at the top of the base is the first directional channel. In some embodiments, the opening at the top of the oral dosage form base is located at the cross section where the bottom of the lid is connected to the base.

[0025] In some embodiments, the moving member is a piston, wherein the swellable material absorbs liquid (such as gastric juice) to swell and push the piston to move from the first compartment to the second compartment.

[0026] In some specific embodiments, the swelling material comprises sodium alginate (SA), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), polyethylene oxide (PEO), polyvinyl alcohol (PVA), microcrystalline cellulose (MCC), cross-linked sodium carboxymethyl cellulose (CCNa), sodium carboxymethyl cellulose (CMC-Na), polyvinyl polypyrrolidone (PVPP), sodium carboxymethyl starch (CMS-Na), polyethylene glycol (PEG), or a mixture thereof.

[0027] In some embodiments, the swelling material comprises a gas-generating substance. In some embodiments, the gas-generating substance comprises an organic salt, an inorganic salt, or a mixture thereof. In some embodiments, the swelling material is a spring. In some embodiments, the swelling material is coated with an erodible material layer.

[0028] In some embodiments, the swellable material expands at least about 1.2 times in volume upon exposure to gastrointestinal fluids. In some embodiments, the swellable material has a volume expansion rate of at least about 1.2 times in 30 minutes.

[0029] In some embodiments, the amount of swellable material in the swellable material chamber is at least about 5 mg.

[0030] In some embodiments, the swellable material has a diameter of about 10 mm. 3 to about 50mm 3 The swelling volume.

[0031] In some embodiments, the swellable material may be pre-pressed. In some embodiments, the bottom of the swellable material is configured to fit the bottom of the base. In some embodiments, the bottom of the swellable material is a curved surface.

[0032] In some embodiments, the main structure forms a swellable material chamber, and the swellable material chamber further comprises a lid and a base, wherein the lid and the base cooperate to form the overall outer structure of the swellable material chamber. In some embodiments, the swellable material chamber comprises a swellable material and a moving member.

[0033] In some embodiments, the moving member in the swellable material chamber has a certain rigidity and strength. In some embodiments, the moving member in the swellable material chamber is located between the swellable material and the base opening.

[0034] In some embodiments, the moving member has a bottom portion proximate to the swelling material and a top portion proximate to the base opening. In some embodiments, the surface area of ​​the bottom portion of the moving member is greater than the surface area of ​​the top portion of the moving member. In some embodiments, the surface area of ​​the bottom portion of the moving member is equal to the surface area of ​​the top portion of the moving member. In some embodiments, the surface area of ​​the bottom portion of the moving member is less than the surface area of ​​the top portion of the moving member.

[0035] In some embodiments, the movable member is configured as a cylinder, a T-shaped platform, a prism, a truncated cone, a frustum, or a truncated cone. In some embodiments, the top of the movable member has a hook-like structure. In some embodiments, the bottom of the movable member is flat. In some embodiments, the bottom of the movable member has a groove.

[0036] In some embodiments, the cover is configured to prevent further movement of the swelling material, the moving member, and thereby maintain the arm in the one or more extended positions.

[0037] In some embodiments, the cover is selectively connected to the arm. In some embodiments, the cover and the arm are configured as an interlocking structure, including a latch, a lock, and a pivot. In some embodiments, the cover further includes a pin hole inside that cooperates with the arm latch.

[0038] In some embodiments, the lid has a top portion that forms an exterior portion of the main structure. In some embodiments, the lid has a bottom portion that is connected to the base. In some embodiments, the lid has a side portion that is located between the lid top portion and the lid bottom portion.

[0039] In some embodiments, the lid has an opening at the top. In some embodiments, the opening is configured to match the shape of the arm near the connection end. In some embodiments, the number of openings in the lid is the same as the number of arms. In some embodiments, the lid has one or more openings, specifically 2, 3, 4, 5, 6, 7, or 8 openings. In some embodiments, the lid has a clover-shaped, four-leaf clover-shaped, or petal-shaped opening. In some embodiments, the opening is trumpet-shaped, rectangular, or arched.

[0040] In some embodiments, the top of the lid is flat. In some embodiments, the top of the lid is provided with reinforcing ribs. In some embodiments, the reinforcing ribs on the top of the lid are shaped like a cross, a rice, a well, or a grid.

[0041] In some embodiments, the inner surface of the cover matches the shape of the top of the moving member.

[0042] In some embodiments, the inner surface of the top of the cover matches the shape of the top of the moving member.

[0043] In some embodiments, the bottom of the lid mates with the top of the base. In some embodiments, a portion of the inner surface of the side of the lid mates with a portion of the outer surface of the top of the base. In some embodiments, a portion of the outer surface of the side of the lid mates with a portion of the inner surface of the top of the base.

[0044] In some embodiments, the bottom of the lid comprises an opening. In some embodiments, the opening in the bottom of the oral dosage form lid is configured to have the same shape as the top of the movable member. In some embodiments, the opening in the bottom of the oral dosage form lid is configured to have a circular, oval, rectangular, or polygonal shape, such as a triangle, quadrilateral, hexagon, or octagon. The diameter of the opening in the bottom of the oral dosage form lid is 4 mm to 8 mm.

[0045] In some embodiments, the cross-section of the lid bottom is configured as a discontinuous arc on a circumference. In some embodiments, the number of arcs in the lid bottom cross-section is the same as the number of arms. In some embodiments, the number of arcs in the lid bottom cross-section is multiple, specifically 2, 3, 4, 5, 6, 7, or 8. In some embodiments, the cross-section of the lid bottom is configured as a continuous shape. In some embodiments, the cross-section of the lid bottom is configured as a circle, a circular ring, an ellipse, an elliptical ring, a rectangle, a rectangular ring, a polygon, or a polygonal ring.

[0046] In some embodiments, the channel formed between the bottom and top of the cover is the second directional channel.

[0047] In some specific embodiments, the swelling material absorbs water and expands upon contact with liquid (e.g., gastric fluid), pushing the movable member to move along the first channel to the second channel until the movable member moves close to the top of the cover, thereby pushing the arm to rotate around the body of the oral dosage form, causing the oral dosage form to change from a deflated state before administration to an expanded state.

[0048] In some embodiments, the oral dosage form body includes a first cover and a second cover, wherein the first cover includes a first top surface, a first bottom surface, and a first side surface located between the first top surface and the first bottom surface. The second cover includes a second top surface, a second bottom surface, and a second side surface located between the second top surface and the second bottom surface. In some embodiments, the second bottom surface of the second cover cooperates with the top of the base. In some embodiments, the first bottom surface of the first cover cooperates with the second top surface of the second cover. In some embodiments, the second bottom surface of the second cover cooperates with the top of the base, and the first bottom surface of the first cover cooperates with the second top surface of the second cover. In some embodiments, the first side surface of the first cover and the second side surface of the second cover partially or completely cooperate with the inner surface of the top of the base. In some embodiments, the connecting portion of the arm to the body is located between the first cover and the second cover.

[0049] In some embodiments, the lid has an opening on the side. In some embodiments, the opening on the side of the lid communicates with an opening on the top of the lid. In some embodiments, when the oral dosage form is in a deflated state prior to administration, the shape of the opening on the side of the lid is the same as the shape of the portion of the lid that contacts the arm.

[0050] In some embodiments, a coupling feature is provided between the components constituting the pharmaceutical dosage form. In some embodiments, the coupling feature comprises a form-fitting surface or a mechanical snap-fit ​​component or an adhesive.

[0051] In some embodiments, the binder may optionally include one or more of the following materials: dextrin, xanthan gum, maltodextrin, povidone, methylcellulose, ethylcellulose, zein, fructose, poloxamer, sodium alginate, pregelatinized starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomer, starch, gum arabic, microcrystalline cellulose, sodium lauryl sulfate, sucrose, cellulose acetate, polysorbate, glucose, dextran, compressible sugar, carrageenan, modified starch, tragacanth gum, honey.

[0052] In some embodiments, the arm includes a connecting end that contacts the main body. In some embodiments, the arm includes a connecting end that mates with an opening in the side of the lid when the oral dosage form is in a deflated state prior to administration. In some embodiments, the arm includes an extension extending away from the main body when the oral dosage form is in an expanded state. In some embodiments, the arm includes a distal end of the arm that is furthest from the main body when the oral dosage form is in the expanded state.

[0053] In some embodiments, the connecting end of the arm is connected to the body. In some embodiments, the connecting end of the arm is connected to the cover.

[0054] In some embodiments, the arm rotates around a rotation axis, wherein the direction of the rotation axis is perpendicular to the extension direction of the arm.

[0055] In some embodiments, the connecting end of the arm has a pin structure. The pin at the connecting end of the arm cooperates with a pin hole within the body, allowing the arm to rotate about the rotation axis. In some embodiments, the pin structure is cylindrical or prism-shaped, such as a triangular prism, a square prism, a pentagonal prism, a hexagonal prism, or an octagonal prism.

[0056] In some embodiments, the width of the connecting end of the arm is 0.5 mm to 2 mm. In some embodiments, the ratio of the width of the connecting end of the arm to the width of the extension section of the arm is in the range of 1:0.5 to 1:5. In some embodiments, the ratio of the width of the connecting end of the arm to the width of the extension section of the arm is in the range of 1:1 to 1:5. The ratio of the width of the connecting end of the arm to the length of the arm is in the range of 1:10 to 1:20. In some embodiments, the connecting end of the arm is configured to be "L"-shaped. In some embodiments, when the oral dosage form is in the expanded state, the connecting end of the arm can rotate within the opening on the side of the cover. In some embodiments, when the oral dosage form is in the expanded state, the connecting end of the arm cooperates with the hook structure at the top of the movable member.

[0057] In some embodiments, when the oral dosage form is in the expanded state, the connected ends of the arms define an internal angle β at the end of the arms near the base, and an internal angle γ at the end of the arms near the top of the lid. In some embodiments, the internal angle β of the arms is between 0° and 180°. In some embodiments, the internal angle β of the arms is between 0° and 120°. In some embodiments, the internal angle β of the arms is between 0° and 70°. In some embodiments, the internal angle β of the arms is between 70° and 120°. In some embodiments, the internal angle γ of the arms is between 0° and 180°. In some embodiments, the internal angle γ of the arms is between 0° and 30°. In some embodiments, the internal angle γ of the arms is between 0° and 90°. In some embodiments, the internal angle γ of the arms is between 30° and 90°.

[0058] In some embodiments, the connecting end of the arm is shaped like a cylinder, cone, truncated cone, prism, pyramid, or truncated pyramid. In some embodiments, the connecting end of the arm is 0.5 mm to 2 mm wide. In some embodiments, the connecting end of the arm is 2 mm to 10 mm long. In some embodiments, the connecting end of the arm is provided with a reinforcing rib. In some embodiments, the thickness of the reinforcing rib of the arm is 1 mm to 3 mm.

[0059] In some embodiments, the extension section of the arm is shaped like a cylinder, a cone, a frustum, a prism, a pyramid, or a truncated pyramid. In some embodiments, when the oral dosage form is in a deflated state before administration, the outer surface of the extension section of the arm constitutes a portion of the outer surface of the dosage form. In some embodiments, when the oral dosage form is in a deflated state before administration, the inner surface of the extension section of the arm is close to the central axis of the main body. In some embodiments, the inner surface of the extension section of the arm has a recess. In some embodiments, the width of the extension section of the arm is 2 mm to 5 mm. In some embodiments, the length of the extension section of the arm is 8 mm to 18 mm. In some embodiments, the extension section of the arm is provided with reinforcing ribs. In some embodiments, the thickness of the reinforcing ribs of the extension section of the arm is 1 mm to 3 mm.

[0060] In some embodiments, the distal end of the arm is curved. In some embodiments, the distal end of the arm has an outer surface that is an arc. In some embodiments, the distal end of the arm has an outer surface that is a smooth, continuous curved surface.

[0061] In some embodiments, there are at least two arms that rotate around the body of the same oral dosage form. In some embodiments, there are 2, 3, 4, 5, 6, 7, or 8 arms. In some embodiments, the arms include a first arm, a second arm, a third arm, and a fourth arm.

[0062] In some embodiments, the length of the arm is 5 mm to 22 mm, specifically 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 mm.

[0063] In some embodiments, the arms are arranged to be distributed around the axis of the body. In some embodiments, the arms are in contact with each other in a collapsed state before administration, forming a collapsed state. In some embodiments, the arms are in an expanded state after administration, extending outward from the axis to form a petal shape.

[0064] In some embodiments, after administration of the arms, the angles between two adjacent arms are equal, and the angles range from 180°, 120°, 90°, 72°, 60°, and 45°.

[0065] In some embodiments, the directional channel is configured to guide the movement of the arm via a swellable material. In some embodiments, the directional channel comprises a swellable material and a movable member. In some embodiments, the directional channel is configured to push the movable member via the swellable material, thereby pushing the arm open and expanding. In some embodiments, the directional channel comprises a straight channel. In some embodiments, the directional channel comprises a curved channel. In some embodiments, the cross-section of the directional channel is circular, oval, square, rectangular, or capsule-shaped.

[0066] In some embodiments, the post-administration state of the pharmaceutical dosage form occurs within 2 hours or less after the pharmaceutical dosage form is administered to the subject.

[0067] In some embodiments, the pharmaceutical dosage form has a gastric residence time of about 6 hours to about 3 months.

[0068] In some embodiments, the pharmaceutical dosage form has a maximum cross-sectional dimension of 24 mm or less in the pre-administration state.

[0069] In some embodiments, at least two perpendicular dimensions of the pharmaceutical dosage form in the post-administration state are 20 mm or greater.

[0070] In some embodiments, the body of the pharmaceutical dosage form further comprises a central column, wherein in the pre-administration state, the length of the central column along the axis does not exceed the length of the arms along the axis.

[0071] In some embodiments, the intermediate pillar is loaded with a drug.

[0072] In some embodiments, the pharmaceutical dosage form further comprises a restraining member configured to inhibit extension of the arm in a pre-dose state. In some embodiments, the restraining member is an erodible restraint disposed on the outside of the pharmaceutical dosage form. In some embodiments, the erodible restraint of the pharmaceutical dosage form is a complete erodible coating applied to the outer surface of the pharmaceutical dosage form. In some embodiments, the erodible restraint can be a localized erodible coating that only covers a portion of the arm. In some embodiments, the erodible restraint of the oral pharmaceutical dosage form is an erodible ring. In some embodiments, the erodible restraint of the pharmaceutical dosage form is a capsule shell, a capsule body, or a capsule cap.

[0073] In some embodiments, the erodible restraint erodes within about 30 minutes after administration to a subject.

[0074] In some embodiments, the drug is selected from one or more of a small molecule compound, a polypeptide, a protein, a nucleic acid, an antibody, a cell-containing hydrogel, a probiotic, or the like. In some embodiments, the pharmaceutically active material is selected from one or more of a small molecule compound, a polypeptide, and a protein.

[0075] In some embodiments, the drug is selected from riociguat, aceclofenac, bicalutamide, carbamazepine, carvedilol, clotrimazole, cinnarizine, danazol, dapsone, estradiol, ezetimibe, glyburide, fenofibrate, griseofulvin, ibuprofen, itraconazole, ketoconazole, mefenamic acid, naproxen, nevirapine, nifedipine, nitrofurantoin, nomegestrol acetate, phenytoin sodium salt, piroxicam, praziquantel, rifampicin, sulfamethoxazole, trimethoprim, verapamil, levodopa, carbidopa, pregabalin, apixaban, tofacitinib, salts One or more of metformin hydrochloride, sitagliptin, diclofenac, ciprofloxacin, gabapentin, risperidone, rosuvastatin, memantine hydrochloride, gabapentin, tapentadol, oxycodone, acetaminophen, levetiracetam, dapagliflozin, aripiprazole, lenalidomide, pioglitazone, valsartan, sacubitril, cetirizine, clozapine, domperidone, dipyridamole, compound gentamicin sulfate, ranitidine, corydalis, vitamin B2, norfloxacin, diltiazem, ropinirole, gentamicin sulfate, mifepristone and their salts and stereoisomers.

[0076] All references cited herein, including patent applications and publications, are hereby incorporated by reference in their entirety.

[0077] Those skilled in the art will also understand that changes in form and details of the implementations described herein may be made without departing from the scope of the present disclosure. Furthermore, although various advantages, aspects, and objects have been described with reference to various implementations, the scope of the present disclosure should not be limited by reference to these advantages, aspects, and objects.

[0078] FIG1 shows a pharmaceutical dosage form comprising a double-arm structure, wherein FIG1a shows an exemplary diagram of the pharmaceutical dosage form in a contracted state, and FIG1b shows an exemplary diagram of the pharmaceutical dosage form in an expanded state.

[0079] FIG2 shows a side cross-sectional view of a pharmaceutical dosage form comprising a three-arm structure in an expanded state.

[0080] FIG3 shows a side cross-sectional view of another pharmaceutical dosage form with a three-arm structure in an unfolded state.

[0081] FIG4 shows a perspective view of a pharmaceutical dosage form comprising a five-arm structure in an unfolded state.

[0082] FIG5 shows a schematic structural diagram of an arm.

[0083] FIG6 shows a schematic structural diagram of a moving component.

[0084] FIG7 shows a schematic structural diagram of the cover.

[0085] FIG8 shows a schematic structural diagram of the base.

[0086] 9a to 9c are top views showing a pharmaceutical dosage form comprising a four-arm structure in an unfolded state.

[0087] Figure 10 shows another drug dosage form with a four-arm structure, wherein Figure 10a shows an example diagram of the drug dosage form in a contracted state, Figure 10b shows an example diagram of the drug dosage form in an expanded state, Figure 10c shows an example diagram of the drug dosage form in a contracted state, and Figure 10d shows an example diagram of the drug dosage form in an expanded state.

[0088] FIG11 shows another pharmaceutical dosage form with a double-arm structure, wherein FIG11 a shows an example diagram of the pharmaceutical dosage form in a contracted state, and FIG11 b shows an example diagram of the pharmaceutical dosage form in an expanded state.

[0089] FIG12 shows a diagram of the development test results of the pharmaceutical dosage form.

[0090] 13a and 13b respectively show schematic structural diagrams of the arms.

[0091] FIG14 shows a diagram of a four-arm pharmaceutical dosage form in an unfolded state.

[0092] FIG15 shows an X-ray image of the pharmaceutical dosage form in a dog.

[0093] Figure 16 shows an example diagram of a five-arm pharmaceutical dosage form in an expanded state.

[0094] The oral dosage forms provided herein include in some aspects a swellable material that, when swollen, drives the expansion of the overall size of the oral dosage form so that the oral dosage form is retained in the stomach for a desired period of time. The oral dosage forms provided herein are based at least in part on the unique views and discoveries of the inventors regarding oral dosage form designs and mechanisms, which provide oral dosage forms that are small enough to facilitate patient administration and have sufficient size increase in the stomach to suppress the time required for passage through the pylorus (i.e., the oral dosage form is retained in the stomach for a longer time, e.g., 6 hours to 3 months). In some aspects, the oral dosage form of the present application includes one or more arms driven by the expansion mode of the swelling material, wherein the oral dosage form maintains sufficient mechanical stability after the size increase so that it remains in the stomach for a longer time without interfering with normal gastric function. The pharmaceutical dosage form of the present application can also be configured to release the drug therefrom after any desired drug release profile (e.g., an immediate release profile, a sustained release profile, a delayed-sustained release profile, a pulsed release profile, a zero-order release profile, or any combination thereof) of one or more drugs.

[0095] Thus, in certain aspects, an oral pharmaceutical dosage form for gastric retention is provided, the oral pharmaceutical dosage form comprising: a main body structure forming a swellable material chamber; wherein the swellable material chamber contains a swellable material; an arm operably connected to the main body; the arm rotating about the main body of the oral pharmaceutical dosage form by a force provided by the swellable material; and a drug. wherein the oral pharmaceutical dosage form is configured to have a pre-dose state having a compact form and a post-dose state having an expanded form that provides gastric retention, and wherein the expanded form of the post-dose state of the oral pharmaceutical dosage form is due, at least in part, to expansion of the swellable material in the presence of gastrointestinal fluids. I. Definitions

[0096] For the purposes of interpreting this specification, the following definitions shall apply, and where appropriate, terms used in the singular shall include the plural, and vice versa. In the event of a conflict between any of the following definitions and any document incorporated herein by reference, the definitions set forth herein shall prevail.

[0097] As used herein, the term "subject" refers to a mammal, including but not limited to a human, cow, horse, feline, canine, rodent, rat, mouse, dog, or primate. In some embodiments, the subject is a human subject.

[0098] As used herein, the terms "comprise," "have," "include," and "includes," and other similar forms and their grammatical equivalents, are intended to be equivalent in meaning and to be open-ended, in that any one or more items within these terms are not intended to be an exhaustive list of such one or more items, or to be limited to only the listed one or more items. For example, an article that "comprises" components A, B, and C can consist of (i.e., consist of) components A, B, and C, or can include not only components A, B, and C, but also one or more additional components. Thus, it is intended and understood that "comprising" and its similar forms, and their grammatical equivalents, encompass disclosure of embodiments that "consist essentially of" or "consist of."

[0099] As used herein, the terms "body axis," "central axis of the body," and other similar forms and grammatical equivalents thereof are intended to refer to the central axis in the longitudinal direction.

[0100] As used herein, the term "vertical dimension" and other similar forms and grammatical equivalents thereof are intended to refer to the dimension of the pharmaceutical dosage form perpendicular to the largest cross dimension.

[0101] Where a range of values ​​is provided, it is understood that unless the context clearly dictates otherwise, each intervening value between the upper and lower limit of that range and any other stated or intervening value in the stated range is included in the disclosed range, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0102] Reference herein to a value or parameter "relating to" includes (and describes) variations of that value or parameter itself. For example, a description referring to "relating to X" includes a description of "X."

[0103] As used herein, including in the appended claims, the singular forms "a," "an," "or," and "the" include plural referents unless the context clearly dictates otherwise.

[0104] In certain aspects, the present disclosure is directed to pharmaceutical dosage forms that are intended to provide a desired retention in an individual based on geometric differences between the dosage form's state before and after administration, e.g., a change in size in one or more dimensions. In certain aspects of the description provided herein, oral dosage forms are exemplified, however, it should be understood that the teachings of such dosage forms can be readily extrapolated to other dosage forms, such as dosage forms suitable for vaginal or rectal administration, or even other dosage forms for similar environments. In certain aspects, provided herein are oral dosage forms and components thereof for gastric retention. The oral dosage forms provided herein are configured with a swellable material, including one or more portions of a swellable material composed of the same or different materials, such that the swellable material swells upon exposure to gastrointestinal fluids and provides a force to drive the oral dosage form to increase in size. The increase in size of the oral dosage form results in the oral dosage form being retained in the stomach for a longer period of time because it cannot easily pass through the pylorus.

[0105] In some embodiments, the pharmaceutical dosage form or a component thereof swells due to body fluids. For example, in some embodiments, the body fluid is gastrointestinal fluid.

[0106] In some embodiments, provided is an oral dosage form for gastric retention, the oral dosage form comprising: a body structure forming a swellable material chamber, wherein the swellable material chamber contains a swellable material; an arm operably connected to the body; the arm rotates about the body of the oral dosage form by a force provided by the swellable material; and a drug; wherein the oral dosage form is configured to have a pre-dose state having a compact form and a post-dose state having an expanded form that provides gastric retention, and the expanded form of the post-dose state of the oral dosage form is due, at least in part, to expansion of the swellable material in the presence of gastrointestinal fluids.

[0107] In some specific embodiments, the swellable material is a chemical material; in some specific embodiments, the swellable material chamber includes a swellable material, a movable member and an orifice, wherein the movable member has a certain rigidity, and the swellable material pushes it to move toward the orifice, thereby pushing the arm to expand; in some specific embodiments, the movable member is pushed out of the orifice; in some specific embodiments, the movable member moves along the direction of the orifice until it is blocked by the cover; in some specific embodiments, the movable member has stronger rigidity than the swelling material.

[0108] In some embodiments, an oral dosage form for gastric retention is provided, the oral dosage form comprising: a body structure forming a swellable material chamber; wherein the swellable material chamber contains a swellable material; wherein the swellable material is at least partially enclosed by a semipermeable membrane; a first arm, a second arm, a third arm, and a fourth arm, wherein the arms are operably connected to the body; wherein the first arm, the second arm, the third arm, and the fourth arm are configured such that each arm rotates about an axis of the body by a force provided by the swellable material; wherein the oral dosage form is configured to have a pre-dose state having a compact form and a post-dose state having an expanded form that provides gastric retention, and wherein the expanded form of the post-dose state of the oral dosage form is due, at least in part, to swelling of the swellable material in the presence of gastrointestinal fluid.

[0109] In some embodiments, an oral pharmaceutical dosage form for gastric retention is provided, comprising: a main body structure defining a swellable material chamber; wherein the swellable material chamber contains the swellable material and a movable member structure. The main body structure comprises a base, a lid, and a directional channel formed by a bottom portion of the base and an opening at a top portion of the base; the base is formed of a semipermeable membrane. The arms comprise a first arm, a second arm, a third arm, and a fourth arm, each operably connected to the main body; the swellable material absorbs liquid and expands, providing a force that propels the movable member along the directional channel to near the top portion of the lid; the first arm, the second arm, the third arm, and the fourth arm are configured such that each arm is rotated about an axis of the main body by the propulsion of the movable member; the oral pharmaceutical dosage form is configured to have a compact pre-administration state and an expanded post-administration state that provides gastric retention, and the expanded post-administration state of the oral pharmaceutical dosage form is due, at least in part, to the expansion of the swellable material in the presence of gastrointestinal fluid.

[0110] In some embodiments, an oral dosage form for gastric retention is provided, comprising: a body structure defining a swellable material chamber; wherein the swellable material chamber contains a swellable material; an arm operably connected to the body; wherein the arm rotates about the body of the oral dosage form due to a force provided by the swellable material; and a drug. The oral dosage form further comprises an erodible restraint configured to inhibit expansion of the arm in a pre-dose state. The oral dosage form is configured to have a pre-dose state having a compact form and a post-dose state having an expanded form providing gastric retention, and the expanded form of the post-dose state of the oral dosage form is due, at least in part, to expansion of the swellable material in the presence of gastrointestinal fluid.

[0111] As described herein, the oral dosage form includes a plurality of mechanical modules that can be assembled together or integrally formed, and other sections are provided below to teach example mechanisms related to providing gastric retention in oral dosage forms, as well as certain aspects of oral dosage forms. This modular description is not intended to limit the scope of the description provided herein, and based on the teachings provided herein, one of ordinary skill in the art will readily understand that the description includes any combination of modules that can be combined together to form an oral dosage form with gastric retention. A. Example of a Drug Dosage Form

[0112] To illustrate and explain the subject matter provided herein, certain pharmaceutical dosage forms, such as oral pharmaceutical dosage forms, are described below. As previously mentioned, the underlying teachings described herein enable various active arm mechanisms to provide for an increase in size of an oral pharmaceutical dosage form, such that the oral pharmaceutical dosage form does not readily pass through the pylorus within a desired period of time, thereby exhibiting a gastric retention period. In certain aspects, the oral pharmaceutical dosage forms taught herein include a mechanism for increasing size after administration.

[0113] Figure 1 illustrates an example of a drug dosage form. As shown in Figure 1a, the drug dosage form is in a compacted state before administration. Externally, it comprises a main body 1 and an arm 2. The main body 1 includes a compartment unit, which refers to one or more cavities formed within the main body, which may or may not be connected to the exterior of the main body. One end of the arm 2 is connected to the main body, and the other end extends away from the main body. This drug dosage form is designed to have two forms: a compacted form before administration and an expanded form after administration. After the drug enters the individual, it transitions from the compacted form to the expanded form within 5 to 120 minutes, depending on the intended use and design. The compartment unit of the main body 1 includes an expandable material 5 and a movable member 6. When a pre-set trigger condition is met, the expandable material deforms, such as increasing in volume or length, prompting the movable member 6 to move. When the expandable material compresses the movable member 6, it generates a kinetic force that pushes the arm 2 to move or rotate, causing the drug dosage form to change from a compacted form to an expanded form, as shown in Figure 1b. The expandable material 5 can be a swelling sheet that expands after absorbing water; a gas-generating sheet that releases gas after absorbing water or other substances; or a spring structure. In some embodiments, the arm 2 can rotate around the main body 1, and the component connecting the arm 2 to the main body is located in the second compartment 4 of the compartment unit. The expandable material 5 and the movable member 6 are located in the first compartment 3 of the compartment unit. There is an orifice between the first compartment 3 and the second compartment 4, through which the movable member 6 can enter the second compartment 4 from the first compartment 3, pushing the arm 2 to rotate around the main body 1 until the drug dosage form is expanded.

[0114] In some specific embodiments, the portion connecting the arm 2 to the main body 1 is located in the second compartment 4 of the compartment unit, the second compartment 4 includes at least one hole, one end of the arm 2 is located in the second compartment 4, and the other end extends from the hole to the outside of the main body 1. In another embodiment, the portion connecting the arm 2 to the main body 1 is located outside the second compartment 4. The second compartment 4 includes at least one hole, and the movable member 6 can extend from the hole to the outside of the main body 1. When the pharmaceutical dosage form is placed in a fluid environment, the fluid can enter the compartment unit through the hole.

[0115] In some embodiments, the first compartment 3 and the second compartment 4 have a seamless transition. In some embodiments, the spaces of the first compartment 3 and the second compartment 4 are not the same size, preferably, the space of the first compartment 3 is larger than the space of the second compartment 4. In some embodiments, the length of the pharmaceutical dosage form from the end of one arm to the farthest end of the pharmaceutical dosage form when unfolded is not less than 12 mm. More preferably, the unfolded length of the pharmaceutical dosage form refers to the length from the end of one arm to the end of the farthest arm, and the unfolded length is not less than 15 mm or not less than 20 mm, or not less than 25 mm, or not less than 30 mm. The maximum length of the pharmaceutical dosage form in the compacted state is not more than 10 mm, or not more than 14 mm, or not more than 16 mm, or not more than 18 mm, or not more than 20 mm, or not more than 22 mm.

[0116] In some specific embodiments, in order to prevent the user from having difficulty swallowing when the drug dosage form is used as an oral drug dosage form and to avoid passing through the pylorus of the stomach when retained in the stomach, the maximum dimension of the oral drug dosage form in the expanded state is greater than the maximum dimension in the compact state. In a preferred embodiment, the maximum dimension in the expanded state is 2 times or less than the maximum dimension in the compact state; or in another preferred embodiment, the maximum dimension in the expanded state is 1.9 times or less than the maximum dimension in the compact state; or in another preferred embodiment, the maximum dimension in the expanded state is 1.8 times or less than the maximum dimension in the compact state; or in another preferred embodiment, the maximum dimension in the expanded state is 1.7 times or less than the maximum dimension in the compact state; or in another preferred embodiment, the maximum dimension in the expanded state is 1.6 times or less than the maximum dimension in the compact state; or in another preferred embodiment, the maximum dimension in the expanded state is 1.5 times or less than the maximum dimension in the compact state; or in another preferred embodiment, the maximum dimension in the expanded state is 1.4 times or less than the maximum dimension in the compact state; or in another preferred embodiment, the maximum dimension in the expanded state is 1.3 times or less than the maximum dimension in the compact state; or in another preferred embodiment, the maximum dimension in the expanded state is 1.2 times or less than the maximum dimension in the compact state; or in another preferred embodiment, the maximum dimension in the expanded state is 1.1 times or less than the maximum dimension in the compact state.

[0117] FIG2 is an implementation structure of another pharmaceutical dosage form provided by the present invention. The pharmaceutical dosage form includes three arms 2a, 2b, and 2c. In this embodiment, the connecting end of the arm 2 enters the second compartment 4 through the opening 7 of the main body, and the opening 7 can also serve as the inlet of the fluid. The main body 1 in this embodiment can be integrally formed by injection molding or 3D printing. The arm 2 can also be printed and formed simultaneously with the main body 1 by stacking layers during the 3D printing process. The three arms 2a, 2b, and 2c have the same angle between each other and are 60° apart.

[0118] As shown in Figure 2, the pharmaceutical dosage form includes a central axis ca, and the pharmaceutical dosage form extends along the central axis ca in the compact state. When the pharmaceutical dosage form is in the expanded state, the central axis aa of the arm is substantially perpendicular to the central axis of the pharmaceutical dosage form. The three arms are located in almost the same plane. In other optional embodiments, when the pharmaceutical dosage form is in the expanded state, the angle formed by the central axis aa of the arm and the central axis ca of the pharmaceutical dosage form can be an acute angle, a right angle, or an obtuse angle, preferably in the range of 45° to 155°, and more preferably in the range of 60° to 135°, or 75° to 120°. The angles of the three arms to the central axis can also be the same or different, that is, in the case of a side view, the highest points of the three arms can be in the same straight line or not in the same straight line.

[0119] In the embodiment shown in FIG2 , arm 2 includes, in order from the central axis ca, a connecting end 21 connected to the main body, an extension 22, and a terminal end 23. In some embodiments, the connecting end 21, the extension 22, and the terminal end 23 have different thicknesses. In some embodiments, a drug can be carried on the extension 22. In some embodiments, the connecting end 21 is connected to the main body via a pivot. The outer side 22a of the extension 22 is substantially parallel to the central axis aa of arm 2a, and the outer side 21a of the connecting end 21 forms an angle of less than 30° with the central axis aa, more preferably less than 20°.

[0120] Figure 3 illustrates the structure of another pharmaceutical dosage form provided by the present invention. This pharmaceutical dosage form includes three arms 2a, 2b, and 2c. The pharmaceutical dosage form structure includes a main body 1 and arms 2a, 2b, and 2c connected to the main body 1. In this embodiment, the connecting end of arm 2 enters the second compartment 4 through an opening 7 in the main body. In addition to the opening 7, the main body 1 includes one or more water inlets 10. In a preferred embodiment, the water inlet 10 is connected to the first compartment. In another preferred embodiment, multiple water inlets 10 are connected to the first compartment and the second compartment, respectively. Arm 2 includes, in sequence from the central axis, a connecting end 21 connected to the main body, an extension 22, and an end 23. In this embodiment, the end 23 of arm 2 includes a protrusion 211. When the arms 2 are in a compact state, the end protrusions 211 of the three arms 2a, 2b, and 2c abut against each other, thereby resisting deformation of the pharmaceutical dosage form due to internal stress or external forces, thereby extending the shelf life. Preferably, the outer contour of the protrusion 211 is triangular or isosceles trapezoidal, so that the lower arms of the structure resist deformation without interfering with each other's deployment. Preferably, the outer contour of the protrusion 211 is smoothly rounded, so that the lower arms of the structure do not cause physical damage to the mucosal surface after deploying into the biological cavity, eliminating the risk of bleeding during drug retention and providing greater safety.

[0121] In some embodiments, the outer contour line of the drug dosage form in a compact state can be regarded as the outer surface. Preferably, the outer contour is in the shape of a capsule, and can also be designed into different shapes such as cylindrical, circular, etc. as needed. The outer surface of the drug dosage form in the compact state does not contain medicine, or the medicine is not exposed on the outer surface. When the drug dosage form is placed in an environment containing liquid water, the internal driving device of the drug dosage form starts to work, and the expandable material expands after absorbing water, pushing the movable arm to rotate. Once the movable arm starts to rotate, the compact state begins to transition to the expanded state, and the drug-containing component located inside the drug dosage form begins to be exposed to the water-containing environment, and the drug begins to be released in a preset manner. The drug-containing component can be placed at any position of the drug dosage form as needed, such as on the movable arm, or in the cavity formed by the movable arm, or on the main body, etc.

[0122] Figure 4 illustrates the structure of another pharmaceutical dosage form provided by the present invention. This dosage form includes five arms. As shown in Figure 4, the angles between each of the five arms are consistent. In the expanded state, the angle α between two arms is 36°. This dosage form includes a main body 1 extending along the Z-axis. The main body includes an internal chamber and an expandable structure housed within the internal chamber. The internal chamber includes a fluid inlet. In the compacted state, the five arms extend along the Z-axis. When the arms are expanded, they extend about the XY axis, that is, in a direction parallel to or at an angle to the XY axis. In a preferred embodiment, the plane in which the multiple arms lie is parallel to or coincides with the plane in which the XY axis lies. In other embodiments, the extension direction of the multiple arms may be at an angle to the plane in which the XY axis lies. If the multiple arms extend at the same angle to the plane in which the XY axis lies, the resulting shape resembles a cone or a flared mouth. If the multiple arms extend at different angles to the plane in which the XY axis lies, the height of each arm along the Z-axis will also vary. In some embodiments, if the angles of the extension directions of the multiple arms to the plane where the XY axes are located are different, it means that the height of the projection of each arm on the Z axis will also be different.

[0123] In this embodiment, the drug is located on the arm. In one embodiment, the drug (API) and the polymer or only the drug are formed into drug particles 55. The preparation method of the drug particles 55 can adopt existing technology, such as incorporating the drug into the polymer matrix and forming the drug particles by hot melt extrusion, or preparing by melting and casting. The size and dimensions of the drug particles 55 can range from nanometer level to millimeter level. The size and drug loading of the drug particles can be designed according to the common knowledge in the field, according to the requirements of the drug selection, solubility, release curve, etc. In one embodiment, the drug particles can be evenly distributed on the arm and continuously released according to the dissolution of the arm. In one embodiment, the drug particles can be distributed on the surface of the arm. In one embodiment, the drug particles can be located on the protrusion and connection end of the arm.

[0124] Each of the drug particles 55 contains a drug and a matrix. The matrix material can be a water-soluble matrix or a water-insoluble material. The matrix material can be microcrystalline cellulose, a synthetic polymer, such as poly(vinyl chloride), poly(vinyl acetate), a copolymer of vinyl acetate and ethylene, polystyrene, etc. The matrix material can also include a release modifier, such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), methylcellulose, poly(N-vinyl-2-pyrrolidone) (PVP), poly(ethylene oxide) (PEO), poly(vinyl alcohol) (PVA), xanthan gum, carrageenan, lactose, sucrose, glucose, mannitol, and other such natural and synthetic materials.

[0125] 5 to 8 are schematic structural diagrams of the various components constituting the pharmaceutical dosage form in one embodiment.

[0126] Figure 5 is a schematic diagram of the movable arm structure. As shown in Figure 5, the movable arm 2 includes a connecting end 21, an extension section 22, and a terminal end 23. In one embodiment, a protrusion 211 extends from the terminal end 23. The connecting end 21 includes a pivot 233 connected to the main body and a neck 232 connected to the pivot. The neck 232 is connected to the extension section 22 via a transition section 231. In some embodiments, the width of the neck can be the same as the width of the extension section 22 and the transition section 231. In some embodiments, the width of the neck can be slightly narrower than that of the extension section 22. The inventors have discovered that setting the ratio of the width of the extension section to the width of the neck within a range of 5:1 or less can both meet mechanical strength requirements and minimize disturbances to the movable arm during deployment. In one embodiment, the extension section 22 of the movable arm 2 includes a drug loading groove 221, which can be filled with a single drug or a mixture of the drug and other pharmaceutical excipients. In one embodiment, the drug or the mixture of the drug and other pharmaceutical excipients can be deposited on the surface of the movable arm 2. In one embodiment, the movable arm 2 may be formed by mixing the drug or the drug with the material of the movable arm 2 .

[0127] A pusher 234 is located adjacent to the pivot point of the connecting end 21. This pusher 234 is configured to abut against the movable member and, when the movable member moves in a directional manner, propels the pusher 234 to pivot. The pusher 234 includes a bottom surface connected to the connecting end 21 and a side surface 234a. In a preferred embodiment, the pusher 234 includes four side surfaces 234a, each of which is triangular or trapezoidal in shape. In a preferred embodiment, the pusher 234 is a hemispherical member.

[0128] The protrusion 211, the end 23 and the extension section 22 of the movable arm are all designed with rounded corners or blunted edges, and all contact surfaces or contact angles with the body cavity are free of sharp points, thereby improving the safety of the drug preparation.

[0129] Figures 6a and 6b are schematic diagrams of different structures of the movable member. As shown in Figure 6, the movable member 6 includes a bottom member 61 and a top member 62. In a preferred embodiment, the maximum width of the bottom member 61 is greater than that of the top member. In some embodiments, the bottom surface of the bottom member 61 is annular or circular. The top member is cylindrical. In a preferred embodiment, the corners between the bottom member 61 and the top member 62 are rounded, and the top member 62 also includes an arc top 64. In a preferred embodiment, the top surface of the top member 62 is flat. The top member 62 of the movable member primarily serves as a guide. When the volume of the expandable material in the first compartment changes, the force applied to any point of the bottom member 61 of the movable member 6 can be converted into a directional displacement of the movable member 6. In some preferred embodiments, the bottom member 61 of the movable member 6 matches the interior space of the first compartment, i.e., the shape of the bottom member 61 is the same as that of the first compartment, and the bottom surface dimensions of the bottom member 61 are slightly smaller than the cross-sectional dimensions of the first compartment, to ensure that the direction of movement of the movable member is substantially parallel to or coincides with the central axis. In some preferred embodiments, the height of the top member 62 is greater than or equal to the height of the bottom surface of the arm connection end to prevent the drug preparation moving member 6 from returning from the second compartment to the first compartment again.

[0130] In a preferred embodiment, the overall outer profile of the movable member 6 is cylindrical, meaning that the bottom member 61 and the top member 62 have the same shape and size. In a preferred embodiment, the overall outer profile of the movable member 6 is cylindrical, and the side surfaces include a coupling feature. In this embodiment, the coupling feature is at least one groove or ridge 65 located on the side of the movable member 6. In this embodiment, the first compartment has sidewalls of the same shape as the movable member 6, and the ridge 65 is accommodated in the space formed by the sidewalls, or the sidewalls are accommodated in the space formed by the groove 65. When the volume of the expandable material in the first compartment changes, the movable member 6 moves from the first compartment to the second compartment. When the movable member 6 fully enters the second compartment, the groove or ridge 65 prevents the movable member 6 from returning to the first compartment. Figure 7 is a schematic diagram of the structure of the cover. As shown in Figure 7, the cover 8 includes openings 7, the number of which matches the number of arms. The interior of the cover 8 includes a cavity forming the second compartment 4. In a compact state, the second compartment 4 is used to accommodate at least a portion of the connecting end of the movable arm, such as the pusher. In the expanded state, the second compartment 4 is used to accommodate at least a portion of the mobile member 6. The cover 8 includes an upper top surface 83 and a lower top surface located inside the second compartment 4. The shape of the lower top surface matches the shape of the arc top and the top component 62 of the mobile member. When the mobile member enters the second compartment 4 from the first compartment 3, the pusher 234 is subjected to the force of the mobile member 6, pivots and rotates to the opening 7 from the space of the second compartment 4. Because the shape of the lower top surface matches the shape of the arc top and the top component 62 of the mobile member, after the mobile member enters the second compartment 4, it can no longer return to the first compartment 3. In some preferred embodiments, the lower top surface of the second compartment 4 can also further include a combination feature for fixing the mobile member, and this combination feature can be a mechanical structure, adhesive, magnetic structure or other methods. For example, a snap-fit ​​blind hole or a snap-fit ​​through hole can be provided on the lower top surface in the second compartment 4, and a buckle consistent with the shape of the snap-fit ​​blind hole or the snap-fit ​​through hole can be provided on the top component of the mobile member. When the buckle of the moving member enters the engaging hole, the two cannot be separated unless excessive external force is applied.

[0131] In another embodiment of the cover 8, the cover 8 has only one opening, and the top member 62 of the movable member 6 can extend from the opening and abut against an arm located on the outer surface of the cover 8. The arm moves or rotates upon application of force, causing the pharmaceutical dosage form to change from a compact pre-dose state to an expanded post-dose state. In this embodiment, the arm can be hingedly connected to the outer surface of the cover 8.

[0132] The second compartment 4 is provided with a pivot hole 82 for accommodating the arm's pivot. In some preferred embodiments, the second compartment 4 and the pivot hole 82 communicate with the exterior through an opening 7. The cover 8 also includes a plurality of snaps 81 for engaging with the base. In some preferred embodiments, the width of the opening 7 includes a first width L1 near the outer side and a second width L2 near the center, where L1 is greater than or equal to L2, to reduce contact and friction between the cover 8 and the arm during opening.

[0133] In another preferred embodiment, the cover 8 can be designed as an integrated structure consisting of an upper cover and a lower cover. When the upper and lower covers are closed, they form a second compartment and a pivot hole. The lower cover can have an annular structure or a bottom surface, the shape and size of which can match the upper surface of the top member of the movable member. The coupling feature with the movable member can also be designed on the bottom surface of the lower cover.

[0134] Figure 8 is a schematic structural diagram of the base. As shown in Figure 8, the base 9 includes a wall 91 forming the first compartment 3, and a water inlet 10 located on the wall 91. The base 9 also includes a snap-fit ​​groove 91 for snap-fit ​​connection with the cover 8.

[0135] Each component of the pharmaceutical dosage form shown in Figures 5 to 8 can be composed of pharmaceutical excipients, which can be selected from one or more of the following materials: ammonium methacrylate copolymer, ammonium methacrylate type B copolymer, stearic acid, ethylcellulose (EC), titanium dioxide, cellulose acetate phthalate (CAP), polylactide-co-glycolide (PLGA), ethylene-vinyl acetate copolymer, polyethylene (PE), polycaprolactone (PCL), polylactic acid (PLA), elsulose acetate butyrate (CAB), cellulose acetate (CA), polyvinyl acetate (PVAc), polyvinyl acetal diethylamino lactate (AEA), polybutyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate), and poly(ethyl acrylate, methyl methacrylate, trimethylaminoethyl methacrylate chloride), or a combination thereof. The material composition of each component may also include any one or more of a plasticizer and another additive, such as a filler, a binder, a lubricant, a glidant, and a disintegrant. In some embodiments, the additive is selected from clay, SiC nanoparticles, Ni powder, carbon nanotubes, carbon fibers, carbon black, graphene, metal oxides (e.g., Fe3O4, TiO2, ZnO), silver (Ag) nanoparticles, gold (Au) nanoparticles, silver and gold nanoparticles, nanorods, nanowhiskers, nanowires, and cellulose nanocrystals. In some embodiments, each component of the pharmaceutical dosage form can be made of a developable material or include components formed of a developable material.

[0136] In another preferred embodiment, the wall of the base 9 is made of a semipermeable material or a semipermeable membrane. The base 9 made of the semipermeable material or the semipermeable membrane is not provided with a water inlet 10.

[0137] Figure 9 is a top view of another pharmaceutical dosage form provided by the present invention in its expanded configuration. This pharmaceutical dosage form comprises four arms. The pharmaceutical dosage form in Figure 9a comprises a main body and arms 20a, 20b, 20c, and 20d. In the top view of the expanded configuration, the connecting end 201 of each arm is connected to the main body through an opening 700. The connecting end includes a pusher 260. The width of the extension section 240 is greater than that of the connecting end 201. In some embodiments, one or more drug-loading grooves 240 may be provided on the inner side of the extension section 240. As shown in Figure 9a, in the top view of the expanded configuration, the drug-loading grooves 240 are exposed in a plane perpendicular to the central axis ca of the pharmaceutical dosage form, facilitating precise control of drug release. In the compacted configuration, the four arms are closed, and the drug-loading grooves 240 are located within the internal spaces of the four arms, leaving no drug exposed on the outer surface of the pharmaceutical dosage form. In this embodiment, the bottom of the drug-loading grooves 240 comprises a developing layer, above which lies a drug-containing layer. The developing layer can track the expansion of the arms and their retention at different locations after the drug enters the human or animal body.

[0138] In another preferred embodiment, the compartment in the main body can also serve as a drug loading reservoir, and the drug can be released through the opening 700 or other through-holes.

[0139] As shown in FIG9b , in some embodiments, the pharmaceutical dosage form further includes a reinforcing rib, such as a reinforcing rib 301 disposed on the upper surface of the main body, a reinforcing rib 302 disposed on the inner side of the connecting end of the arm, or a reinforcing rib 302 disposed on the outer side of the connecting end of the arm.

[0140] The shape of the reinforcement ribs can be an I-shaped, a X-shaped, a M-shaped, a Well-shaped, an Ω-shaped, a U-shaped, or a grid-shaped.

[0141] As shown in Figure 9c, in some embodiments, the pharmaceutical dosage form has reinforcing ribs 302 disposed on the necks of arms 20a, 20b, 20c, and 20d. When the arms are deployed, the reinforcing ribs 302 at the necks abut or approach the outer wall of the body, providing improved resistance to lateral bending. In some embodiments, the pharmaceutical dosage form has reinforcing ribs 301 disposed on the inner wall of the body's lid.

[0142] Figures 10a and 10b illustrate another embodiment of a pharmaceutical dosage form provided by the present invention, including cross-sectional views in a compact state and in an expanded state. This pharmaceutical dosage form includes four arms. The pharmaceutical dosage form comprises a main body and arms 20a, 20b, 20c, and 20d (not shown). The main body comprises a base 30, a cover 40, and a push plunger 50. In the compact state, the push plunger 50 is located within the first compartment 70. Arms 20a, 20b, 20c, and 20d include connecting ends and protrusions 211 distal to the connecting ends. The arms include a rotation center Ra at the connecting ends, and the arms are rotatable about rotation center Ra by 45° to 135°. The connecting ends include an outer side 200a, a bottom surface 200b, and an inner side 200c. The bottom surface 200b and the inner side 200c extend to form a pusher 90. In some preferred embodiments, in the compact state, the outer side 200a of the connecting end is substantially flush with the outer side 42 of the main body. In some preferred embodiments, in the compact state, the outer side surface 200a of the connecting end does not exceed the outer side surface 42 of the main body. The angle β formed by the outer side surface 200a of the connecting end and the bottom surface 200b is greater than or equal to 90°, so that the rotation center Ra is closer to the direction of the central axis. The angle γ between the bottom surface 200b of the connecting end and the side surface 200c of the pushing member is less than 90°, and more preferably less than 60°. In the compact state, the pushing member 90 of the connecting end is located in the second compartment 80. In the expanded state, the connecting end rotates around Ra, and the pushing member 90 moves from the second compartment 80 to the position of the opening.

[0143] Figure 10c provides a cross-sectional view of another four-arm pharmaceutical dosage form in a compact state. This pharmaceutical dosage form includes a main body and arms 20a, 20b, 20c, and 20d (not shown). The main body includes an expandable material 5 located in a first compartment, a movable member 6, and a water inlet 10 located on the main body. The main body also includes a second compartment that accommodates the connecting end 200 of the arm. The arm includes a drug assembly 800 housed in a drug loading groove. The interior of the movable member 6 may include a cavity in which the drug assembly 800 can be loaded. In some preferred embodiments, the cavity of the movable member 6 has one and only one opening, which faces the expandable material 5. After the pharmaceutical dosage form enters the body cavity of a human or animal, bodily fluids come into contact with the expandable material 5 through the water inlet 10. The expandable material 5 expands, pushing the movable member 6 into the second compartment. The connecting end 200 of the arm is pushed by the movable member 6, causing it to expand. The drug assembly 800 in the arm can be either an immediate-release or sustained-release drug assembly, and is released after the arm expands. The expandable material 5 can be selected from materials that dissolve after expansion, and a specific dissolution rate can be selected based on the required retention time. After the expandable material 5 is completely or partially dissolved, body fluid enters the cavity of the moving member 6, and the drug component 800 located in the cavity begins to be released.

[0144] In some preferred embodiments, the peripheral side surface 200a of the connecting end of the arm includes a reinforcing rib 303. The reinforcing rib 303 can serve as a connecting feature between the arm and the main body after the arm is unfolded. In some preferred embodiments, the reinforcing rib 303 is used to provide stability of the arm in the unfolded state. The arm rotates 90° around the pivot from a compact pre-drug state to an expanded state after administration, and the reinforcing rib 303 abuts the outer surface of the main body, that is, the reinforcing rib 303 is in contact with the outer surface of the main body. When the drug dosage form is located in the human stomach and is affected by external forces, such as when the arm is overstressed due to gastric peristalsis or food factors, the reinforcing rib 303 can share the force and provide stability to the overall unfolded structure.

[0145] In some preferred embodiments, the bottom surface 200b of the connecting end includes a coupling feature 280 for coupling with a coupling feature on the push plunger 50. In the deployed state, the push plunger 50 moves from the first compartment 70 to the second compartment 80, and the push member 90 simultaneously moves from the second compartment 80 to the opening. The coupling feature of the push plunger 50 cooperates with the coupling feature 280 on the bottom surface 200b of the connecting end, locking the arms and preventing the arms from returning from the second compartment 80 to the first compartment 70. In some preferred embodiments, the coupling feature of the push plunger 50 and / or the coupling feature 280 on the bottom surface 200b of the connecting end can be made of an erodible material. When a predetermined retention time is reached, the coupling feature disappears, allowing the push plunger 50 to return from the second compartment 80 to the first compartment 70. The arms 20a, 20b, 20c, and 20d, free of external support, can retract or close in response to the external environment, thus ending retention.

[0146] In some preferred embodiments, the engaging feature on the push plunger 50 is an annular groove that extends a full circle along the outer surface of the push plunger 50. This embodiment can overcome the failure of the engaging feature caused by the push plunger 50 rotating around the central axis in the first compartment 70 and / or the second compartment 80.

[0147] In some preferred embodiments, the outer peripheral surface of the push plunger 50 may have an adhesive that can bond to the bottom surface of the arm to support the arm in the deployed position. The adhesive is selected from one or more of the following materials: dextrin, xanthan gum, maltodextrin, povidone, methylcellulose, ethylcellulose, corn gluten, fructose, poloxamer, sodium alginate, pregelatinized starch, hydroxypropyl cellulose, hypromellose, carbomer, starch, gum arabic, microcrystalline cellulose, sodium lauryl sulfate, sucrose, cellulose acetate, polysorbate, glucose, dextran, compressible sugar, carrageenan, modified starch, tragacanth gum, and honey.

[0148] In some preferred embodiments, the combining feature can also be set in the internal space of the main body, such as on the inner wall of the base 30. For example, the inner wall of the first compartment 70 formed by the base 30 is provided with a slope section with an inclined angle. When the plunger 50 is pushed along the slope section from the first compartment 70 to the second compartment 80, it cannot return to the first compartment 70 due to the existence of the slope section.

[0149] In some preferred embodiments, the protrusions 211 of the arms 20a, 20b, 20c, and 20d are in contact with each other in the compact state. In other preferred embodiments, an erodible component is present between the protrusions 211 of the arms 20a, 20b, 20c, and 20d. The erodible component may be in the shape of a quadrilateral that matches the shape of the protrusions 211, and is used to keep the arms in a compact state and prevent premature expansion before or during drug administration.

[0150] In some preferred embodiments, the entire drug dosage form can be loaded into the capsule shell, and the capsule shell can only be broken, dissolved or disintegrated after the water can enter the expandable material chamber from the fluid inlet.

[0151] In some preferred embodiments, as shown in Figure 10 d, the shape of mobile member 6 also constitutes a combination feature. In a preferred embodiment, mobile member 6 comprises a bottom member 61 and a top member 62. In this embodiment, the top member 62 is a flat top. The height value of the top member 62 is greater than or equal to the length value of the arm connecting end bottom surface 200b. In a preferred embodiment, the height value of the top member 62 is approximately 1.1 times to 1.3 times the length value of the arm connecting end bottom surface 200b. The height value of the top member 62 is greater than or equal to the length value of the arm connecting end bottom surface 200b, which can prevent mobile member 6 from returning to the first compartment after being combined with the connecting end of the arm. In a preferred embodiment, the outer peripheral surface of the top member 62 of mobile member 6 forms an angle less than or equal to 90 ° between the top surface of the bottom member 61. In a preferred embodiment, the value range of this angle δ is 89 ° to 70 °.

[0152] Figures 11a and 11b are cross-sectional views of another embodiment of a pharmaceutical dosage form provided by the present invention in a compact state and an expanded state, respectively. As shown in Figure 11a, the pharmaceutical dosage form includes a main body 1010 and a movable arm 1020. The main body forms a first compartment 1030 and a second compartment 1040. The first compartment 1030 and the second compartment 1040 are interconnected via an orifice. An expandable material 1050 is located within the first compartment 1030. In the compact state, the first compartment 1030 also includes a movable member 1060. The movable member 1060 can be in the form of a plunger, a hollow cylinder, or any other shape that can reasonably fit within the first compartment 1030.

[0153] In some embodiments, the upper surface of the main body 1010 is further provided with an intermediate column 1011. The intermediate column 1011 can enhance the mechanical properties of the pharmaceutical dosage form and maintain the length along the central axis within a preset range when the pharmaceutical dosage form changes from a compact state to an expanded state. In a two-arm pharmaceutical dosage form, the design containing the intermediate column 1011 can enable the pharmaceutical dosage form to extend at least along the YZ plane in the expanded state. In a three-arm or more-arm pharmaceutical dosage form, the design containing the intermediate column 1011 can enable the pharmaceutical dosage form to extend simultaneously along the XY and YZ planes in the expanded state.

[0154] In some embodiments, the intermediate column 1011 is a drug-loaded column. The intermediate column 1011 may be provided with at least one drug-loading groove, or coated with a drug-loading layer, or the entire intermediate column may be an erodible structure containing drug particles, or the intermediate column may be a layered structure including a drug-containing layer and an erodible structure, etc.

[0155] In some embodiments, in the compact state, the middle column 1011 is located in the accommodation space formed by the multiple arms 1020, and the length of the middle column 1011 is less than the length of the arms. In the expanded state, after the arms 1020 move, the drug in the middle column 1011 is exposed to the body fluid and the drug begins to be released.

[0156] In some embodiments, the pharmaceutical dosage form further includes a restraining member 1070. The restraining member 1070 can be designed as a capsule shell, a restraining ring, a restraining band, a restraining cover, and the like. In a preferred embodiment, the restraining member 1070 is made of a material that dissolves quickly, such as polyvinyl pyrrolidone, TEC, gelatin, hydroxypropyl methylcellulose, pullulan, and the like. In various embodiments, the length of the restraint period can also be controlled by the geometric features of the restraining member.

[0157] In some embodiments, the restraining member 1070 can release the inhibition on the movement of the movable arm within 45 minutes. In a more preferred embodiment, the restraining member 1070 can release the inhibition within 35 minutes, or within 25 minutes. In a more preferred embodiment, the restraining time of the restraining member 1070 is not less than 5 minutes, or not less than 8 minutes, or not less than 12 minutes, or not less than 15 minutes. The appropriate release time can ensure that the drug does not expand prematurely in the mouth or esophagus, and that it quickly switches from a compact state to an expanded state after reaching the predetermined position, preventing it from leaving the pylorus of the stomach in a compact state.

[0158] In some embodiments, the components of the oral dosage form can be manufactured, for example, by 3D printing, injection molding, ultrasonic welding, or any combination thereof, and then assembled to form the oral dosage form prior to administration. For example, in some embodiments, the base, lid, and movable arms can be prepared separately, and these components can then be assembled to form the oral dosage form. B. Components of the Dosage Form and Materials Thereof

[0159] The pharmaceutical dosage forms described herein include one or more features that generate a force that facilitates the transition from a pre-dose state to a post-dose state of the pharmaceutical dosage form. In some embodiments, the pharmaceutical dosage form includes a swellable material. The swellable material described herein is configured to swell in the presence of gastrointestinal fluid and generate a force applied to the arm, or together with the swellable material, propel the movable member within the directional channel toward the top of the lid, the force applied to the arm causing the arm to rotate about the body and unfold into a petal-like configuration, thereby transforming the oral pharmaceutical dosage form into an unfolded post-dose form.

[0160] In some embodiments, the swellable material and / or swellable material is configured to expand at a desired rate and / or with a desired force. For example, in some embodiments, the swellable material and / or swellable material is configured to expand rapidly upon contact with gastrointestinal fluids (including contact of an oral dosage form with gastrointestinal fluids) to prevent the oral dosage form from passing through the stomach before the gastric retention period required for retention in the stomach. In some embodiments, the swellable material and / or swellable material is configured to expand with the necessary force to move a component of the oral dosage form to a gastric retention state, such as by moving one or more movable arms.

[0161] In some embodiments, the volume of the swellable material is at least about 1.2 times, such as at least about 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, or 2.0 times, after exposure to gastrointestinal fluids. In some embodiments, the swelling occurs within about 1 hour, such as within about any one of 50 minutes, 40 minutes, 30 minutes, 20 minutes, 10 minutes, or 5 minutes. In some embodiments, the swellable material swells at least about 1.2 times within 30 minutes, such as at least about 1.3 times within 30 minutes, 1.4 times within 30 minutes, 1.5 times within 30 minutes, 1.6 times within 30 minutes, 1.7 times within 30 minutes, 1.8 times within 30 minutes, 1.9 times within 30 minutes, or 2.0 times within 30 minutes after exposure to gastrointestinal fluids. In some embodiments, the swellable material reaches a substantially fully swollen state (e.g., absorbs at least about 90% of its fluid capacity) in about 1 hour or less, such as within about 50 minutes, 40 minutes, 30 minutes, 20 minutes, 10 minutes, or 5 minutes.

[0162] In some embodiments, the swellable material, when swollen, at least partially conforms to the shape of the directional channel and / or the orifice, or a portion thereof. In some embodiments, when the swellable material expands, the swellable material propels the movable member within the directional channel toward the top of the lid. In some embodiments, the swellable material is partially or completely surrounded by the base. In some embodiments, the swellable material is completely or partially surrounded by the semipermeable material.

[0163] The terms "semipermeable," "semipermeable membrane," or "semipermeable material" mean that water can readily diffuse through the membrane, but solutes dissolved in the water generally cannot readily diffuse through the membrane relative to the rate at which water diffuses through the membrane.

[0164] In some embodiments, the swellable material is selected from sodium alginate (SA), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropyl methyl cellulose (HPMC), polyethylene oxide (PEO), polyvinyl alcohol (PVA), microcrystalline cellulose (MCC), cross-linked sodium carboxymethyl cellulose (CCNa), sodium carboxymethyl cellulose (CMC-Na), polyvinyl polypyrrolidone (PVPP), sodium carboxymethyl starch (CMS-Na), polyethylene glycol (PEG), or a mixture thereof. In some embodiments, HPC includes L-HPC or H-HPC, or a combination thereof.

[0165] In some embodiments, the swellable material comprises a material selected from the group consisting of polyvinyl acetate (PVAc), povidone, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, ethylcellulose (EC), hydroxypropyl methylcellulose (HPMC), tocopheryl polyethylene glycol succinate (TPGS), polycaprolactone (PCL), polyethylene (PE), guar gum, polyetheretherketone (PEEK), polyphenylsulfone (PPSU), polysulfone (PSU), polypropylene (PP), ethylene vinyl acetate (EVA), polymethyl methacrylate (PMMA), polylactic acid (PLA), polyglycolide (PGA), polylactic-glycolic acid copolymer (PLGA), or a combination thereof.

[0166] In some embodiments, the swellable material comprises a material selected from the group consisting of a cross-linked polymer and a shape memory material. In some embodiments, the swellable material comprises a material selected from the group consisting of polyethylene oxide-polyethylene glycol (PEO-PEG) cross-linked polymer, polycaprolactone-polyethylene glycol-polycaprolactone (PCL-PEG-PCL), hydroxypropyl cellulose, polyethylene oxide (PEO), such as high molecular weight PEO, sodium alginate, carbomer, high molecular weight hydroxypropyl cellulose (HPC), high molecular weight hydroxypropyl methylcellulose (HPMC), methylcellulose cellulose (MC), high molecular weight polyvinyl alcohol (PVA), polyvinyl acetate (PVAc) and polyvinyl pyrrolidone (PVP) 80 / 20, methacrylate copolymer, aminoalkyl methacrylate copolymer, aminoalkyl methacrylate copolymer E, hydroxypropyl methylcellulose succinate or hydroxypropyl methylcellulose succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), or a combination thereof. In some embodiments, the shape memory material is selected from polyurethane, block copolymers of polyethylene terephthalate (PET) and polyethylene oxide (PEO), block copolymers containing polystyrene and poly(1,4-butadiene), ABA triblock copolymers made from poly(2-methyl-2-oxazoline) and polytetrahydrofuran, polynorbornene (e.g., Norsorex, developed by CdF Chemie / Nippon Zeon), polynorbornene with partially substituted polyhedral oligomeric silsesquioxanes (POSS), composites composed of polycyclooctene (PCOE) and poly(5-norbornene-exo, exo-2,3-dicarboxylic anhydride) (PNBEDCA), polyester-urethane, polyol (soft segment) and diisocyanate combined with chain extenders (hard phase) (poly(ε-caprolactone) (PCL), polyethylene adipate (PEA) glycol), polyester-polyurethane (PUR), and PCL. L, combinations of ethylene oxide-ethylene terephthalate segmented copolymers, PUR based on PUR (ε-caprolactone) and oligo(p-dioxalanone), poly(p-dioxalanone)-b-poly(tetramethylene glycol) multiblock copolymers, polymethyl methacrylate-polyethylene glycol (PMMA-PEG) semi-interpenetrating networks (IPNs), polycyclohexyl methacrylate (PCHMA) backbone crosslinked with bifunctional PCL polymers, polymers with short PEG side chains grafted onto the PCL backbone, Copoly(ester-urethane) networks, covalently cross-linked poly[ethylene-co-(vinyl acetate)] (cPEVA), a combination of PCL and poly(tetramethylene ether) glycol (PTMEG), or a combination thereof. In some embodiments, the material can have multiple properties, including swellable materials and shape memory materials.

[0167] In some embodiments, the swellable material further comprises a salt or a mixture of salts, for example, to promote absorption of gastrointestinal fluids to promote swelling. In some embodiments, the salt is selected from the group consisting of sodium salts, magnesium salts, and potassium salts. In some embodiments, the sodium salt is sodium sulfate.

[0168] In some embodiments, the swellable material further comprises a gas-generating substance, for example, generating carbon dioxide upon contact with gastrointestinal fluid. In some embodiments, the gas-generating substance is selected from carbonates, bicarbonates, or a combination thereof.

[0169] In some embodiments, the amount of swelling material in the swellable material chamber is at least about 5 mg, such as at least about any of 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg.

[0170] In some embodiments, the swellable material has a diameter of about 10 mm. 3 to about 50mm 3 In some embodiments, the swellable material has a swelling volume of at least about 5 mm 3 A swelling volume of at least about 10 mm 3 , 15mm 3 , 20mm 3 , 25mm 3 , 30mm 3 , 35mm 3 , 40mm 3 , 45mm 3 or 50mm 3 Any of the above.

[0171] In some embodiments, the swellable material can be printed by a three-dimensional printing process, injection molding, ultrasonic welding, or any combination thereof, as described in other aspects of the present disclosure. In some embodiments, the swellable material is a thermoformable material.

[0172] In some embodiments, the body comprises two or more components configured to form the body. In some embodiments, the body comprises one or more bases and one or more lids. In some embodiments, the body is comprised of two or more materials. In some embodiments, the body of the oral dosage form is a monolithic structure. In some embodiments, the body may be partially or entirely composed of a semipermeable membrane. In some embodiments, the base and lid are joined together to form a monolithic structure using snap fastening, threading, mortise and tenon joints, gluing, riveting, 3D printing, or injection molding. In some embodiments, the base partially surrounds the lid. In some embodiments, the lid is configured to prevent further movement of the swelling material, plunger, or moving member, thereby maintaining the arm in one or more extended positions. In some embodiments, the lid has a pre-defined opening shape, including trumpet, circular, semicircular, square, or oval. In some embodiments, the lid is provided with reinforcing ribs in the shape of a cross, a "M" (rice), or a "h" (well). In some embodiments, the body can be printed using 3D printing, injection molding, ultrasonic welding, or any combination thereof, as described in other aspects of the present disclosure. In some embodiments, the body is comprised of a thermoformable material.

[0173] In some embodiments, the body is connected to the arm. In some embodiments, the cover is connected to the arm. In some embodiments, the cover and the arm are provided with a locking structure, including a latch, a catch, or a pivot. In some embodiments, a swellable material chamber surrounds the swellable material; the swellable material chamber can be of any size and / or shape.

[0174] As described herein, the oral dosage form includes one or more arms, such as any one of 1, 2, 3, 4, 5, 6, 7, 8, or 10. The arms can be designed using several mechanisms based on the swelling of the swellable material, and the oral dosage form can implement one or more such mechanisms. In some embodiments, the arm or a portion thereof is configured to slide within a directional channel. In some embodiments, the arm is configured to rotate along an axis. In some embodiments, at least two movable arms or oral dosage forms have different motion mechanisms. In some embodiments, at least two arms of the oral dosage form have the same motion mechanism. In some embodiments, at least two arms of the oral dosage form are configured such that at least a portion of each arm can be extended beyond or further from the main body of the oral dosage form by the force provided by the swellable material. In some embodiments, at least two arms of the oral dosage form are configured such that at least a portion of each arm can be extended beyond or further from the main body of the oral dosage form by being pushed by a moving member.

[0175] In some embodiments, the distal ends of the arms are curved. In some embodiments, when the oral dosage form is in the expanded state, the connected ends of the arms define an internal angle α near the base and an internal angle β near the top of the lid. The internal angle α is between 70 and 120°, for example, 70°, 75°, 80°, 85°, 90°, 95°, 100°, 105°, 110°, 115°, or 120°; and the internal angle β is between 30 and 90°, for example, 30°, 35°, 40°, 45°, 50°, 55°, 60°, 65°, 70°, 75°, 80°, 85°, or 90°. In some embodiments, the arms contact each other before administration and are in the collapsed state. In some embodiments, the outer surface of the arms is a smooth, continuous curved surface.

[0176] In some embodiments, the oral dosage form further comprises an erodible restraint configured to inhibit the extension of one or more arms over a period of time. Generally speaking, the erodible restraint is configured to facilitate oral administration of the oral dosage form, for example, by preventing one or more arms from prematurely extending prior to entry into the stomach of an individual. In some embodiments, the erodible restraint is eroded within about 30 minutes after administration to the individual, for example, within any one of about 25 minutes, 20 minutes, 15 minutes, 10 minutes, or 5 minutes.

[0177] In some embodiments, the erodible restraint can be a capsule shell, a restraining ring, a restraining band, a restraining cover, etc. The erodible restraint is a material selected from the group consisting of polyvinyl pyrrolidone, TEC, gelatin, hydroxypropyl methylcellulose, and pullulan.

[0178] In some embodiments, a component of an oral dosage form, such as a body or movable arm, comprises an insoluble material, a pH-sensitive erodible material, for example, a material that does not erode or erode slowly at gastric pH but erodes after exiting the stomach. In some embodiments, the body or arm of the dosage form comprises a material selected from the group consisting of ammonium methacrylate copolymer, ammonium methacrylate type B copolymer, stearic acid, ethylcellulose (EC), titanium dioxide, cellulose acetate phthalate (CAP), polylactide-co-glycolide (PLGA), ethylene-vinyl acetate copolymer, polyethylene (PE), polycaprolactone (PCL), polylactic acid (PLA), elsulose acetate butyrate (CAB), cellulose acetate (CA), polyvinyl acetate (PVAc), polyvinyl acetal diethylamino lactate (AEA), polybutyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate), and poly(ethyl acrylate, methyl methacrylate, trimethylaminoethyl methacrylate chloride), or a combination thereof.

[0179] In some embodiments, the components of the pharmaceutical dosage form, for example the material of the main body or arm is a thermoplastic material. In some embodiments, the thermoplastic material is a thermoplastic polymer. In some embodiments, the thermoplastic material comprises any one or more of a plasticizer and another additive, for example, a filler, a binder, a lubricant, a glidant and a disintegrant. In some embodiments, the additive is selected from clay, SiC nanoparticles, Ni powder, carbon nanotubes, carbon fiber, carbon black, graphene, metal oxides (for example Fe 3 O 4 , TiO 2 , ZnO), silver (Ag) nanoparticles, gold (Au) nanoparticles, silver and gold nanoparticles, nanorods, nanowhiskers, nanowires and cellulose nanocrystals.

[0180] In some embodiments, the body is configured to have a wall thickness (e.g., from the swellable material compartment to the exterior portion of the oral dosage form or from the directional passageway to the exterior portion of the oral dosage form) of at least about 0.3 mm, for example, at least about 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.0 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2.0 mm, 2.1 mm, 2.2 mm, 2.3 mm, 2.4 mm, or 2.5 mm. In some embodiments, the body is configured to have a wall thickness (e.g., from the swellable material compartment to the exterior portion of the oral dosage form or from the directional passageway to the exterior portion of the oral dosage form) of about 0.3 mm to about 2.5 mm, e.g., any from about 0.5 mm to about 2.2 mm or from about 0.4 mm to about 1.2 mm.

[0181] In some embodiments, the body or at least a portion thereof is composed of a semipermeable membrane. The semipermeable membrane material is selected from the group consisting of polyamide, polyesteramide, polyacetate, polyetherketone membrane, polypropylene, polyether, polyethersulfone, polyimide, polyesteramide, polyesteramide-imide copolymer, polyether carbonate, fluoropolymers such as polyvinyl fluoride, tetrafluoroethylene-hexafluoropropylene copolymer, polyvinyl alcohol, cellulose acetate, polymethacrylate, polyvinyl chloride, polyethylene, polysiloxane, ethylene-vinyl acetate copolymer, silicone rubber, ethyl cellulose, acrylic resin, cellulose acetate phthalate, carboxymethyl ethyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl alcohol acetate phthalate, polyvinyl acetate, shellac, nanopores such as graphene oxide membrane, alumina, silicon membrane, polyester, polyester carbonate.

[0182] In some embodiments, the binder is selected from the group consisting of dextrin, xanthan gum, maltodextrin, povidone, methylcellulose, ethylcellulose, zein, fructose, poloxamer, sodium alginate, pregelatinized starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomer, starch, gum arabic, microcrystalline cellulose, sodium lauryl sulfate, sucrose, cellulose acetate, polysorbate, glucose, dextran, compressible sugar, carrageenan, modified starch, tragacanth gum, and honey.

[0183] In some embodiments, the arms are configured to have a thickness of about 1 mm to about 2 mm, such as about 1.1 mm to about 1.6 mm.

[0184] In some embodiments, the oral dosage form comprises a component that is a plunger or moving member, for example, a plunger configured to be pushed into contact with one or more arms by a swellable material. In some embodiments, the plunger comprises a wall thickness of about 0.3 mm to about 2.5 mm, for example, about 0.4 mm to about 2.2 mm. In some embodiments, the plunger comprises a wall thickness of at least about 0.3 mm, for example, at least about 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.0 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2.0 mm, 2.1 mm, 2.2 mm, 2.3 mm, 2.4 mm, or 2.5 mm.

[0185] In some specific embodiments, an angle δ is formed between the outer circumference of the top member 62 of the mobile member 6 and the top surface of the bottom member 61, which is less than or equal to 90°. The value range of the angle δ is 89°, 88°, 87°, 86°, 85°, 84°, 83°, 82°, 81°, 80°, 79°, 78°, 77°, 76°, 75°, 74°, 73°, 72°, 71° or 70°.

[0186] C. Loading one or more drugs into oral dosage forms

[0187] The oral dosage forms described herein include one or more drugs. In some embodiments, the oral dosage form includes 2 or more drugs, such as any one of 3, 4, or 5 drugs. The drugs of the oral dosage form can be released at any time point in the life cycle of the oral dosage form. For example, in some embodiments, the oral dosage form is configured and formulated to release the drug in the stomach of an individual. In some embodiments, substantially all, such as at least about 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the drug is released in the stomach. In some embodiments, the drug dosage form is configured to release the drug after leaving the stomach.

[0188] In some embodiments, the drug is a poorly water-soluble drug. In some embodiments, the poorly water-soluble drug is a Biopharmaceutical Classification System (BCS) Class II active pharmaceutical ingredient (API), such as a drug with high permeability and low solubility. In some embodiments, the poorly water-soluble drug is a Biopharmaceutical Classification System (BCS) Class IV active pharmaceutical ingredient (API), such as a drug with low permeability and low solubility. In some embodiments, the drug is a Biopharmaceutical Classification System (BCS) Class III active pharmaceutical ingredient (API), such as a drug with low permeability and high solubility. In some embodiments, the drug is selected from one or more of riociguat, aceclofenac, bicalutamide, carbamazepine, carvedilol, clotrimazole, cinnarizine, danazol, dapsone, estradiol, ezetimibe, glyburide, fenofibrate, griseofulvin, ibuprofen, itraconazole, ketoconazole, mefenamic acid, naproxen, nevirapine, nifedipine, nitrofurantoin, nomegestrol acetate, phenytoin sodium salt, piroxicam, praziquantel, rifampicin, sulfamethoxazole, trimethoprim and verapamil hydrochloride or its salts or stereoisomers.

[0189] Oral dosage forms can be configured to release drugs based on any desired release profile and expand to release more than one drug, each drug having any desired release profile. Typically, since the oral dosage forms described herein are designed to remain in the stomach for a long time, the release profile of at least one drug will be configured based on the expected gastric residence of the oral dosage form. In some embodiments, when two or more drugs are in the oral dosage form, the oral dosage form is configured to release each drug according to the desired release profile. In some embodiments, the oral dosage form is configured so that all drug contents (or substantially all, e.g., at least about 90%) in the oral dosage form (or a portion thereof) are released during the expected gastric residence of the oral dosage form. In some embodiments, the oral dosage form is configured to release a certain amount of drug content (e.g., a second drug) in the oral dosage form after the oral dosage form or its components are expected to be discharged from the stomach. In some embodiments, the oral dosage form is formulated and configured such that the drug is released according to a delayed release profile, a sustained release profile, a delayed-sustained release profile, a zero-order release profile, a first-order release profile, an immediate release profile plus a sustained release profile, an immediate release profile plus a delayed release profile, an immediate release profile plus a delayed-sustained release profile, a pulsatile release profile, an iterated pulsatile release profile, an immediate release profile plus a pulsatile release profile, or a combination.

[0190] The oral dosage forms described herein can be configured and formulated to release the drug according to a desired drug release profile using various techniques. In some embodiments, the release of the drug from the oral dosage form is based on the erosion of the drug-containing substance, for example, when the drug-containing substance is exposed to gastrointestinal fluid. In some specific embodiments, the drug-containing material is configured as a layer having a predetermined surface area, this surface area is exposed to gastrointestinal fluid, thickness and drug mass fraction, wherein these characteristics of the drug-containing material provide the desired drug release. In some embodiments, the drug-containing material is in the form of a multilayer structure. In some embodiments, the drug-containing material is embedded, including being partially embedded in the materials of the components of the pharmaceutical dosage form. The design, configuration and materials of such drug-containing materials to provide the desired drug release are known in the art, for example, see U.S. Patent No. 10,350,822, which is incorporated herein in its entirety.

[0191] In some embodiments, an oral dosage form is configured with a drug-containing compartment, wherein the compartment has an orifice for releasing the drug from the oral dosage form. In some embodiments, the orifice is blocked by an erodible material (e.g., a plug). In some embodiments, the feature of the blocked orifice keeps the drug within the compartment of the oral dosage form and is configured to no longer block the orifice at a desired time. For example, in some embodiments, the drug-containing compartment is sealed with an erodible plug, wherein the erodible plug dissolves at a certain time after administration to an individual, thereby releasing the drug from the oral dosage form. The time of release can be based on the thickness of the plug and / or the material of the plug, etc. The drug-containing compartment can be configured in any component. In some embodiments, the oral dosage form includes multiple drug-containing compartments. In some embodiments, the component is an insoluble material, such as an insoluble shell material. In some embodiments, the component is eroded after the drug leaves the drug-containing compartment, for example, after the oral dosage form leaves the stomach.

[0192] In some embodiments, oral drug dosage forms are configured such that the drug will leach or diffuse from the material.

[0193] In some embodiments, the drug is loaded onto one or more arms; in some embodiments, each movable arm is loaded with drug. In some embodiments, the drug is loaded onto one or more caps. In some embodiments, the drug is loaded into a swellable material chamber. D. Oral drug dosage forms provide gastric retention characteristics in the post-administration state

[0194] As described herein, swelling of one or more swellable materials or portions thereof increases the size of an oral pharmaceutical dosage form, thereby allowing the drug to remain in the stomach for a longer period of time. In some embodiments, the post-administration state of an oral pharmaceutical dosage form is referred to as a gastric retentive state. One of ordinary skill in the art will readily appreciate that characteristics of an oral pharmaceutical dosage form, such as size, can be dynamic and change over time during the expansion of a swellable material or portion thereof. Description of certain states of an oral pharmaceutical dosage form, such as a post-administration gastric retentive state, is not intended to limit the disclosure herein to a single static embodiment of a pharmaceutical dosage form.

[0195] In some embodiments, when the oral dosage form is in the expanded state (e.g., gastric retention state), the size of the oral dosage form is such that the oral dosage form is inhibited and / or prevented from passing through an aspect of the pylorus (e.g., the pyloric antrum, the pyloric canal, or the pyloric orifice created by the pyloric sphincter) to reach the duodenum. In some embodiments, when the oral dosage form is in the expanded state, the size of the oral dosage form is such that the oral dosage form is inhibited and / or prevented from passing through the pyloric orifice created by the pyloric sphincter. In some embodiments, when the oral dosage form is in the expanded state, at least two perpendicular dimensions of the oral dosage form are independently at least about 20 mm to about 70 mm in length, e.g., at least about 20 mm to about 50 mm in length, about 30 mm to about 60 mm in length, or about 40 mm to about 70 mm in length. In some embodiments, when the dosage form is in the expanded state, at least two vertical dimensions of the dosage form are independently at least about 20 mm, for example, at least about 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, 50 mm, 55 mm, 60 mm, 65 mm, or 70 mm in length. In some embodiments, when the oral dosage form is in the expanded state, at least two vertical dimensions of the dosage form are independently about any one of 20 mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, 50 mm, 55 mm, 60 mm, 65 mm, or 70 mm in length. In some embodiments, when the oral dosage form is in the expanded state, one of the at least two vertical dimensions is different from the other dimension. In some embodiments, when the dosage form is in the expanded state, one of the at least two vertical dimensions is the same as the other dimension. It should be noted that individuals may have different anatomical features and sizes (e.g., adults versus children), and the present application includes oral dosage forms designed with these considerations in mind to achieve desired gastric retention.

[0196] The oral dosage forms described herein are configured to be retained in the stomach for an extended period of time, e.g., compared to a dosage form without gastroretentive characteristics (e.g., an oral dosage form passes through the stomach based on the natural flow of ingested material out of the stomach). In some embodiments, the oral dosage form is configured to be retained in the stomach for about 6 hours to about 3 months, e.g., about 6 hours to about 24 hours, about 6 hours to about 36 hours, about 8 hours to about 24 hours, about 8 hours to about 36 hours, about 18 hours to about 30 hours, about 20 hours to about 28 hours, about 12 hours to about 36 hours, about 1 day to about 3 days, about 3 days to about 7 days, about 6 hours to about 1 month, or about 6 hours to about 2 months. In some embodiments, the oral dosage form is configured to be retained in the stomach for at least about 6 hours, such as at least about 7 hours, about 8 hours, about 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, or 36 hours. In some embodiments, the oral dosage form is configured to be retained in the stomach for at least about 1 day, such as at least about any of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 21 days, 1 month, 1.5 months, 2 months, 2.5 months, or 3 months. In some embodiments, the oral dosage form is configured to be retained in the stomach for no more than about 7 days, such as no more than about any of 6 days, 5 days, 4 days, 3 days, 2 days, 36 hours, 30 hours, 24 hours, 18 hours, or 12 hours. In some embodiments, the oral dosage form is configured to be retained in the stomach for no more than about 3 months, such as no more than about any of 2.5 months, 2 months, 1.5 months, 1 month, 21 days, 14 days, or 7 days. In some embodiments, the oral dosage form is configured to be retained in the stomach for about 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 21 days, 1 month, 1.5 months, 2 months, 2.5 months, or 3 months.

[0197] In some embodiments, the post-administration state of the oral pharmaceutical dosage form occurs within about 1 hour or less after administering the oral pharmaceutical dosage form to a subject. For example, in some embodiments, the oral pharmaceutical dosage form achieves a gastric retentive state within about 1 hour or less, 50 minutes or less, 40 minutes or less, 30 minutes or less, 20 minutes or less, 10 minutes or less, or 5 minutes or less after administration to a subject.

[0198] In some embodiments, the oral dosage form is configured such that the oral dosage form, or a portion thereof, is able to pass through the pylorus and be expelled from the stomach. For example, in some embodiments, one or more components of the oral dosage form, such as one or more movable arms, erode and / or soften in the stomach, thereby allowing expulsion from the stomach in one or more portions. In some embodiments, the oral dosage form softens after a period of residence in the stomach and is configured to pass through the pylorus as a whole. In some embodiments, the erosion or dissolution of a component or a portion thereof of the oral dosage form is due to prolonged exposure to gastrointestinal fluids in the stomach (e.g., due to prolonged exposure to low pH). E. Characteristics of the Oral Dosage Form in the Pre-Dosage State

[0199] The oral dosage forms described herein can be formed into any number of shapes, sizes, weights, and appearances. As described herein, the oral dosage forms of the present application can take forms having different characteristics (e.g., size and shape) over the life cycle of the oral dosage form administered (e.g., administration state and post-administration gastric retention state).

[0200] In some embodiments, the oral dosage forms described herein are suitable for oral administration to human subjects. Such oral dosage forms of the application can be, for example, any size, shape or weight suitable for oral administration to a specific human subject, such as children and adults. In some embodiments, the oral dosage form is suitable for oral administration to an individual, wherein the size, shape or weight of the dosage form is selected based on the attributes of the individual, for example, one or more dimensions of height, weight, age or anatomical characteristics, such as those associated with oral administration.

[0201] In some embodiments, a surface of the oral dosage form, e.g., an outer surface, e.g., a body, has a capsule shape, circle, oval, bullet shape, arrow shape, triangle, arc triangle, square, arc square, rectangle, arc rectangle, diamond, pentagon, hexagon, octagon, half moon, almond shape, or a combination thereof.

[0202] In some embodiments, the maximum cross-sectional dimension of the oral dosage form is from about 5 mm to about 26 mm, e.g., from about 5 mm to about 15 mm, from about 6 mm to about 13 mm, or from about 7 mm to about 11 mm. In some embodiments, the maximum cross-sectional dimension of the oral dosage form is at least about 5 mm, e.g., at least about 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, or 24 mm. In some embodiments, the maximum cross-sectional dimension of the pharmaceutical dosage form is less than about 26 mm, e.g., less than about 25 mm, 24 mm, 23 mm, 22 mm, 21 mm, 20 mm, 19 mm, 18 mm, 17 mm, 16 mm, 15 mm, 14 mm, 13 mm, 12 mm, 11 mm, 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, or 5 mm. In some embodiments, the maximum cross dimension of the pharmaceutical dosage form is about 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 20.5 mm, 21 mm, 21.5 mm, 22 mm, 22.5 mm, 23 mm, 23.5 mm, or 24 mm. In some embodiments, the maximum cross dimension is measured on a surface of the pharmaceutical dosage form, such as an outer surface (e.g., represented by the length or width of the oral pharmaceutical dosage form). In some embodiments, the maximum cross dimension is measured across or diagonally across the oral pharmaceutical dosage form.

[0203] In some embodiments, the oral dosage form has a cross dimension perpendicular to the maximum cross dimension of about 5 mm to about 20 mm, for example, any one of about 5 mm to about 15 mm, about 6 mm to about 13 mm, or about 7 to about 11 mm. In some embodiments, the oral dosage form has a cross dimension perpendicular to the maximum cross dimension of at least about 5 mm, for example, at least about 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, or 20 mm. In some embodiments, the oral dosage form has a cross dimension perpendicular to the maximum cross dimension of less than about 20 mm, for example, less than about 19 mm, 18 mm, 17 mm, 16 mm, 15 mm, 14 mm, 13 mm, 12 mm, 11 mm, 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, or 5 mm. In some embodiments, the oral dosage form has a cross dimension perpendicular to the maximum cross dimension of about any one of 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, or 20 mm. In some embodiments, the cross dimension perpendicular to the maximum cross dimension is measured on a surface of the oral dosage form. In some embodiments, the cross dimension perpendicular to the maximum cross dimension is measured across or diagonally across the oral dosage form.

[0204] In some embodiments, the oral dosage form has a thickness of about 5 mm to about 20 mm, for example, any one of about 5 mm to about 15 mm, about 6 mm to about 13 mm, or about 7 mm to about 11 mm. In some embodiments, the oral dosage form has a thickness of at least about 5 mm, for example, at least about 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, or 20 mm. In some embodiments, the oral dosage form has a thickness of less than about 20 mm, for example, less than any one of about 19 mm, 18 mm, 17 mm, 16 mm, 15 mm, 14 mm, 13 mm, 12 mm, 11 mm, 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, or 5 mm. In some embodiments, the oral dosage form has a thickness of about any of 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, or 20 mm.

[0205] In some embodiments, the total weight of the oral dosage form is from about 50 mg to about 1,000 mg, e.g., from about 50 mg to about 100 mg, from about 100 to about 200 mg, from about 200 mg to about 300 mg, from about 300 mg to about 400 mg, from about 400 mg to about 500 mg, from about 500 mg to about 600 mg, from about 600 mg to about 700 mg, from about 700 mg to about 800 mg, from about 800 mg to about 900 mg, or from about 900 mg to about 1,000 mg. In some embodiments, the total weight of the oral dosage form is at least about 50 mg, for example, at least about 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1,000 mg. In some embodiments, the total weight of the oral dosage form is less than about 1,000 mg, for example, less than about 950 mg, 900 mg, 850 mg, 800 mg, 750 mg, 700 mg, 650 mg, 600 mg, 550 mg, 500 mg, 475 mg, 450 mg, 425 mg, 400 mg, 375 mg, 350 mg, 325 mg, 300 mg, 275 mg, 250 mg, 225 mg, 200 mg, 175 mg, 150 mg, 125 mg, 100 mg, 75 mg, or 50 mg. In some embodiments, the total weight of the oral dosage form is about 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1,000 mg. F. Additional Features of the Pharmaceutical Dosage Form

[0206] In some embodiments, the oral dosage form includes a gas-filled compartment, e.g., to provide buoyancy to the oral dosage form. In some embodiments, the gas-filled compartment is embedded in a component of the oral dosage form, e.g., the body or one or more movable arms. In some embodiments, the gas-filled compartment has a sprayable plug, wherein the sprayable plug is configured to open the gas-filled compartment at some point after the oral dosage form is administered to a subject.

[0207] In some embodiments, the oral dosage form includes additional features, such as an outer coating, an outer layer (e.g., a capsule shell), or external markings. In some embodiments, the outer coating or coating comprises / is a flavor coating. In some embodiments, the outer coating or layer comprises / is a sugar coating. In some embodiments, the outer coating or coating comprises / is a cosmetic coating. In some embodiments, the outer coating or layer comprises / is a color coating. In some embodiments, the outer coating or layer is a film coating. In some embodiments, the outer coating or layer is a polymer coating. In some embodiments, the outer coating completely surrounds the dosage form. In some embodiments, the outer layer forms part of the exterior of the oral dosage form. In some embodiments, the additional component is a label, such as a drug logo, a company name or abbreviation, a graphic, a drug label, a drug chemical name or abbreviation, a drug package insert, an identification bar code, or a combination thereof. G. Exemplary Medical Devices

[0208] The above-described inventive concepts can be applied to medical devices. In some embodiments, a medical device is provided, comprising: a body structure forming a swellable material chamber; wherein the swellable material chamber contains a swellable material; an arm operably connected to the body; wherein the arm rotates about the body of the medical device by a force provided by the swellable material. wherein the medical device is configured to have a compacted state and an expanded state in which the arm is pushed by expansion of the swellable material in the presence of a liquid. H. Exemplary Oral Pharmaceutical Dosage Forms

[0209] An oral drug dosage form for gastric retention, the oral drug dosage form comprising: a main body structure, the main body structure forming a swellable material chamber; wherein the swellable material chamber contains a swellable material and a movable member structure. wherein the main body structure comprises a base and a cover; the base is formed of a semipermeable membrane. the arms comprise a first arm, a second arm, a third arm and a fourth arm, the arms being operably connected to the main body; the swellable material absorbs liquid to swell, and the force provided pushes the movable member to move in a directional channel to near the top of the cover, wherein the first arm, the second arm, the third arm and the fourth arm are configured so that each arm is pushed by the movable member to rotate around the axis of the main body; wherein the oral drug dosage form is configured to have a pre-dose state having a compact form and a post-dose state having an expanded form providing gastric retention, and wherein the expanded form of the post-dose state of the oral drug dosage form is due, at least in part, to the expansion of the swellable material in the presence of gastrointestinal fluid. I. Drug dosage forms configured for other cavities

[0210] The concept of the pharmaceutical dosage form or medical device of the present invention can be applied not only to oral administration, but also to other parts of the human body, such as the large intestine, small intestine, rectum, cecum, colon, vagina and other parts, and the pharmaceutical dosage form or medical device of the present invention is also applicable. It will be easily understood by those of ordinary skill in the art that these other cavities may have anatomical features that guide the pharmaceutical dosage forms described herein. For example, the anatomical size of the rectum can guide the size of the pre-dose pharmaceutical dosage form for this purpose, which in certain embodiments may be different from the size of the oral pharmaceutical dosage form. Having said that, the mechanism of retention in an individual taught herein still applies. III. Commercial Batches

[0211] In certain aspects, provided herein are commercial batches of oral dosage forms described herein. In some embodiments, the commercial batches include at least 100, 150, 200, 250, 500, 750, 1,000, 2,500, 5,000, 7,500, 10,000, 20,000, 30,000, 40,000, 50,000, 60,000, 70,000, 80,000, 90,000, or 100,000 of any one of the oral dosage forms described herein. In some embodiments, each oral dosage form of the commercial batch is produced using the same technology, for example, involving one or more components of the oral dosage form by three-dimensional (3D) printing, injection molding, ultrasonic welding, or any combination thereof.

[0212] In some embodiments, the standard deviation of a commercial batch is about 0.1 or less, e.g., 0.05 or less, for one or more of the following: the amount of drug in the oral dosage form; the weight of the oral dosage form; the size of the oral dosage form (e.g., in a pre-dose state and / or a post-dose state); and the gastric residence time of the oral dosage form. In some embodiments, the size of the oral dosage form is the maximum cross-dimension of the oral dosage form in the pre-dose state. In some embodiments, the size of the oral dosage form is the cross-dimension perpendicular to the maximum cross-dimension of the oral dosage form in the pre-dose state. In some embodiments, the size of the oral dosage form is the maximum cross-dimension of the oral dosage form after the swellable material has expanded (e.g., in a post-dose state in the stomach, where the swellable material has expanded to a substantially complete state). In some embodiments, the size of the oral dosage form is the size of the oral dosage form after the swellable material has expanded (e.g., in a post-dose state in the stomach, where the swellable material has expanded to a substantially complete state) perpendicular to the maximum cross-dimension of the oral dosage form. IV. Preparation Methods

[0213] In certain aspects, provided herein are methods for preparing oral dosage forms described herein. In some embodiments, the manufacturing method includes three-dimensional (3D) printing technology to form at least one component or a portion thereof of the pharmaceutical dosage form described herein. In some embodiments, the manufacturing method includes using 3D printing, injection molding, ultrasonic welding, or any combination thereof. In some embodiments, the components of the oral dosage form taught herein are produced separately and then assembled by machine and / or hand.

[0214] As used herein, "printing," "three-dimensional printing," "3D printing," "additive manufacturing," or their equivalents, refers to the process of producing a three-dimensional object, such as a delayed-release oral pharmaceutical dosage form, layer by layer using a digital design. The basic process of 3D printing is described in U.S. Patent Nos. 5,204,055; 5,260,009; 5,340,656; 5,387,380; 5,503,785; and 5,633,021. Other U.S. patents and patent applications related to 3D printing include: U.S. Patent Nos. 5,490,962; 5,518,690; 5,869,170; 6,530,958; 6,280,771; 6,514,518; 6,471,992; 8,828,411; and U.S. Patent Publication Nos. 2002 / 0015728; 2002 / 0106412; 2003 / 0143268; 2003 / 0198677; and 2004 / 0005360. The contents of the aforementioned U.S. patents and patent applications are hereby incorporated by reference in their entirety. In some embodiments, additive manufacturing techniques are used to produce the oral pharmaceutical dosage forms described herein, or components thereof. In some embodiments, a layer-by-layer technique is used to produce the oral pharmaceutical dosage forms described herein, or components thereof. For example, in some embodiments, the layer-by-layer technique includes printing an entire first layer of one or more materials of an oral pharmaceutical dosage form or a component thereof, and then continuing to print an entire second layer of one or more materials of an oral pharmaceutical dosage form or a component thereof. In some embodiments, the layer, such as the first layer or the second layer, is a cross-section of the oral pharmaceutical dosage form or a component thereof. Because 3D printing can process a range of pharmaceutical materials and locally control composition and structure, 3D printing is well suited for manufacturing pharmaceutical dosage forms with complex geometries and compositions according to the present invention.

[0215] In some embodiments, when used with reference to a component of a pharmaceutical dosage form, such as a swellable material, a layer refers to a configuration of a component of an oral pharmaceutical dosage form and may include multiple printed layers of the same material. In some embodiments, the layer has a predetermined packing density, such as a packing density for three-dimensional printing. In some embodiments, the layer includes between about 5 printed layers and about 2500 printed layers, such as between about 10 printed layers and about 2500 printed layers, between about 25 printed layers and about 100 printed layers, between about 50 printed layers and about 200 printed layers, between about 100 printed layers and about 200 printed layers, between about 150 printed layers and about 250 printed layers, between about 200 printed layers and about 250 printed layers, between about 500 printed layers and about 1000 printed layers, or between about 2000 printed layers and about 2400 printed layers. In some embodiments, the printed layer has a thickness of no more than about 5 mm, such as no more than about 4 mm, 3 mm, 2 mm, 1 mm, 0.9 mm, 0.8 mm, 0.7 mm, 0.6 mm, 0.5 mm, 0.4 mm, 0.3 mm, 0.2 mm, 0.1 mm, 0.09 mm, 0.08 mm, 0.07 mm, 0.06 mm, 0.05 mm, 0.04 mm, 0.03 mm, 0.02 mm, or 0.01 mm. In some embodiments, the printed layer has a thickness of about 5 mm, 4 mm, 3 mm, 2 mm, 1 mm, 0.9 mm, 0.8 mm, 0.7 mm, 0.6 mm, 0.5 mm, 0.4 mm, 0.3 mm, 0.2 mm, 0.1 mm, 0.09 mm, 0.08 mm, 0.07 mm, 0.06 mm, 0.05 mm, 0.04 mm, 0.03 mm, or 0.01 mm.

[0216] Different 3D printing methods have been developed for manufacturing in terms of raw materials, equipment, and curing. These 3D printing methods include adhesive deposition (see Gibson et al., Additive Manufacturing Technologies: 3D Printing, Rapid Prototyping, and Direct Digital Manufacturing., 2 ed. Springer, New York, 2015; Katstra et al., Oral dosage forms fabricated by three dimensional printing, J Control Release, 66, 2000; Katstra et al., Fabrication of complex oral delivery forms by three dimensional printing, Dissertation in Materials Science and Engineering, Massachusetts Institute of Technology, 2001; Lipson et al., Fabricated: The New World of 3D printing, John Wiley & Sons, Inc., 2013; Jonathan, Karim, 3D printing in pharmaceuticals: a new tool for designing customized drug delivery systems, Int J Pharm, 499, 2016), material jetting (see Jonathan, Karim, 3D printing in pharmaceuticals: a new tool for designing customized drug delivery systems,Int J Pharm, 499, 2016), extrusion (see Gibson et al., Additive Manufacturing Technologies: 3D Printing, Rapid Prototyping, and Direct Digital Manufacturing. 2 ed. Springer, New York, 2015), and photopolymerization (see Melchels et al.,A review on stereolithography and its application in biomedical engineering. Biomaterials, 31, 2010). .

[0217] In some embodiments, the oral dosage forms described herein are produced by injection molding. Different raw materials for different components are loaded into an injection molding machine, prepared according to the mold shape, and then assembled.

[0218] In some embodiments, the oral pharmaceutical dosage forms described herein are 3D printed using an extrusion method. In some embodiments, the 3D printing method includes using a twin-screw extrusion method. During the extrusion process, material is extruded from a robotically driven print head through a print nozzle. Unlike adhesive deposition, which requires a powder bed, extrusion methods can print on any substrate. A variety of materials can be extruded for 3D printing, including thermoplastic materials disclosed herein, pastes and colloidal suspensions, silicones, and other semisolids. One extrusion printing method is melt extrusion deposition (MED), which uses extruded material from a print head to print layers of material to form components or components of an oral pharmaceutical dosage form. Another common type of extrusion printing is fused deposition modeling, which uses solid polymer filaments for printing. In fused deposition modeling, a gear system drives the filament into a heated nozzle assembly for extrusion (see Gibson et al., Additive Manufacturing Technologies: 3D Printing, Rapid Prototyping, and Direct Digital Manufacturing, 2nd ed., Springer, New York, 2015).

[0219] In some embodiments, 3D printing is performed by melt extrusion deposition (MED). In some embodiments, the melt extrusion deposition technique includes preparing the material to be printed, such as preparing a powder in a hot melt extruder, and then feeding the material into a MED print head. The MED print head then prints the material in an additive manner (layer-by-layer deposition) to form an oral pharmaceutical dosage form or a component thereof. In some embodiments, each material or component of the oral pharmaceutical dosage form is printed from a different MED print head. In some embodiments, the MED print head prints the material according to instructions in one or more G-code files. For example, WO2019 / 137333, WO2018137686, and U.S. Patent No. 10,201,503 disclose exemplary MED technologies, each of which is incorporated herein by reference in its entirety.

[0220] In some embodiments, 3D printing is performed by fused deposition modeling (FDM). In some embodiments, 3D printing is performed by fused extrusion deposition or hot melt extrusion combined with a 3D printing technology such as FDM. In some embodiments, 3D printing is performed by non-wire FDM. In some embodiments, 3D printing is performed by inkjet printing. In some embodiments, 3D printing is performed by selective laser sintering (SLS). In some embodiments, 3D printing is performed by stereolithography (SLA or SL). In some embodiments, 3D printing is performed by PolyJet, MultiJet Printing System (MJP), Perfactory, Solid Object UV Laser Printer, Bioplotter, 3D Bioprinting, Rapid Freeze Prototyping, Desktop System, Selective Deposition Lamination (SDL), Layered Object Manufacturing (LOM), Ultrasonic Merging, Color Inkjet Printing (CJP), EOSINT System, Laser Engineered Net Shaping (LENS) and Aerosol Jet System, Electron Beam Melting (EBM), Laser Selective Laser Melting (SLM), Phenix PXTM Series, Micro-Sintering, Digital Part Materialization (DPM) or VX Systems.

[0221] In some embodiments, the 3D printing methods described herein comprise a continuous production method. In some embodiments, the 3D printing methods described herein comprise a batch production method.

[0222] In some embodiments, the methods described herein for producing pharmaceutical dosage forms include 3D printing technology, such as a combination of 3D printing and another method, such as a combination of injection molding and 3D printing. In some embodiments, the method for production also includes injection molding technology. In some embodiments, the method for production also includes ultrasonic welding. In some embodiments, 3D printing technology, injection molding technology, and ultrasonic welding technology can be used alone or in any combination.

[0223] The method instructions for 3D printing pharmaceutical dosage forms disclosed herein can be generated in a variety of ways, including direct coding, derivation from a solid CAD model, or other means specific to the computer interface and application software of the 3D printer. These instructions may include information about the number and spatial position of droplets, as well as information about general 3D printing parameters, such as the droplet spacing in each linear dimension (X, Y, Z) and the volume or mass of each droplet. For a given set of materials, these parameters can be adjusted to improve the quality of the created structure. The overall resolution of the created structure is a function of the powder particle size, droplet size, printing parameters, and material properties.

[0224] In some embodiments, one or more components of the oral dosage form are created separately, e.g., printed separately, and then assembled to form the oral dosage form. In some embodiments, all components of the oral dosage form are created in a single process, e.g., printed in a single process, without the need for subsequent assembly.

[0225] The oral dosage forms and their components described herein can be printed on a commercial scale. For example, in some embodiments, the methods disclosed herein can be used to 3D print 1,000 to 100,000 units of oral dosage forms per hour, including printing their components for later assembly.

[0226] In some embodiments, materials used to print the oral pharmaceutical dosage form or components thereof are printed separately by different print heads.The 3D printing methods described herein include printing materials in any order to allow for the production of oral pharmaceutical dosage forms or components thereof.

[0227] In some embodiments, a method for 3D printing comprises designing all or part of an oral drug dosage form or a component thereof on a computer system. In some embodiments, the method comprises inputting desired gastric retention, drug release profile, and / or parameters of the oral drug dosage form and / or components into a computer system. In some specific embodiments, the method comprises providing one or more parameters to be printed, e.g., layer surface area, thickness, drug mass fraction, erosion rate. In some embodiments, the method comprises providing a desired drug release profile. In some embodiments, the method comprises creating a virtual image of the item to be printed. In some embodiments, the method comprises creating a computer model comprising predetermined parameters. In some embodiments, the method comprises feeding the predetermined parameters to a 3D printer and printing the item according to these predetermined parameters. In some embodiments, the method comprises creating a 3D drawing of the item to be printed based on the predetermined parameters, wherein the 3D drawing is created on a computer system. In some embodiments, the method comprises converting a 3D drawing, such as a slice, into a 3D printing code, e.g., a G-code. In some embodiments, the method comprises using a computer system to execute the 3D printing code to print according to the methods described herein. 5. Methods of delivering drugs to individuals

[0228] In some aspects, a method for delivering an oral drug dosage form to an individual is provided so that the oral drug dosage form is retained in the stomach of the individual for a long time, the method including orally administering any oral drug dosage form as described herein to the individual. In some aspects, a method for delivering a drug to the stomach and / or upper digestive tract of an individual is provided, the method including orally administering any oral drug dosage form as described herein to the individual, wherein the oral drug dosage form includes a drug. In some embodiments, the drug is released from the oral drug dosage form to the stomach and / or upper digestive tract (including quick-release dosage form, sustained-release dosage form, pulse release dosage form or its any combination) over a long period of time. In some embodiments, the oral drug dosage form is configured to retain a long time (for example, at least about 6 hours to about 3 months) in the stomach of an individual. In some embodiments, the drug in the oral drug dosage form can be released from the oral drug dosage form at a predetermined time after the oral drug dosage form is applied to the individual. For example, in some embodiments, the drug or at least a portion thereof is released in the stomach of an individual because or subsequently, the oral drug dosage form reaches a state after administration designed for gastric retention. In some embodiments, the drug, or at least a portion thereof, is released in the stomach of the individual for at least about 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 26 hours, 28 hours, 30 hours, 32 hours, 34 hours, or 36 hours after administration of the pharmaceutical dosage form to the individual. In some embodiments, the pharmaceutical dosage form is retained in the stomach for at least about 72 hours, 80 hours, 88 hours, 96 hours, 104 hours, 112 hours, 120 hours, 128 hours, 136 hours, 144 hours, 152 hours, 160 hours, or 168 hours.

[0229] In certain aspects, a method for delivering an oral drug dosage form to an individual is provided. After the individual ingests the drug dosage form, the drug dosage form undergoes three phases: retention initiation, retention time control, and retention termination. Retention initiation occurs when the drug dosage form enters the gastric space, and the expandable material within the drug dosage form body absorbs water and expands, causing the movable arm to begin rotating as the expandable material increases in volume. Retention initiation also involves the restraining member releasing the restraint on the movable arm before the expandable material absorbs water and expands. Retention time control can be controlled by selecting the materials and dimensions of the various components. Gastric retention termination can also be achieved by the dissolution / decomposition / degradation of the components. For example, the expandable material dissolves / decomposes / degrades, causing the movable component to return to the first compartment and the movable arm to retract; or the connection between the movable arm and the body partially or completely dissolves / decomposes / degrades, causing the movable arm to detach from the body; or the drug dosage form as a whole or the movable arm softens, weakening the mechanical strength of the drug dosage form, causing deformation and subsequent displacement from the intended retention position.

[0230] Those skilled in the art will recognize that several embodiments may be implemented within the scope and spirit of the present disclosure. The following examples further illustrate the disclosure, which should not be construed as limiting the scope or spirit of the disclosure to the specific procedures described therein.

[0231] Those skilled in the art will recognize that within the scope and spirit of the present application, the components, parts, structures, and materials disclosed in the present application can be arranged and combined according to the objectives or technical effects to be achieved by the pharmaceutical dosage form, and these arrangements and combinations should all be within the scope of protection of the present invention. Example Example 1

[0232] This example illustrates the design, production, and testing of an oral dosage form described herein. FIG9a provides a schematic diagram of an expanded oral dosage form. The component composition of the prepared dosage form is shown in Table 1. The oral dosage form comprises: a main body structure, the main body structure forming an expandable material chamber; wherein the main body structure is composed of a cover and a base, the base being a semipermeable membrane; the expandable material chamber containing a swelling block and a push post, the swelling block containing expandable material; four arms, the four arms being operably connected to the main body; the arms being rotated around the main body of the oral dosage form by a force provided by the expandable material; wherein the oral dosage form is configured to have a pre-dose state having a compact form and a post-dose state having an expanded form providing gastric retention, and the expanded form of the post-dose state of the oral dosage form is due, at least in part, to the expansion of the expandable material in the presence of gastrointestinal fluid.

[0233] Table 1 Components of oral dosage forms

[0234] The preparation method of the oral pharmaceutical dosage form described herein is as follows: (1) Preparation of a swelling block: Accurately weigh cross-linked polyvinylpyrrolidone according to the prescribed amount, and compress it into a cylindrical swelling block using a tablet press; (2) Model assembly: The swelling block, a push column, and a lid are sequentially placed into the interior of a semipermeable membrane, four arms are assembled on the lid, the various components are connected by glue, and the components are placed into a No. 1 hard gelatin capsule shell to obtain a capsule of the oral pharmaceutical dosage form described herein.

[0235] Six capsules of the oral pharmaceutical dosage form described herein were subjected to an expansion test. The test method was as follows: six capsules of the oral pharmaceutical dosage form described herein were freely placed in a hydrochloric acid medium with a pH of approximately 1.2, the dissolution apparatus speed was set to 100 rpm, and the capsules were observed from the initial state to the final fully opened state, and the time was recorded. The test results are shown in Figure 12, indicating that the oral pharmaceutical dosage form described herein fully expanded in approximately 1 hour, meeting the swelling and expansion requirements. Example 2

[0236] This example demonstrates the design, production, and testing of arms for the oral dosage form described herein. Two arms were prepared, as shown in Figures 13a and 13b . The arm in Figure 13b has lateral reinforcement ribs on either side of the connecting end. Both arms have a material composition (by mass ratio) of 8:2: Eudragit / polyacrylic acid resin:triacetin, and have identical design dimensions.

[0237] The mechanical properties of the arms of Figures 13a and 13b were tested separately. The test method was as follows: (1) Compression fixture installation: The four arms of Figures 13a and 13b were placed in a cyclic compression fixture, and the cyclic compression fixture was fixed on the tensile testing machine. The immersion medium (pH 1.2 hydrochloric acid) was poured in so that the arms were immersed. (2) Cyclic compression: Cyclic compression was performed according to the following parameters: ① Compression speed: 1 mm / min ② Maximum trigger pressure 3.2 N (pressing down to this pressure will cause upward movement), minimum trigger pressure 0.1 N (pressing down to this pressure will cause upward movement), and ③ The total number of cycles was 100. (3) Bending observation: The bent arms were placed under a digital microscope for observation and the bending angle was measured. The test results are shown in Table 2.

[0238] Table 2 Mechanical properties test results

[0239] As can be seen from Table 2, the arms of the oral drug dosage form described herein all have strong lateral bending resistance. The bending resistance of the arms with reinforced ribs is even better.

[0240] This example illustrates the design, production, and testing of an oral dosage form described herein. FIG9a provides a schematic diagram of an oral dosage form. The component composition of the prepared dosage form is shown in Table 3. The oral dosage form comprises: a main body structure, the main body structure forming an expandable material chamber; wherein the main body structure is composed of a cover and a base, and the base is provided with a water inlet as shown in FIG8; the expandable material chamber contains a swelling block and a push post, the swelling block containing expandable material; four arms, the four arms operably connected to the main body; the arms rotate around the main body of the oral dosage form by a force provided by the expandable material; wherein the oral dosage form is configured to have a pre-dose state having a compact form and a post-dose state having an expanded form providing gastric retention, and the expanded form of the post-dose state of the oral dosage form is due, at least in part, to the expansion of the expandable material in the presence of gastrointestinal fluid.

[0241] Table 3 Components of oral dosage forms

[0242] The preparation method of the oral drug dosage form described herein is as follows: (1) Preparation of a swelling block: Accurately weigh each component according to the prescribed amount, and compress the components using a tablet press to form a cylindrical swelling block; (2) Model assembly: The swelling block, push column, and lid are sequentially placed into the base, four arms are assembled on the lid, the components are connected by glue, and a No. 0 hard gelatin capsule shell is placed therein to obtain a capsule of the oral drug dosage form described herein.

[0243] Four capsules of the oral pharmaceutical dosage form described herein were subjected to an expansion test. The test method was as follows: (1) Medium preparation: Sodium chloride was dissolved in purified water, the pH was adjusted to 1.6 with hydrochloric acid, FaSSGF powder was added, and the mixture was stirred evenly. 900 mL was measured and poured into the dissolution apparatus; (2) Four capsules of the oral pharmaceutical dosage form described herein were mounted on an expansion fixture, which was fixed to the dissolution apparatus rotating basket at a speed of 100 rpm. The capsules were immersed in the medium, and the expansion time of the capsules was observed and recorded. The test results are shown in Table 4, and the expansion state is shown in Figure 14.

[0244] Table 4 Test results

[0245] The test results in Table 4 show that the oral dosage form described herein fully expands in about 1 hour, meeting the swelling and expansion requirements.

[0246] This example illustrates the design, production, and testing of an oral dosage form described herein. FIG9a provides a schematic diagram of an oral dosage form. The component composition of the prepared dosage form is shown in Table 6. The oral dosage form comprises: a main body structure, the main body structure forming an expandable material chamber; wherein the main body structure is composed of a cover and a base, the base including a water inlet; the expandable material chamber comprising a swelling block and a push post, the swelling block comprising an expandable material; four arms, the four arms operably connected to the main body, the drug loading slot being located in the interior space of the four arms, the bottom of the drug loading slot including a developing layer; the arms rotating around the main body of the oral dosage form by a force provided by the expandable material; wherein the oral dosage form is configured to have a pre-dose state having a compact form and a post-dose state having an expanded form providing gastric retention, and the expanded form of the post-dose state of the oral dosage form is due, at least in part, to the expansion of the expandable material in the presence of gastrointestinal fluid.

[0247] Table 6 Components of oral dosage forms

[0248] The preparation method of the oral drug dosage form described herein is as follows: (1) Preparation of a swelling block: Accurately weigh each component according to the prescribed amount, and compress the tablet using a tablet press to form a cylindrical swelling block; (2) Model assembly: The swelling block, push column, and lid are sequentially placed into the base, four arms are assembled on the lid, and the components are connected by glue, and then transferred into a No. 0 hard gelatin capsule shell to obtain a capsule of the oral drug dosage form described herein.

[0249] The oral drug formulation described herein was tested in dogs. Specifically, 8-12 kg male beagle dogs were selected. Prior to administration of the oral drug formulation, the beagles were fasted for at least 14 hours and had free access to water. On the day of the experiment, the beagles were first gavage-fed approximately 120 mL of a special liquid diet (canine maintenance feed: water = 1:3 (w / w)) into the throat. Ten minutes after eating, one capsule was orally administered, along with 50 mL of water to ensure that the capsule entered the stomach. After administration, the dogs were allowed free access to water. 5.83 and 11.83 hours after administration (i.e., 10 minutes before the 6-hour and 12-hour sampling points) were administered 120 mL of food in the same manner. In order to evaluate the retention time and state of the formulation, X-ray images of the dog were taken from the front and side views before administration and 0.5 hours, 1 hour, 10 hours, 24 hours, and 36 hours after administration to observe the position and state of the formulation in the dog's body. The X-ray images are shown in Figure 15. As can be seen from Figure 15, the oral dosage form described herein can be retained in the stomach for more than 24 hours and can be disintegrated in the body, avoiding the potential risk of intestinal obstruction. Example 5

[0250] This example illustrates the design, production, and testing of an oral pharmaceutical dosage form described herein. FIG9a provides a schematic diagram of an oral pharmaceutical dosage form. The component composition of the prepared dosage form is shown in Table 7. The oral pharmaceutical dosage form comprises: a main body structure, the main body structure forming an expandable material chamber; wherein the main body structure is composed of a cover and a base, the base including a water inlet; the expandable material chamber is used to load a swelling mass and a push column; four arms, the four arms being operably connected to the main body; the arms being rotated around the main body of the oral pharmaceutical dosage form by a force provided by the expandable material; wherein the oral pharmaceutical dosage form is configured to have a pre-dose state having a compact form and a post-dose state having an expanded form providing gastric retention, and the expanded form of the post-dose state of the oral pharmaceutical dosage form is due, at least in part, to the expansion of the expandable material in the presence of gastrointestinal fluid. The expandable material chamber of the oral pharmaceutical dosage form described in this example is not loaded with a swelling mass and a push column.

[0251] Table 7 Components of oral dosage forms

[0252] The preparation method of the oral drug dosage form described herein is as follows: assemble four arms on the lid, assemble the base and the lid, connect the components by gluing, and fill them into a size 0 hard gelatin capsule shell to obtain the oral drug dosage form capsule described herein.

[0253] The oral pharmaceutical dosage forms described herein were subjected to an immersion test, specifically as follows: (1) Preparation of immersion medium: Take 5 L of degassed pure water and adjust the pH to approximately 1.2 with hydrochloric acid; Measure 900 mL and pour into the dissolution apparatus; (2) Immersion test: Place 6 oral pharmaceutical dosage forms described herein into the medium and immerse them. Three of them were taken out after 10 hours and the other three were taken out after 24 hours, and each was subjected to a reverse compression strength test; (3) Reverse compression test: Take 3 unsoaked oral pharmaceutical dosage forms described herein, 3 oral pharmaceutical dosage forms described herein that were soaked for 10 hours, and 3 oral pharmaceutical dosage forms described herein that were soaked for 24 hours and place them upside down on a fixture. The fixture was fixed on a tensile testing machine and reversely compressed at a compression speed of 4 mm / min. The maximum compression strength was recorded. The test results are shown in Table 8.

[0254] Table 8 Immersion test results

[0255] As shown in Table 8, the oral drug dosage form described herein has good mechanical strength, and as the soaking time increases, the mechanical strength of the structure can gradually decrease, which is conducive to the disintegration of the preparation structure and discharge from the pylorus, reducing the safety risk during the medication process.

[0256] This example illustrates the design, production, and testing of an oral pharmaceutical dosage form described herein. FIG16 provides a schematic diagram of an oral pharmaceutical dosage form. The component composition of the prepared dosage form is shown in Table 9. The oral pharmaceutical dosage form comprises: a main body structure, the main body structure forming an expandable material chamber; wherein the main body structure is composed of a cover and a base, the base including a water inlet; the expandable material chamber is used to load a swelling mass and a push plunger; five arms, the five arms being operably connected to the main body; the arms being rotated around the main body of the oral pharmaceutical dosage form by a force provided by the expandable material; wherein the oral pharmaceutical dosage form is configured to have a pre-dose state having a compact form and a post-dose state having an expanded form providing gastric retention, and the expanded form of the post-dose state of the oral pharmaceutical dosage form is due, at least in part, to the expansion of the expandable material in the presence of gastrointestinal fluid. The expandable material chamber of the oral pharmaceutical dosage form described in this example is not loaded with a swelling mass and a push plunger.

[0257] Table 9 Components of oral dosage forms

[0258] The preparation method of the oral drug dosage form described herein is as follows: assemble five arms on the lid, assemble the base and the lid, connect the components by gluing, and fill them into a size 0 hard gelatin capsule shell to obtain the oral drug dosage form capsule described herein.

[0259] The oral pharmaceutical dosage forms described herein were subjected to an immersion test, specifically as follows: (1) Preparation of immersion medium: Take 5 L of degassed pure water and adjust the pH to approximately 1.2 with hydrochloric acid; Measure 900 mL and pour into the dissolution apparatus; (2) Immersion test: Place 6 oral pharmaceutical dosage forms described herein into the medium and immerse them. Three of them were taken out after 10 hours and the other three were taken out after 24 hours, and each was subjected to a reverse compression strength test; (3) Reverse compression test: Take 3 unsoaked oral pharmaceutical dosage forms described herein, 3 oral pharmaceutical dosage forms described herein that were soaked for 10 hours, and 3 oral pharmaceutical dosage forms described herein that were soaked for 24 hours and place them upside down on a fixture. The fixture was fixed on a tensile testing machine and reversely compressed at a compression speed of 4 mm / min. The maximum compression strength was recorded. The test results are shown in Table 10.

[0260] Table 10 Immersion test results

[0261] As shown in Table 10, after 24 hours of immersion, the oral dosage form described herein still exhibited at least 45% of its unimmersed reverse compressive strength, indicating that the mechanical properties of the oral dosage form described herein were excellent. For the same size, the mechanical strength of the five-arm oral dosage form was greater than that of the four-arm oral dosage form.

Claims

1. A pharmaceutical dosage form configured to have a pre-administration state in a compact form and a post-administration state in an expanded form, the pharmaceutical dosage form comprising: an arm and a body connected to the arm; The body includes: a first compartment configured to accommodate an expandable member; a second compartment; the first compartment and the second compartment are connected through an orifice; a movable member movable from the first compartment to the second compartment; and a fluid inlet connected to the first compartment and / or the second compartment; a force provided by the expandable member extends to the movable member, causing at least a portion of the movable member to be accommodated in the second compartment and pushing the arm to extend outside the body or rotate around the body; and A drug is carried on the arm and / or the main body.

2. The pharmaceutical dosage form according to claim 1, wherein The expandable member comprises a swellable material.

3. The pharmaceutical dosage form according to claim 2, wherein The pharmaceutical dosage form is an oral pharmaceutical dosage form, the expanded form of the oral pharmaceutical dosage form in the post-administration state is at least partially due to the expansion of the swellable material in the presence of gastrointestinal fluids.

4. The pharmaceutical dosage form according to any one of claims 1 to 3, characterized in that The oral dosage form has a gastric residence time of about 6 hours to about 3 months.

5. The pharmaceutical dosage form according to any one of claims 1 to 4, characterized in that The swellable material swells at least about 1.2 times its volume upon exposure to gastrointestinal fluids.

6. The pharmaceutical dosage form according to any one of claims 1 to 5, characterized in that The amount of the swellable material in the first compartment is at least about 5 mg.

7. The pharmaceutical dosage form according to any one of claims 1 to 6, characterized in that The arm, the first compartment, the second compartment, the moving member, and the expandable member are all composed of pharmaceutically acceptable materials.

8. The pharmaceutical dosage form according to any one of claims 1 to 7, characterized in that The number of the arms is 2 to 6.

9. The pharmaceutical dosage form according to any one of claims 1 to 8, characterized in that In the post-drug administration state, the angles between two adjacent arms are equal and range from 60° to 120°.

10. The pharmaceutical dosage form according to any one of claims 1 to 9, characterized in that The body includes an opening through which the arm passes, and at least a portion of the arm is received in the second compartment.

11. The pharmaceutical dosage form according to any one of claims 1 to 10, characterized in that The first compartment is formed by the base and the second compartment is formed by the lid.

12. The pharmaceutical dosage form according to claim 11, wherein The arm includes a connecting end received in the second compartment, an extending section connected to the connecting end, and a terminal end opposite to the connecting end.

13. The pharmaceutical dosage form according to claim 12, wherein The connecting end of the arm comprises a pivot and a pushing member, wherein the pivot is connected to the cover; and the pushing member abuts against the moving component.

14. The pharmaceutical dosage form according to claim 13, wherein The connecting end of the arm further includes a neck connected to the pivot and a transition section.

15. The pharmaceutical dosage form according to claim 14, wherein The ratio of the width of the extension section to the width of the neck is in the range of 5:1 to 1:

1.

16. The pharmaceutical dosage form according to claim 13, wherein The pushing member includes four side surfaces, and the shapes of the four side surfaces are selected from a trapezoid, a triangle or a combination thereof.

17. The pharmaceutical dosage form according to any one of claims 12 to 16, characterized in that The distal ends of the arms include projections, and in the pre-administration state, the projections at the distal ends of adjacent arms abut against each other.

18. The pharmaceutical dosage form according to claim 1, wherein In the pre-drug administration state, the arms form a relatively independent accommodation space, and the drug is located in the accommodation space.

19. The pharmaceutical dosage form according to any one of claims 1 to 18, characterized in that The main body further comprises a middle column, wherein in the pre-dose state, the length of the middle column along the axis does not exceed the length of the arm along the axis.

20. The pharmaceutical dosage form according to claim 19, wherein The intermediate column is loaded with drugs.

21. The pharmaceutical dosage form according to claim 1, wherein The moving component includes a bottom and a convex portion connected to the bottom, and the convex portion abuts against the pushing member.

22. The pharmaceutical dosage form according to claim 21, wherein The bottom surface of the bottom is circular or annular.

23. The pharmaceutical dosage form according to claim 21 or 22, characterized in that The bottom portion and the convex portion are in smooth transition, or the bottom portion and the convex portion have chamfers.

24. The pharmaceutical dosage form according to any one of claims 21 to 23, characterized in that The convex portion has a curved top or a flat top.

25. The pharmaceutical dosage form according to any one of claims 21 to 24, characterized in that The outer surface of the movable member matches the outer side surface and bottom surface of the connecting end of the arm. In the post-dose state, the outer side surface of the connecting end of the arm abuts the bottom of the movable member, and the bottom surface of the connecting end abuts the outer side surface of the convex portion of the movable member.

26. The pharmaceutical dosage form according to any one of claims 1 to 25, characterized in that The movable member is provided with a coupling feature, and in the post-administration state, the coupling feature on the movable member is coupled with the coupling feature on the arm and / or the cover and / or the base and / or the expandable member.

27. The pharmaceutical dosage form according to claim 26, wherein The joining feature is a form-fitting surface or a mechanical snap-fit ​​component or an adhesive.

28. The pharmaceutical dosage form according to any one of claims 1 to 27, characterized in that The opening includes a first width close to the central axis and a second width away from the central axis.

29. The pharmaceutical dosage form according to claim 28, wherein The second width is greater than the first width.

30. The pharmaceutical dosage form according to any one of claims 1 to 29, characterized in that Reinforcing ribs are provided on the cover and / or the arm.

31. The pharmaceutical dosage form according to claim 30, wherein The reinforcing rib is located at the neck of the arm.

32. The pharmaceutical dosage form according to claim 30 or 31, characterized in that In the post-dose state, the reinforcing rib abuts against the main body.

33. The pharmaceutical dosage form according to any one of claims 1 to 32, characterized in that At least one water inlet is provided on the base.

34. The pharmaceutical dosage form according to any one of claims 1 to 32, characterized in that The base is formed of a semi-permeable membrane.

35. The pharmaceutical dosage form according to any one of claims 1 to 34, characterized in that The pharmaceutical dosage form further includes a restraining member configured to inhibit extension of the arm.

36. The pharmaceutical dosage form according to claim 35, wherein The restraining member is made of an erodible material, and the restraining member releases the inhibition on arm extension within about 30 minutes after administration to a subject.

37. A pharmaceutical dosage form comprising: a main body extending along the Z-axis direction, the main body including an internal chamber and an expandable structure accommodated in the internal chamber, the internal chamber including a fluid inlet; an arm rotatable about the body; and medications; wherein the pharmaceutical dosage form is configured to have a first state extending along the Z axis and a second state extending along both the XY axis and the Z axis; The second state occurs at least in part due to expansion of the inflatable structure; and the extension along the XY axis occurs due to rotation of the arm about the body.

38. The pharmaceutical dosage form according to claim 37, wherein The number of the arms is 2 to 6.

39. The pharmaceutical dosage form according to claim 38, wherein In the second state, the arm is parallel to or coincides with the plane where the XY axis is located, or intersects with the plane where the XY axis is located.

40. The pharmaceutical dosage form according to claim 38, wherein When the arms are in the second state, the projection heights of each arm on the Z axis are the same or different.

41. A pharmaceutical dosage form configured to have a pre-administration state in a compact form and a post-administration state in an expanded form, the pharmaceutical dosage form comprising: An arm and a body connected to the arm, wherein the arm is rotatable around the body, and the body includes a pushing device, wherein the pushing device is triggered by external conditions and pushes the arm to rotate around the body to form an expanded post-administration state; The pharmaceutical dosage form is configured to have a compact form before administration and includes an outer surface and an inner portion opposite the outer surface; A drug component is carried in the interior of the drug dosage form, wherein the drug is at least partially exposed in the expanded form after administration of the drug dosage form.

42. The pharmaceutical dosage form according to claim 41, wherein The urging means comprises an expandable material.

43. The pharmaceutical dosage form according to claim 41 or 42, characterized in that The pushing device further includes a moving member.

44. The pharmaceutical dosage form according to any one of claims 41 to 43, characterized in that The drug component is carried on the arm and / or the body.

45. The pharmaceutical dosage form according to any one of claims 41 to 44, characterized in that When the pharmaceutical dosage form is in a compact state before administration, no drug is exposed on the surface of the pharmaceutical dosage form.

Images