The present application claims the benefit of and priority to U .S.

Provisional Application Serial No. 62/006,541, filed on June 2, 2014 and U .S. Provisional Application Serial No. 62/093,763, filed on December 18, 2014, the entire contents of both of which are incorporated herein by reference.

FIELD OF THE DISCLOSURE

[0002] The present disclosure relates to a pharmaceutical product. More particularly, the present disclosure relates to an oral pharmaceutical or gastric retentive dosage form and formulations relating thereto.

BACKGROUND

[0003] There has been extensive research in the area of gastric retentive drug delivery systems and dosage forms. These systems and dosage forms are particularly useful for the delivery of drugs that:

(1) have a "narrow absorption window" in the gastrointestinal tract, for example, drugs that are preferentially absorbed in the duodenum and/or jejunum over ileum and/or colon, or have better solubility in upper parts of the gastrointestinal tract (GI);

(2) are intended for local treatment of proximal parts of the gastrointestinal tract (stomach and/or duodenum); and/or

(3) degrade in the colon or in the intestines, etc.

[0004] Gastric retentive drug delivery systems or dosage forms have focused research in three areas of technology: namely, floating systems; systems with expanding geometry through swelling or unfolding; and bioadhesive systems.

l

[0005] The general concept of the expandable gastroretentive systems and dosage forms is that the system or dosage form starts in a condition or configuration suitable for swallowing . The system or dosage form then expands in the stomach to prevent gastric emptying. Eventually, the system or dosage form reduces in size to pass through the pylorus or disintegrates. Some of the original formulations with this approach are known from the veterinary world. For example, U .S. Patent No. 3,844,285 discloses the concept of a pill that can be swallowed with wings taped down that eventually expand once water- degradable tape disintegrates. Such veterinary gastroretentive devices and formulations are sold under the tradenames Captec® and Ivomec® SR Bolus. In the area of commercialized animal products, Paratect Flex® bolus is a trilaminate sheet with a central polymeric matrix and drug load which is rolled up and held by a piece of water-soluble adhesive tape in the form of a cylindrical pill .

[0006] In the area of human oral application, U.S. Patent No. 5,002,772 discloses a device with a plurality of compressible retention arms attached to a controlled release device which, in the expanded configuration, resists gastrointestinal transit. U.S. Patent Nos. 4,735,804 and 4,767,627 disclose a series of substantially planar geometric shapes, e.g ., a tetrahedron formed of a bioerodible polymer that may be compressed and collapsed for oral administration. U .S. Patent No. 8,298,574 discloses an "Accordion pill", a sheet with a length of more than 20mm, folded like an accordion and placed in a capsule.

[0007] There have been many challenges in designing gastric retentive dosage forms relating to ability to scale up/manufacture/assemble, drug loading capacity, retention during fasted state, the inclusion of an emergency release mechanism to expel the delivery system or dosage form in an emergency situation, using pharmaceutically acceptable ingredients etc. Improvements concerning any one of these challenges would provide a significant contribution to the area of gastric retentive drug delivery systems and dosage forms.

SUMMARY OF THE DISCLOSURE

[0008] Improvements concerning any one of these challenges and needs would provide a significant contribution to the area of gastric retentive drug delivery systems and dosage forms. The present disclosure relates to a gastroretentive dosage form (GRDF) that includes one or more of the following characteristics:

• Rapidly unfolds within less than 3min. to maximum gastric retentive size;

• Maintains a sufficient size integrity and rigidity throughout the time period under gastric physiology or conditions; and/or

• Delays gastric emptying for a specific time dependent on the extent of API

[0009] According to an aspect of the present disclosure a gastroretentive dosage form (GRDF) for extended retention in a stomach is provided which includes: a body configured to transform between a collapsed configuration for ingestion, an expanded configuration for retention within the stomach and a third configuration wherein after a predetermined time period has elapsed, the GRDF disassembles into two or more parts such that each of the disassembled parts of the GRDF is sized for exiting the stomach; and an active pharmaceutical ingredient (API) or diagnostic. In aspects, the third configuration is induced by at least a partial release of the API or diagnostic or compositions thereof.

[00010] In any of the aspects described herein, the body is configured to transform between a collapsed configuration for ingestion and an expanded configuration suitable for gastric retention within less than 5 minutes, in aspects, less than 4 minutes, in aspects, less than 3 minutes. In aspects described herein, a method is provided for gastric retention wherein a GRDF transforms to an expanded configuration for gastric retention within less than 5 minutes, in aspects, less than 4 minutes, in aspects, less than 3 minutes. Once the capsule at least partially dissolves, the body automatically transitions to the expanded configuration.

[00011] In any of the aspects, after a pre-determined period of time, the GRDFs described herein will eventually lose their mechanical integrity as a single unit, disassemble and pass from the stomach for subsequent evacuation. There are many possible mechanisms to achieve this result, all of which are encompassed by the present disclosure.

[00012] In any of the aspects described herein, the predetermined period of time is more than about 4 hours, in aspects, more than about 6 hours, in aspects, more than about 7 hours, in aspects more than 12 hours, in aspects more than 24hs.

[00013] In any of the aspects described herein, transforming to the third configuration occurs when more than 70% of the active pharmaceutical ingredient is released, in aspects, when more than 75% of the active pharmaceutical ingredient is released, in aspects, when more than 80% of the active pharmaceutical ingredient is released, in aspects, when more than 85% of the active pharmaceutical ingredient is released, in aspects, when more than 90% of the active pharmaceutical ingredient is released, in aspects, when more than 95% of the active pharmaceutical ingredient is released, in aspects, when 100% of the active pharmaceutical ingredient is released .

[00014] It should be understood that any method or mechanism that is configured to transition or open the GRDF to the expanded configuration is encompassed by the present disclosure.

[00015] In one aspect, a superporous hydrogel system may be incorporated into the inner part of the arms which expands upon exposure to the gastric environment thereby forcing the two arms apart and to the expanded configuration. In another aspect, a leaf spring (similar to those described above) springs outwards and extends from the inner area of one or both of the arms once the expanding configuration is initiated or once the mechanical integrity of the collapsed condition has been compromised, e.g., capsule is dissolved. In other aspects, various mechanisms may be employed to lock the arms in an expanded configuration until the insert has sufficiently erodes to disassemble the GRDF.

[00016] For example, in any of the aspects described herein, an inner facing surface of one of the arms may include a locking mechanism to lock the leaf spring in place in the expanded configuration. Alternatively and in addition to the hinge assemblies described above, the hinge assembly may include one or more mechanical interfaces or mechanisms, gear, spring, cam, etc. that are configured to maintain or lock the GRDF in an expanded configuration until disassembly. In aspects, the leaf spring may simply be configured to bias the GRDF from the collapsed configuration and not necessarily lock to maintain the GRDF in the expanded configuration but may be configured to simply prevent the GRDF from transitioning back to the collapsed configuration.

[00017] In any of the aspects described herein, the leaf spring or biasing mechanism may be configured to lock the two arms in the expanded configuration until disassembly. One or more locking mechanisms may be employed for this purpose, or, alternatively, the leaf spring may be configured to engage one of the arms to keep the two arms apart until disassembly. In other aspects, the biasing mechanism, e.g ., leaf spring, may be configured to engage the opposing arm to keep the two arms and separated as the insert slowly erodes. As the insert erodes (API is released), the bias of the leaf spring gradually lessens or the leaf spring regresses into the arm such that the angle β between the two arms and lessens to a point when the size or formation (e.g., triangular shape) of the GRDF is small enough to pass through the pyloric valve in the stomach. As can be appreciated, in this instance the GRDF does not necessarily need to disassembly for it to safely pass through the pyloric valve.

[00018] In any of the aspects described herein, the GRDF further comprises a biasing element configured to maintain the two arms apart once the two arms transition to the expanded configuration. In aspects, the biasing element is configured to transition the two arms from the collapsed configuration.

[00019] In aspects according to the present disclosure, the body may include at least two arms, or in other aspects, two arms. In any of the aspects described herein, two arms are capable of providing a size relevant for gastric retention. In any of the aspects described herein, the GRDF further comprises a biasing element configured to maintain the two arms apart once the two arms transition to the expanded configuration. In aspects, the biasing element is configured to transition the two arms from the collapsed configuration. Once in expanded position, the length between the tips of two arms is about 26-30mm in length.

[00020] In aspects described herein, the biasing element forms part of the hinge assembly.

[00021] In any of the aspects described herein a size of at least one of the two arms is substantially maintained during transition between configurations. For example, even after 24hr exposure to simulated gastric fluids - there is less than 10% preferably less than 5% change in weight, length and thickness of each arm, hinge etc.

[00022] In any of the aspects described herein, one of the at least two arms includes a cavity defined therein configured to engage the hinge assembly and the API or diagnostic or composition thereof. In any of the aspects described herein, at least a portion of the hinge assembly, may be sandwiched between at least one of the at least two arms of the body and the API or diagnostic or composition thereof hold one and other in place. Thus, any erosion or partial release of any of the API or API composition, the hinge assembly, arm or diagnostic will result in release from expanded state or end of gastric retention. For example, the hinge assembly, may be configured to disengage from the at least one arm upon partial release of the API. In another example, the hinge, API or arm may be coated or partially comprise a pH or temperature sensitive polymer which may be caused to erode via change in environment.

[00023] In any of the aspects described herein, in the expanded configuration, the at least two arms define an interior angle between about 45 degrees and about 90 degrees, in aspects, the at least two arms define an interior angle between about 45 degrees and about 80 degrees. In any of the aspects described herein, in the expanded configuration, the at least two arms define an interior angle of less than about 90° therebetween.

[00024] In any of the aspects described herein, at least one of the at least two arms may be configured to releasably engage the API or diagnostic. In any of the aspects described herein, the API or diagnostic is positioned within a cavity defined in the body. In any of the aspects described herein, the API may be positioned within the cavity in the form of a composition. The cavity may be formed for example, using injection molding, 3D printing, etc. In any of the aspects described herein, the at least two arms may be pivotably connected together or in articulated relationship by a hinge assembly and may be configured to disengage from one another due to partial degradation of at least one of the at least two arms or hinge assembly or partial release of the API or diagnostic. The partial degradation of at least one of the at least two arms or hinge assembly or partial release the API or diagnostic may be due to a pH dependent polymer. In any of the aspects described herein, the pH dependent polymer may be configured to erode in a basic environment.

[00025] In any of the aspects described herein, the API or diagnostic is encased or positioned within a cavity within the at least one of the at least two arms.

[00026] In any of the aspects described herein, the API or diagnostic is released via an opening defined within at least one of the two arms.

[00027] In any of the aspects described herein, the API or diagnostic is in the form of an insert tablet shaped to fit within a cavity defined in at least one of the at least two arms.

[00028] In any of the aspects described herein, the GRDFs are designed to maximize the volume and/or weight ratio of API to total excipients, in an effort to maximize the drug volume and/or weight load to be processed in the stomach while minimizing the volume of non-drug material that must pass through the gastrointestinal tract although any relevant amount of API is encompassed by the present disclosure. According to one aspect of the disclosure, a ratio of the weight of the active pharmaceutical ingredients to the weight of total excipients is from about 0.8 to about 0.05, in embodiments, from about 0.7 to about 0.3, and in other embodiment, from about 0.6 to about 0.4 or 0.5 to about 0.95. The total excipients may include the arms, the hinge, the excipients in the insert, and the capsule. In embodiments, the load of the excipients may be from about 500mg to about 2000mg. In any of the aspects described herein, the amount of API present in the insert may be an amount greater than 400mg, 600mg, 800mg, lOOOmg, or 1500mg . Alternatively, in aspects, the API drug load is about 400 milligrams to about 1.5 grams, in aspects, the API drug load is about O. lmg to about 2 grams or lOmg to about 1.8grams or 500 milligrams to about 1.5 grams. In aspects, the API drug load is about 600 milligrams to about 1.5 grams. The amount of API may depend on a variety of factors such as the need for additional excipients and the size of tablet. In aspects, the amount of API in the GRDF is a therapeutically effective amount for treating a particular disease or condition over a prescribed time period, e.g., hourly (q lh), q2h - q8h, b.d .s., and o.d.

[00029] In any of the aspects described herein, the body may include at least two arms.

[00030] In any of the aspects described herein, the at least two arms may be pivotably connected to one another about a hinge assembly.

[00031] In any of the aspects described herein, at least one of the at least two arms comprises a cavity defined therein configured to receive at least a first portion of the API or diagnostic. In aspects, the cavity includes a volume ranging from about 100 mm3 to about 2000 mm3 or from about 200 mm3 to about 1800 mm3. In aspects, the volume of the body may range from about 500 mm3 to about 1500 mm3. In embodiments, the volume of the body may range from about 800 mm3 to about 1200 mm3. In aspects, the volume of the body may be about 950 mm3. In aspects, the at least one arm that includes the cavity includes an opening defined therein which may be in communication with the gastric environment. This hole would be distally located from the hinge assembly.

[00032] In any of the aspects described herein, at least one of the at least two arms may be configured to releasably engage the API or diagnostic. In any of the aspects described herein, the API or diagnostic is positioned within a cavity defined in the body. In any of the aspects described herein, the API may be positioned within the cavity in the form of a composition. In any of the aspects described herein the API positioned in the cavity is released at a controlled rate over more than 6 hours, in aspects, over more than 8 hours, in aspects, over more than 10 hours.

[00033] In aspects according to the present disclosure, the body may include two arms.

[00034] In any of the aspects described herein, the body comprising the at least one arm, hinge and cavity may be is produced by for example, using injection molding, 3D printing, etc. In any of the aspects described herein, the body injection molding or 3D printing. In any of the aspects described herein, the biasing element, the at least one of the at least two arms, and hinge assembly is manufactured from pharmaceutically acceptable excipients as listed in IIG guidelines.

[00035] In any of the aspects described herein, the body is maintained in the collapsed configuration by a retention mechanism and the body is transitioned to the expanded configuration by a hinge assembly. It should be understood that any retention method or mechanism that is configured to maintain the collapsed configuration of the GRDF prior to swallowing is envisioned . Several different aspects have been described herein and include a capsule that erodes or dissolves upon contact with gastric fluid . In another aspects, in a case where the natural state of the GRDF is open (natural or biased configuration of one of the hinge assemblies described herein is open to expand the GRDF), there may be a material holding the GRDF closed which dissolves or erodes in the presence of gastric fluid thereby releasing the GRDF to an expanded configuration. In other aspects, the material may be in the shape of an erodible band which encompasses the arms to maintain the GRDF in a collapsed configuration until the band erodes allowing expansion of the GRDF. Still other aspects include a glue-like material that keeps the two arms together until the glue-like material erodes allowing expansion of the GRDF. In another aspect, the retention mechanism may be a capsule which

maintains the closed state and dissolves when introduced to a fluid environment, may be the capsule itself

[00036] In any of the aspects described herein, the oral pharmaceutical further comprises a capsule configured to encompass the body when disposed in the collapsed configuration, the capsule configured to at least partially dissolve upon introduction to fluid to expose and release the body from the collapsed configuration.

[00037] In any of the aspects described herein, the GRDF maintains a shelf life durability or shelf life stability for more than 2 years under accelerated conditions.

[00038] In any of the aspects described herein, each arm may include a cavity defined therein configured to receive an API or diagnostic.

[00039] In any of the aspects described herein, the at least two arms are movable or pivotable about a hinge assembly.

[00040] In aspects, the at least two arms and the hinge assembly are releasable engaged to one another.

[00041] In any of the aspects described herein, the at least two arms detach from the hinge assembly at the predetermined period of time.

[00042] In any of the aspects described herein, the at least two arms detach from the hinge assembly when the API or diagnostic has been substantially released .

[00043] In any of the aspects described herein, the at least two arms include a first arm comprising a first API or diagnostic and a second arm comprising a second API or diagnostic. In aspects, the second API or diagnostic is incompatible with the first API or diagnostic.

[00044] In any of the aspects described herein, the at least two arms of the body are configured to disengage from one another upon partial release of the API. In any of the aspects described herein, the predetermined time period is at least 4 hours, in aspects, at least 6 hours, in aspects, at least 8 hours, in aspects, at least 10 hours, in aspects, at least 12 hours, in aspects, at least 18 hours. In any of the aspects described herein, the predetermined time period is in mammals such as dog or pig and preferably human.

[00045] In any of the aspects described herein, the size of each of individual arms and hinge is substantially maintained during transition between configurations. In aspects, there is less than 10%, in apsects, less than 5% change in size of each of the parts which make up the body, i.e., the hinge, arms etc. In aspects, this is so after exposure to 24hrs simulated gastric conditions. In any of the aspects described herein, the size of at least one of the at least two arms is substantially maintained during transition between the first and second and then the second and third configurations.

[00046] In any of the aspects described herein, the hinge assembly may be made from one or more pharmaceutically acceptable ingredients. In any of the aspects described herein, the hinge assembly can include two interconnected hinge portions that are pivotably coupled to each other, each hinge portion being connected to one of the at least two arms. In aspects, each hinge portion is connected to one of the at least two arms by a mechanically engaging component such as the inner wall of the cavity in the arm. In aspects, the hinge assembly or portions are configured to rotate with respect to each other within a limited range of motion that is less than or equal to 90 degrees. In any of the aspects described herein, the hinge assembly is a unitary component.

[00047] In any of the aspects described herein, after the predetermined time period has lapsed, the hinge assembly is configured to disengage from the at least two arms for release from the stomach. In any of the aspects described herein, the hinge assembly can disengage from the at least two arms once the API is substantially released or the API composition is substantially eroded . Substantially released or eroded may be more than 70%, more than 75% or more than 80%. In aspects, the hinge assemblies or other connection mechanisms composed of one or more base-sensitive materials can begin to disintegrate or erode once exposed to

the proximal end of the arm's internal matrix (the API release system or API composition) which includes basic material . In other aspects, the hinge assemblies or other connection mechanisms composed of one or more time sensitive polymers can begin to disintegrate at a certain point in time. In yet other aspects, the hinge assemblies or other connection mechanisms are connected to the arms in a certain mechanical fashion, with a certain mechanical shape or by one or more mechanical features such that once the arms, insert tablet or hinge assembly erode via the introduction of gastric fluids, the mechanical integrity of the hinge assembly or arms (or parts thereof) is compromised due to a change of shape of one or more mechanical elements and, as a result, the mechanical engagement is lost.

[00048] In any of the aspects described herein, the hinge assembly may be environment-sensitive, for example pH sensitive or preferably base sensitive, and is configured to deteriorate prior to expiration of the predetermined period of time once the hinge assembly is exposed to a basic solution.

[00049] In any of the aspects described herein, at least a portion of the hinge assembly is manufactured using injection molded materials.

[00050] In aspects, the partial degradation of at least one of the at least two arms or hinge assembly or partial release the API or diagnostic may be due to a pH dependent polymer. In any of the aspects described herein, the pH dependent polymer may be configured to erode in a basic environment. In another aspect, a method is provided for ending gastric retention of the GRDF by inducing a change in a basic environment. In any of the aspects described herein, as long as the hinge assembly engagement with the arms is environment sensitive, and the environment changes or can be induced to change, one can induce an end to gastric retention. In aspects, the pH dependent polymer may be coating or involved in physical make up of an arm or hinge assembly.

[00051] In any of the aspects described herein, the body is produced by injection molding or 3D printing .

[00052] According to an aspect of the present disclosure, a gastroretentive dosage form (GRDF) for extended retention in a stomach is provided and includes: a body including a hinge assembly, the body configured to move between a collapsed configuration for ingestion to an expanded configuration for retention in the stomach; and at least one insert retained within a portion of the body and comprising an active pharmaceutical ingredient (API) and an excipient, wherein a ratio of the API to a total load of the both the API and the excipient is from about 0.5 to about 0.95.

[00053] In any of the aspects described herein, the insert includes excipients for immediate release. According to another aspect of the disclosure, the ratio of the weight of the active pharmaceutical ingredients to the weight of the total weight of the insert tablet in the insert is from about 0.1 to about 0.99, in aspects, from about 0.5 to about 0.95, and in other aspects, from about 0.7 to about 0.9.

[00054] According to an aspect of the present disclosure, a pharmaceutical formulation suitable for retention in the stomach is provided and includes: a cellulose ester and a plasticizer combined in a ratio ranging from about 3 : 1 to about 8: 1, wherein the pharmaceutical formulation is retained in the stomach for a time period of more than 4 hours.

[00055] In any of the aspects described herein, the pharmaceutical formulation is retained in the stomach for a time period of more than 6 hours, in aspects, for a time period of more than 8 hours, in aspects, for a time period of more than 12 hours, in aspects, for a time period of more than 18 hours, in aspects, for a time period of more than 24 hours, in aspects, for a time period of more than 36 hours. In any aspect, the period of time is under fasted conditions or after a light meal .

[00056] In any of the aspects described herein, the GRDF is folded and positioned in a capsule. In any of the aspects described herein the formulation further comprises retention arms or a hinge assembly.

[00057] According to an aspect of the present disclosure, a gastroretentive dosage form (GRDF) is provided that includes: a pharmaceutically acceptable

material folded inside a capsule, wherein the pharmaceutical acceptable material unfolds into a size suitable for gastric retention in a time period of less than 5 minutes. In aspects, the time period for unfolding of the pharmaceutically acceptable material into a size suitable for gastric retention is less than 4 minutes, in aspects, less than 3 minutes, in aspects, less than 2 minutes.

[00058] In any of the aspects described herein, the GRDF further comprises an active pharmaceutical ingredient

[00059] According to an aspect of the present disclosure, a gastroretentive dosage form (GRDF) is provided that includes: a pharmaceutically acceptable material folded inside a capsule and including an active pharmaceutical ingredient, wherein an end to gastric retention of the dosage form is controlled by a release of the active pharmaceutical ingredient.

[00060] In any of the aspects described herein, the end to gastric retention occurs when more than 70% of the active pharmaceutical ingredient is released, in aspects, when more than 75% of the active pharmaceutical ingredient is released, in aspects, when more than 80% of the active pharmaceutical ingredient is released, in aspects, when more than 85% of the active pharmaceutical ingredient is released, in aspects, when more than 90% of the active pharmaceutical ingredient is released, in aspects, when more than 95% of the active pharmaceutical ingredient is released, in aspects, when 100% of the active pharmaceutical ingredient is released .

[00061] According to an aspect of the present disclosure, a gastroretentive dosage form (GRDF) is provided that includes: a body including two arms transitionable between a collapsed configuration and an expanded configuration for retaining the GRDF within the stomach for a predetermined time period; and an active pharmaceutical ingredient (API) or diagnostic at least partially positioned within the body.

[00062] In any of the aspects described herein, a biasing element is configured to maintain the two arms apart once the two arms transition to the expanded

configuration. In aspects, the biasing element is configured to transition the two arms from the collapsed configuration.

[00063] According to an aspect of the present disclosure, a gastroretentive dosage form (GRDF) is provided that includes a body including two arms transitionable from a first configuration swallowable by a user, a second configuration for retaining the GRDF within the stomach for a predetermined period of time, and a third configuration wherein the two arms disassemble after the elapse of the predetermined period of time.

[00064] According to an aspect of the present disclosure, a gastroretentive dosage form (GRDF) is provided that includes: at least two arms pivotably connected together and transitionable between a collapsed configuration wherein the at least two arms are disposed in close proximity relative to one another and the GRDF is suitable for swallowing and an expanded configuration wherein the at least two arms are further apart from one another; an active pharmaceutical ingredient (API) or diagnostic at least partially contained within a cavity defined in at least one of the at least two arms; and a biasing element configured to maintain the at least two arms apart once the at least two arms transition to the expanded configuration.

[00065] In any of the aspects described herein, the at least two arms are pivotable about a hinge assembly. In aspects described herein, the biasing element forms part of the hinge assembly. In aspects, the at least two arms and the hinge assembly are releasable engaged to one another.

[00066] In any of the aspects described herein, the hinge assembly is a unitary component.

[00067] In any of the aspects described herein, the hinge assembly includes two interconnected hinge portions that are pivotably coupled to each other, each hinge portion being connected to one of the at least two arms. In aspects, each hinge portion is connected to one of the at least two arms by a mechanically engaging component. In aspects, the hinge portions are configured to rotate with respect to each other within a limited range of motion that is less than or equal to 90 degrees.

[00068] According to an aspect of the present disclosure, a gastroretentive dosage form (GRDF) is provided that includes: a body including at least two arms each having a predetermined length and configured to move between a collapsed configuration for ingestion to an expanded configuration for retention in the stomach; and an active pharmaceutical ingredient positioned within at least one of the two arms, wherein the predetermined length of the at least one arm including the active pharmaceutical ingredient remains substantially the same during the release of the active pharmaceutical ingredient.

[00069] According to an aspect of the present disclosure, a gastroretentive dosage form (GRDF) is provided that includes: a body including at least two arms each having a predetermined length and configured to move between a collapsed configuration for ingestion to an expanded configuration for retention in the stomach; and an active pharmaceutical ingredient positioned within at least one of the two arms, wherein the predetermined length of at least one of the two arms remains substantially the same following disassembly of the body

[00070] According to an aspect of the present disclosure, an oral pharmaceutical for extended retention in a stomach is provided that includes: a body configured to transform about a hinge assembly between a collapsed configuration for ingestion and an expanded configuration for retention within the stomach for a predetermined time period; and an active pharmaceutical ingredient (API) or diagnostic at least partially positioned within the body.

[00071] In any of the aspects described herein, another portion of the API or diagnostic is concealed by the at least one arm of the body.

[00072] According to an aspect of the present disclosure, a gastroretentive dosage form (GRDF) is provided that includes: a body comprising a pH sensitive material and including at least two arms configured to transform from a collapsed configuration for ingestion to an expanded configuration for retention in the

stomach, wherein the pH sensitive material is configured to force the disassembly of the body.

[00073] According to an aspect of the present disclosure, a gastroretentive dosage form (GRDF) for extended retention in a stomach is provided that includes: a body configured to transform between a collapsed configuration for ingestion and an expanded configuration for retention within the stomach for a predetermined time period; and an active pharmaceutical ingredient (API) or diagnostic configured to releasably engage the body, wherein the body is configured to disassemble upon partial disintegration of the API, and wherein the body is made from a pharmaceutically acceptable material wherein the size, shape and durability of the body is substantially maintained while in the stomach for the predetermined period of time.

[00074] In any of the aspects described herein the API is released at a controlled rate over more than 6 hours, in aspects, over more than 8 hours, in aspects, over more than 10 hours

[00075] In any of the aspects described herein, the API or diagnostic is encased by at least one of the at least two arms.

[00076] In any of the aspects described herein, the API or diagnostic is released via an opening defined within at least one of the two arms.

[00077] In any of the aspects described herein, the API or diagnostic is an insert shaped to fit within a cavity defined in at least one of the at least two arms.

[00078] In any of the aspects described herein, the insert includes excipients for immediate release.

[00079] In any of the aspects described herein, in the expanded configuration, the at least two arms define an interior angle of less than about 90° therebetween. [00080] In any of the aspects described herein, the hinge assembly is pH sensitive and is configured to deteriorate prior to expiration of the predetermined period of time once the hinge assembly is exposed to a basic solution.

[00081] In any of the aspects described herein, in the expanded configuration, the at least two arms define an interior angle between about 45 degrees and about 90 degrees, in aspects, the at least two arms define an interior angle between about 45 degrees and about 80 degrees.

[00082] According to an aspect of the present disclosure, a gastroretentive dosage form (GRDF) is provided that includes: a body including at least two arms, the body configured to transform between a collapsed configuration for ingestion and an expanded configuration for retention within the stomach for a predetermined time period, wherein the gastroretentive dosage form maintains a mechanical strength and dimensions such that:

a . after 12hr exposure to simulated gastric fluids [Rotating apparatus having 37°C, pH2 + Xanthan gum 0.125gr/L, 25RPM mixing] - less than 5%, preferably less than 3% decrease in size when placed in a compression modulus with repeated force applied in the direction of refolding of 150g/mm, up to 750g

b. after more than 8hr exposure to simulated gastric fluids [Rotating apparatus having 37°C, pH2 Xanthan gum 0.125gr/L, 25RPM mixing] - size maintained to prevent passage through the 18mm pipe test under 600gr/F

c. after more than 24hrs in a pig stomach - size maintained

d . after more than 24hrs in a beagle dog stomach, 50% of the GRDFs maintained size

e. after 24hr exposure to simulated gastric fluids - less than 10% preferably less than 5% change in weight, length and thickness of body.

[00083] According to an aspect of the present disclosure, a gastroretentive dosage form (GRDF) is provided that includes: a hinged body configured to

transform between a collapsed configuration for ingestion and an expanded configuration for retention within the stomach for a predetermined time period, wherein the gastroretentive dosage form maintains a mechanical strength and dimensions such that.

a . after 12hr exposure to simulated gastric fluids [Rotating apparatus having 37°C, pH2 + Xanthan gum 0.125gr/L, 25RPM mixing] - less than 5%, preferably less than 3% decrease in size when placed in a compression modulus with repeated force applied in the direction of refolding of 150g/mm, up to 750g

b. after more than 8hr exposure to simulated gastric fluids [Rotating apparatus having 37°C, pH2 Xanthan gum 0.125gr/L, 25RPM mixing] - size maintained to prevent passage through the 18mm pipe test under 600gr/F

c. after more than 24hrs in a pig stomach - size maintained

d . after more than 24hrs in a beagle dog stomach, 50% of the GRDFs maintained size

e. after 24hr exposure to simulated gastric fluids - less than 10% preferably less than 5% change in weight, length and thickness of body.

[00084] According to an aspect of the present disclosure, a gastroretentive dosage form (GRDF) for extended retention in a stomach is provided that includes: a non-biodegradable body including a first arm and a second arm configured to move between a collapsed configuration for ingestion to an expanded configuration for retention in the stomach, the non-biodegradable body comprising a mixture including a pharmaceutically acceptable material and a plasticizer in a ratio ranging from about 3 : 1 to about 12 : 1.

[00085] According to an aspect of the present disclosure, a gastroretentive dosage form (GRDF) for extended retention in a stomach is provided that includes: a body configured to transform between a collapsed configuration for ingestion and an expanded configuration for retention within the stomach for a predetermined time period, wherein the GRDF exhibits gastric retention for more than 24hrs under fasted conditions in about 50% beagle dog .

[00086] According to an aspect of the present disclosure, a gastroretentive dosage form (GRDF) is provided that includes: a body configured to transform between a collapsed configuration for ingestion and an expanded configuration for retention within the stomach for a predetermined time period, wherein the GRDF does not pass the 18mm pipe test under 300grForce after exposure to simulated gastric conditions for 24hrs.

[00087] According to an aspect of the present disclosure, a gastroretentive dosage form (GRDF) is provided that includes: a body made of a pharmaceutically acceptable material and including an API having a size and strength maintained after more than 85% API is release, such that it cannot pass the 18mm pipe test under 300grForce.

[00088] According to an aspect of the present disclosure, a gastroretentive dosage form (GRDF) is provided that includes: a body configured to transform between a collapsed configuration for ingestion and an expanded configuration for retention within the stomach for a predetermined time period, wherein the GRDF does not pass the leaf durability test under 1250grForce and exposure to simulated gastric conditions for 12hrs.

[00089] According to an aspect of the present disclosure, a gastroretentive dosage form (GRDF) is provided that includes: a body configured to transform between a collapsed configuration for ingestion and an expanded configuration for retention within the stomach for a predetermined time period, wherein the body displays less than 6% deformation when compressed by 350grF after exposure to simulated gastric conditions for 12hrs.

[00090] In any of the aspects described herein, the GRDF further comprises an active pharmaceutical ingredient. In any of the aspects described herein, the GRDFs described herein may include a body which includes a volume ranging from about 100 mm3 to about 2000 mm3. In aspects, the volume of the body may range from about 200 mm3 to about 1800 mm3. In aspects, the volume of the body may range from about 500 mm3 to about 1500 mm3. In embodiments, the volume of the body may range from about 800 mm3 to about 1200 mm3. In aspects, the volume of the body may be about 950 mm3. In any of the aspects described herein, the GRDF is folded and positioned in a capsule.

[00091] In any of the aspects described herein, any of the GRDFs described or envisioned herein may include an emergency release feature that allows the GRDF to pass through the pyloric valve for immediate removal from the stomach and gastrointestinal tract, if needed or causes immediate disassembly outside of the gastric environment. Either in the presence or upon exposure to an antidote or environment different than typical gastric, the GRDF is configured to disassemble for passage from the stomach prior to expiration of the predetermined period of time or disassemble if it has passed the gastric environment. An antidote or other triggering mechanism may be employed to initiate the emergency release of the GRDF. In aspects, the GRDF includes a hinge assembly (or any other portion thereof) that is pH sensitive (for example sensitive to a pH 5 - 5.5) such that under normal gastric conditions the hinge assembly (or any portion thereof) remains intact and the GRDF functions as intended . However, if needed, the environmental pH can be slightly increased (to within the above pH sensitive range or any other specified range) causing the mechanical integrity of the hinge assembly (or any portion thereof) to erode causing the hinge assembly to disassemble from one or both arms and pass through the pyloric valve for subsequent evacuation. For example, in aspects, the erosion may cause reduced mechanical pressure between the insert and the hinge assembly (or a portion thereof) to eventually release the hinge assembly from one or both arm(s) and pass from the stomach.

[00092] In any of the aspects described herein, the pH-sensitive materials making up only part of the GRDF for the emergency release may include materials which dissolve, erode, and/or degrade at a pH higher than 5, and more particularly from a pH which ranges from about 5 to 7.5. Some non-limiting examples of suitable pH-sensitive materials include polyacrylamides, phthalate derivatives (i.e., compounds with covalently attached phthalate moieties) such as acid phthalates of carbohydrates, amylose acetate phthalate, cellulose acetate phthalate, other cellulose ester phthalates, cellulose ether phthalates, hydroxypropyl cellulose phthalate, hydroxypropyl ethylcellulose phthalate, hydroxypropyl methyl cellulose phthalate, methyl cellulose phthalate, polyvinyl acetate phthalate, polyvinyl acetate hydrogen phthalate, sodium cellulose acetate phthalate, starch acid phthalate, styrene-maleic acid dibutyl phthalate copolymer, styrene-maleic acid polyvinyl acetate phthalate copolymer, styrene and maleic acid copolymers, formalized gelatin, gluten, shellac, salol, keratin, keratin sandarac-tolu, ammoniated shellac, benzophenyl salicylate, cellulose acetate trimellitate, cellulose acetate blended with shellac, hydroxypropylmethyl cellulose acetate succinate, oxidized cellulose, polyacrylic acid derivatives such as acrylic acid and acrylic ester copolymers, methacrylic acid and esters thereof, vinyl acetate and crotonic acid copolymers.

[00093] In any of the aspects described herein, the body or the GRDF including any of the components of the GRDF, i.e., the body, arms, hinge assembly, etc., is made from at least one pharmaceutically acceptable material and preferably it is comprised of only pharmaceutically acceptable material, for example based on FDA's IIG list. In any of the aspects described herein, the formulation may be nonbiodegradable or biodegradable or particularly suitable for the injection molding process. The choice of pharmaceutically acceptable materials for GRDFs includes all materials that will maintain stability in the gastric environment and provide enough rigidity to prevent disassembly or disintegration prior to the desired time (preferably through fasted and fed states). Any acceptable pharmaceutically approved polymeric materials such as cellulose acetate, ethocel, eudragit, or hydroxypropyl cellulose acetate succinate, with or without addition of a plactisizer, can be used for preparation of the GRDF. If the desire is a non-biodegradable formulation, one may provide, for example, a cellulose ester with plasticizer. In any aspect described herein, the materials are selected and processed in a way that will enable each of the components of the GRDF to operate according to its defined functionality (e.g ., rigidity for the arms and hinge, elasticity of spring, and stability in dissolution, as defined above). Different materials may be used in order to better balance between durability and safety or eventual disintegration; pH independence and dependence, etc. For example, in aspects, the ratio of cellulose

acetate (CA) to plasticiser may contribute to the durability, elasticity, reduced brittleness, independence from pH changes and decreased erodability.

[00094] In any aspect described herein, the body is in a size, shape and durability suitable for be maintained while in the stomach for the predetermined time period. For example, the body may comprise : cellulose ester, HPMC acetate succinate, ethocel, eudragit or a plasticizer. The cellulose ester may be selected from the group consisting of cellulose acetate, cellulose triacetate, hydroxypropylmethylcellulose acetate succinate, cellulose proprionate, cellulose acetate proprionate, cellulose acetate butyrate, and combinations thereof. In aspects, the cellulose ester comprises cellulose acetate. In any of the aspects described herein, the cellulose ester and the plasticizer are combined in a ratio ranging from about 3 : 1 to about 8: 1. In aspects, the cellulose ester and the plasticizer are combined in a ratio ranging from about 4: 1 to about 6 : 1, in aspects, the cellulose ester and the plasticizer are combined in a ratio of about 4: 1. In aspects, the polymer may be selected from a listing comprising any one or more of the following : cellulose ester, HPMC acetate succinate, ethocel or eudragit. The plasticizer may be any one or more of the following : dibutyl sebacate, triethyl citrate, polyethylene glycol, polyethylene glycol monomethyl ether, acetyl tributyl citrate, triacetine, glycerin, sorbitol, sorbitan solutions, castor oil, diacetylated monoglycerides, triethyl citrate, tributyl citrate and combinations thereof. More specifically, the cellulose ester may be cellulose acetate (CA). The cellulose acetate (CA) to plasticiser ratio may be from about 3 : 1 to about 12 : 1, or in other aspects from about 3.5 to about 8: 1 or in another aspect from about 4 : 1 to about 6: 1, or specifically 4: 1.

[00095] In any of the aspects described herein, the body of GRDF comprises a plasticizer selected from the group consisting dibutyl sebacate, triethyl citrate, polyethylene glycol, polyethylene glycol monomethyl ether, acetyl tributyl citrate, triacetine, glycerin, sorbitol, sorbitan solutions, castor oil, diacetylated monoglycerides, triethyl citrate, tributyl citrate and combinations thereof. In any of the aspects described herein, the body may include more than about 50mg of the plasticizer per unit dosage form, in aspects, more than about lOOmg of the

plasticizer per unit dosage form, in aspects, more than about 150mg of the plasticizer per unit dosage form, in aspects, more than about 180mg of the plasticizer per unit dosage form, in aspects, more than about 190mg of the plasticizer per unit dosage form .

[00096] In any of the aspects described herein, the body may include more than about 50mg, or more than about 200mg of the cellulose ester per unit dosage form . In aspects, the body includes more than about 400mg of the cellulose ester per unit dosage form, in aspects, more than about 600mg of the cellulose ester per unit dosage form, in aspects, more than about 700mg of the cellulose ester per unit dosage form, in aspects, more than about 750mg of the cellulose ester per unit dosage form .

[00097] In any of the aspects described herein, the pharmaceutically acceptable material is hydroxypropylmethylcellulose and the plasticizer is triethyl citrate. In any of the aspects described herein, the pharmaceutically acceptable material is hydroxypropylmethylcellulose and the plasticizer is polyethylene glycol. In any of the aspects described herein, the pharmaceutically acceptable material is ethylcellulose and the plasticizer is triethyl citrate. In any of the aspects described herein, the pharmaceutically acceptable material includes methacrylic acid and methyl methacrylate and the plasticizer is triethyl citrate.

[00098] In any of the aspects described herein, the GRDF formulation or controlled release formulation comprises cellulose ester and triacetin and is capable of less than 10% preferably less than 5% change in weight, length and thickness after 24hr exposure to simulated gastric fluids.

[00099] In any of the aspects described herein, the body includes an opening defined therein configured to expose the API or diagnostic to gastric fluids in the stomach once the capsule at least partially dissolves. Thus, depending on the rate of API/diagnostic release or desired end point for gastric retention, the one or more openings may increase the surface area for release and erosion of the API/diagnostic or composition thereof.

[000100] In any of the aspects described herein, the GRDF provides mechanical strength and is capable of resisting forces applied by the stomach under both fed and fasted condition. The mechanical strength is sufficient to enable, upon expansion of the GRDF, the preservation of the expanded configuration to provide gastric retention. More specifically, there is provided a GRDF with collapsed and expanded configurations which resists mechanical gastric forces even for a period of time.

WHAT IS CLAIMED:

1. A gastroretentive dosage form (GRDF) for extended retention in a stomach, comprising :

a body configured to transform between a collapsed configuration for ingestion, an expanded configuration for retention within the stomach and a third configuration wherein after a predetermined time period has elapsed, the GRDF disassembles into two or more parts such that each of the disassembled parts of the GRDF is sized for exiting the stomach; and

an active pharmaceutical ingredient (API) or diagnostic,

wherein the third configuration is induced by at least a partial release of the API or diagnostic.

2. The GRDF of claim 1, wherein the body includes at least two arms.

3. The GRDF of claim 1, wherein the body includes two arms.

4. The GRDF of claims 1 or 2, wherein at least one of the at least two arms is configured to releasably engage the API or diagnostic.

5. The GRDF according to any preceding claim, wherein the API or diagnostic is positioned within a cavity defined in the body.

6. The GRDF of claim 5, wherein the API is positioned within the cavity in the form of a composition .

7. The GRDF of claims 2, 4 or 5 wherein the at least two arms are pivotably

connected together by a hinge assembly and are configured to disengage from one another due to partial degradation of at least one of the at least two arms or hinge assembly or partial release of the API or diagnostic.

8. The GRDF of claim 7, wherein partial degradation of at least one of the at least two arms or hinge assembly or partial release the API or diagnostic is due to a pH dependent polymer.

9. The GRDF of claims 7 or 8, wherein the pH dependent polymer erodes in a basic environment.

10. The GRDF of claims 7, 8 or 9, wherein one of the at least two arms includes a cavity defined therein configured to engage the hinge assembly and the API or diagnostic.

11. The GRDF of claims 7, 8, 9 or 10 wherein at least a portion of the hinge

assembly is sandwiched between at least one of the at least two arms of the body and the API or diagnostic, the hinge assembly configured to disengage from the at least one arm upon partial release of the API.

12. The GRDF of claims 2, 4, 5, 6, 7 or 8 wherein the at least two arms of the body are configured to disengage from one another upon partial release of the API.

13. The GRDF according to any preceding claim, wherein the predetermined time period is at least 4 hours.

14. The GRDF according to any preceding claim, wherein the predetermined time period is at least 6 hours.

15. The GRDF according to any preceding claim, wherein the predetermined time period is at least 8 hours.

16. The GRDF according to any preceding claim, wherein the predetermined time period is at least 10 hours.

17. The GRDF according to any preceding claim, wherein the predetermined time period is at least twelve hours.

18. The GRDF according to any preceding claim, wherein the predetermined time period is at least 18 hours.

19. The GRDF according to any preceding claim, wherein the API is in an amount less than 1.5 grams.

20. The GRDF according to any preceding claim, wherein the body is made from at least one pharmaceutically acceptable material wherein the size, shape and durability of the body are maintained while in the stomach for the predetermined time period.

21. The GRDF of claims 7 to 20 wherein after the predetermined time period has lapsed, the hinge assembly is configured to disengage from the at least two arms for release from the stomach.

22. The GRDF of claims 7 to 21, wherein the hinge assembly disengages from the at least two arms once the API is substantially released .

23. The GRDF of claim 22, wherein substantially released is more than 70%.

24. The GRDF of claims 22 wherein substantially released is more than 75%.

25. The GRDF of claim 22, wherein substantially released is more than 80%.

26. The GRDF of claims 2 to 25 wherein the size of at least one of the at least two arms is substantially maintained during transition between

configurations.

27. The GRDF according to any preceding claim, wherein the body is maintained in the collapsed configuration by a retention mechanism and the body is transitioned to the expanded configuration by a hinge assembly.

28. The GRDF of claim 27, wherein the retention mechanism is a capsule that dissolves when introduced to a fluid environment.

29. The GRDF of claims 27 or 28, wherein once the capsule at least partially dissolves, the body automatically transitions to the expanded configuration.

30. The GRDF of claims 27, 28, or 29, wherein the body automatically transitions to the expanded configuration suitable for gastric retention in less than 5 minutes.

31. The GRDF of claims 27, 28, or 29, wherein the body automatically transitions to the expanded configuration suitable for gastric retention in less than 4 minutes.

32. The GRDF of claims 27, 28, or 29, wherein the body automatically transitions to the expanded configuration suitable for gastric retention in less than 3 minutes.

33. The GRDF of claims 2 - 32, wherein the at least two arms include a first arm comprising a first API or diagnostic and a second arm comprising a second API or diagnostic.

34. The GRDF of claim 33, wherein the second API or diagnostic is incompatible with the first API or diagnostic.

35. The GRDF according to any preceding claim, wherein the body includes a potential volume of ranging from about 500mm3 to about 1500mm3 for housing the API or diagnostic composition.

36. The GRDF according to any preceding claim, wherein the body includes a potential volume of about 950mm3 for housing the API or diagnostic composition.

37. The GRDF according to any preceding claim, wherein the amount of the API ranges from about O. lmg to about 2grams.

38. The GRDF according to any preceding claim, wherein the amount of the API ranges from about lOmg to about 1.8grams.

39. The GRDF according to any preceding claim, wherein the amount of the API is in an amount greater than 400mg .

40. The GRDF according to any preceding claim, wherein the amount of the API is greater than 600mg .

41. The GRDF of claims 2 - 36, wherein the amount of the API is greater than 800mg.

42. The GRDF of claims 2 - 36, wherein the amount of the API is greater than lOOOmg .

43. The GRDF of claims 2 - 36, wherein the amount of the API is greater than 1500mg .

44. The GRDF of claims 6 to 43, wherein the composition comprises an excipient:

API in a ratio ranging from about 0.8 to about 0.05 by weight.

45. The GRDF of claim 44, wherein the ratio ranges from about 0.7 to about 0.3.

46. The GRDF of claims 43 or 44, wherein the ratio ranges from about 0.6 to

about 0.4.

47. The GRDF of claims 6 to 46, wherein a ratio of the API to a total load of the both the API and an excipient by weight is from about 0.5 to about 0.95.

48. The GRDF of claims 6 to 47, wherein the composition is an insert.

49. The GRDF of claims 20 to 48, wherein the pharmaceutically acceptable

material comprises a cellulose ester and a plasticizer.

50. The GRDF of claim 49, wherein the cellulose ester is selected from the group consisting of cellulose acetate, cellulose triacetate,

hydroxypropylmethylcellulose acetate succinate, cellulose proprionate, cellulose acetate proprionate, cellulose acetate butyrate, and combinations thereof.

51. The GRDF of claims 49 or 50, wherein the cellulose ester comprises cellulose acetate.

52. The GRDF of claims 49, 50 or 51 wherein the plasticizer is selected from the group consisting dibutyl sebacate, triethyl citrate, polyethylene glycol, polyethylene glycol monomethyl ether, acetyl tributyl citrate, triacetin, and combinations thereof.

53. The GRDF of claims 49 to 52, wherein the cellulose ester and the plasticizer are combined in a ratio ranging from about 3 : 1 to about 8: 1.

54. The GRDF of claims 49 to 52, wherein the cellulose ester and the plasticizer are combined in a ratio ranging from about 4: 1 to about 6: 1.

55. The GRDF of claims 49 to 52, wherein the cellulose ester and the plasticizer are combined in a ratio of about 4: 1.

56. The GRDF of claims 49 to 55, wherein the body includes more than about 200mg of the cellulose ester per unit dosage form.

57. The GRDF of claims 49 to 55, wherein the body includes more than about 400mg of the cellulose ester per unit dosage form.

58. The GRDF of claims 49 to 55, wherein the body includes more than about 600mg of the cellulose ester per unit dosage form.

59. The GRDF of claims 49 to 55, wherein the body includes more than about 700mg of the cellulose ester per unit dosage form.

60. The GRDF of claims 49 to 55, wherein the body includes more than about 750mg of the cellulose ester per unit dosage form.

61. The GRDF of claims 49 to 60, wherein the body includes more than about 50mg of the plasticizer per unit dosage form .

62. The GRDF of claim 49 to 60, wherein the body includes more than about lOOmg of the plasticizer per unit dosage form .

63. The GRDF of claims 49 to 60, wherein the body includes more than about 150mg of the plasticizer per unit dosage form .

64. The GRDF of claims 49 to 60, wherein the body includes more than about 180mg of the plasticizer per unit dosage form .

65. The GRDF of claims 49 to 60, wherein the body includes more than about 190mg of the plasticizer per unit dosage form .

66. The GRDF according to any preceding claim, wherein the body comprises a mechanical durability to remain intact over a period of time of at least 1 hour and under a repeated force of at least 400 grF.

67. The GRDF of claims 65 or 66, wherein the time period is at least 3 hours.

68. The GRDF of claims 65 or 66, wherein the time period is at least 6 hours.

69. The GRDF of claims 65 or 66, wherein the time period is at least 9 hours.

70. The GRDF of claims 66 to 69, wherein the repeated force ranges from about 400 to about 3000 grF.

71. The GRDF according to any preceding claim, wherein the body is produced by injection molding or 3D printing .

72. A gastroretentive dosage form (GRDF) for extended retention in a stomach, comprising :

a body including a hinge assembly, the body configured to move between a collapsed configuration for ingestion to an expanded configuration for retention in the stomach; and

at least one insert retained within a portion of the body and comprising an active pharmaceutical ingredient (API) and an excipient, wherein a ratio of the API to a total load of the both the API and the excipient is from about 0.5 to about 0.95.

73. A pharmaceutical formulation suitable for retention in the stomach,

comprising :

a cellulose ester and a plasticizer combined in a ratio ranging from about 3 : 1 to about 8: 1, wherein the pharmaceutical formulation is retained in the stomach for a time period of more than 4 hours.

74. The pharmaceutical formulation of claim 73, wherein the ratio ranges from about 4: 1 to 6: 1.

75. The pharmaceutical formulation of claims 73 or 74, wherein the ratio is about 4: 1.

76. The pharmaceutical formulation of claims 73, 74 or 75 wherein the

pharmaceutical formulation is retained in the stomach for a time period of more than 6 hours.

no

77. The pharmaceutical formulation of claims 73, 74 or 75, wherein the pharmaceutical formulation is retained in the stomach for a time period of more than 8 hours.

78. The pharmaceutical formulation of claims 73, 74 or 75, wherein the

pharmaceutical formulation is retained in the stomach for a time period of more than 12 hours.

79. The pharmaceutical formulation of claims 73, 74 or 75, wherein the

pharmaceutical formulation is retained in the stomach for a time period of more than 18 hours.

80. The pharmaceutical formulation of claims 73, 74 or 75, wherein the

pharmaceutical formulation is retained in the stomach for a time period of more than 24 hours.

81. The pharmaceutical formulation of claims 73, 74 or 75, wherein the

pharmaceutical formulation is retained in the stomach for a time period of more than 36 hours.

82. The pharmaceutical formulation of claims 73 to 81, wherein the cellulose ester is selected from the group consisting of cellulose acetate, cellulose triacetate, hydroxypropylmethylcellulose acetate succinate, cellulose proprionate, cellulose acetate proprionate, cellulose acetate butyrate, and combinations thereof.

83. The pharmaceutical formulation of claims 73 to 82, wherein the plasticizer is selected from the group consisting dibutyl sebacate, triethyl citrate, polyethylene glycol, polyethylene glycol monomethyl ether, acetyl tributyl citrate, triacetine, and combinations thereof.

84. The pharmaceutical formulation of claims 73 to 83, wherein the formulation is folded and positioned in a capsule.

in

85. The pharmaceutical formulation of claims 73 to 84, wherein the formulation further comprises retention arms or a hinge assembly.

86. The pharmaceutical formulation of claims 73 to 85, further comprising a

mechanical durability to remain intact over a period of time of at least 1 hour and under a repeated force of at least 400 grF.

87. The pharmaceutical formulation of claim 86, wherein the period of time to remain intact is at least 3 hours.

88. The pharmaceutical formulation of claim 86, wherein the time period to

remain intact is at least 6 hours.

89. The pharmaceutical formulation of claim 86, wherein the time period to

remain intact is at least 9 hours.

90. The pharmaceutical formulation of claim 86, wherein the time period to

remain intact is at least 24 hours.

91. The pharmaceutical formulation of claims 86 to 90, wherein the repeated force of at least 600 grF.

92. The pharmaceutical formulation of claims 86 to 90, wherein the repeated force ranges from about 400 to about 3000 grF.

93. The pharmaceutical formulation of claims 73 to 92, wherein the formulation is produced by injection molding or 3D printing .

94. The pharmaceutical formulation of claims 73 to 93, wherein the formulation is non-biodegradable.

95. The pharmaceutical formulation of claims 73 to 94, wherein the formulation includes more than about 50mg of the cellulose ester per unit dosage form .

96. The pharmaceutical formulation of claims 73 to 94, wherein the formulation includes more than about 200mg of the cellulose ester per unit dosage form.

97. The pharmaceutical formulation of claims 73 to 94, wherein the formulation includes more than about 400mg of the cellulose ester per unit dosage form.

98. The pharmaceutical formulation of claims 73 to 94, wherein the formulation includes more than about 600mg of the cellulose ester per unit dosage form.

99. The pharmaceutical formulation of claims 73 to 94, wherein the formulation includes more than about 700mg of the cellulose ester per unit dosage form.

100. The pharmaceutical formulation of claims 73 to 94, wherein the formulation includes more than about 750mg of the cellulose ester per unit dosage form.

101. The pharmaceutical formulation of claims 73 to 100, wherein the formulation includes more than about 50mg of the plasticizer per unit dosage form .

102. The pharmaceutical formulation of claims 73 to 100, wherein the formulation includes more than about lOOmg of the plasticizer per unit dosage form .

103. The pharmaceutical formulation of claims 73 to 100, wherein the formulation includes more than about 150mg of the plasticizer per unit dosage form .

104. The pharmaceutical formulation of claims 73 to 100, wherein the formulation includes more than about 180mg of the plasticizer per unit dosage form .

105. The pharmaceutical formulation of claims 73 to 100, wherein the formulation includes more than about 190mg of the plasticizer per unit dosage form .

106. A gastroretentive dosage form (GRDF), comprising :

a pharmaceutically acceptable material folded inside a capsule, wherein the pharmaceutical acceptable material unfolds into a size suitable for gastric retention in a time period of less than 5 minutes.

107. The GRDF of claim 106, wherein the time period for unfolding of the

pharmaceutically acceptable material into a size suitable for gastric retention is less than 4 minutes.

108. The GRDF of claim 106, wherein the time period for unfolding of the pharmaceutically acceptable material into a size suitable for gastric retention is less than 3 minutes.

109. The GRDF of claim 106, wherein the time period for unfolding of the

pharmaceutically acceptable material into a size suitable for gastric retention is less than 2 minutes.

110. The GRDF of claims 106 to 109, wherein the pharmaceutically acceptable material includes a cellulose ester and a plasticizer.

111. The GRDF of claim 110, wherein the cellulose ester is selected from the

group consisting of cellulose acetate, cellulose triacetate,

hydroxypropylmethylcellulose acetate succinate, cellulose proprionate, cellulose acetate proprionate, cellulose acetate butyrate, and combinations thereof.

112. The GRDF of claims 110 or 111 wherein the plasticizer is selected from the group consisting dibutyl sebacate, triethyl citrate, polyethylene glycol, polyethylene glycol monomethyl ether, acetyl tributyl citrate, triacetine, and combinations thereof.

113. The GRDF of claims 106 to 112, further comprising an active pharmaceutical ingredient

114. A gastroretentive dosage form (GRDF), comprising :

a pharmaceutically acceptable material folded inside a capsule and including an active pharmaceutical ingredient, wherein an end to gastric retention of the dosage form is controlled by a release of the active pharmaceutical ingredient.

The GRDF of claim 114, wherein the end to gastric retention occurs when more than 70% of the active pharmaceutical ingredient is released .

116. The GRDF of claim 114, wherein the end to gastric retention occurs when more than 75% of the active pharmaceutical ingredient is released .

117. The GRDF of claim 114, wherein the end to gastric retention occurs when more than 80% of the active pharmaceutical ingredient is released .

118. The GRDF of claim 114, wherein the end to gastric retention occurs when more than 85% of the active pharmaceutical ingredient is released .

119. The GRDF of claim 114, wherein the end to gastric retention occurs when more than 90% of the active pharmaceutical ingredient is released .

120. The GRDF of claim 114, wherein the end to gastric retention occurs when more than 95% of the active pharmaceutical ingredient is released .

121. The GRDF of claim 114, wherein the end to gastric retention occurs when 100% of the active pharmaceutical ingredient is released .

122. The GRDF of claims 114 to 121, wherein the pharmaceutically acceptable material includes a cellulose ester and a plasticizer.

123. The GRDF of claim 122, wherein the cellulose ester is selected from the

group consisting of cellulose acetate, cellulose triacetate,

hydroxypropylmethylcellulose acetate succinate, cellulose proprionate, cellulose acetate proprionate, cellulose acetate butyrate, and combinations thereof.

124. The GRDF of claims 122 or 123, wherein the plasticizer is selected from the group consisting dibutyl sebacate, triethyl citrate, polyethylene glycol, polyethylene glycol monomethyl ether, acetyl tributyl citrate, triacetine, and combinations thereof.

125. A gastroretentive dosage form (GRDF), comprising :

a body including two arms transitionable between a collapsed configuration wherein the two arms are disposed in close proximity relative to one another and an expanded configuration wherein the two arms are further apart from one another for retaining the GRDF within the stomach for a predetermined time period; and

an active pharmaceutical ingredient (API) or diagnostic at least partially positioned within the body.

126. The GRDF according to claim 125 further comprising a biasing element configured to maintain the two arms apart once the two arms transition to the expanded configuration.

126. The GRDF according to claim 126, wherein the biasing element is configured to transition the two arms from the collapsed configuration.

127. A gastroretentive dosage form (GRDF) for extended retention in a stomach, comprising :

a body including two arms transitionable from a first configuration swallowable by a user, a second configuration for retaining the GRDF within the stomach for a predetermined period of time, and a third configuration wherein the two arms disassemble after the elapse of the predetermined period of time.

128. The GRDF according to claim 127, wherein a size of at least one of the two arms is substantially maintained during transition between configurations.

129. The GRDF according to claims 127 or 128 further comprising a biasing element configured to maintain the two arms apart once the two arms transition to the expanded configuration.

130. The GRDF according to claim 129, wherein the biasing element is configured to transition the two arms from the collapsed configuration.

131. A gastroretentive dosage form (GRDF), comprising :

at least two arms pivotably connected together and transitionable between a collapsed configuration wherein the at least two arms are disposed in close proximity relative to one another and the GRDF is suitable for swallowing and an expanded configuration wherein the at least two arms are further apart from one another;

an active pharmaceutical ingredient (API) or diagnostic at least partially contained within a cavity defined in at least one of the at least two arms; and

a biasing element configured to maintain the at least two arms apart once the at least two arms transition to the expanded configuration.

132. The GRDF according to claim 131, wherein the at least two arms are pivotable about a hinge assembly.

133. The GRDF according to claims 131 or 132, wherein the biasing element forms part of the hinge assembly.

134. The GRDF according to claims 131, 132 or 133 wherein the at least two arms and the hinge assembly are releasable engaged to one another.

135. The GRDF according to claims 131 to 134, wherein at least a portion of at least one arm of the at least two arms is composed of an API or diagnostic.

136. The GRDF according to claims 131 to 135, wherein each arm includes a cavity defined therein configured to receive an API or diagnostic.

137. The GRDF according to claims 131 to 136, wherein the amount of API is about 500mg to 1.5 grams.

138. The GRDF according to claims 132 to 137, wherein at least one of the at least two arms, biasing element and hinge assembly is manufactured from pharmaceutically acceptable excipients as listed in IIG guidelines.

139. The GRDF according to claims 132 to 138, wherein the hinge assembly is a unitary component.

140. The GRDF according to claims 132 to 139, wherein the hinge assembly includes two interconnected hinge portions that are pivotably coupled to each other, each hinge portion being connected to one of the at least two arms.

141. The GRDF according to claim 140, wherein each hinge portion is connected to one of the at least two arms by a mechanically engaging component.

142. The GRDF according to claims 140 or 141, wherein the hinge portions are configured to rotate with respect to each other within a limited range of motion that is less than or equal to 90 degrees.

143. A gastroretentive dosage form (GRDF), comprising :

a body including at least two arms each having a predetermined length and configured to move between a collapsed configuration for ingestion to an expanded configuration for retention in the stomach; and

an active pharmaceutical ingredient positioned within at least one of the two arms, wherein the predetermined length of the at least one arm including the active pharmaceutical ingredient remains substantially the same during the release of the active pharmaceutical ingredient.

144. A gastroretentive dosage form (GRDF), comprising :

a body including at least two arms each having a predetermined length and configured to move between a collapsed configuration for ingestion to an expanded configuration for retention in the stomach; and

an active pharmaceutical ingredient positioned within at least one of the two arms, wherein the predetermined length of at least one of the two arms remains substantially the same following disassembly of the body

145. An oral pharmaceutical for extended retention in a stomach, comprising :

a body configured to transform about a hinge assembly between a collapsed configuration for ingestion and an expanded configuration for retention within the stomach for a predetermined time period; and

an active pharmaceutical ingredient (API) or diagnostic at least partially positioned within the body.

146. The oral pharmaceutical of claim 145, further comprising a capsule configured to encompass the body when disposed in the collapsed configuration, the capsule configured to at least partially dissolve upon introduction to fluid to expose and release the body from the collapsed configuration.

147. The oral pharmaceutical of claims 145 or 146 wherein the body includes an opening defined therein configured to expose the API or diagnostic to gastric fluids in the stomach once the capsule at least partially dissolves.

148. The oral pharmaceutical of claims 145, 146 or 147 wherein the body includes at least two arms that are pivotably connected to one another about the hinge assembly, at least one of the at least two arms including a cavity defined therein configured to receive at least a first portion of the API or diagnostic.

149. The oral pharmaceutical of claim 148, wherein the at least one arm that includes the cavity includes an opening defined therein in communication with the cavity.

150. The oral pharmaceutical of claims 148 or 149 wherein another portion of the API or diagnostic is concealed by the at least one arm of the body.

151. A gastroretentive dosage form (GRDF), comprising :

a body comprising a pH sensitive material and including at least two arms configured to transform from a collapsed configuration for ingestion to an expanded configuration for retention in the stomach, wherein the pH sensitive material is configured to force the disassembly of the body.

152. A gastroretentive dosage form (GRDF) for extended retention in a stomach, comprising :

a body configured to transform between a collapsed configuration for ingestion and an expanded configuration for retention within the stomach for a predetermined time period; and

an active pharmaceutical ingredient (API) or diagnostic configured to releasably engage the body, wherein the body is configured to disassemble upon partial disintegration of the API, and wherein the body is made from a pharmaceutically acceptable material wherein the size, shape and durability of the body is substantially maintained while in the stomach for the predetermined period of time.

153. The GRDF according to claim 152, wherein the API drug load is about 400 milligrams to about 1.5 grams.

154. The GRDF according to claim 152 wherein the API drug load is about 700 milligrams to about 1.5 grams.

155. The GRDF according to claims 152, 153 or 154 wherein the API is released at a controlled rate over more than 6 hours.

156. The GRDF according to claims 152, 153 or 154 wherein the API is released at a controlled rate over more than 8 hours.

157. The GRDF according to claims 152, 153 or 154 wherein the API is released at a controlled rate over more than 10 hours.

158. The GRDF according to claims 152 to 157 wherein the body includes at least two arms.

159. The GRDF according to claim 158, wherein the API or diagnostic is encased by at least one of the at least two arms.

160. The GRDF according to claims 158 or 159 wherein the API or diagnostic is released via an opening defined within at least one of the two arms.

161. The GRDF according to claims 158, 159 or 160 wherein the API or diagnostic is an insert shaped to fit within a cavity defined in at least one of the at least two arms.

162. The GRDF according to claim 161, wherein the insert includes excipients for immediate release.

163. The GRDF according to claims 158 to 162, wherein, in the expanded configuration, the at least two arms define an interior angle of less than about 90° therebetween.

164. The GRDF according to claims 158 to 163, wherein the at least two arms are movable about a hinge assembly.

165. The GRDF according to claim 164, wherein at least a portion of the hinge assembly is manufactured using injection molded materials.

166. The GRDF according to claims 164 or 165, wherein the hinge assembly is made from one or more pharmaceutically acceptable ingredients.

167. The GRDF according to claims 152 to 166, wherein, either in the presence of an antidote or upon exposure to the antidote, the GRDF is configured to disassemble for passage from the stomach prior to expiration of the predetermined period of time.

168. The GRDF according to claim 164 to 167, wherein the hinge assembly is pH sensitive and is configured to deteriorate prior to expiration of the predetermined period of time once the hinge assembly is exposed to a basic solution.

169. The GRDF according to claims 152 to 168, wherein the predetermined period of time is more than about 4 hours.

170. The GRDF according to claims 152 to 168, wherein the predetermined period of time is more than about 6 hours.

171. The GRDF according to claims 152 to 168, wherein the predetermined period of time is more than about 7 hours.

172. The GRDF according to claims 158 to 171, wherein, in the expanded configuration, the at least two arms define an interior angle between about 45 degrees and about 90 degrees.

173. The GRDF according to claims 158 to 171, wherein, in the expanded configuration, the at least two arms define an interior angle between about 45 degrees and about 80 degrees.

174. The GRDF according to claims 164 to 173, wherein the at least two arms detach from the hinge assembly at the predetermined period of time.

175. The GRDF according to claim 164 to 174, wherein the at least two arms detach from the hinge assembly when the API or diagnostic has been substantially released.

176. A gastroretentive dosage form (GRDF) for extended retention in a

stomach, comprising :

a non-biodegradable body including a first arm and a second arm configured to move between a collapsed configuration for ingestion to an expanded configuration for retention in the stomach, the non-biodegradable body comprising a mixture including a pharmaceutically acceptable material and a plasticizer in a ratio ranging from about 3 : 1 to about 12 : 1.

177. The GRDF of claim 176, wherein the ratio is from about 4: 1 to 12 : 1

178. The GRDF of claims 176 or 177, wherein the pharmaceutically acceptable material is selected from the group consisting of cellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methacrylic acid, methyl methacrylate and combinations thereof.

179. The GRDF of claims 176, 177 or 178, wherein the plasticizer is selected from the group consisting triethyl citrate, polyethylene glycol, and triacetin, dibutyl sebacate, triethyl-citrate, acetyl tributyl citrate , acetyl triethyl citrate polyethylene glycol monomethyl ether, glycerin, sorbitol sorbitan solutions, castor oil, diacetylated monoglycerides,triethyl citrate, tributyl citrate.

180. The GRDF of claims 176 to 179, wherein the pharmaceutically acceptable material is hydroxypropylmethylcellulose and the plasticizer is triethyl citrate.

181. The GRDF of claims 176 to 179, wherein the pharmaceutically acceptable material is hydroxypropylmethylcellulose and the plasticizer is polyethylene glycol.

182. The GRDF of claims 176 to 179, wherein the pharmaceutically acceptable material is cellulose and the plasticizer is triacetin.

183. The GRDF of claims 176 to 179, wherein the pharmaceutically acceptable material is ethylcellulose and the plasticizer is triethyl citrate.

184. The GRDF of claims 176 to 179, wherein the pharmaceutically acceptable material includes methacrylic acid and methyl methacrylate and the plasticizer is triethyl citrate.

185. A gastroretentive dosage form (GRDF) for extended retention in a stomach, comprising :

a body configured to transform between a collapsed configuration for ingestion and an expanded configuration for retention within the stomach for a predetermined time period,

wherein the GRDF exhibits gastric retention for more than 24hrs under fasted conditions in about 50% beagle dog .

186. A gastroretentive dosage form (GRDF), comprising :

a body configured to transform between a collapsed configuration for ingestion and an expanded configuration for retention within the stomach for a predetermined time period,

wherein the GRDF does not pass the 18mm pipe test under 300grForce after exposure to simulated gastric conditions for 24hrs.

187. A gastroretentive dosage form (GRDF), comprising :

a body made of a pharmaceutically acceptable material and including an API having a size and strength maintained after more than 85% API is release, such that it cannot pass the 18mm pipe test under 300grForce.

188. A gastroretentive dosage form (GRDF), comprising :

a body configured to transform between a collapsed configuration for ingestion and an expanded configuration for retention within the stomach for a predetermined time period,

wherein the GRDF does not pass the leaf durability test under

1250grForce and exposure to simulated gastric conditions for 12hrs.

189. A gastroretentive dosage form (GRDF), comprising :

a body configured to transform between a collapsed configuration for ingestion and an expanded configuration for retention within the stomach for a predetermined time period,

wherein the body displays less than 6% deformation when compressed by 350grF after exposure to simulated gastric conditions for 12hrs.

190. A method of assembling a gastroretentive dosage form (GRDF), comprising :

inserting an insert tablet into a cavity of a body formed by injection molding; and

combining the body with a hinge assembly.

191. A method of delivery of an API or diagnostic, comprising :

administering to a patient a GRDF of any of the previous claims in a closed configuration.

192. A method of manufacturing a dosage form for gastric retention, comprising :

forming a body of the dosage form including a cellulose ester composition.

193. The method of claim 192, wherein the cellulose ester composition includes a cellulose ester and a plasticizer.

194. The method of claim 192 or 193, wherein the cellulose ester is cellulose acetate and the plasticizer is triacetin.

195. A method of forcing a disassembly of a GRDF within a patient, comprising

administering a GRDF to a patient; and

administering an antidote to the patient, wherein the antidote increases a pH of the patient's stomach forcing the GRDF to disassemble into pieces of sufficient size to evacuate the stomach.

196. The method of claim 195, wherein the GRDF includes a body comprising a pH sensitive material which represents less than about 20% of a total weight of the body, wherein the pH sensitive material is configured to force the GRDF to disassemble.

197. Use of an immediate release formulation in the manufacture of a GRDF.

198. The use of claim 197 wherein the formulation is an insert tablet.

199. A controlled release formulation, comprising :

a body including a cavity suitable for retaining an API composition, wherein the body defines a surface area of exposure of the API composition which allows for the controlled release of the API.

200. The controlled release formulation of claim 199, wherein the API is released over more than 4 hours.

201. The controlled release formulation of claim 199, wherein the API is released over more than 8 hours.

202. The controlled release formulation of claim 199, wherein the API is released over more than 12 hours.

203. The controlled release formulation of claim 199, wherein the API is released over more than 18 hours.
204. The controlled release formulation of claim 199, wherein the API is released over more than 24 hours.