# US 8,771,730 B2 · Carbidopa/Levodopa gastroretentive drug delivery

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- Number: US 8,771,730 B2
- Document ID: US8771730B2
- Status: Granted
- Kind: B2
- Application number: 12/937,955
- Filed: 2009-04-17
- Published: 2011-05-19
- Granted: 2014-07-08
- Earliest claimed: 2008-04-18
- Assignees: Intec Pharma Ltd.
- Applicants: Nadav Navon; Eytan Moor; David Kirmayer; Elena Kluev; Giora Carni
- Inventors: Nadav Navon; Eytan Moor; David Kirmayer; Elena Kluev; Giora Carni
- Web page: https://patentgrep.com/patent/US8771730B2

## CPC

- A61K 9/0065: {Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus}
- A61K 9/282: {Organic compounds, e.g. fats}
- A61K 9/2846: {Poly(meth)acrylates}
- A61K 9/2866: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/2873: {Proteins, e.g. gelatin}
- A61K 9/2886: {having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer (of the type active core-drug layer-inactive layer A61K9/209)}
- A61K 9/48: Preparations in capsules, e.g. of gelatin, of chocolate {(A61K9/0004 takes precedence; bite capsules A61K9/0056)}
- A61K 9/4808: {characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release (capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084)}
- A61K 9/4866: {Organic macromolecular compounds}
- A61K 9/4875: {Compounds of unknown constitution, e.g. material from plants or animals (oils, fats, waxes, shellac A61K9/4858)}
- A61K 9/4891: {Coated capsules; Multilayered drug free capsule shells (with drug coating for immediate release A61K9/4808; osmotic devices A61K9/0004)}
- A61K 9/7007: {Drug-containing films, membranes or sheets (A61K9/0041, A61K9/0043, A61K9/006, A61K9/0063 take precedence)}
- A61K 31/195: having an amino group
- A61K 31/198: Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00)
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 25/16: Anti-Parkinson drugs
- A61P 31/02: Local antiseptics
- A61P 35/00: Antineoplastic agents
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

A gastroretentive drug formulation for the sustained release of an active agent in the gastrointestinal tract comprises an internal layer or compartment comprising an active agent and one or more pharmaceutical excipients, of which at least one is a polymer and two membranes forming together an envelope around the inner membrane, each membrane comprising at least one polymeric combination of an enteric polymer which is not soluble in gastric juice, and an hydrophilic swelling polymer, and at least one plasticizer.

## Claims

### Claim 1

A gastroretentive drug delivery system for the sustained release of an active agent in the stomach and gastrointestinal tract of a patient, comprising:
an internal layer, including a first side and an opposing second side, comprising a degradable polymer composition, which is not instantly soluble in gastric fluid, and an active agent, said active agent and said degradable polymer composition being uniformly distributed throughout the internal layer, wherein said internal layer has uniform strength throughout; and
at least one outer membrane being directly secured to and covering said first side and said second side of said internal layer and comprising at least one polymeric combination of a hydrophilic polymer and a polymer that is insoluble in gastric media, said at least one outer membrane being hydratable at a rate greater than that of said internal layer and permitting passage of gastric media from the stomach environment to said internal layer and permitting passage of said active agent from said internal layer through said at least one outer membrane to the stomach environment;
wherein said internal layer and said at least one outer membrane secured thereto are arranged in an accordion folded configuration of a size permitting placement within a capsule for oral intake, which capsule is dissolvable within the stomach, and wherein said internal layer and said at least one outer membrane secured thereto provide sufficient mechanical force to unfold from the initial accordion folded configuration to an unfolded configuration having a length of at least 20 mm within 30 minutes of being exposed to gastric medium,
with the proviso that a scaffold, containing no active agent, is not present.

### Claim 2 (depends on 1)

The gastroretentive drug delivery system of claim 1, wherein said at least one outer membrane and said internal layer provide sufficient mechanical force to unfold them from the initial accordion folded configuration to an unfolded configuration having a length of at least 20 mm within 15 minutes of being exposed to gastric fluid.

### Claim 3 (depends on 1)

The gastroretentive drug delivery system of claim 1, wherein said internal layer has a mechanical strength described with Young's modulus ranging from about 0.5 to 15 Kgf/mm2 and stress of about 0.03 to about 0.6 Kgf/mm2 after 1 hour in simulated gastric fluid.

### Claim 4 (depends on 1)

The gastroretentive drug delivery system of claim 1, comprising two separate outer membranes, one of said outer membranes being directly secured to and covering the first side of said internal layer and the other of said outer membranes being directly secured to and covering the second side of said internal layer, the two outer membranes being directly joined together along an outer periphery thereof that is outside the outer periphery of said internal layer, said internal layer being located between said outer membranes.

### Claim 5 (depends on 4)

The gastroretentive drug delivery system of claim 4, wherein said outer membranes are joined together by ultrasonic welds.

### Claim 6 (depends on 5)

The gastroretentive drug delivery system of claim 5, wherein said outer membranes are secured to said internal layer by ultrasonic welds along a region adjacent the outer periphery of said internal layer.

### Claim 7 (depends on 6)

The gastroretentive drug delivery system of claim 6, wherein a central portion of the sides of said internal layer is essentially free from ultrasonic welds.

### Claim 8 (depends on 4)

The gastroretentive drug delivery system of claim 4, wherein said internal layer and said outer membranes are free of an additional adhesive member.

### Claim 9 (depends on 1)

The gastroretentive drug delivery system of claim 1, comprising two outer membranes covering said internal layer, being a first outer membrane and a second outer membrane, each of said first and second outer membranes having a width and length greater than a width and length of said internal layer,
said first and second outer membranes being affixed or attached directly together along the periphery of said first and second outer membranes, said first outer membrane being attached to the first side of said internal layer, said second membrane being attached to the second side of said internal layer, said internal layer and said first and second outer membranes having a length greater than 20 mm in a planar orientation,
the affixation or attachment of said first and second outer membranes to one another having sufficient mechanical strength to remain intact upon being exposed to gastric medium.

### Claim 10 (depends on 9)

The gastroretentive drug delivery system according to claim 9, wherein said outer membranes are affixed or attached to one another by ultrasonic welds.

### Claim 11 (depends on 10)

The gastroretentive drug delivery system of claim 10, wherein said internal layer and said first and second outer membranes include a central region that is substantially free of ultrasonic welds.

### Claim 12 (depends on 10)

The gastroretentive drug delivery system of claim 10, wherein the ultrasonic welds between said outer membranes and said internal layer do not penetrate entirely through said internal layer.

### Claim 13 (depends on 12)

The gastroretentive drug delivery system of claim 12, wherein the ultrasonic welds between said outer membranes and said internal layer are in a pattern that is not continuous.

### Claim 14 (depends on 13)

The gastroretentive drug delivery system of claim 13, wherein the ultrasonic welds on the periphery of said outer membranes form a skirt region that surrounds but does not capture said internal layer.

### Claim 15 (depends on 14)

The gastroretentive drug delivery system of claim 14, wherein said internal layer and said first and second outer membranes include a central region that is substantially free of ultrasonic welds.

### Claim 16 (depends on 12)

The gastroretentive drug delivery system of claim 12, wherein said ultrasonically welded internal layer and outer membranes have a stress from about 0.05 to 0.4 Kgf/mm2 after 1 hour in simulated gastric fluid.

### Claim 17 (depends on 16)

The gastroretentive drug delivery system of claim 16, wherein said outer membranes and said internal layer provide sufficient mechanical force to unfold them from the initial accordion folded configuration to an unfolded configuration having a length of at least 20 mm within 15 minutes of being exposed to gastric fluid.

### Claim 18 (depends on 17)

The gastroretentive drug delivery system of claim 17, wherein the length of said outer membranes in the planar orientation is at least 30 mm in an unfolded configuration.

### Claim 19

A gastroretentive drug delivery system for the sustained release of an active agent in the gastrointestinal tract, comprising:
an internal layer having a first side and an opposing second side, said internal layer comprising an active agent and a degradable hydrophilic polymer and a degradable enteric polymer which is substantially insoluble at pH less than 5.5, and a plasticizer, the active agent, the degradable hydrophilic polymer and the degradable enteric polymer being uniformly distributed throughout said internal layer; and at least one outer membrane covering said internal layer and comprising at least one polymeric combination of a hydrophilic polymer, a polymer that is insoluble in gastric media, and at least one plasticizer, said at least one outer membrane swelling in the presence of gastric medium,
wherein one of the materials comprised in said internal layer and one of the materials comprised in said at least one outer membrane are capable of being ultrasonically welded together,
wherein said at least one outer membrane is directly secured to a side of said internal layer and covers the side of said internal layer to which it is secured, said at least one outer membrane having a length greater than 20 mm in a planar orientation,
wherein said at least one outer membrane and said internal layer are arranged in an accordion folded configuration of a size permitting placement within a capsule for oral intake, which capsule is dissolvable within the stomach, said at least one outer membrane permitting passage of gastric fluid from the stomach to said internal layer and permitting passage of gastric fluid and said active agent from said internal layer through said at least one outer membrane to the stomach, and
wherein said internal layer and said at least one outer membrane secured thereto provide mechanical force sufficient to unfold from the accordion folded configuration to an unfolded configuration having a length of at least 20 mm within 30 minutes of being exposed to gastric fluid
with the proviso that a scaffold, containing no active agent, is not present.

### Claim 20 (depends on 19)

The gastroretentive drug delivery system of claim 19, wherein the enteric polymer in said internal layer is selected from the group consisting of cellulose acetate phthalate, hypromellose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate and methylmethacrylate-methacrylic acid copolymers.

### Claim 21 (depends on 19)

The gastroretentive drug delivery system of claim 19, wherein the polymeric combination in said outer membranes comprises gelatin.

### Claim 22 (depends on 19)

The gastroretentive drug delivery system of claim 19, wherein the enteric polymer in said at least one outer membrane is selected from the group consisting of one or more types of polymethacrylate USP.

### Claim 23 (depends on 19)

The gastroretentive drug delivery system of claim 19, wherein the at least one plasticizer in said at least one outer membrane comprises propylene glycol.

### Claim 24 (depends on 21)

The gastroretentive drug delivery system of claim 21, wherein the amount of gelatin in said at least one outer membrane is an amount of between about 20% and about 45% of the total outer membrane composition.

### Claim 25 (depends on 19)

The gastroretentive drug delivery system of claim 19, wherein said internal layer has a mechanical strength described with Young's modulus of from about 0.5 to about 15 Kgf/mm2 and stress of from about 0.03 to about 0.6 Kgf/mm2 after 1 hour in simulated gastric fluid.

### Claim 26 (depends on 19)

The gastroretentive drug delivery system of claim 19, wherein said at least one outer membrane swells at a rate faster than that of said internal layer, causing the accordion folded internal layer and outer membrane secured thereto to unfold in gastric medium.

### Claim 27 (depends on 26)

The gastroretentive drug delivery system of claim 26, wherein said at least one outer membrane is tightly secured to the said internal layer to exert the force resulting in unfolding.

### Claim 28 (depends on 1)

The gastroretentive drug delivery system of claim 1, wherein said inner layer and said outer membrane are formulated as to be fully degradable within 3 hours in simulated intestinal fluid.

### Claim 29 (depends on 1)

The gastroretentive drug delivery system of claim 1, formulated to provide gastric retention of said active agent for up to 24 hours under low or medium calorie diet in humans.

### Claim 30 (depends on 1)

The gastroretentive drug delivery system of claim 1, wherein said active agent is a drug for the local treatment of the gastrointestinal tract.

### Claim 31 (depends on 1)

The gastroretentive drug delivery system of claim 1, further comprising at least one immediate release layer secured to at least one side of said internal layer and said at least one outer membrane secured thereto, wherein said at least one immediate release layer comprises at least one active agent and at least one water soluble polymer, and wherein said at least one immediate release layer further comprises at least one additive selected from the group consisting of a plasticizer, a solubilizing agent intended for immediate release of the drug in the stomach, a disintegrant, a glidant, and any combination thereof.

### Claim 32 (depends on 31)

The gastroretentive drug delivery system of claim 31, wherein said active agent comprised in said internal layer, said active agent comprised in said immediate release layer, or said active agent comprised in both said internal layer and said immediate release layer, is selected from the group consisting of levodopa, carbidopa, and levodopa/carbidopa mixture.

### Claim 33 (depends on 32)

The gastroretentive drug delivery system of claim 32, containing 250 mg of levodopa and 50 mg of carbidopa.

### Claim 34 (depends on 33)

The gastroretentive drug delivery system of claim 33, wherein 70 mg of the levodopa and 25 mg of the carbidopa are formulated as an immediate release component, whereas the remaining 25 mg of carbidopa and 180 mg of levodopa are formulated so as to be released in a controlled manner over 8-10 hours.

### Claim 35 (depends on 32)

The gastroretentive drug delivery system of claim 32, containing 375 mg of levodopa and 50 mg of carbidopa.

### Claim 36 (depends on 35)

The gastroretentive drug delivery system of claim 35, wherein 100 mg of the levodopa and 25 mg of the carbidopa are formulated as an immediate release component, and wherein the remaining 25 mg of carbidopa and 275 mg of levodopa are formulated so as to be released in a controlled manner over 8-10 hours.

### Claim 37

A gastroretentive drug delivery system for the sustained release of an active agent in the gastrointestinal tract, comprising:
an internal layer, including a first side and an opposing second side, comprising an active agent and a degradable hydrophilic polymer which is not instantly soluble in gastric fluid and a degradable enteric polymer which is substantially insoluble at pH less than 5.5, and a plasticizer, the active agent and the degradable hydrophilic polymer and the degradable enteric polymer being uniformly distributed throughout the internal layer, and
a first and a second outer membrane directly secured to and covering both sides of said internal layer, said first and second outer membranes including at least one polymeric combination of a hydratable swelling polymer and an enteric polymer, and at least one plasticizer, wherein said membranes swell in the presence of gastric fluid,
wherein one of the materials in said internal layer and one of the materials in each of said first and second outer membranes is capable of being ultrasonically welded together,
wherein said internal layer and said first and second outer membranes have a length greater than 20 mm in a planar orientation, said internal layer and said outer membranes attached thereto being arranged in an accordion folded configuration of a size permitting placement within a capsule for oral intake, which capsule is dissolvable within the stomach,
wherein said internal layer and said first and second outer membranes secured thereto provide sufficient mechanical force to unfold from the accordion folded configuration to an unfolded configuration having a length of at least 20 mm within 30 minutes of being exposed to gastric fluid,
wherein said first and second outer membranes have a width and length greater than a width and length of said internal layer, said first and second outer membranes being ultrasonically welded together along the periphery of said first and second outer membranes, said first outer membrane being ultrasonically welded to the first side of said internal layer, and said second outer membrane being ultrasonically welded to the second side of said internal layer, said outer membranes permitting passage of gastric fluid from the stomach to said internal layer and permitting passage of gastric fluid and said active agent from said internal layer through said outer membrane to the stomach, and
wherein the ultrasonic welds have sufficient mechanical strength to remain intact upon being exposed to gastric medium.

### Claim 38 (depends on 1)

The gastroretentive drug delivery system of claim 1, further comprising at least one additional layer affixed to said outer membrane covering one or both sides of said inner layer, and wherein said additional layer comprises a drug or a combination of drugs, together with one or more additives selected from the group consisting of water soluble polymers, a plasticizer, a solubilizing agent intended for immediate release of the drug in the stomach, a disintegrant and a glidant.

### Claim 39 (depends on 1)

The gastroretentive drug delivery system of claim 1, wherein said active agent comprises a drug selected from the group consisting of levodopa, carbidopa, and levodopa/carbidopa mixture.

### Claim 40 (depends on 1)

The gastroretentive drug delivery system of claim 1, containing 250 mg of levodopa and 50 mg of carbidopa.

### Claim 41 (depends on 1)

The gastroretentive drug delivery system of claim 1, containing 375 mg of levodopa and 50 mg of carbidopa.

### Claim 42

A gastroretentive drug delivery system for the sustained release of an active agent in the stomach and gastrointestinal tract of a patient, comprising:
an internal layer, including a first side and an opposing second side, comprising a degradable polymer composition, which is not instantly soluble in gastric fluid,
and an active agent, said active agent and said degradable polymer composition being uniformly distributed throughout the internal layer; and
two outer membranes, each being equal in size with said internal layer, one of said outer membranes being directly secured to and covering the first side of said internal layer and the other of said outer membranes being directly secured to and covering the second side of said internal layer, said two outer membranes each comprising at least one polymeric combination of a hydrophilic polymer and a polymer that is insoluble in gastric media, said outer membranes being hydratable at a rate greater than that of said internal layer and permitting passage of gastric media from the stomach environment to said internal layer and permitting passage of said active agent from said internal layer through said outer membranes to the stomach environment;
wherein said internal layer and said two outer membranes secured thereto are arranged in an accordion folded configuration of a size permitting placement within a capsule for oral intake, which capsule is dissolvable within the stomach, and wherein said
internal layer and said two outer membranes secured thereto provide sufficient mechanical force to unfold from the initial accordion folded configuration to an unfolded configuration having a length of at least 20 mm within 30 minutes of being exposed to gastric medium.

### Claim 43 (depends on 42)

The gastroretentive drug delivery system of claim 42, further comprising an additional layer covering said outer membranes, wherein said additional layer comprises a powder or a film that prevents adherence of said outer membranes onto themselves when in the accordion folded configuration.

### Claim 44 (depends on 31)

The gastroretentive drug delivery system of claim 31, further comprising an additional layer covering said outer membranes or said at least one immediate release layer, wherein said additional layer comprises a powder or a film that prevents adherence of said outer membrane and/or said immediate release layer onto themselves when in the accordion folded configuration.

### Claim 45 (depends on 1)

The gastroretentive drug delivery system of claim 1, further including a capsule suitable for oral intake, which capsule is dissolvable within the stomach, wherein said internal layer and said at least one outer membrane arranged in said accordion folded configuration are contained in said capsule.

### Claim 46 (depends on 19)

The gastroretentive drug delivery system of claim 19, further including a capsule suitable for oral intake, which capsule is dissolvable within the stomach, wherein said internal layer and said at least one outer membrane arranged in said accordion folded configuration are contained in said capsule.

### Claim 47 (depends on 37)

The gastroretentive drug delivery system of claim 37, further including a capsule suitable for oral intake, which capsule is dissolvable within the stomach, wherein said internal layer and said first and second outer membranes arranged in said accordion folded configuration are contained in said capsule.

### Claim 48

A gastroretentive drug delivery system for the sustained release of an active agent in the gastrointestinal tract, comprising:
an internal layer having a first side and an opposing second side, said internal layer comprising an active agent and a degradable hydrophilic polymer and a degradable enteric polymer which is substantially insoluble at pH less than 5.5, and a plasticizer, wherein the active agent and the degradable hydrophilic polymer and the degradable enteric polymer are uniformly distributed throughout said internal layer; and
two outer membranes covering said internal layer, each being equal in size with said internal layer, each said outer membrane comprising at least one polymeric combination of a hydrophilic polymer and a polymer that is insoluble in gastric media, and at least one plasticizer, each said outer membrane configured for swelling in the presence of gastric medium,
wherein one of the materials comprised in said internal layer and one of the materials comprised in each said outer membrane are capable of being ultrasonically welded together,
wherein each one of said two outer membranes covers and is directly secured to a different one of said first side and said second side of said internal layer, said two outer membranes having a length greater than 20 mm in a planar orientation,
wherein said two outer membranes and said internal layer are arranged in an accordion folded configuration of a size permitting placement within a capsule for oral intake, which capsule is dissolvable within the stomach, said two outer membranes permitting passage of gastric fluid from the stomach to said internal layer and permitting passage of gastric fluid and the active agent from said internal layer through said two outer membranes to the stomach, and
wherein said internal layer and said two outer membranes secured thereto provide mechanical force sufficient to unfold from the accordion folded figuration to an unfolded configuration having a length of at least b 20 mm within 30 minutes of being exposed to gastric fluid.

### Claim 49

A gastroretentive drug delivery system for the sustained release of an active agent in the gastrointestinal tract, comprising:
an internal layer, including a first side and an opposing second side, comprising an active agent, a degradable hydrophilic polymer which is not instantly soluble in gastric fluid, a degradable enteric polymer which is substantially insoluble at pH less than 5.5, and a plasticizer, the active agent, the degradable hydrophilic polymer and the degradable enteric polymer being uniformly distributed throughout the internal layer; and
first and second outer membranes covering said internal layer and each being equal in size with said internal layer, said outer membranes including at least one polymeric combination of a hydratable swelling polymer, an enteric polymer, and at least one plasticizer, said outer membranes swelling in the presence of gastric fluid, said outer membranes being directly secured to and covering both sides of the internal layer,
wherein one of the materials in said internal layer and one of the materials in each of said outer membranes are capable of being ultrasonically welded together,
wherein said internal layer and said first and second outer membranes have a length greater than 20 mm in a planar orientation, said internal layer and said outer membranes attached thereto being arranged in an accordion folded configuration of a size permitting placement within a capsule for oral intake, which capsule is dissolvable within the stomach,
wherein said internal layer and said outer membranes secured thereto are capable of providing mechanical force sufficient to unfold from the accordion folded configuration to an unfolded configuration having a length of at least 20 mm within 30 minutes of being exposed to gastric fluid,
wherein said first outer membrane is ultrasonically welded to the first side of said internal layer, and said second outer membrane is ultrasonically welded to the second side of said internal layer, said outer membranes permitting passage of gastric fluid from the stomach to said internal layer and permitting passage of gastric fluid and the active agent from said internal layer through said outer membrane to the stomach,
wherein said internal layer and said first and second outer membranes have a length greater than 20 mm in a planar orientation, said internal layer and said outer membranes attached thereto being arranged in an accordion folded configuration of a size permitting placement within a capsule for oral intake, which capsule is dissolvable within the stomach, and
wherein the ultrasonic welds have sufficient mechanical strength to remain intact upon being exposed to gastric medium.

### Claim 50

A gastroretentive drug delivery system for the sustained release of an active agent in the stomach and gastrointestinal tract of a patient, comprising:
an internal layer, including a first side, an opposing second side, and an outer-facing peripheral side extending between respective edges of the first side and the second side, comprising
a degradable polymer composition, which is not instantly soluble in gastric fluid
and an active agent, the active agent and the degradable polymer composition being uniformly distributed throughout the internal layer; and
two outer membranes, each being larger in size than said internal layer, one of said outer membranes covering the first side of said internal layer and the other of said outer membranes covering the second side of said internal layer and contacting said peripheral side, said two outer membranes each having a length greater than 20 mm in a planar orientation and each comprising at least one polymeric combination of a hydrophilic polymer and a polymer that is insoluble in gastric media, said outer membranes being hydratable at a rate greater than that of said internal layer and permitting passage of gastric media from the stomach environment to said internal layer and permitting passage of said active agent from said internal layer through said outer membranes to the stomach environment;
wherein said internal layer and said two outer membranes are arranged in an accordion folded configuration of a size permitting placement within a capsule for oral intake, which capsule is dissolvable within the stomach, and wherein said
internal layer and said two outer membranes provide sufficient mechanical force to unfold from the initial accordion folded configuration to an unfolded configuration having a length of at least 20 mm within 30 minutes of being exposed to gastric medium.

### Claim 51

A gastroretentive drug delivery system for the sustained release of an active agent in the gastrointestinal tract, comprising:
an internal layer, including a first side, an opposing second side, and an outer-facing peripheral side extending between respective edges of the first side and the second side,
comprising an active agent, degradable hydrophilic polymer, degradable enteric polymer which is substantially insoluble at pH less than 5.5, and a plasticizer, the active agent, the degradable hydrophilic polymer and the degradable enteric polymer being uniformly distributed throughout said internal layer; and
two outer membranes, each being larger in size than said internal layer, one of said outer membranes covering the first side of said internal layer and the other of said outer membranes covering the second side of said internal layer and contacting said peripheral side, each said outer membrane having a length greater than 20 mm in a planar orientation and each comprising at least one polymeric combination of a hydrophilic polymer, a polymer that is insoluble in gastric media, and at least one plasticizer, each said outer membrane being configured for swelling in the presence of gastric medium,
wherein one of the materials comprised in said internal layer and one of the materials comprised in each said outer membrane are capable of being ultrasonically welded together,
wherein said two outer membranes and said internal layer are arranged in an accordion folded configuration of a size permitting placement within a capsule for oral intake, which capsule is dissolvable within the stomach,
wherein said two outer membranes permit passage of gastric fluid from the stomach to said internal layer and permit passage of gastric fluid and the active agent from said internal layer through said two outer membranes to the stomach, and
wherein said internal layer and said two outer membranes secured thereto provide mechanical force sufficient to unfold from the accordion folded configuration to an unfolded configuration having a length of at least 20 mm within 30 minutes of being exposed to gastric fluid.

### Claim 52

A gastroretentive drug delivery system for the sustained release of an active agent in the gastrointestinal tract, comprising:
an internal layer, including a first side, an opposing second side, and an outer-facing peripheral side extending between respective edges of the first side and the second side, comprising an active agent, a degradable hydrophilic polymer which is not instantly soluble in gastric fluid, a degradable enteric polymer which is substantially insoluble at pH less than 5.5, and a plasticizer,
the active agent, the degradable hydrophilic polymer, and the degradable enteric polymer being uniformly distributed throughout said internal layer; and
first and second outer membranes, each having a width and length larger in size that those of said internal layer, the first outer membrane covering and being secured, by ultrasonic welding, to the first side of said internal layer and the second outer membrane covering and being secured, by ultrasonic welding, to the second side of said internal layer and contacting said peripheral side, said outer membranes each including at least one polymeric combination of a hydratable swelling polymer, an enteric polymer, and at least one plasticizer, the membrane swelling in the presence of gastric fluid, the outer membranes permitting passage of gastric fluid from the stomach to said internal layer and permitting passage of gastric fluid and the active agent from said internal layer through said outer membranes to the stomach,
one of the materials in said internal layer and one of the materials in each of said outer membranes being capable of being ultrasonically welded together,
wherein said internal layer and said first and second outer membranes have a length greater than 20 mm in a planar orientation, said internal layer and said outer membranes attached thereto being arranged in an accordion folded configuration of a size permitting placement within a capsule for oral intake, which capsule is dissolvable within the stomach,
wherein said internal layer and said outer membranes secured thereto are capable of providing mechanical force sufficient to unfold from the accordion folded configuration to an unfolded configuration having a length of at least 20 mm within 30 minutes of being exposed to gastric fluid, and
wherein the ultrasonic welds having sufficient mechanical strength to remain intact upon being exposed to gastric medium.

### Claim 53 (depends on 50)

The gastroretentive drug delivery system according to claim 50, wherein said two outer membranes are ultrasonically welded together along the periphery of the first and second outer membranes outside of the periphery of said internal layer.

### Claim 54 (depends on 1)

The gastroretentive drug delivery system according to claim 1, wherein said internal layer is formulated to provide the necessary mechanical strength for retention of the unfolded device in the gastric medium for at least 5 hours.

### Claim 55 (depends on 30)

The gastroretentive drug delivery system according to claim 30, wherein said active agent is a drug for the treatment of a local infection within the gastrointestinal tract, obesity, or a GI pathology.