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WO2003015745A1 - Dispositif de retention gastrique expansible - Google Patents

Dispositif de retention gastrique expansible Download PDF

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Publication number
WO2003015745A1
WO2003015745A1 PCT/US2001/046146 US0146146W WO03015745A1 WO 2003015745 A1 WO2003015745 A1 WO 2003015745A1 US 0146146 W US0146146 W US 0146146W WO 03015745 A1 WO03015745 A1 WO 03015745A1
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WO
WIPO (PCT)
Prior art keywords
agents
retention device
gastric retention
gastric
gel
Prior art date
Application number
PCT/US2001/046146
Other languages
English (en)
Inventor
James W. Ayres
Original Assignee
The State Of Oregon Acting By And Through The State Board Of Higher Education On Behalf Of Oregon State University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The State Of Oregon Acting By And Through The State Board Of Higher Education On Behalf Of Oregon State University filed Critical The State Of Oregon Acting By And Through The State Board Of Higher Education On Behalf Of Oregon State University
Priority to JP2003520705A priority Critical patent/JP2005501097A/ja
Priority to KR10-2004-7002254A priority patent/KR20040032918A/ko
Priority to EP01995328A priority patent/EP1416914A1/fr
Priority to BR0117123-2A priority patent/BR0117123A/pt
Priority to IL16036301A priority patent/IL160363A0/xx
Priority to NZ531461A priority patent/NZ531461A/en
Priority to CA002456976A priority patent/CA2456976A1/fr
Priority to MXPA04001388A priority patent/MXPA04001388A/es
Publication of WO2003015745A1 publication Critical patent/WO2003015745A1/fr
Priority to NO20040611A priority patent/NO20040611L/no
Priority to US10/778,917 priority patent/US20040219186A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A61K49/0409—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is not a halogenated organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A61K49/0409—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is not a halogenated organic compound
    • A61K49/0414—Particles, beads, capsules or spheres
    • A61K49/0419—Microparticles, microbeads, microcapsules, microspheres, i.e. having a size or diameter higher or equal to 1 micrometer

Definitions

  • gastric retention devices formed from compositions comprising polymeric materials, such as polysaccharides, and optional additional materials including excipients, therapeutics, and diagnostics, that reside in the stomach for a controlled and prolonged period of time.
  • Recent oral drug delivery systems can control drug release in a predetermined manner for a period of time ranging from a few hours to more than 24 hours.
  • the effects of drug therapy depend not only on the drug release pattern from the formulation, however, but also on the kinetics of drug absorption from the gastrointestinal tract. Some drugs are absorbed only in certain regions of the small intestine called “windows of absorption.” Once such drugs pass this region, very little or no drug absorption takes place. Accordingly, there is significant interest in the development of a gastric retention device (GRD) that retains drugs in the stomach for a prolonged and predictable period of time.
  • GTD gastric retention device
  • HBS hydrodynamically balanced
  • HBS-type drug dosage forms leave the stomach within a short time. They are swept out of the stomach by the "housekeeping wave," which is also called the interdigestive myoelectric complex (IMC) or migrating myoelectric complex (MMC).
  • the housekeeping wave has the function of clearing the stomach of undigested materials and is the action responsible for sweeping nickels, quarters, and other solids swallowed by children (and adults) out of the stomach once any food present is digested and gone.
  • a second approach to gastric retention devices involves tablets that swell in gastric fluid, as described in U.S. Patent Nos. 3,574,820 and 4,434,153. Unfortunately, these tablets fall apart when hydrated. The dimensional stability of the materials used to produce swelling tablets greatly decreases with swelling, which leads to premature erosion or dissolution of the gel layer. Further, both swelling tablets and hydrodynamically balanced systems require that drug products be formulated in total, i.e. it is not possible to incorporate into the GRD a pre-existing tablet.
  • a third approach to gastric retention devices involves mechanical operations, such as a polymer envelope that is expanded by the release of a gas after swallowing (see, for example, U.S. Patent No. 4,207,890).
  • the device can function via the opening of a "flower" structure (U.S. Patent No. 4,767,627), the unfurling of a rolled up sheet (U.S. Patent No. 4,308,250 for veterinary use), or via a self-actuated valve with a propellant and a collapsed bag that is converted to a balloon. Expansion of the balloon causes the device to be retained in the stomach (U.S. Patent No. 3,797,492). Unfortunately, these approaches have not performed well in humans.
  • GRD needs to remain in a fasting stomach during times of the MMC, collapse or disintegrate after a predetermined time in the stomach, and it must not prevent the passage of food out of the stomach through the pylorus while the device is in place and food is present. No device has satisfied all of these criteria.
  • GRDs have been made from a new category of synthetic acrylamide/sulfopropyl acrylate/acrylic acid polymers containing croscarmellose sodium, also known as "superporous hydrogel composites" (Chen, et al, “Gastric retention properties of superporous hydrogel composites", Journal of Controlled Relese 64, 39-51 (2000); Hwang, et al).
  • Dried hydrogels typically perform poorly because swelling, especially in sizes that people can swallow (tablets and capsule size made from 1.36 g of starting materials)), takes a few hours and may be emptied from the stomach before reaching a fully swollen state. Additionally, even after swelling, the hydrogel is not large enough to prevent the expanded device from passing through the pylorus over an extended period; Chen et al.'s GRD traveled to the colon in only three hours when administered to fasted dogs. In addition, these new polymers do not have FDA or any other governmental regulatory approval.
  • GRDs that avoid many of the problems of the prior art because sufficient dimensional stability and flexibility are simultaneously possible in an expandable material that is formed from a mixture comprising a polysaccharide.
  • This mixture can be processed to produce a swelling polymer gel that is retained in the stomach whether it is administered with or without food.
  • this composition allows uninterrupted passage of food through the stomach; the device remains in the stomach while the stomach fills and empties normally.
  • the device can be tailored to degrade sufficiently in gastric fluid to leave the stomach in a predetermined time, usually 12-24 hours, but shorter or longer retention times are possible, if desired.
  • the gastric retention device is suitable for administration into cavities other than the stomach, i.e., oral, rectal, vaginal, nasal, or intestinal.
  • the device can incorporate diagnostic and/or therapeutic agents including, but not limited to, products that already have been formulated and/or marketed, such as solutions, suspensions, emulsions, powders, tablets, capsules, or beads, and can provide gastric retention of the product and controlled release of the drug in the stomach.
  • diagnostic and/or therapeutic agents including, but not limited to, products that already have been formulated and/or marketed, such as solutions, suspensions, emulsions, powders, tablets, capsules, or beads, and can provide gastric retention of the product and controlled release of the drug in the stomach.
  • the GRDs disclosed herein typically comprise gels formed from a polysaccharide or mixture of polysaccharides.
  • the devices are formed, such as by removing at least a portion of any liquid fraction (e.g. dehydration) followed by compression, to a size suitable for administering to subjects, including humans and animals.
  • the formed devices have coatings erodible by gastric fluid applied to an outer surface thereof or are housed within ingestible capsules erodible by gastric fluid.
  • the formed devices may have enteric coatings or be housed within enteric capsules.
  • the polysaccharides comprise carbohydrate gums, and in some embodiments the GRD is formed from a mixture comprising a sugar, a polysaccharide, or combinations thereof.
  • the GRD may be processed to form a gel as desired, but described embodiments typically concern thermally induced gels.
  • the GRD may be substantially dehydrated, and in particular embodiments it is freeze-dried.
  • Xanthan gum and locust bean gum are examples of materials used to form working embodiments.
  • the weight ratio of xanthan gum to locust bean gum typically varies from about 1 :4 to about 4:1, and in particular embodiments the GRD has a weight ratio of xanthan gum to locust bean gum of about 1.5:1 to about 1:1.
  • the GRD may further comprise a material selected from the group consisting of a plasticizer, a pH adjuster, a GI motility adjuster, a viscosity adjuster, a therapeutic agent, a diagnostic agent, an imaging agent, an expansion agent, a surfactant, and mixtures thereof.
  • the diagnostic or therapeutic agent can be used as a solution, suspension, emulsion, tablet, capsule, powder, bead, pellet, granules, solid dispersion, or combinations thereof.
  • the diagnostic or therapeutic agent may be more soluble in gastric fluid than intestinal fluid; more soluble in intestinal fluid than gastric fluid; absorbed better within small intestine than within large intestine; absorbed better within stomach than within intestines; and in still other embodiments the diagnostic or therapeutic agent can be absorbed better within intestines than within stomach.
  • the GRD comprises a compressed device that, upon ingestion, expands sufficiently, and is sufficiently robust upon expansion, to preclude passage of the device through a subject's pylorus for a predetermined time up to 24 hours (for example, 2, 6, 9, 12, or 24 hours or more) while still allowing food to pass.
  • the device can be designed to produce virtually any geometric shape upon expansion, such as a cube, a cone, a cylinder, a pyramid, a sphere, a column, or a parallelepiped.
  • the GRD has an expansion coefficient of at least 3.0, and preferably, though not necessarily, the gel expands substantially to 80% of its final size within 2 hours in an aqueous environment, or, optionally, within 2 hours following ingestion by a subject. While not limited to one theory of operation, the expanded gel may have at least one dimension greater than a diameter of a pylorus.
  • the GRD typically erodes in the presence of gastric fluids and passes through the pylorus after a predetermined time.
  • the GRD may include enzymes that aid erosion of the coating or capsule following ingestion of the device, for example hydrolases, proteases, cellulases, or gluconases.
  • a particular working embodiment of the GRD was a gel prepared from a mixture comprising, by weight, from about 0.1% to about 2.0% xanthan gum, from about 0.1% to about 2.0% locust bean gum, about 5% polyethylene glycol, about 1% sodium lauryl sulfate, about 1% Carbopol by weight, and a biologically effective amount of a therapeutic, a diagnostic, or combinations thereof, the remainder comprising liquid such as water.
  • the device was formed to a suitable size for administration to a subject by drying and compressing sufficiently and into a shape suitable for insertion into a gastrically erodible capsule.
  • Disclosed embodiments of the method for making gastric retention devices comprised forming a mixture comprising polymeric materials, processing the mixture to form a dried gel, and optionally coating the dried gel with a material erodible by gastric fluid or placing the gel into a capsule erodible by gastric fluid. Processing may comprise heating the mixture effectively to form a thermally induced gel and freeze-drying the gel. The dried gel may be compressed to a size and shape suitable for administration to a subject prior to coating the gel or placing it in a capsule. Also disclosed herein is a method for using gastric retention devices. Embodiments of the method comprise providing a gastric retention device and administering the gastric retention device as generally described herein to a subject.
  • an embodiment for appetite suppression comprising providing a gastric retention device that expands sufficiently in the stomach of a subject to at least partially suppress appetite in the subject.
  • the gastric retention device is administered periodically to the subject.
  • the device further comprises an effective amount of a fatty acid, an appetite suppressant, a weight loss agent, or combinations thereof.
  • methods of producing a modified pharmacological response without a change in total dose for example, an increase in urine output with a given oral dose of diuretic.
  • FIG. 1 is a graph of percent hydration in water of xanthan gum/locust bean gum films at various solids ratios.
  • FIG. 2 is a graph of percent hydration in simulated gastric fluid of xanthan gum/locust bean gum films at various solids ratios.
  • FIG. 3 is a graph of percent initial hydration in water of xanthan gum/locust bean gum films at various solids ratios.
  • FIG. 4 is a graph of percent hydration in simulated gastric fluid of xanthan gum/locust bean gum films at various solids ratios during hours 0-3.
  • FIG. 5 shows the shapes and sizes of four GRDs tested.
  • FIG. 6 is a graph of the hydration of a GRD in simulated gastric fluid during hours 3-24.
  • FIG. 7 is a graph of the hydration of a GRD in simulated gastric fluid during hours 0-3.
  • FIG.8 is a graph of mg of amoxicillin released over a 20-hour period from an amoxicillin caplet as compared to an amoxicillin caplet in a GRD.
  • FIG. 9 is a graph of the mg of amoxicillin released over a 20-hour period from an amoxicillin core caplet as compared to an amoxicillin core caplet in a GRD.
  • FIG. 10 is a graph of the mg of ranitidine HC1 released over a 20-hour period from a Zantac ® tablet as compared to a Zantac ® tablet in a GRD.
  • FIG. 11 is a graph of the percent of available riboflavin released over time from riboflavin beads as compared to riboflavin beads in a GRD.
  • FIG. 12 is a graph of the percent of available riboflavin released over time from riboflavin beads in a modified GRD.
  • FIG. 13 is a graph of the percent of available riboflavin released over time from a riboflavin solid dispersion in a modified GRD.
  • FIG. 14 is a digital image of an X-ray view of a fasted dog stomach showing a GRD in the stomach immediately after dosing.
  • FIG. 15 is a digital image of an X-ray view of a dog stomach showing a GRD in the stomach 2 hours post-dosing.
  • FIG. 16 is a digital image of an X-ray view of a dog stomach showing a GRD in the stomach 9 hours post-dosing.
  • FIG. 17 is a digital image of an X-ray view of a dog showing a disintegrated GRD in the colon 24 hours post-dosing.
  • FIG. 18 is a digital image of an X-ray view of a dog showing a GRD in the stomach 2 hours post-dosing. Food administered after the GRD was admimstered has emptied from the stomach while the GRD has not.
  • FIG. 19 is a digital image of an X-ray of a dog's stomach showing a GRD containing radio-opaque threads.
  • the X-rays show the empty stomach of the dog before dosing, immediately after dosing (0 hr), 1 hour and 2 hours post-dosing.
  • FIG.20 is a digital image of an X-ray of a dog's stomach showing a GRD containing radio-opaque threads.
  • the X-rays show the presence of the GRD in the stomach of the dog at 3 hours, 7 hours and 9 hours, and the absence of the GRD at 24 hours post-dosing.
  • FIG.21 shows the excretion rate of amoxicillin following administration of an amoxicillin caplet as compared to an amoxicillin caplet in a GRD, both under fasted conditions.
  • FIG. 22 is a graph showing the excretion rate of amoxicillin following admimstration of amoxicillin alone as compared to amoxicillin in a GRD under fasted conditions.
  • FIG. 23 is a graph showing the cumulative amount of riboflavin excreted over time when delivered as an immediate release formulation, or in small, medium, and large GRDs.
  • FIG. 24 is a graph showing the urinary excretion rate of riboflavin when delivered as an immediate release formulation, or in small, medium, and large GRDs.
  • FIG. 25 is a graph showing the deconvolved input functions from biostudy data for immediate release and GRD formulations of riboflavin.
  • FIG. 26 is a graph of the cumulative amount of hydrochlorothiazide excreted vs. time following administration of an immediate release formulation of hydrochlorothiazide as compared to hydrochlorothiazide in a GRD.
  • FIG. 27 is a graph of the excretion rate of hydrochlorothiazide vs. time for the immediate release (IR) capsule and for the new formulation (GRD)
  • FIG. 28 is a comparison of urine production and water-intake and the cumulative amount of urine output from hydrochlorthiazide in both IR and GRD.
  • Active agent means any therapeutic or diagnostic agent now known or hereinafter discovered that can be formulated as described herein. Examples of therapeutics, without limitation, are listed in U.S. Patent No. 4,649,043, which is incorporated herein by reference. Additional examples are listed in the American Druggist, p. 21-24 (February, 1995).
  • Controlled release includes timed release, sustained release, pulse release, delayed release and all terms which describe a release pattern other than immediate release.
  • Diagnostic means without limitation, a material useful for testing for the presence or absence of a material or disease, and/or a material that enhances tissue or cavity imaging.
  • An effective amount is an amount of a diagnostic or therapeutic agent that is useful for producing a desired effect.
  • Erodible means digestible, dissolvable, soluble, enzymatically cleavable, etc., and combinations of such erosion processes. While not meant to be limiting, one way to measure erodibility is to determine the degree of loss of cohesion of a coating, capsule, or GRD in a given period of time, such as 1, 3, 6, 9,12 or 24 hours, when the coating, capsule, or GRD is exposed to an appropriate aqueous environment, such as simulated gastric fluid, in a United States Pharmacopeia paddle stirring dissolution apparatus operated at 50 rpm.
  • An appropriate aqueous environment can include one or more than one aqueous media, including changes of media during the study, and often will depend on the specific intended use of the GRD as is well known to those skilled in the art.
  • a Gastric Retention Device is a device that can be administered to a subject either with or without additional materials.
  • the GRD device can be tailored for various body cavities, including stomach (gastric), intestine, oral, rectal, vaginal, or nasal. Most commonly, for gastric delivery, the device is formed to a size suitable for administration to a subject and, following administration, absorbs liquid and expands to a size greater than the administration size, which is tailored to prevent the passage of the device through a pylorus for a predetermined time. For other body cavities, the device forms a size appropriate for the cavity, e.g.
  • the device is typically administered orally into the gastric cavity and tailored to form a size appropriate for the intestine.
  • Dehydrated polysaccharide gels typically are used to make the device.
  • the GRD does not necessarily, but typically does, absorb liquid.
  • Hydrophilic gel-forming materials or agents also referred to as hydrogels, are materials that hydrate in water and exhibit the ability to retain a significant fraction of water within its structure.
  • the hydrogels can be non-cross linked or they may be cross-linked with covalent or ionic bonds.
  • the hydrogels can be of plant or animal origin, hydrogels prepared by modifying naturally occurring structures, and synthetic polymeric hydrogels.
  • Monosaccharides are aldehyde or ketone derivatives of straight-chain polyhydroxy alcohols containing at least three carbon atoms.
  • Polysaccharides consist of monosaccharides linked together by glycosidic bonds. Tablet is a term that is well known in the art, and is used herein to include all compacted, molded, or otherwise formed materials without limitation in terms of sizes or shapes, and all methods of preparation. Thus, as one common example, compressed or molded shapes known as caplets are included.
  • the GRD is made by selecting the material or materials useful for forming an expandable gel matrix, generally monomeric or polymeric materials, such as a polysaccharide. Thereafter, additional excipients, diagnostic agents, therapeutic agents, imaging agents or combinations thereof, optionally may be selected and used to form the GRD.
  • the selected polymeric material, excipient, and/or diagnostic or therapeutic agents and/or imaging agents are combined with a liquid to produce a mixture, and the mixture is processed to form a gel containing liquid.
  • the liquid is then removed from the gel to produce a dried gel film, and, optionally, the dried gel film may be compressed to a size suitable for admimstration.
  • the dried gel film may be coated with or encapsulated by a gastrically erodible and/or enteric coating. Following administration the dry gel imbibes liquid. Thus, at various stages the gel may contain liquid or be a dry gel. Each of these steps will be discussed in greater detail below.
  • GRDs that are generally formed from a mixture comprising polymeric materials.
  • monomeric materials form the same polymeric materials, such as forming such polymeric materials in situ, they may be used as well.
  • the polymeric materials may be hydrophilic gel-forming agents.
  • hydrophilic gel-forming agents examples include materials like acacia, tragacanth, guar gum, pectin, xanthan gum, locust bean gum, Carbopol® acidic carboxy polymer, hydroxypropyl methyl cellulose, polycarbophil, polyethylene oxide, poly(hydroxyalkyl methacrylate), poly(electrolyte complexes), poly(vinyl acetate) cross-linked with hydrolyzable bonds, water-swellable N- vinyl lactams polysaccharides, natural gum, agar, agarose, sodium alginate, carrageenan, fucoidan, furcellaran, laminaran, hypnea, eucheuma, gum arabic, gum ghatti, gum karaya, arbinoglactan, amylopectin, gelatin, hydrophilic colloids such as carboxylmethyl cellulose gum or alginate gum, including both non-cross linked and cross linked alginate gum
  • hydrogels are discussed in U.S. patents, Nos. 3,640,741, 3,865,108, 3,992,562, 4,002,173, 4,014,335, and 4,207,893. Hydrogels also are discussed in the Handbook of Common Polymers, by Scott and Roff, published by the Chemical Rubber Company, Cleveland, Ohio. Polysaccharides have been used to form working embodiments of GRDs.
  • the GRD may comprise a carbohydrate gum or may be formed from a mixture comprising a sugar, sugars, a polysaccharide, polysaccharides, or combinations thereof.
  • Working embodiments have used xanthan gum and locust bean gum to form the GRD, and have had a weight ratio of xanthan gum to locust bean gum of from about 1 :4 to about 4:1.
  • Particular working embodiments of the GRD have had a weight ratio of xanthan gum to locust bean gum of about 1.5 : 1 to 1 : 1.
  • the polysaccharide comprised from about 0.1% to 5% of the starting materials, and more typically comprised from about 1% to 4%, and more typically still from about 1% to about 3%, with most comprising about 1% of the starting ingredients. Percentages are percent of the total ingredients, including the liquid fraction.
  • the GRDs may also include an excipient, such as a plasticizer, a pH adjuster, a GI motility adjuster, a viscosity adjuster, an expansion agent, a surfactant, or mixtures thereof.
  • a plasticizer can be added to the composition to increase the plasticity of the mixture to a level suitable for administering to a subject.
  • Plasticizers may be hydroxylated compounds, particularly poly-hydroxylated organic compounds.
  • PEG polyethylene glycol
  • Persons skilled in the art could substitute other plasticizers, for example glycerin or surface-active materials.
  • working embodiments have included from about 1% to 8% plasticizer.
  • a pH adjuster can be added to adjust the pH of the GRD to a desired pH level. For example, it currently is believed that increasing the pH in the area of the GRD increases expansion in the acidic environment of the stomach.
  • PH adjusters also may be used to modify the viscosity of some polymer excipients such as Carbopol.
  • Suitable pH adjusters include buffers, mineral acids or bases, or organic acids or bases.
  • the pH adjuster is optionally a buffer, and in working examples disodium phosphate and sodium phosphate have been used.
  • pH adjusters are known to those of skill in the art, and can include, without limitation, hydrochloric acid, sodium hydroxide, potassium hydroxide, organic acids, such as acetic acid, and organic amines, particularly lower (10 carbon atoms or fewer) alkyl amines, such as triethyl amine.
  • a viscosity adjuster can be added to adjust viscosity to a viscosity level that permits retention of the GRD in a stomach for a predetermined time.
  • Viscosity adjusters can include, but are not limited to, Carbopol, polyvinyl pyrollidone, alginates, celluloses, gums, and hydrogels.
  • Working embodiments have included the viscosity adjusters, Carbopol and polyvinyl pyroUodone.
  • Other viscosity adjusters can be selected by those of skill in the art.
  • working embodiments have included from about 0.25% to 1% Carbopol and/or polyvinyl pyroUodone.
  • the GRD may also incorporate a diagnostic or therapeutic agent selected from the group consisting of nucleic acids, proteins, naturally occurring organic compounds, synthetic and semi-synthetic compounds, and combinations thereof. More particularly, the diagnostic or therapeutic agent may be an AIDS adjunct agent, alcohol abuse preparation, Alzheimer's disease management agent, amyotrophic lateral sclerosis therapeutic agent, analgesic, anesthetic, antacid, antiarythmic, antibiotic, anticonvulsant, antidepressant, antidiabetic agent, antiemetic, antidote, antifibrosis therapeutic agent, antifungal, antihistamine, antihypertensive, anti- infective agent, antimicrobial, antineoplastic, antipsychotic, antiparkinsonian agent, antirheumatic agent, appetite stimulant, appetite suppressant, biological response modifier, biological, blood modifier, bone metabolism regulator, cardioprotective agent, cardiovascular agent, central nervous system stimulant, cholinesterase inhibitor, contraceptive, cystic fibrosis management agent,
  • AIDS adjunct agent
  • Such therapeutics and diagnostics include, without limitation, abacavir sulfate, abacavir sulfate/ lamivudine/zidovudine, acetazolamide, acyclovir, albendazole, albuterol, aldactone, allopurinol BP, amoxicillin, amoxicillin/clavulanate potassium, amprenavir, atovaquone, atovaquone and proguanil hydrochloride, atracurium besylate, beclomethasone dipropionate, berlactone betamethasone valerate, bupropion hydrochloride, bupropion hydrochloride SR, carvedilol, caspofungin acetate, cefazolin, ceftazidime, cefuroxime (no sulfate), chlorambucil, chlorpromazine, cimetidine, cimetidine hydrochloride, cisatracurium besilate,
  • Effective amounts of the diagnostic or therapeutic agent may be incorporated into the GRD in the form of a solution, suspension, emulsion, tablet, capsule, powder, bead, pellet, granules, solid dispersion, or combinations thereof.
  • the diagnostic or therapeutic agent may be more soluble in gastric fluid than intestinal fluid, more soluble in intestinal fluid than gastric fluid, better absorbed within small intestine than within large intestine, better absorbed within stomach than within intestines, or better absorbed within intestines than within stomach.
  • the polymeric material, excipient, and/or diagnostic or therapeutic agent can be dissolved and/or suspended in any fluid in which they are at least partly soluble.
  • the preferred liquid is water.
  • Other liquids include polar organic compounds, such as alcohols. Generally, liquid makes up the remainder of the mixture after the polymeric materials, diagnostics and/or therapeutics, and excipients are added.
  • the GRD is made by combining and mixing the selected ingredients, inducing gelation, drying the resulting gel, and optionally encapsulating the resulting dried, formed gel in a gastrically erodible coating. Each of these steps will be described in greater detail below.
  • the method for forming the gel mixture comprises combining the selected polymeric material or materials in the appropriate amounts with the desired amount of liquid and mix with stirring.
  • the excipient or excipients and/or the diagnostic or therapeutic agent or agents may be combined directly with the polymeric material, or, optionally, they may be mixed separately and combined with the mixture of polymeric materials later.
  • Existing dosage forms such as capsules or tablets may be added into the polymeric materials just before gelling, or inserted into the gel after it is formed.
  • Gelation of the gel can be induced by any method known to those skilled in the art, for example, chemical gelation or thermal gelation.
  • Working examples have used thermally induced gelation primarily to avoid using chemical gelling agents.
  • gelation has comprised heating the mixture sufficiently to achieve dissolution of at least a portion of the solid ingredients, for example heating to a temperature of from about 50° to about 100°C, and typically about 80°C and maintaining the mixture at such temperature until sufficient dissolution occurs to allow subsequent gelation. Typical heating times have been from about 10 minutes to about 30 minutes for small batches but variable heating times may occur depending on batch size. Following heating, the mixture is generally cooled to induce gelation, thereby forming a gel.
  • Working processes have cooled the mixture to about room temperature.
  • Drying Liquid can be removed from the formed gel to form a dried film by any means known to those skilled in the art, including air-drying, freeze-drying, vacuum-drying, or any other means of drying or dehydration known to those of skill in the art. Some working embodiments have been dehydrated by vacuum drying at room temperature. Other working embodiments were dehydrated by oven drying at a temperature of from about 35°C to about 75°C. In other embodiments the gel was dehydrated by freeze-drying.
  • Drying or dehydration means that more than 50% of the liquid solvent total is removed, and usually 90% or more of any liquid present is removed. Liquids used in the formulation may remain in the device as desired either because they help the "dried" gel film retain some pliability and strength, or promote swelling, or because there is no need to completely remove them.
  • the dried film may be compressed to a size and shape suitable for administration to a subject prior to coating the GRD or placing it in a capsule. Any means of compression known to those of skill in the art may be used, though in working embodiments, the dried film has been compressed with compression dies, by rolling, or by squeezing or folding the dried film to fit in a size 2, 1, 0, 00 or 000 * capsule. Smaller size capsules may be appropriate for delivering the device through the stomach and into the intestine. In other working examples, the dried film has been compressed in a punch and die with a pressure of from about 500-3000 pounds per square inch.
  • the dehydrated GRD can have coatings erodible by gastric fluid applied to an outer surface by any means known to those skilled in the art, for example spray coating or dip coating, or by insertion into a capsule. Additionally or alternatively, the GRD can have enteric coatings, such as ⁇ udragit® or Opadry®, applied to an outer surface or can be inserted into a capsule. Working embodiments of the GRD were inserted into size 2, 1, 0, 00, or 000 capsules. One of ordinary skill in the art may choose any known means of coating or encapsulating the GRD.
  • the GRDs are admimstered orally.
  • the GRD may be administered into cavities other than the stomach, i.e., oral, rectal, vaginal, nasal, or intestinal.
  • the device may be used as an imaging aid by containing a dye or other imaging material and swelling to fill the cavity.
  • the device may be used to deliver a therapeutic or diagnostic agent to the walls of a cavity for local or systemic effect by swelling and releasing materials into the cavity.
  • the device may be placed into a capsule, and the capsule enteric coated so the device is not released into the stomach, but expands in the intestine to come into contact with the intestinal walls. Swelling of the GRD can also serve to retain the GRD in position in the desired cavity.
  • the preferable dimensions of the swollen device can differ from a device designed to be retained in the stomach, and often will be much smaller.
  • presence of the device in the intestine may be used to attenuate hunger and suppress appetite; in this embodiment, the desired GRD size typically is smaller than the gastric-use GRD, particularly when multiple doses are given over time. Even smaller dimensions are preferable for the nasal cavity.
  • the invention is illustrated by the following non-limiting Examples. EXAMPLES EXAMPLE 1
  • This example concerns methods for making GRDs.
  • the listed materials were obtained and processed as stated.
  • Tablets made by direct compression of powders of XG mixed with LBG as received from the suppliers did not produce cohesively hydrated gels in either water or gastric fluid. In fact, the tablet fell apart when placed in water or gastric fluid. Dissolution of both the gums in water produces an interaction that causes gelation to occur. Dissolving XG and LBG in water at 80°C produced a solution, which, upon cooling, produced a gel that dried to produce a film. Gel strength depended on the temperature at which the interaction between two gums occurred, i.e. temperature at which gel was made, interaction above the T m of XG results in a gel that has better gel strength. Dissolution of gums at 70-75°C, first LBG followed by XG, gives a gel with better gel strength.
  • Gels thus made were dried in the oven to produce gel films that were then powdered, and the powder was compressed into tablets. Such tablets fell apart when contacting water or simulated gastric fluid; however, individual particles hydrated extensively when in contact with the medium.
  • GRDs were made according to the following method:
  • Xanthan gum (XG; spectrum Chemical Mfg. Corp., Gardena, CA), Locust bean gum (galactomannan polysaccharide from seeds of Ceratonia Siliqua, Sigma catalogue # G-0753, Sigma Chemicals, St. Louis, MO), polyvinyl pyrrolidone (PVP), and riboflavin (Sigma Chemicals, St. Louis, MO), sodium lauryl sulphate (SLS;
  • the regular GRD was prepared by dissolving LBG (0.5 gm) and XG (0.75 gm) in 100 ml water.
  • the modified GRD was prepared by dissolving PVP (0.5 gm), LBG (0.5gm), SLS (0.15 gm), and XG (0.75 gm) in 100 ml water (in that order) with constant stirring. Both solutions were heated to a temperature of 85°C. 6 ml of PEG 400 was then added to each of the hot viscous solution. Accurately weighed riboflavin in the form of powder, beads, or solid dispersion was then added to hot viscous solution with constant stirring to produce a homogenous mass.
  • the highly viscous solution was then poured into suitably shaped moulds, and the resulting gel was left to cool for 4 hours at room temperature and was cut into desired sizes.
  • the cut gels were dried in a vacuum oven at 50°C for about 16 hours.
  • the process of drying produced flexible films that could be easily shaped by hand and fitted into capsules.
  • the GRD consisting of a capsule containing the dried gel (film) with drug, was then suitable for use. Three different size capsules ('0', '00', and '000' size) were filled with differently sized GRD containing riboflavin.
  • the two main ingredients of the described GRDs are XG and LBG.
  • XG and LBG were used in the ratio of 1.5: 1 respectively. Increasing the ratio of XG more than 1.5 produced very viscous gels and harder films after drying. It is difficult to prepare solutions containing more than 3% gums because both XG and LBG are high- viscosity colloids.
  • XG was used in higher ratio than LBG as better pH stability is obtained when the colloid ratio favors XG.
  • XG is stable over the entire pH spectrum, whereas LBG is less acid-stable. Since some GRDs are intended to stay in the acidic environment of the stomach for more than 9 hours, higher XG ratio will produce stronger gel after hydration in gastric fluid and the resulting gel will not degrade rapidly.
  • the gums' solution was heated to 85°C.
  • the viscosity of the solution drops sharply at this temperature, which allows the viscous solution to be poured into molds.
  • the viscosity increases sharply again at around 40-50°C as the solution is cooled from 85°C.
  • Addition of therapeutics, diagnostics, or imaging agents as a solution, suspension, powder, tablet, capsule, bead, pellet, granule, emulsion, solid dispersion, or combinations thereof can occur before the gel is fully formed by cooling.
  • This section concerns methods for drying gels into films.
  • Drying at a lower temperature took more than 24 hours for the gel to dry into films.
  • loss of PEG was negligible. Drying time was about 12-18 hours.
  • Flexible soft films were obtained when the gels were dried in a vacuum oven at 50-55°C for about 16-17 hours. Flexible, soft films facilitate easy rolling and fitting into capsules as well as for quick swelling when immersed in SGF. When higher temperatures were tried (60-70°C) for shorter time (12-15 hours), harder films were obtained that broke more easily when rolled into capsules and did not swell as well when immersed in SGF. When lower temperatures were tried (30-40°C) it took about 48 hours to obtain dried films and the dried films did not swell as fast as films produced at 50° - 55°C. EXAMPLE 3
  • This section concerns compression of the dried films into sizes suitable for administration.
  • Example 2A Having dried the gel of Example 1 A, section IN to form the dried film of Example 2A, the dried films were compressed with the help of specially made punches and dies. A series of dies with decreasingly narrow internal diameters were used. A punch pushes the film from one die into the next die, followed by pushing of the film by another punch into the next die. This process takes place in succession until a point is reached where the film is small enough to put into a desired capsule size, such as a'OOO' capsule. Other size capsules can be used with other size films or caplets.
  • Example 3 Having prepared the gel according to Example 1 A, section IN, dried the gel to form a dried film as outlined in Example 2A, and compressed the dried film as shown in Example 3, hydration studies of films made in different shapes and from various ratios of xanthan gum and locust bean gum were carried out in both water and simulated gastric fluid. Hydration studies in simulated gastric fluid were carried out at 37°C. Percent hydration is calculated as:
  • Films that had been cut into different sizes and shapes were hydrated in water or in gastric fluid. Hydration studies also were carried out in diluted gastric fluid (1 part of SGF and 3 parts water) for comparison. Shapes such as circle, star, cube, rectangle, triangle, etc., were studied.
  • a cubic shaped gel that had been dried into a somewhat flat, generally rectangular film that was uneven and non-uniform in height, width, and depth was found to have the fastest swelling and maximum volume, and also had greater gel strength.
  • a preferred shape was a rectangular gel shape having dimensions of about 4 cm X 4 cm X 1 cm, prior to drying.
  • a GRD ingested in a capsule should ideally start hydrating as soon as the capsule dissolves and should attain a large enough size within 15-20 minutes to avoid passage through the pyloric sphincter.
  • the structural integrity of the hydrated gel should be sufficient to withstand MMC. Therefore, initial hydration rate and structural integrity are very important.
  • the hydration of films in SGF is extensive, but comparatively less than that in water. Hydration in water is approximately 10 times greater than in SGF. Hence, in order to make the film swell faster and to a larger size in SGF, addition of the buffering agents disodium phosphate or sodium phosphate was tested. Films containing disodium phosphate or sodium phosphate (twice the amount of gums solids) swell completely in SGF in about 12 hours time. After 12 hours time, the SGF (about 500ml volume) used for hydration studies was found to have a pH of 6.8.
  • SGF media simulates the expected conditions when the GRD is ingested with 8-10 ounces of water.
  • Addition of other additives such as polyethylene oxide, carboxy methylcellulose (CM), and/or Water-Loc ® into gels during formation were used to improve the initial hydration of films in SGF.
  • Table 2 depicts various formulations containing different additives. All the above-mentioned studies were evaluated by visual examination of hydration of film after regular intervals of time.
  • PEG polyethylene glycol
  • Fig. 5 The percent increase in weight of the hydrated films was determined after 15, 30, 45, 60, 120 and 180 minutes and determined again after 12 and 24 hours.
  • the hydrated films retained their integrity for up to 24 hours in simulated gastric fluid.
  • a rectangular shaped gel that had been dried into an approximately flat rectangular film was found to have the fastest swelling and maximum volume. Based on this study the rectangular shape was chosen for further in vitro and in vivo studies.
  • Fig. 6 Complete hydration of the films in simulated gastric fluid (SGF) for 24 hr is depicted in Fig. 6.
  • Initial hydration of the films in SGF is shown in Fig.7.
  • the initial hydration is a very important factor into the development of a GRD. Ideally it is best to make a device that is small enough to fit into a capsule for easy swallowing, but that expands upon contact with gastric juice to a size that is too large to pass through the pylorus. For certain application, the swelling to this large size should be fast (e.g. from aobut 15 to about 30 minutes) to avoid gastric emptying by the strong contractions of the housekeeper wave, which lasts about 5 to 15 minutes. Therefore, fast swelling of the released dried gel and integrity of the swollen gel are very important.
  • EXAMPLE 5 This section concerns methods for incorporation diagnostic or therapeutic agents into GRDs.
  • Amoxicillin was incorporated into the GRD from Example IA, section IN in the form of a tablet with a caplet shape. Amoxicillin was chosen as a model drug because it has a 'window of absorption'.
  • the hot viscous solution of gums prepared by the methods described in
  • Example 1 A, part IN was poured into suitable moulds so that tablets incorporated into the gel remain suspended in the gel. This tablet-containing gel was then cut into the desired size. Following drying for 12-18 hours, these dried films containing tablets were compressed in a punch and die with a hydraulic press to fit into a '000' capsule.
  • Riboflavin was incorporated into a GRD from Example IB in the form of powder, beads, or solid dispersion. Riboflavin incorporated into the gel by stirring into the hot, viscous mixture immediately prior to cooling into a gel, remained suspended in the gel. The dried gels (films) containing drug beads, powder, or solid dispersion were easily rolled and fitted into suitable size capsules. The GRDs containing drug beads, powder, or solid dispersion were then subjected to in vitro dissolution and/or in vivo studies.
  • EXAMPLE 6 This section concerns preparation of amoxicillin caplets and 'core' caplets for use with GRDs. Amoxicillin caplets were prepared by combining the ingredients listed in Table 3 and formed by direct compression.
  • amoxicillin caplets were centered in a bigger die and punch with microcrystalline cellulose and compressed again such that the amoxicillin caplet is inside the shell formed by microcrystalline cellulose.
  • New caplets thus formed had an amoxicillin caplet as a core, and are commonly known as “core tablets” or a “tablet-within-a-tablet”.
  • Riboflavin was incorporated in the GRD in the form of powder, beads, or solid dispersion. Riboflavin beads were prepared by mixing known amounts of riboflavin, Avicel PH-101, and polyethylene oxide 200,000 with water to produce a wet mass. This mass was then extruded and spheronized using a laboratory extruder (model 10/25) and spheronizer (model 120, Caleva Process LTD, England) to produce drug beads (1.5-2.0 mm in diameter). The beads were left to dry overnight in an oven at 50°C. Beads incorporated into the gel by stirring into the hot, viscous mixture immediately prior to cooling into a gel, remained suspended in the gel.
  • Riboflavin beads were prepared by extrusion and spheronization using the formula shown in Table 4. Riboflavin when used in powder form was dried for 2 hours at 120°C before being incorporated into the gel to remove moisture. Table 4: Formula for riboflavin beads
  • Riboflavin solid dispersion was prepared by melting a weighed quantity of PEG 3500 in an evaporating dish. A weighed quantity of drug was then added to yield the desired ratio of drug to PEG (1:3). The system was heated until complete dissolution of the drug was achieved. The dish was then transferred to an ice bath and the material stirred until cold. The final solid mass was crushed, pulverized and screened to produce a fine powder. The prepared solid dispersion was dried over night in a vacuum oven at room temperature before being incorporated into gels.
  • This section concerns dissolution studies carried out on GRDs containing diagnostics and/or therapeutics.
  • A. This example demonstrates that a therapeutic agent in the form of a tablet can be incorporated into a gastric retention device formed from a polysaccharide, and the device can be formed to a size suitable for administration to a subject, and housed in an ingestible capsule erodible by gastric fluid.
  • Dissolution studies were carried out using GRDs made according to the method of Example IA, section IV, and containing the model drugs amoxicillin or ranitidine HCl, using the USP XXII paddle method at 37°C at 75 rpm for 20 hours.
  • Dissolution medium consisted of 900 ml simulated gastric fluid (without enzymes).
  • Samples were collected at 0.5, 1, 1, 3, 4, 6, 8, 12 and 20 hours with replacement of equal volume of media.
  • the samples were assayed at 280nm using an HP diode array spectrophotometer for amoxicillin and at 219nm for ranitidine HCl (Zantac ® ).
  • Dissolution studies were carried out on GRDs prepared according to the methods of Example IB that contained the model drug, riboflavin, using the USP XXII paddle method at 37°C and 50 rpm for 24 hours.
  • Dissolution medium consisted of 900 ml simulated gastric fluid without added enzymes. Samples were collected at 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24 hours. The samples were assayed for riboflavin at 446 nm using a HP diode array spectrophotometer.
  • riboflavin powder from an immediate release capsule 50 mg riboflavin + 200 mg lactose
  • the immediate release capsule of riboflavin released 100% of drug in about 1 hr, whereas the GRD in a capsule released about 50% of drug in 24 hrs.
  • the release of riboflavin powder from regular GRD was also nearly zero order.
  • the prepared modified GRD was used to vary the rate and amount of drug release.
  • the modified GRD differs from the regular GRD in that it contains PVP and SLS.
  • the dissolution of riboflavin powder from the modified GRD is shown in Fig. 12.
  • the modified GRD released about 65% of drug in 24 hrs.
  • the pattern of release also looked zero order.
  • the increased dissolution from the modified GRD may be attributed to the presence of the hydrophilic polymer PVP and the surface-active agent, SLS. Both PVP and SLS may have helped diffusion of the vitamin from the hydrogel.
  • the presence of PVP and SLS in the formulation also produced more flexible dried films that were easier to fit into capsules when compared to the regular films from the formulation without PVP and SLS.
  • the increased flexibility facilitates in fitting larger GRD in capsules.
  • This section concerns subjects for in vivo testing of GRDs in dogs
  • This section concerns dosage forms and dosing of subjects for in vivo testing of GRDs in dogs
  • GRDs were administered to the subjects described in Example 9A.
  • Four different shapes of GRDs incorporated in size "0" capsules were used.
  • a 7 x 1.5 x 1 cm rectangular shape GRD incorporated in '000' capsule also was tested in these studies.
  • All the dosage forms contained radio-opaque threads for x-ray visualization.
  • Four different shaped GRDs incorporated into size '0' capsules were tested in dogs to determine gastric residence time. The dimensions of these four shapes are listed in Fig. 8.
  • All GRDs contained not less than 10 small pieces of radio-opaque threads. These threads helped visualize the GDRs in the GI tract by x-rays. They also helped in viewing the hydration and disintegration of the gels.
  • GRDs were admimstered to the subjects described in Example 9B.
  • a gastric retention device enclosed in '000' capsule containing barium sulphate caplets, radio- opaque threads, or bismuth impregnated polyethylene spheres (BIPS) was used. The system was followed using X-rays.
  • Dogs were fasted overnight and dosage forms were administered orally early in the morning with 10 ounces of water. Food was provided 3 hours after-dosing. A radiograph was taken just prior to dosing to ensure that the stomach was empty. The gastric retention device was followed by X-ray and the dogs were fed 3 hours after dosing. Presence of food can be readily recognized in X-rays as a darker area in the stomach.
  • radio-opaque agents such as barium sulphate tablets, radio-opaque threads and radio- opaque BIPS in the same dogs on different days.
  • Normal gastric emptying of radio- opaque marker in the dogs under the conditions of fasting was determined by feeding a capsule containing radio-opaque threads.
  • BaSO 4 tablets were made in a Carver press in the shape of a caplet.
  • Various methods were explored to incorporate the tablet. Basically, the method included pouring a layer of gel into a mold, putting tablets into the mold at desired distances, and immediately adding another gel layer. These gels were dried under vacuum. Dried films were compressed into a '000' capsule. On subjecting these films to hydration studies, films were found to separate into two layers after hydration, and release the tablet prematurely.
  • caplets were suspended with the help of threads in such a way that they stood in the middle of the inner side of the mold. When poured, hot gel entrapped the caplet. BaSO 4 was found to leak from the gel or tablet during gel expansion studies which would make it difficult to determine GRD location. Keeping this limitation in view, in vivo studies in dogs were carried out. As expected, it was difficult to trace the system in the stomach of dogs since the BaSO 4 tablet dissolved and spread throughout the GIT.
  • GRDs were administered as described in Example 10A. Radiographic examinations were performed using a Transworld 360 V x-ray generating unit. X-ray cassettes used were 3 M Trimax 12 paired with 3M ultradetail (1416) film. Radiography was used to follow passage of GRDs in the GI tract. Radiographs for dogs were exposed at 0 minutes (just before dosing to ensure an empty stomach), at 5 min (just after dosing to assure that the device is in the stomach), at 2 hours (to see if the GRD is not removed by the housekeeper wave), and at 9 hours. The dogs were fed after the 2 hours radiographs. Food was sometimes mixed with BIPS (barium impregnated polyethylene spheres) to study the effect of the dosage form on food emptying from the stomach.
  • BIPS barium impregnated polyethylene spheres
  • BIPS have a density similar to food but are sufficiently radiodense to show clearly on abdominal radiographs.
  • the small BIPS used (1.5mm) mimic the passage of food and their transit through the GI tract provides an accurate estimate of the gastric emptying rate and intestinal transit time of food.
  • Hills d/d diet is known to suspend BIPS and it is the only diet in which the correlation between BIPS emptying and food emptying has been investigated and proven.
  • BIPS can be differentiated from radio-opaque threads in radiographs. For each animal, radiographic examinations were performed from two angles, a lateral view and a dorsoventral view.
  • the rectangular shape was found to stay in the stomach of one of the dogs for at least 9 hours.
  • the other three shapes were emptied from the stomach in less than 2 hours.
  • X-rays at 24 hours indicated absence of radio-opaque threads in the stomach for the rectangular shape GRD, and disintegration of the four different shape GRDs as indicated by the spread of threads in the colon.
  • a total of four studies were conducted using the rectangular shape GRD. In all four studies the GRDs stayed in the stomach of the same dog but not in the other one. The results of these studies are shown in Figs. 14-17.
  • GRDs were administered as described in Example 10B.
  • X-rays were employed to follow the passage of the gastric retention device in gastrointestinal tract of dogs. Radiographs were taken just before dosing to ensure an empty stomach and immediately after dosing. Subsequent X-rays were taken at 0.5 hour, 1 hour, 2, 3, 6, 9, and 24 hours. All X-rays were lateral view, and some anterioposterior (ventrodorsal, VD) X-rays were also taken to confirm the position of the dosage form in the dog stomach.
  • VD anterioposterior
  • Radiographic examinations were performed using a Transworld 360V X-ray generating unit (360 milliamperage and 125 kilovoltage potential).
  • X-ray cassettes used were 3M Trimax 12 paired with 3M Ultradetail (1416) film. Exposure settings are shown in Table 5.
  • Table 5 Exposure settings of X-ray machine for the two dogs
  • Bismuth Impregnated Polyethylene Spheres are polyethylene spheres containing bismuth and this makes them radio-opaque. These spheres were incorporated in the GRD for study in dogs.
  • the system containing two large BIPS was followed with x-rays at different time points including 0, 0.5 hr, 1 hr, 2, 3, 6, 8, 9, and 24 hours.
  • the system was present in the stomach of one of the dogs at the 9th hour of experimentation. The next x-ray was not taken until 24 hours. Of the 2 BIPS, one was still in the stomach, whereas the other one was found in the intestine, indicating that the system must have eroded with the release of one BIPS.
  • GRDs made according to Example 1 A, part TV.
  • One dog was used for this study. The animal was fasted 14-16 hr prior to dosing. The dog was dosed while awake. The animal was induced with ketamine (259 mg) in combination with diazepam (7.5 mg) given intravenously. The animal was intubated with a cuffed endotracheal tube and maintained under general anesthesia with isoflurane gas and oxygen. Following attainment of a suitable anesthetic plane, a flexible fiber optic endoscope (135 cm length; 9 mm o.d.) was introduced into the mouth and esophagus and guided to the stomach.
  • the GRD was monitored by a camera attached to the endoscope, and the expansion process was recorded on videotape over a period of 45 minutes.
  • the animal was scheduled for endoscopic exam, and the endoscopic procedure was well tolerated.
  • the total procedure time as defined as the time from anesthetic induction to extubation, was about 1 hr.
  • the endoscope was directed to the stomach of the animal. Endoscopic views showed the location of GRD in the stomach.
  • the GRD was then monitored continuously by the endoscopic camera over a period of 45 minutes.
  • the capsule shell dissolved in few minutes and the GRD was released.
  • the GRD swelling occurred gradually over a period of 30 minutes. After 45 minutes the swollen gel was recovered from the stomach to study its dimensions and compare it to in vitro results.
  • This section concerns administration of GRDs to humans.
  • a cross over bio-study under fasted and fed conditions was conducted in one subject for a gastric retention device containing 200mg of amoxicillin or just the 200mg amoxicillin tablet without the device.
  • the subject was asked to fast overnight in both studies. During the study, under conditions of fasting, breakfast was provided two hours after dosing. In the fed state study, the subject received the dosage form with breakfast.
  • the standard breakfast was a plain bagel, one ounce of cream cheese and 125ml of fruit juice. After a washout period of 48 hours, the alternate dose was given.
  • Urine was collected at 0 hr, 1 hr, 2, 3, 4, 5, 6, 8, 12 and 24 hours. Urine samples were analyzed immediately by HPLC.
  • Riboflavin was selected as the therapeutic (Sigma Chemicals, St. Louis, MO). All test formulations, either in form of GRD or immediate release containing 100 mg riboflavin in powder form, were produced at College of Pharmacy, Oregon State University, Corvallis, OR. GRD formulations were prepared as described previously.
  • Immediate release (IR) capsules were size "1" capsules that contained lactose as the principal excipient (200 mg) and 100 mg of previously dried riboflavin.
  • Large GRD capsules (LGRD) were size '000' capsules filled with dried GRD containing 100 mg riboflavin. The dimensions of incorporated GRD before drying were 7 * 1.5 * 1 cm.
  • Intermediate GRD capsules (IGRD) were size '00' capsules filled with dried
  • Small GRD capsules were size '0' capsules filled with dried GRD containing 100 mg riboflavin. The dimensions of the incorporated GRD before drying were 3 * 1.5 * 1 cm.
  • This section concerns HPLC analysis of drug excretion following administration of GRDs to human subjects.
  • the buffer was prepared by adding 100 ml 0.5M disodium hydrogen phosphate to 350 ml deionized water. The pH is adjusted to 6 with IM citric acid. The resulting solution is made up to 500 ml volume with deiomzed water. Mobile phase preparation: 0.26 g potassium dihydrogen phosphate was added to 3800 ml of deiomzed water. 200 ml HPLC grade methanol was added. The solution was filtered to remove any particulate and stirred under vacuum for approximately 20 minutes to remove air bubbles.
  • HPLC instrument Waters Intelligent Sample Processor (WISPTM) 712, automatic sample injection module for up to 48 sample vials for injection on to the column.
  • WISPTM Waters Intelligent Sample Processor
  • Buffered sample 2 ml from each urine sample are added to 2 ml pH 6 buffer. The solution is vortex-mixed to ensure proper mixing.
  • HPLC sample 1ml buffered urine was diluted with 5 ml deiomzed water. To 50 microliters of this diluted sample, 50 microliters internal standard solution was added in a small plastic centrifuge tube. The resulting solution was vortex-mixed to ensure mixing. The HPLC sample vial was assembled and capped and placed in a WISPTM autoinjector for HPLC analysis. 20 microliters of sample was injected. All other parameters for HPLC are listed below.
  • Run time approx. 23 minutes.
  • amoxicillin calibration curve was generated by the following method: 0.03g amoxicillin trihydrate was placed in a 100ml volumetric flask, dissolved and made up to 100ml with 1:10 mixture of drug-free (blank) urine: deionized water. This was stirred at room temperature for approximately 40 minutes to ensure complete dissolution. A series of 1 :1 dilutions are made with deiomzed water to obtain 6 samples. This process of serial dilution resulted in a series of samples within a range of concentrations that was used to produce the calibration curve. The method of sample preparation for HPLC analysis was as given previously. A total of 20 microliters of each sample was injected.
  • the mobile phase was prepared by mixing exact volumes of methanol and 0.01 potassium monobasic phosphate solution adjusted to pH 5 with 1 N sodium hydroxide and then filtering under vacuum through a 0.2 ⁇ m filter. The mobile phase was degassed before use.
  • the detector was a fixed-wavelength spectrofluorometer (Gilson Spectra/Glo
  • the excitation wavelength was 450 nm.
  • the wavelength range for the emission filter was 520-650 nm. Peak areas were determined with a Schimadzu integrator (C-R3A Chromatopac, Schimadzu Corp.,
  • Urine samples were collected in 16 oz containers at 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dosing. Nolume and time elapsed since vitamin ingestion were recorded for each urine sample and a portion was saved for vitamin concentration measurement.
  • Riboflavin standard stock solutions were prepared to contain 100 ⁇ g/ml of reference standard by addition of 100 mg of riboflavin, previously dried at 105°C for 2 hours, 750 ml of water and 1.2 ml of glacial acetic acid to a 1-liter flask, dissolving with heat, and diluting to volume with water. This stock solution was diluted with blank urine to contain 1, 2, 4, 6, 8, 10, and 15 ⁇ g/ml of riboflavin. All solutions were protected from light. These standards were injected onto the column, the chromatogram was recorded and the peak areas determined. The retention time of riboflavin was about 6 minutes.
  • Riboflavin excretion data was obtained as outlined in Example 14B, sections 1-5. The different treatments were compared in terms of their urinary recovery of riboflavin during the first 24 h after administration, Recovery 0-24 , the maximum urinary excretion rate, R max and the time, T max required to reach R max . All parameters were determined from the individual urinary excretion rate-time curves, a plot of urinary excretion rate against the mid-point of a urine collection interval. Recovery o- 24 h was determined from the individual cumulative urinary drug excretion-time curve, a plot relating the cumulative drug excreted to the collection time interval.
  • EXAMPLE 17 This section concerns deconvolution of urinary excretion rate data.
  • Deconvolved input functions from biostudy data were determined using computer software PCDCON by Williams Gillespie. Deconvolution generates an input function (cumulative amount dissolved in vivo versus time) from an input response and the drugs' characteristic impulse response function. The cumulative drug input over time predicted by deconvolution was used to determine the gastric retention time of GRDs of different sizes. The gastric retention time was calculated from the deconvolved curve as the time observed when absorption stops.
  • the input response used was the urinary excretion rate of riboflavin from the different formulations (dU/dt), while the impulse response used was a literature-derived elimination rate constant as determined from an intravenous bolus dose of riboflavin.
  • Amoxicillin (a ⁇ -lactam antibiotic) incorporated in a GRD in the form of a caplet was tested for its bioavailability. Elevation of ⁇ -lactam concentration demonstrates increased bacterial killing, only until a finite point that tends to be about 4 times the minimum inhibitory concentration (MIC), which can be termed as therapeutic concentration. Further elevation is not associated with increased bactericidal potency (18, e.g., MIC for Strep, pneumococci is 0.02 mcg/ml and therapeutic concentration is 0.08 mcg/ml). A direct correlation exists between the time the ⁇ -lactam antibiotic concentrations are maintained above therapeutic concentration and clinical actions. Bacterial regrowth occurs rapidly after these concentrations fall below the bacterial MIC. Therefore a dosage regimen for each individual ⁇ -lactam should be to prevent the drug-free interval between doses from being large enough for bacterial pathogens to resume growth.
  • MIC minimum inhibitory concentration
  • Amoxicillin has a very short half-life of about 1 hour and a limited 'absorption window' following oral administration. Drug is well absorbed in duodenum and jejunum, but absorption is decreased in ileum and is rate dependent. Absorption is very poor in all colonic regions. Therefore, using GRDs to deliver ⁇ -lactam antibiotics such as amoxicillin would expand the time over MIC in vivo in relation to regular TR formulations. Bioavailability would also improve as amount of drug reaching the site of absorption is prolonged over a period of time and thus preventing saturation at that site.
  • Urinary drug excretion data can be used to estimate bioavailability because the cumulative amount of drug excreted in the urine is directly related to the total amount of drug absorbed and then excreted through a first-order elimination process. In order to obtain valid estimates, the drug must be excreted in significant amounts in the urine and complete samples of urine must be collected.
  • Fig. 23 shows that the largest mean value for Recovery 0-24h was observed for LGRD capsule, followed by IGRD capsule, IR capsule, and SGRD capsule.
  • the mean Recovery 0-24h estimate from the LGRD capsule (17.3mg) was determined to be 225% larger and statistically significantly (P ⁇ 0.05) different relative to the mean from IR capsule (5.33 mg).
  • Mean Recovery o-24h estimate from SGRD capsule (4.09 mg) was less but not statistically sigmficantly (P ⁇ 0.05) different relative to the mean from the TR capsule (5.33 mg).
  • the mean Recovery 0- 24h estimate from the IGRD capsule (9.3mg) was higher but not significantly different from the TR capsule.
  • LGRD stayed in the stomach for enough time to slowly release its vitamin content and consequently the released vitamin passed gradually through the absorption window and was absorbed more efficiently.
  • Fig. 25 shows the cumulative amount of drug absorbed versus time deconvolved from biostudy data for the JR, SGRD, IGRD, and LGRD capsules.
  • Absorption continued for up to 15 hours for the LGRD capsule before it stopped. This may indicate that the LGRD stayed in the stomach and slowly released the drug for about 15 hours.
  • the absorption from the IGRD capsule continued for about 9 hours before it became constant, indicating that the device did not stay long enough in the stomach to release all of its' drug content.
  • Absorption from SGRD capsule continued only for 3 hours indicating that the device was emptied from the stomach by the housekeeper wave (due to its small size) as rapidly as the JR dose.
  • This section concerns the production of a sustained release formulation of hydrochlorthiazide.
  • HCTZ layered spheres were coated with suspension of Surelease and Opadry mixture.
  • Drug layered spheres 100 g were coated with the suspension of 1 g Opadry and 8.06 g Surelease in 10 ml de-ionized water.
  • Total percent of coating applied on HCTZ layered spheres was 3% which consisted of 66.6% Surelease and 33.3% Opadry.
  • This section concerns the admimstration of GRDs containing hydrochlorothiazide to human subjects.
  • Subjects fasted overnight and at least 2 hours following dosing They voided their bladder before receiving a single dose of hydrochlorthiazide in each study and took the dose with 12 ounces of water. After dosing, subjects received a set of containers in which to collect their urine and a time sheet on which to record the time of urination. Subjects collected all urine within a 24-hour period after oral admimstration of the formulations. Urine samples were collected during the period 0-1,1-2, 2-3, 3-4, 4-6, 6-8, 8-10, 10-12, 12-24, 24-36, and 36-48 hours. Urine samples were refrigerated until delivered to the researcher. The volume of urine collected was measured in order to calculate total amount of drug recovered. A modified method for HPLC (High performance Liquid Chromatography) assay of Papadoyannis et al. (1998) was used to analyze small portions of urine samples for the drug content.
  • HPLC High performance Liquid Chromatography
  • This section concerns the analysis of pharmacokinetic parameters and urine output data following admimstration of GRDs containing hydrochlorothiazide.
  • GRDs containing the drug, hydrochlorothiazude, were admimstered to human subjects as outlined in Example 21. Average pharmacokinetic parameters for each treatment under fasting conditions are provided in the following Table 14, and Fig. 26 shows cumulative amount of drug excreted vs. time. Elimination half-life (t 2 ) was approximately 7 hours. The values of A 0-36 were compared for statistical analysis because it was not possible to obtain the value at 48 hours for an JR from one subject due to the short half-life. EXAMPLE 23
  • This section concerns the effects of GRD admimstration of hydrochlorothiazide to fasting subjects.
  • GRDs containing the drug, hydrochlorothiazide, were admimstered to human subjects as outlined in Example 21 and average pharmacokinetic parameters for each treatment were analyzed as outlined in Example 23.
  • Mean Ao -36 from JR (33.3mg, 66.6%) was found to be significantly different (P ⁇ 0.05) relative to that from GRD (37 mg, 75.4%) in fasting conditions, although the difference is less than 10%.
  • a difference less than 20% is generally considered to be insignificant from FDA BA/BE guidance.
  • mean values for total drug absorbed and collected in the urine were equivalent, (A 0-48 ⁇ ) were 38.12 mg (76.2%) and 38.95mg (77.9%) for JR and GRD in fasting conditions, respectively.
  • Ao ⁇ s was based on assuming 50% of absorbed dose appears intact in the urine.
  • the GRD resulted in essentially the same amount of drug being absorbed as from an JR up to 48 hours in fasting subjects.
  • the effects on urinary excretion were surprisingly quite different.
  • Fig. 27 shows that, as expected, a higher maximum excretion rate of drug (Rmax) occurred at an earlier time (t max ) from the immediate release (JR) capsule than that from the new formulation (GRD) (4.84 mg/hr at 2.5hr vs 2.5mg/hr at 5hr).
  • This section concerns the profile for HCTZ-50mg over 48-hours in fasting subjects.
  • GRDs containing the drug, hydrochlorothiazide, were administered to human subjects as outlined in Example 21 and average pharmacokinetic parameters for each treatment were analyzed as outlined in Example 23.
  • the cumulative amount of HCTZ-50mg vs. time was analyzed as outlined in Example 23.
  • Cmax and Tmax is 4.84 and 2.46 (mg/ml), and 2.5 and 5 (hr) for TR and GRD, respectively.
  • the initial equal amount of diuresis is surprising since less drug is absorbed initially from the GRD (Rmax 4.8 ( ⁇ g/ml) at t max , 2.5 hours and 2.5 ( ⁇ g/ml) at t max , 5 hours in fasting condition for JR and GRD, respectively) which now teaches that less drug can be more effective which is not common for drugs. In fact, if less amount of drug is input, less effect is expected but the opposite effect occurred with this new GRD and the diuretic.
  • results from this bioavailability study of hydrochlorthiazide establishes that the device was retained long enough to release all or most drug in the stomach, but also that the dosage form controlled drug release to prolong drug effect.
  • the GRD is an excellent device for admimstering hydrochlorthiazide as well as other diuretics that exhibit limited absorption sites in the upper part of the intestine.
  • This dosage form can improve patient care by avoiding high drug peak concentrations that may induce undesirable side effects (see side effects information below), increase drug effect per dose administered, and achieving prolonged drug effect.
  • This section concerns the side effects in human subjects following administration of hydrochlorothiazide in a GRD.
  • GRDs containing the drug, hydrochlorothiazide, were admimstered to human subjects as outlined in Example 21, and the following side effects were reported: • Three out of 7 subjects reported side effects from an IR dosage form between

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Abstract

La présente invention concerne des dispositifs de rétention gastrique fait à partir de compositions comprenant des matières polymères telles que des polysaccharides, et éventuellement des matières additionnelles telles qu'excipients, produits thérapeutiques et produits de diagnostic, qui restent dans l'estomac de façon prolongée, pendant une durée que l'on peut maîtriser.
PCT/US2001/046146 2001-08-16 2001-10-22 Dispositif de retention gastrique expansible WO2003015745A1 (fr)

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Application Number Priority Date Filing Date Title
JP2003520705A JP2005501097A (ja) 2001-08-16 2001-10-22 膨張可能な胃内滞留装置
KR10-2004-7002254A KR20040032918A (ko) 2001-08-16 2001-10-22 팽창 가능한 위 정지 장치
EP01995328A EP1416914A1 (fr) 2001-08-16 2001-10-22 Dispositif de retention gastrique expansible
BR0117123-2A BR0117123A (pt) 2001-08-16 2001-10-22 Dispositivo de retenção gástrica expansìvel
IL16036301A IL160363A0 (en) 2001-08-16 2001-10-22 Expandable gastric retention device
NZ531461A NZ531461A (en) 2001-08-16 2001-10-22 Expandable gastric retention device
CA002456976A CA2456976A1 (fr) 2001-08-16 2001-10-22 Dispositif de retention gastrique expansible
MXPA04001388A MXPA04001388A (es) 2001-08-16 2001-10-22 Dispositivo de retencion gastrica expandible.
NO20040611A NO20040611L (no) 2001-08-16 2004-02-11 Ekspanderbar gastrisk retensjonsanordning.
US10/778,917 US20040219186A1 (en) 2001-08-16 2004-02-13 Expandable gastric retention device

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EP1701705A2 (fr) * 2003-12-24 2006-09-20 Advancis Pharmaceutical Corporation Absorption amelioree de formes de dosage a liberation modifiee
US7699863B2 (en) 2005-03-01 2010-04-20 Tulip Medical Ltd. Bioerodible self-deployable intragastric implants
US8343462B2 (en) 2001-11-21 2013-01-01 Bracco Diagnostics Inc. Formulations for use in medical and diagnostic procedures
US8845673B2 (en) 2005-03-01 2014-09-30 Tulip Medical Ltd. Bioerodible self-deployable intragastric implants and methods for use thereof
US10182985B2 (en) 2014-06-11 2019-01-22 Massachusetts Institute Of Technology Residence structures and related methods
US10507127B2 (en) 2012-06-07 2019-12-17 Epitomee Medical Ltd. Expandable device
US10596110B2 (en) 2014-06-11 2020-03-24 Massachusetts Institute Of Technology Residence structures and related methods
US10953208B2 (en) 2015-05-01 2021-03-23 Massachusetts Institute Of Technology Triggerable shape memory induction devices
US11129793B2 (en) 2013-12-05 2021-09-28 Epitomee Medical Ltd Retentive devices and systems for in-situ release of pharmaceutical active agents
WO2022195476A1 (fr) 2021-03-15 2022-09-22 Clexio Biosciences Ltd. Dispositifs de rétention gastrique pour l'évaluation d'états intragastriques
US11576866B2 (en) 2016-09-30 2023-02-14 Lyndra Therapeutics, Inc. Gastric residence systems for sustained delivery of adamantane-class drugs
US11576859B2 (en) 2015-10-23 2023-02-14 Lyndra Therapeutics, Inc. Gastric residence systems for sustained release of therapeutic agents and methods of use thereof
EP4031115A4 (fr) * 2019-09-17 2023-06-21 Yeditepe Universitesi Procédé de production de cryogels avec des biomatériaux naturels et utilisation de tels cryogels en tant qu'échafaudages de tissu mou ou systèmes d'administration de médicament
US11992552B2 (en) 2015-12-08 2024-05-28 Lyndra Therapeutics, Inc. Geometric configurations for gastric residence systems
US12023406B2 (en) 2017-06-09 2024-07-02 Lyndra Therapeutics, Inc. Gastric residence systems with release rate-modulating films
US12109305B2 (en) 2016-05-27 2024-10-08 Lyndra Therapeutics, Inc. Materials architecture for gastric residence systems

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KR20090053783A (ko) * 2006-07-19 2009-05-27 스미스클라인 비참 코포레이션 감마 섬광조영술 평가를 위한 제형의 방사선표지 방법
CN102552103B (zh) * 2010-12-20 2013-11-20 西安力邦医药科技有限责任公司 拉米夫定固体分散体、其制备方法、药物组合物和用途
CA3086153A1 (fr) * 2017-12-18 2019-06-27 Tris Pharma, Inc. Composition de poudre de medicament a liberation modifiee comprenant des systemes de formation de raft de retention gastrique ayant une liberation de medicament par impulsions de declenchement

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Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8343462B2 (en) 2001-11-21 2013-01-01 Bracco Diagnostics Inc. Formulations for use in medical and diagnostic procedures
EP1701705A2 (fr) * 2003-12-24 2006-09-20 Advancis Pharmaceutical Corporation Absorption amelioree de formes de dosage a liberation modifiee
JP2007517039A (ja) * 2003-12-24 2007-06-28 アドバンシス ファーマスーティカル コーポレイション 変性放出製剤の吸収増強
EP1701705A4 (fr) * 2003-12-24 2007-08-08 Advancis Pharmaceutical Corp Absorption amelioree de formes de dosage a liberation modifiee
AU2004308419B2 (en) * 2003-12-24 2011-06-02 Victory Pharma, Inc. Enhanced absorption of modified release dosage forms
US7699863B2 (en) 2005-03-01 2010-04-20 Tulip Medical Ltd. Bioerodible self-deployable intragastric implants
US8845673B2 (en) 2005-03-01 2014-09-30 Tulip Medical Ltd. Bioerodible self-deployable intragastric implants and methods for use thereof
US8858496B2 (en) 2005-03-01 2014-10-14 Tulip Medical Ltd. Bioerodible self-deployable intragastric implants
US8864784B2 (en) 2005-03-01 2014-10-21 Tulip Medical Ltd. Bioerodible self-deployable intragastric implants
US11712356B2 (en) 2012-06-07 2023-08-01 Epitomee Medical Ltd Expanded device
US10507127B2 (en) 2012-06-07 2019-12-17 Epitomee Medical Ltd. Expandable device
US11129793B2 (en) 2013-12-05 2021-09-28 Epitomee Medical Ltd Retentive devices and systems for in-situ release of pharmaceutical active agents
US10596110B2 (en) 2014-06-11 2020-03-24 Massachusetts Institute Of Technology Residence structures and related methods
US11357723B2 (en) 2014-06-11 2022-06-14 Massachusetts Institute Of Technology Residence structures and related methods
US10517820B2 (en) 2014-06-11 2019-12-31 Massachusetts Institute Of Technology Residence structures and related methods
US10610482B2 (en) 2014-06-11 2020-04-07 Massachusetts Institute Of Technology Residence structures and related methods
US10716751B2 (en) 2014-06-11 2020-07-21 Massachusetts Institute Of Technology Residence structures and related methods
US10716752B2 (en) 2014-06-11 2020-07-21 Massachusetts Institute Of Technology Residence structures and related methods
US10182985B2 (en) 2014-06-11 2019-01-22 Massachusetts Institute Of Technology Residence structures and related methods
US10517819B2 (en) 2014-06-11 2019-12-31 Massachusetts Institute Of Technology Residence structures and related methods
US11246829B2 (en) 2014-06-11 2022-02-15 Massachusetts Institute Of Technology Residence structures and related methods
US10532027B2 (en) 2014-06-11 2020-01-14 Massachusetts Institute Of Technology Residence structures and related methods
US11389399B2 (en) 2014-06-11 2022-07-19 Massachusetts Institute Of Technology Residence structures and related methods
US10953208B2 (en) 2015-05-01 2021-03-23 Massachusetts Institute Of Technology Triggerable shape memory induction devices
US11576859B2 (en) 2015-10-23 2023-02-14 Lyndra Therapeutics, Inc. Gastric residence systems for sustained release of therapeutic agents and methods of use thereof
US11992552B2 (en) 2015-12-08 2024-05-28 Lyndra Therapeutics, Inc. Geometric configurations for gastric residence systems
US12109305B2 (en) 2016-05-27 2024-10-08 Lyndra Therapeutics, Inc. Materials architecture for gastric residence systems
US11576866B2 (en) 2016-09-30 2023-02-14 Lyndra Therapeutics, Inc. Gastric residence systems for sustained delivery of adamantane-class drugs
US12023406B2 (en) 2017-06-09 2024-07-02 Lyndra Therapeutics, Inc. Gastric residence systems with release rate-modulating films
EP4031115A4 (fr) * 2019-09-17 2023-06-21 Yeditepe Universitesi Procédé de production de cryogels avec des biomatériaux naturels et utilisation de tels cryogels en tant qu'échafaudages de tissu mou ou systèmes d'administration de médicament
WO2022195476A1 (fr) 2021-03-15 2022-09-22 Clexio Biosciences Ltd. Dispositifs de rétention gastrique pour l'évaluation d'états intragastriques

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