WO1998002146A2 - Systeme de distribution chimiomecanique a expansion - Google Patents

Systeme de distribution chimiomecanique a expansion Download PDF

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Publication number
WO1998002146A2
WO1998002146A2 PCT/US1997/012704 US9712704W WO9802146A2 WO 1998002146 A2 WO1998002146 A2 WO 1998002146A2 US 9712704 W US9712704 W US 9712704W WO 9802146 A2 WO9802146 A2 WO 9802146A2
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WO
WIPO (PCT)
Prior art keywords
container
compartment
biological environment
biologically active
pores
Prior art date
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PCT/US1997/012704
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English (en)
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WO1998002146A3 (fr
Inventor
Eyal S. Ron
Original Assignee
Medlogic Global Corporation
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Publication date
Application filed by Medlogic Global Corporation filed Critical Medlogic Global Corporation
Priority to EP97938003A priority Critical patent/EP0853474A2/fr
Priority to JP10506332A priority patent/JPH11513041A/ja
Publication of WO1998002146A2 publication Critical patent/WO1998002146A2/fr
Publication of WO1998002146A3 publication Critical patent/WO1998002146A3/fr

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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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin

Definitions

  • This invention relates to method and apparatus for delivering a biologically active compound to a biological environment in a controlled fashion.
  • the more precise control of the release of orally administered drugs has long been sought.
  • an orally administered drug or other biologically active compound be released only upon the occurrence of a desired environmental condition within a biological system.
  • a biologically active compound be released only in the intestines rather than being released as the material passes through the mouth and stomach.
  • Prior art controlled release techniques typically result in initiation and/or continuation of controlled release as a function of time after ingestion.
  • An example of a controlled release oral delivery system is the so-called osmotically-controlled delivery system. See, for example, Wang et al. U.S. Patent No. 5,413,572; Theeuwes et al, U.S. Patent No. 3,845,770; Wang, U.S. Patent No. 5.312,390; Eckenhoff er al, U.S. Patent No. 4,474,575; Place et al, U.S. Patent No. 5.147.654; Eckenhoff er al, U.S. Patent No. 4.539,004; Magruder et al, U.S. Patent No. 4,777,049; and EP 0427 519 A2.
  • the technology disclosed in these patents utilizes the osmotic pressure resulting from concentration gradients to expel a biologically active substance into the body.
  • the osmotic pressure moves a moveable partition to effect drug release.
  • Wang et al. in the '572 patent also teaches the use of a hydrogel which expands when contacted with water, the expansion serving to expel the biologically active material.
  • Osmotic pressure based systems have the shortcoming that they depend on flux and pressure for their operation. It is known that a desirable drug delivery system should be independent of both flux and pressure.
  • an osmotic pressure based system has release kinetics that are highly dependent on orifice size.
  • the osmotic pumps of the prior art operate on the principle of net flux of water across a semipermeable membrane into a compartment that contains the osmotic driving agent.
  • the rate of flux is controlled by the water permeable membrane characteristics and the difference in osmotic and hydrostatic pressure between the compa ⁇ ment containing the osmotic driving agent and the outside of the device.
  • the flux J of water may be represented as
  • K K • A • ( ⁇ • ⁇ - ⁇ P)
  • A the membrane's surface area
  • ⁇ the osmotic coefficient of the membrane
  • ⁇ the osmotic pressure
  • ⁇ P the hydrostatic pressure
  • the prior art osmotic systems are also very sensitive to the size of the delivery orifice. See, Theeuwes et al, "Elementary Osmotic Pump,” J. Pharm. Sci, 64(1987), 1975.
  • the orifice size must be small so as to minimize diffusion through the orifice and yet still be sufficiently large to minimize hydrostatic pressure inside the system that would affect the zero-order release kinetics.
  • the release kinetics in osmotic systems are independent of pH and motility of the gastrointestinal tract. See, Fara et ai, "Osmotic Pumps in Drug Delivery Devices ⁇ Fundamentals and Applications," Praveen Tyle, ed., Marcel Dekker, Inc., pi 37 (New York).
  • Other systems for non-continuous delivery of drugs, for example, the Pulsncap system are known in the prior art. In this system there is a limiting osmotic pressure which, when achieved, pushes out a cap to begin drug release.
  • volumetric change phenomena have been observed in three-dimensional. permanently crosslinked polymer gel networks.
  • an external environmental condition e.g., temperature, solvent composition, pH, electric field, light intensity and wavelength, pressure, ionic strength, osmolarity
  • the polymer gel network contracts and/or expands in volume.
  • the volume of such a gel may, under certain circumstances, change reversibly by a factor as large as several hundred when the gel is presented with a particular external condition (i.e., the gel is a "responsive" gel; see, for example, Tanaka Phys. Rev. Lett. 40(820), 1978; Tanaka et al, Phys. Rev. Lett. 38(771), 1977; Tanaka et al, Phys. Rev.
  • Interpenetrating network polymers have also demonstrated similar volume change phenomena; see, for example, Tanaka et al. in U.S. Patent No. 5,403.893 and Tanaka et al in U.S. Patent No. 5,580,929.
  • Thermally responsive polymers have been used in the preparation of deliver * ' devices in which release of a biologically active agent into the host is dependent upon the temperature; see, R. Dinarvand and A. D'Emanuele, J. Control. Res. 36(3):221 (October 1995).
  • the devise incorporates the thermally responsive polymer as a valve which is swollen (and closed) at room temperature and contracted (an open) at biological temperatures.
  • the polymer functions as an on-off switch, but has no means of actively delivering the active agent into the environment.
  • Bae et al (U.S. Patent 5,226,902) report a drug delivery device which includes a hydrogel swollen with a solution containing a biologically active agent.
  • the hydrogel is capable of contracting under certain environmental conditions. As the hydrogel contracts, the agent is released into the portion of the device previously occupied by the swollen hydrogel.
  • the device provides orifices which allow movement of the agent out of the device; however, there is no means of active delivery of the active agent into the environment.
  • a drug delivery device be provided which provides improved control over the mode of delivery of the bioactive and over the kinetics of the deliver.
  • an apparatus for controlled delivery of a biologically active compound to a biological environment which includes a container comprised of a single member or two mated members, the container defining first and second compartments and comprising pores in at least a portion of the container defining the first compartment.
  • the first compa ⁇ ment contains a polymer gel network which undergoes a volume expansion in response to an environmental condition which varies in the biological environment.
  • the second compartment contains an effective amount of a biologically active compound and including at least one passageway communicating with the biological environment. Upon volume expansion of the polymer gel network, the biologically active compound is discharged into the biological environment through the passageway.
  • pores as that term is used herein it is meant a passageway in a material through which fluid can pass with no control of flow direction or rate.
  • ores may encompass passageways of any size, including conventional "screens” of large dimension and ranging down to "membranes” of small dimension.
  • an apparatus for controlled delivery of a biologically active compound to a biological environment includes a container comprising pores in at least a portion of the container.
  • a first compartment within the container contains a polymer gel network which undergoes a volume expansion in response to an environmental condition which varies in the biological environment.
  • a second compartment contains an effective amount of a biologically active compound and including at least one passageway communicating with the biological environment. The second compartment is disposed within the first compartment.
  • an apparatus for controlled delivery of a biologically active compound to a biological environment includes a container comprising pores in at least a portion of the container.
  • a first compartment within the container contains a polymer gel network which undergoes a volume expansion in response to an environmental condition which varies in the biological environment.
  • a second compartment contains an effective amount of a biologically active compound in communication with the biological environment through the pores, the first compartment disposed within the second compartment.
  • an apparatus for controlled delivery of a biologically active compound to a biological environment includes a container comprised of a single member or two mated and comprising pores in at least a portion of the container, the container defining a space housing upper and lower compartments containing a polymer gel network which undergoes a volume expansion in response to an environmental condition which varies in the biological environment.
  • the upper and lower compartment are in communication with the biological environment through the container pores.
  • An inner compartment contains an effective amount of a biologically active compound and including at least one passageway communicating with the biological environment.
  • Figure 1 is a cross-sectional view of an embodiment of the invention disclosed herein;
  • Figure 2 is a graph of cumulative release versus time
  • Figure 3 is a graph of cumulative release versus time of a hydrophobic material into an aqueous environment
  • Figure 4 is a graph of hydrogel weight increase factor versus hydrostatic pressure (log load).
  • Figure 5 represents cross-sectional views of several embodiments of the invention in which the hydrogel is of spherical form
  • Figure 6 is a cross-sectional view of a third embodiment of the invention disclosed herein;
  • Figure 7 is a cross-sectional view of another embodiment of the invention disclosed herein;
  • Figure 8 is an illustration of the moving front in a dried gel;
  • Figure 9 is a pH response curve for an HPCAA hydrogel at 37 °C;
  • Figure 10 plot of gel volume v. time for an HPCAA hydrogel at 37 °C in a Simulated Gastric Fluid (a) and in a Simulated Intestinal Fluid (b);
  • Figure 1 1 is a plot of swell factor v. time for a hydrated HPCAA disc in SIF at 37 °C;
  • Figure 12 represents the pH response at 37 °C of a hydrogel disc dried at 60 °C;
  • Figure 13 is a response surface plot to optimize delivered volume from an apparatus of the invention
  • Figure 14 is a response surface plot to optimize linearity of delivery from an apparatus of the invention
  • Figure 15 is a schematic illustration of an apparatus of the invention
  • Figure 16 is a plot of released volume v. time for release of a model substance from the apparatus of the invention
  • Figure 17 is a plot of cumulative release v. time for release of nifedipine from the apparatus of the invention vs.
  • the chemo-mechanical delivery system of the present invention consists of a biologically active component, e.g., a drug, to be delivered, and an environmentally responsive, volume expandable hydrogel enclosed within a container which permits communication of the interior with its environment.
  • a biologically active component e.g., a drug
  • an environmentally responsive, volume expandable hydrogel enclosed within a container which permits communication of the interior with its environment.
  • the chemo-mechanical delivery system may be designed to provide time-based release of the biologically active component. It can also be designed to provide linear, non-linear or pulsatile drug delivery, as desired, over a specific time period in the presence of pre-determined trigger, such as pH.
  • pre-determined trigger such as pH.
  • the hydrogel can be designed to swell in response to changes in the environment, such as pH, releasing the pharmaceutic at a controlled rate that can range from a few minutes to over 24 hours.
  • a major advantage of the chemo-mechanical drug delivery system is that delivery is not dependent upon residence time in the digestive tract. Many conventional timed-release designs are limited because they depend on an estimate of residence time of the drug capsule as it moves through the digestive system. Because the residence/transport time in humans from time of uptake is variable, this presents a serious challenge to effective drug delivery.
  • release rates from the chemo-mechanical drug delivery system can be designed to be independent of the drug's properties.
  • the system could also logically contain different hydrogels that will provide swelling kinetics in response to different stimuli or different levels of the same stimuli (e.g., different pH levels) and thereby provide a nonlinear or pulsatile release.
  • the device and method of its use described herein provide a superior delivery system because it allows for the initiation of drug release at a desired pH, release rates that are independent of drug properties and delivery of compounds of heretofore difficult to deliver bioactive components, e.g., macromolecules. unusual ionic species, labile, lyophilic. insoluble and other drugs that require unique formulations.
  • bioactive components e.g., macromolecules. unusual ionic species, labile, lyophilic. insoluble and other drugs that require unique formulations.
  • a drug delivery system 10 includes a container 11 encompassing a first compartment or region 12 and a second compartment or region 14.
  • the regions 12 and 14 may be adjacent to one another or they may be separated by an optional partition 16.
  • the container 11 includes pores 18 which may occupy a small portion of the container surface area (in proximity to the region 12) or which may occupy substantially the entire surface area of the container 11.
  • the second compartment 14 may include at least one passageway 20.
  • First compartment 12 contains environmentally responsive, volume expandable hydrogel 22 and the second compartment 14 contains a biologically active material or drug 24.
  • the pores 18 retain the hydrogel 22 within the compartment 12 but allow communication with fluids in a biological environment (not shown) into which the device 10 is placed.
  • the pores 18 may form a permeable or semipermeable membrane as desired.
  • the hydrogel 22 is selected to undergo a volume expansion in response to the occurrence of an environmental condition such as pH. Upon occurrence of such a condition, the hydrogel 22 will expand, thereby displacing the compartment or region of the hydrogel to the right in Figure 1. This movement will decrease the volume in the second compartment 14, causing the biologically active material 24 to exit through the passageway 20 into a biological environment (not shown).
  • the pores may serve as the passageway and the biologically active material 24 may exit through pores 18 in the container defining the second compartment.
  • the device 10 In use, the device 10 would be placed into the mouth and swallowed. The pH of the esophagus and stomach are low so that no drug is released. When, however, the device 10 reaches the intestines, there will be encountered an environment having a higher pH. Communication with the higher pH environment through the pores 18 causes the hydrogel 22 to expand to expel the drug 24 into the intestinal region. It will be recognized and appreciated that following the teachings of this application and applications serial numbers WO 96/02276 published February 1, 1996, 08/473,218 and 08/749,758, which are incorporated herein by reference their entirety, permit the design and engineering of hydrogels which undergo a volume expansion at a desired environmental condition or in a range of environmental conditions.
  • the gel in the device 10 may be triggered by a gradient in an ionic species in solution, for example, a potassium ion gradient. Such a trigger has application to drug delivery into the gastrointestinal tract.
  • Figure 3 illustrates the result of an experiment in which a hydrophobic material was released into an aqueous environment.
  • a hydrophobic material a mixture petrolatum and mineral oil
  • the loaded system was then placed into a beaker containing a buffer. Cumulative release was measured by weighing the amount of petrolatum/mineral oil emitted from the apparatus and plotting the percent released over time.
  • the hydrogel used to generate the expansion force was hydroxypropylcellulose crosslinked lightly with adipoyl chloride.
  • This experiment demonstrates zero-order release of a hydrophobic material into a hydrophilic environment to complement the delivery of a hydrophilic material ( Figure 2), thereby indicating the ability of the apparatus of the present invention to deliver formulations irrespective of their physicochemical properties.
  • Figure 2 This experiment demonstrate that it is possible to release a component into its environment upon introduction of a triggering environmental change. It is desired to develop a device which may be structured and arranged so as to permit any desired release kinetics. For example, it may be desirable in some circumstances to have a linear release of the bioactive material. In other circumstances, it may be desirable to have rapid non-linear release occurring at a pre-determined point in the digestive tract.
  • the advantage of the chemo-mechanical delivery system of the invention is its ability to allow design and engineering of the release kinetics based on manipulation of the environmentally responsive, volume expandable hydrogel and the ability to precisely control its swell kinetics.
  • the device further may be designed to take advantage of an important difference from existing technology which is dependent on osmotic forces.
  • Osmotic fluid uptake is sensitive to applied pressure.
  • Osmotic forces require semi-permeable membranes which allow one-way flow of liquid into the device.
  • the chemo-mechanical system requires simply a permeable membrane or screen which is capable of fluid flow in both directions. Because the hydrogel will only expand (swell) in the proper triggering environment, there is no need use a semi-permeable membrane.
  • the hydrogel 22 in the compartment 12 is substantially independent of hydrostatic pressure as shown in the curves in Figure 4.
  • the material used in Figure 4 is hydroxypropylcellulose (HPC) crosslinked with adipic acid. Volume expansion of the hydrogel against a load (to simulate hydrostatic pressure) was determined over time. Regardless of the magnitude of hydrostatic pressure on the hydrogel. the gel achieved its free swelling volume (expansion in the absence of a load) within about 24 hours. This confirms that the pore design is not a critical factor for the successful fluid uptake in a drug delivery device of the invention.
  • the hydrogel and the biologically active agent are located in two separate compartments or regions of a container structure.
  • the container may be comprised of a single member defining the two compartments.
  • the container may be comprised of discreet members defining the hydrogel and biologically active agent compartments, respectively, which are mated to form the container.
  • the two members comprising the container may be joined by methods known in the art such as crimping.
  • the container may be made from inert non-erodible materials such as thermoplastic polymers (e.g., polyethylene, polyfluoroethylene. polyurethane, etc.), ethylene vinylacetate, polyvinylidene difluoride, polycarbonate, polyhydroxyethyl methacrylate, polyvinylpirrolidone, polyacrylamide, polystyrene, cellulosic derivatives (e.g., cellulose esters, cellulose ethers, cellulose acrvlate, cellulose acetate, cellulose butyrate, cellulose propionate. ethylcellulose. hydroxypropyl methylcellulose), and mixtures of thereof.
  • thermoplastic polymers e.g., polyethylene, polyfluoroethylene. polyurethane, etc.
  • ethylene vinylacetate e.g., polyvinylidene difluoride
  • polycarbonate polyhydroxyethyl methacrylate
  • polyvinylpirrolidone polyacrylamide
  • the container T/US97/12704 of the device is prepared from non-dissolvable, non-bioerodible materials, which are referred to as "Ghost" materials. These materials are able to pass through the digestive system without erosion so that any hydrogel contained within the container will not come in contact with the biological host. Thus, even hydrogels of unknown toxicity profiles may be used in the preparation of the device.
  • the container desirably contains pores in order to allow both water penetration into the device and the release of the drug.
  • pore size within the container is restricted only in that the hydrogel is constrained from leaving the device through the pores. No pore design to control the osmotic pressure is required.
  • the device container may contain pores over the entire container surface area or the pores may be contained to a specific region localized in proximity to the volume expandable hydrogel which is contained therein.
  • pores of the container may be pre-existing. In such cases they would be made at time of manufacturing. For example, holes could be introduced into the container with a laser drill or the container could be fabricated from a porous sheet of thermoplastic polymer(s). Laser holes are commonly required in existing systems because the precise size of the hole is critical to the create precise back pressure in such devices and thereby control the total osmotic pressure and the delivery rate; however, the present invention is not so limited. Alternatively, and preferably, pores may be formed in situ. In one such design, porosigens (pore forming agents) would be incorporated into the container, such as e.g., inorganic salts, such as alkali metals (e.g., NaCl.
  • inorganic salts such as alkali metals (e.g., NaCl.
  • KCI, NaBr. Na-.C0 3 KC1, etc. alkaline earth metals (e.g., calcium phosphate, calcium nitrate, calcium chloride, etc.); saccharides (e.g., glucose, sucrose, pentose, hexose. fructose, mannitol, manose, talose, sorbitol, etc.); and soluble polymers (e.g., polyethylene glycol (PEG), cellulosics; etc).
  • the porosigens could be environmentally sensitive to formation of pores at a desired site in the GI tract. Once the device is placed in the environment of use, the porosigens dissolve and form desired pores in the container.
  • pores could be uniformly or non-uniformly disposed throughout the container, that the pores could be of uniform or non-uniform size, and that such pores could desirably be formed only under specific conditions, thus adding yet additional dimensions of control to the chemo-mechanical system design.
  • the hydrogel compartment is separated from the biologically active agent compartment of the container using a partition.
  • the partition may be movable, that is, it may be displaced along the expansion front of the hydrogel as the hydrogel expands in response to an environmental stimuli.
  • the partition may be fixed at one point within the device; however, it is sufficiently flexible so as to deform in response to the expanding hydrogel. In this respect, it is similar to a balloon or other such flexible membrane.
  • the partition may be permeable or impermeable to fluids depending upon whether it is desired to dilute or solubilize the biologically active agent with body fluids.
  • the partition may take the form of a layer of waxy polymer that melts at body temperature, or another hydrogel or superabsorbent hydrogel that will swell faster then the environmentally responsive, volume expandable hydrogel and will provide a water barrier.
  • the device may be designed without any partition.
  • the particle size of the environmentally responsive, volume expandable hydrogel is selected to be sufficiently large so as to minimize entrainment of the drug within hydrogel.
  • the hydrogel in the form of a disk or monolith is well-suited for use in a partitionless device.
  • the swelling of the environmentally responsive, volume expandable hydrogel will form a squeezing action to expel the drug solution out of the orifice at the opposite side of the system device.
  • a partitionless configuration is particularly preferred in drug formulations that do not interfere with the swelling stimuli.
  • the biologically active material or drug 24 may be any material approved for use in a particular diagnostic or treatment protocol.
  • Classes of biologically active compounds which can be loaded into the second compartment 14 include, but are not limited to, prodrugs, antisense, oligonucleotides, DNA, antibodies, vaccines, other recombinant proteins, anti-AIDS substances, anti-cancer substances, antibiotics, immunosuppressants (e.g. cyclosporine) anti-viral substances, enzyme inhibitors, neurotoxins, opioids, hypnotics, antihistamines.
  • lubricants tranquilizers include anti-convulsants, muscle relaxants and anti-Parkinson substances, anti-spasmodics and muscle contractants, miotics and anti-cholinergics, anti-glaucoma compounds, anti-parasite and/or anti-protozoal compounds, anti-hypertensives, analgesics, anti-pyretics and anti-inflammatory agents such as NSAIDs. local anesthetics, ophthalmics, prostaglandins, anti-depressants, anti-psychotic substances, anti-emetics. imaging agents, specific targeting agents, neurotransmitters, proteins, cell response modifiers, genes and enzymes.
  • the drug may be formulated as a liquid in either aqueous or oil phase.
  • the drug may be formulated as a solid with or without solubilizers (agents that promote drug dissolution into the media) to control the dissolution rate of the drug in which case it may be desirable to transport water (or body fluids) into the drug compartment.
  • Fluid transport will be driven by the osmotic gradient and/or controlled by the pore size in the container structure. It also may be established by incorporation of a semipermeable membrane into the container region defining the drug compartment.
  • the osmotic gradient may be caused by the drug alone (i.e., it's charge, size), by osmotic agents, or by excipients.
  • Solubilizing agents include: soluble polymers (PEG, PEO, cellulosics), carbohydrates (mannitol, sorbitol, dextrane), low molecular weight molecules (small organic acids, organic salts, quaternary amines) surfactants (SDS, fatty acids, poloxamers) etc. These agents are mixed with the drug during or prior to device manufacturing.
  • excipients could be dry mixed with the drug or wet processed (spray drying, casting, granulation, lyophilization, direct compression or spheronization).
  • excipients include binders (macrocrystalline cellulose), plasticizers (PEG), buffering agents (sodium phosphate) and stabilizing agents (sugars).
  • Preferred crosslinked polymer networks for use in the device 10 of the invention are gels that are "responsive" - i.e., gels that, when challenged with an environmental condition, are affected by that environmental condition so as to cause the entire gel, or a component thereof, to undergo a volumetric change in which the gel expands from a less liquid-filled state or a dry state to a more liquid-filled state.
  • the degree of volumetric change between unexpanded and expanded states of preferred responsive gels at their particular environmental transition region is quantitatively much greater than the volume change of the gel outside the environmental transition region.
  • Suitable gels for use in the present invention may be a single material such as a single polymer network which meets the volumetric response requirement.
  • the gel may also be a co-polymer, whether a random, alternating, graft or block co-polymer.
  • Other suitable polymers include those which include those of known acceptable toxicity profile which meet the volume responsive requirement.
  • the gel may also include two or more polymers, so long as the result is a physical polymer blend, wherein at least one polymer meets the volumetric response requirement.
  • the gel may also be an interpenetrating polymer network (IPN) in which each polymer maintains its integrity.
  • IPN interpenetrating polymer network
  • the volume change of the entire gel, or a component thereof, may be either continuous or discontinuous.
  • the crosslinked gels suitable for use in the invention may undergo a "discontinuous" volume change in which the transition from swollen to collapsed states, and back again, occurs over a small change in environmental condition, such as less than 1/10° C or 1/10 pH unit. It is preferred that the discontinuous volume change occur within a range of approximately 5° C and one pH unit.
  • Such gels are often called "phase-transition" gels (see, for example, Tanaka et al. J. Chem. Phys. 87(15), p.1392-4, 1987. which describes synthetic polymeric gels that undergo phase transitions).
  • the crosslinked gels suitable for use in the invention may undergo a "continuous" volume change in which the transition from unexpanded to expanded states occurs over a larger change in environmental condition or over a greater period of time.
  • a gel undergoing a continuous phase-transition may have a similar order of magnitude total volume change as a gel undergoing a discontinuous phase -transition.
  • the volume transition may be either reversible or irreversible.
  • Hydrogels prepared for use in the apparatus of the invention for example, the hydrogels reported in Example 2, were tested for toxicology in standard animal models. In all cases, initial toxicological evaluations demonstrated that the materials were safe. The results are reported in Table 1.
  • the drug could be delivered in a variety of ways, depending upon its solubility and physical state.
  • a liquid dose could be administered as follows. Once the volume expandable hydrogel "senses" the right environment (i.e., pH) it starts to swell in a controlled rate. As a result of this swelling it operates as an actuator and expels the liquid drug/drug solution out to the environment at a controlled rate.
  • a solid dose could be administered as follows. Once the device comes in contact with water or other body fluid, the drug compartment is filled with fluids at a known and, as described, potentially controlled rate as a result of pores or membrane included in the container. As a result the solid drug dissolves to form a solution that is contained within the device. Dosage proceeds is as described for liquid dose. Similarly, the drug dissolution rate is timed with the swelling rate, where only the needed amount of drug solution is present at any moment.
  • a spherical device 50 may include a core 51 comprising an environmentally responsive, volume expandable hydrogel 52 which is coated with a solid drug 54 mixed with or without another solubilizing excipient/s through granulation, coating apparatus, spray drying, or other similar system.
  • the core 51/solid drug coating 54 are encompassed by a container 55 containing pores 56 as described hereinabove.
  • a spherical device 60 could be made of a solid drug core 62 (mixed with or without another solubilizing excipient s) surrounded by the environmentally responsive, volume expandable hydrogel 64.
  • the solid drug core 62 and hydrogel 64 are encompassed by a container 66 containing pores 68 as described hereinabove.
  • the spherical device 69 could be made of a homogenous or heterogeneous mixture of volume responsive hydrogel beads 62 mixed with solid drug 64 (mixed with or without another solubilizing excipient/s).
  • the solid drug core 62 and hydrogel 64 are encompassed by a container 66 containing pores 68 as described hereinabove.
  • the chemo-mechanical system may take the form of a three-compartment sandwich device 70, as shown in Figure 6.
  • outer top and bottom components of the device, 72 and 74, respectively, are made of an environmentally responsive, volume expandable hydrogel.
  • a core 76 of the device is made of the drug in a solid form.
  • a device container 78 including pores 79 could be made as described above.
  • the device may include partitions 80 located between the hydrogel layers 72, 74 and the drug core 76.
  • the device may be made from two discs of environmentally responsive, volume expandable hydrogel, which would not require the use of a partition. Once the device is come in contact with bodily fluids the drug will be solubilized as described above.
  • this device as a sandwich is not intended to be restrictive.
  • outer hydrogel layers of differing thicknesses, multi-layer structures, use of different environmentally responsive volume expandable hydrogel for the top and bottom components e.g., different hydrogels, different porosigens, etc.
  • top and bottom components e.g., different hydrogels, different porosigens, etc.
  • multi-layer version of the for delivery of different drugs and/or drugs in a pulsatile form e.g., different drugs, different porosigens, etc.
  • FIG. 8 Another embodiment of the invention is shown in Figure 8.
  • a rigid inner porous or perforated wall 81 is covered with an outer biocompatible. flexible membrane 82.
  • the inner wall provides support allowing the device to retain its shape.
  • the outer membrane provides biocompatibility, and could be permeable to both the chemical stimuli triggering volume expansion and the drug. Alternatively, the drug will be delivered either through orif ⁇ ce(s) 84 or through the membrane 82.
  • the drug and the hydrogel are housed in compartments 86 and 88, respectively.
  • the membrane 82 could be a dialysis membrane (membrane with a certain molecular weight cut-off). Materials of construction for such a membrane could be: cellulose, polysulfone, polymethylmethacrylate.
  • membrane could be, by way of example only, ethylene vinylacetate, polyptropylene, polyvinylidene, difluoride, polycarbonate, and other water soluble polymers such as: polyhydroxyethyl methacrylate, polyvinylpirrolidone, polyacrylamide.
  • the swelling kinetics of the present system has been investigated and is disclosed hereinbelow.
  • the investigation demonstrates, among other things, that the physical structure and geometry of the hydrogel component has an effect on the swelling kinetics and hence the release rates of the drug.
  • hydrogel beads exhibit a non-linear swelling rate in Simulated Gastrointestinal Fluid
  • hydrogel disks exhibit a linear swelling rate.
  • This knowledge may be used as a guide to one skilled in the art in selecting from the variety of device structures in order to provide the desired release kinetics of the drug of interest.
  • Volumetric changes in aqueous gels are driven primarily by four fundamental forces: ionic, hydrophobic, hydrogen bonding and van der Waals bonding interactions, either alone or in combination.
  • Each of these interactions may be independently responsible for a volume transition in preferred gels of the invention.
  • Each of these fundamental forces is most strongly affected by a particular trigger.
  • Changes in solvent concentration most strongly affect the van der Waals interaction: changes in temperature most strongly affect hydrophobic interactions and hydrogen bonding; and changes in pH and ion concentration most strongly affect ionic interactions.
  • the volumetric changes of the hydrogels described herein result from competition between intermolecular forces, usually electrostatic in nature, that act to expand the polymer network; and at least one attractive force that acts to shrink it.
  • the swelling of hydrogels is a complicated phenomenon that consists of several separate but interrelated physical processes: (1) collective diffusion of the network, (2) diffusion of solvent into the network, (3) diffusion of ions into the network, and (4) plastification of the dried gel.
  • the solutions reach equilibrium exponentially with a time constant ⁇ « a 2 /D, where a is the gel size.
  • a is the gel size.
  • the solution is exact for spheres; it is slightly more complicated for other shapes. Thus, one can control the rate of swelling by changing the size of the gel particles.
  • H is the hydration ration (weight of water/total weight)
  • H eq is the equilibrium hydration
  • r 0 is the initial radius.
  • D is the chemical diffusion coefficient of solvent within the network. It can be controlled by changing the solvent-polymer interaction and or the gel porosity. The diffusion of ions into the gel follows similar dynamics. The diffusion coefficient should be different because there are interactions of the ions with the charges on the network. Therefor this process is pH dependent. Given an adequate supply of solvent, the plastification of the dry gel is a linear
  • any particular application such as pH responsive swelling of a hydrogel places some constraints on the gel characteristics. Nevertheless, there are plenty of parameters that can be freely adjusted to obtain the desired kinetic behavior.
  • the polymer-solvent interactions are affected, influencing the elastic moduli, the solvent diffusion rate and the plastification rate.
  • Changing the crosslink level affects the phenomena, but to a different degree.
  • the amount of charged groups is related to the ion diffusion and also affects the pH response.
  • the carboxyl groups (and other polar, hydrogen bonding groups) also play another role by hydrogen bonding the gel at low pH values, thus increasing the pH responsiveness.
  • the gel particle size and shape is a factor in determining the overall relaxation time.
  • the gel designer has a lot of room to tailor the gel behavior to the particular demands of the application.
  • a gel whose volume change is governed by ionic interactions would include components that are weakly acidic and weakly basic, such as poly(methylmethacrylate)/dimethylaminoethyl methacrylate (see. for example, Siegel et al, Macromolecules 21(3254), 1988) and cellulose ethers such as HPC crosslinked by methods described herein. Gels of this type are sensitive to pH (see Example 1). Gels whose volume change is governed by hydrogen bonding will collapse with a decrease in temperature and are exemplified by interpenetrating polymers that comprise acrylamide as one polymer, acrylic acid as the other polymer, and water as the liquid medium.
  • Gels may be formulated in which the volume change is governed by more than one fundamental force.
  • gels consisting of copolymers of positively and negatively charged groups meet this requirement.
  • polymer segments interact with each other through ionic interactions and hydrogen bonding. The combination of these forces results in the existence of several pH-driven phases (see, for example. Annaka et al. Nature 355(430), 1992, incorporated herein by reference).
  • Polymer gel compositions of the present invention are particularly useful for oral delivery compositions. It should also be noted that the device 10 could be located outside the body for other drug delivery applications such as cyclic infusions or transdermal delivery.
  • polymer gel networks of the present invention that are responsive to changes in pH or the other triggers discussed above can be utilized to effect controlled release of compounds at specific locations along the gastrointestinal tract.
  • polymer gel networks that are responsive to changes in pH can be utilized, for example, to effect controlled release of substances into only one of a cow's stomachs.
  • a cellulose ether gel such as hydroxypropylcellulose (HPC) with a lower critical solution temperature (LCST) near body temperature (e.g. 42° C) should have its LCST shifted to a lower temperature at lower pH.
  • HPC hydroxypropylcellulose
  • LCST critical solution temperature
  • very few -COOH and/or -OH groups are ionized at low pH and the gel would tend to have a reduced hydrophilicity.
  • the gel is therefore very sensitive to pH change and would be collapsed at low pH (i.e.
  • a responsive gel may be made from starting materials (i.e. cellulose ethers of various configurations) that vary in their hydrophobic/hydrophilic nature when ionized, so that the methods described herein may be used to make a reversibly responsive, pH-sensitive gel with an LCST designed to match the body temperature of a desired subject.
  • the LCST of preferred cellulose ethers is well known and can be easily determined and verified.
  • Exemplary LCST's are 49° (MEC): 42°-46° (HPC); 59° (methyl(hydroxypropyl)cellulose: HPMC); 60° methyl(hydroxyethyl)cellulose; and 55°-70° (ethyl(hydroxyethyl)cellulose).
  • the device 10 of the present invention provides better control of drug release than prior art. osmotic-type pump systems.
  • the prior art devices release drugs solely as a function of time after ingestion rather than upon the encounter of an environmental condition such as pH.
  • An example is U.S. Patent 5,413,572 to Wang et al which suggests the use of a hydrogel which expands upon contact with water whose expansion then disgorges a drug.
  • hydrogels contemplated by Wang might exhibit a volume change in response to an environmental condition, this property is neither utilized nor appreciated by Wang et al.
  • the Wang et al. hydrogels begin expanding upon contact with water immediately upon ingestion and thus the drug is continuously released.
  • the hydrogels suitable for use in the device of the invention expand only upon the achievement of a selected environmental condition such as a preselected narrow pH range or other disclosed triggers.
  • a general protocol for forming a polymer network suitable for use in the present invention using a crosslinkable polymer includes the steps of dissolving the polymer(s) in a suitable solvent and allowing the polymer(s) and solvent to mix. A crosslinking agent is then added to the polymer solution, and the solution and crosslinker are further mixed together. The resulting solution may be poured into a solid mold (e.g. between two glass plates), and the crosslinking reaction carried out.
  • backbone polymers include hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC) and hydroxypropyl starch (HPStarch).
  • multifunctional carboxylic acid crosslinkers include acyl halide derivatives of adipic acid, sebacic acid and succinic acid.
  • a chemical crosslinking reaction is carried out in the homogenous polymer state at room temperature to form a certain amount of polymer network. Total crosslinking time will vary but is generally less than 24 hours. The network is then removed from its mold, and repeatedly washed to leach out any leachable material present in the network.
  • a polymer network can be made from any polymer with side groups that can react with a di- or multifunctional crosslinking molecule. Temperature and/or pH responsiveness, strength, degree of swelling and swelling rate are designed into the hydrogels by choosing the appropriate backbone polymer, crosslinker, crosslinker level and fabrication methodology.
  • the polymer solution may also be formed into beads or spheres using crosslinking in a non-solid mold where the reacting solution (polymer, crosslinker and catalyst, if needed) is dispersed in a non-solvent to form a droplet.
  • the solution reacts within the droplet to form a bead.
  • the non-solvent may be considered to be a "mold" for polymer network droplets.
  • U.S. Patent No. 3,208,994 to Flodin et ai generally discloses methods of preparing polysaccharide gel beads using suspension crosslinking.
  • One introduces a water soluble polysaccharide and crosslinker into a suspension medium under agitation to obtain suspended drops of the polysaccharide solution.
  • Another method of preparing gel beads uses inverse emulsion polymerization, in which a monomer solution is introduced into a dispersion solvent to form monomer droplets and polymerization is initiated to form polymer gel beads (see, for example, Hirose et ai, Macromolecules 20(1342), 1987. incorporated herein by reference).
  • an aqueous cellulose ether solution, a non-polar saturated hydrocarbon solvent, and a crosslinker are provided and admixed to form a two-phase system.
  • the two-phase system is agitated sufficiently to form droplets of aqueous cellulose ether solution in the two-phase system.
  • the agitation of the two-phase system is maintained to form crosslinked cellulose ether gel beads and the crosslinked cellulose ether gel beads are thereafter recovered from the two-phase system.
  • Polymer networks of the invention also may consist, in whole or in part, of polymers made by copolymerization/crosslinking of monofunctional and polyfunctional polymerizable monomers.
  • a preferred method for making gels from cellulose ethers involves dissolving a sample of cellulose ether such as HPC or HPMC in an anhydrous solvent that does not contain active hydrogen, such as for example N-methyl pyrolidone (21 C.F.R. 176.300), dimethylsulfoxide (DMSO), dimethylformamide (DMF), methylethylketone (MEK), tetrahydroftiran (THF), and the like.
  • the concentration of polymer in the solution may range from about 5-20% by weight of polymer per volume of solution, with a preferred concentration primarily a function of the kind of polymer used in the synthesis.
  • the molecular weight of the cellulose ether should be at least about 20,000.
  • Preferred molecular weights range from about 75,000 to about 150,000. The higher the molecular weight of the polymer, the sharper will be the volume change of the resulting responsive gel. This is because a higher molecular weight will result in formation of a more consistent three-dimensional polymer network. Molecular weights may range up to 1 ,000,000 or more although it will be understood that viscosity effects will place an upper limit on the molecular weight of the polymer starting material. Those having ordinary skill in the art may readily determine using the methods described herein the extent to which viscosity constraints interfere with the gel formation process and/or prevent the crosslinker from mixing with the polymer.
  • azeotropic distillation is a preferred method.
  • a first solvent such as DMSO is added to a distillation flask containing the polymer and crosslinker reagents. Both are mixed to achieve a clear solution.
  • a second solvent e.g. toluene.
  • This solution is allowed to react under azeotropic distillation until a gel forms in the flask.
  • the gel is then removed and placed in an excess of deionized water.
  • the water is removed and excess primary alcohol (e.g. methanol) is added to remove excess solvent.
  • the gel is washed and then dried in a desiccator.
  • Synthesis of gels using acyl halide derivatives of dicarboxylic acids generally occurs as follows: While stirring the cellulose ether polymer solution under anhydrous conditions, the solution is cooled slightly below room temperature (in some embodiments to between about 10-20 °C) and a cold solution (in some embodiments between about 2-8 °C) of a preferred acyl halide derivative of a multifunctional carboxylic acid is added as crosslinker to the polymer solution. This solution is stirred and then allowed to sit until gelation has occurred. Gelation time will necessarily vary and may occur within about 2 hours (e.g. for HPC) or as long as 24 hours (e.g. for HPMC). The polymer/crosslinker weight ratio is between about 12/1 and 8/1. The lower the ratio, the more highly crosslinked the resulting gel will be.
  • a gel which has basic (amine) groups rather than acid groups this may be achieved for example by allowing the acyl halide, cellulose ether reaction product to react with a diamine such as ethylenediamine or hexamethylenediamine (21 C.F.R. 175.300 (b)(3) (xxxii) to produce an amine- terminated amide.
  • a diamine such as ethylenediamine or hexamethylenediamine (21 C.F.R. 175.300 (b)(3) (xxxii) to produce an amine- terminated amide.
  • the amine-terminated amide will survive the workup.
  • These amine groups will cause the gel to be pH and temperature responsive in a range different from the acid group-containing gel.
  • This opacity signifies that the gel has undergone a volumetric change at a lower critical solution temperature (LCST), and therefore that the gel has temperature responsive characteristics.
  • LCST critical solution temperature
  • the LCST is between 42 and 46 °C.
  • the degree of responsiveness to pH may be assayed using the device and procedures given in Example 1.
  • the first compartment 12 of the device 10 is loaded with a suitable hydrogel, as described above.
  • a desired biologically active material or drug 24 is loaded into the second compartment 14. The thus loaded device is ingested and fluids in the environment pass through the screen or membrane 18 to interact with the hydrogel 22.
  • the hydrogel 22 When, for example, the pH is high (and only in that circumstance), the hydrogel 22 will undergo a volume expansion moving the moveable partition 16 to expel the drug 24 through the orifice 20. After drug 24 release, the device 10 will continue its passage through the system with subsequent natural elimination from the system.
  • Example 2 This example investigates the swelling characteristics of hydrogels suitable for use in the apparatus of the invention.
  • Swelling is an attribute related to the suitability of the hydrogel for use in the apparatus of the invention. Swelling is determined by the mass of aqueous solution uptake per gram of gel and is approximated by the equation:
  • Methods of measuring the swell factor involve hydrating a known mass of dry hydrogel in a particulate or disc form and determining the mass of the hydrated hydrogel after a predetermined amount of time.
  • Table 2 summarizes the swelling characteristics of a variety of hydrogels at low and physiological pH. Swelling measurements are taken at 24 hours. HPC and HPMC hydrogels demonstrated significant pH responsiveness, whereas HPStarch hydrogels had a lesser response.
  • Example 3 This example demonstrates the pH response of HPC hydrogel crosslinked with adipic acid. Gels exhibiting a swell curve with minimal response at pH ⁇ 5.0 and a significant response for pH > 5.0 are considered suitable for intestinal delivery applications. Swell response over pH is an indication of such a response.
  • a weighed amount of gel particles having a size greater than 600 microns were placed into a range of citric acid buffers (pH of ca. 1.0, 2.2, 4.0, 5.1 , 6.0, 7.0, 7.4) with Simulated Gastric Fluid (SGF) and Simulated Intestinal Fluid (SIF) at the pH extremes.
  • SGF Simulated Gastric Fluid
  • SIF Simulated Intestinal Fluid
  • the citric phosphate buffers provided a complete range of pH values with minimal changes to ionic strength.
  • HPC hydrogel crosslinked with adipic acid exhibited nearly ideal results with zero water absorbance at pH ⁇ 5.0. moderate swelling for 5 ⁇ pH ⁇ 7 and over 20 fold swelling for pH > 7. Results are shown in Figure 9.
  • Example 4 This example investigates the effects of hydrogel geometry and size on the rate of hydrogel swelling.
  • Controlling the rate of swelling by selective use of hydrogel compositions and geometries is desirable.
  • the control of hydrogel expansion by the hydrogel itself permits the design of apparatuses with specific expansion and delivery properties.
  • Two sets of experiments were conducted. The first examined the swelling characteristics of dry 600 micron gel particles. The second examined the swelling characteristics of solid gel discs which were hydrated, but in a collapsed state. Dry particle swell rate was determined by allowing HPCAA gel particles (600 micron) to swell at 37 °C in a disposable cuvette. The height of the hydrated gel was recorded hourly to determine the volume change. Change in volume was plotted against time and presented in Figure 10.
  • Curve 70 represents swelling in SGF and curve 72 represents swelling of the hydrogel in SIF. The hydrogel particles reached maximum swell in SIF within an hour of exposure to the aqueous media and thereafter leveled off.
  • the kinetics of swelling for hydrated solid HPCAA disks were determined.
  • the discs were hydrated in SGF, bringing the hydrogel into a collapsed states.
  • the collapsed, hydrated gels were placed into SIF and analyzed for solution uptake gravimetrically.
  • the swell factor (hydrated volume-initial volume/initial volume) is plotted as a function of time in Figure 11 and demonstrates a near zero order swelling rate.
  • Example 5 This example demonstrates the ability of a hydrogel to swell under pressure, i.e., the expansion force exerted by the hydrogel upon swelling.
  • a hydrogel sample (e.g., HPCAA) is placed in a 0.15 M NaCl solution and a series of weights of increasing value were placed on top of the hydrogel sample.
  • the uptake of NaCl solution was measured and the uptake (expressed as a swell factor) was plotted against the log of the applied pressure, as is shown in Figure 4.
  • the linear relationship observed was used to estimate the pressure required to prevent uptake of solution, e.g., expansion force.
  • the material being evaluated should reach equilibrium swelling.
  • HPCAA has not reached equilibrium, however, it can be noted that the expansion of the hydrogel is limited with higher pressure at early time points but that as time progresses, the hydrogel is able to expand and take up more solution.
  • the hydrogel eventually reaches free swell volume, that is, the volume to which it swells when no pressure is applied. The ability to expand to free swell volume was observed up to a pressure of 0.6 ATM.
  • Example 6 This example describes the preparation of an apparatus of the invention and demonstration of delivery of a substance therefrom.
  • a system was designed and constructed to demonstrate the principles of the apparatus of the invention.
  • the design was cylindrical having a height of approximately 3.5 cm and a diameter of 2.5 cm.
  • a 100 mesh stainless steel screen covered the bottom of the cylinder and provided access to solution.
  • the bottom of the demonstration unit was covered with approximately one gram of particulate HPCAA hydrogel.
  • a solid partition was placed on top of the hydrogel to serve as a barrier between the hydrogel and the substance to be delivered.
  • the substance to be delivered was a viscous carbopol gel.
  • a cover was attached to the cylinder flush with the carbopol gel and a hole was punched in the top. The system was then placed in an aqueous solution and the mass of carbopol emitted was plotted against time to obtain the release kinetics.
  • Performance of this system provided zero order release over 24 hours.
  • a similar study was conducted using a hydrophobic mixture of petrolatum and mineral oil as the substance to be delivered. The system containing the material was placed into PBS and the mass of material emitted was plotted against time. A graph of the release kinetics is shown in Figure 3. Delivery of a lipophilic material into a hydrophilic environment demonstrates the superior performance of the device as a means for delivery in a biological system, regardless of the physiochemical properties of the substance being delivered. Another experiment was conducted to demonstrate the ability of the pH responsive HPCAA hydrogel system to selectively deliver at intestinal pH. The demonstration unit described above was charged with carbopol gel and was initially placed into a pH 2.2 buffer solution. After one and one half hours, the system was removed and placed into a pH 7.5 buffer system. Release of carbopol over time was plotted in Figure 2 and demonstrates selective delivery to a neutral environment.
  • Example 7 This example demonstrates systematic approach to developing a device for delivery into a biological system with acceptable performance criteria.
  • the goal is to optimize the delivery of 1 mL of a substance as a function of hydrogel height and degree of crosslinking.
  • Response surface plots are shown in Figure 13 and Figure 14.
  • a working system may fabricated to have acceptable performance criteria based upon these response surface plots. This demonstrates the versatility of the design system to control hydrogel response to fit a particular system constraints.
  • Dimensional constraints The desirability of reducing the size of the device was identified. Dimensional constraints of an intermediate size device were defined as having a height of 1.5 cm and a width of 0.7 cm. The volume system thus defined is approximately 0.6 mL. Prototypes developed to meet this dimensional constraint are shown schematically in Figure 15. The device was evaluated for deliverable volume and linearity using various conformations and types of hydrogels as described above in Examples 2-6. Kinetic release curves from such a HPCAA prototype device is shown in Figure 16 and demonstrates zero order release of 180 ⁇ L volume over a 24 hour period.
  • Example 8 This example demonstrates delivery of a pharmaceutically active materials from an apparatus of the invention.
  • the device described in Example 7 was used to demonstrate controlled release of nifedipine. This compound was chosen because of its lipophilic character, and demonstrated commercial acceptance in a controlled release product.
  • the nifedipine was formulated in a glycerol vehicle and was charged into the apparatus described in Example 7.
  • a variety of hydrogel formulations were used to demonstrate release properties, which are designated by "GP" in Figure 17.
  • the apparatus was then placed into and SIF solution and allowed to deliver.
  • the released nifedipine was collected at regular time intervals over six hours and assayed for concentration.
  • responsive hydrogels may provide the motive force on the plunger of a syringe-like device to provide an external continuous IV/IM/SQ infusion.
  • a syringe-like device may provide an external continuous IV/IM/SQ infusion.
  • such a device can be implemented within the body to provide controlled release of a suitable drug.

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Abstract

Système de distribution d'une substance biologiquement active dans un milieu. On décrit un contenant à un seul élément ou à deux éléments jumeaux définissant un premier et un deuxième compartiment. Le contenant a des pores au moins sur une partie qui définit le premier compartiment, lequel contient un réseau en gel de polymère qui subit une expansion de volume suite à une modification d'état dans le milieu biologique. Le deuxième compartiment renferme une quantité efficace de composés biologiquement actifs et peut comporter au moins une communication avec le milieu biologique. La distribution du ou des médicaments est amorcée et se poursuit uniquement lorsque l'état ou le seuil approprié du milieu est rencontré, moyennant quoi l'expansion du volume du réseau en gel de polymère induit l'introduction du composé biologiquement actif dans le milieu biologique.
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US11717411B2 (en) 2015-03-31 2023-08-08 Cartiva, Inc. Hydrogel implants with porous materials and methods
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US11141486B2 (en) 2015-10-23 2021-10-12 National University Corporation Tokyo Medical And Dental University Drug delivery device

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JPH11513041A (ja) 1999-11-09
WO1998002146A3 (fr) 1998-03-12
CA2230656A1 (fr) 1998-01-22

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