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WO1998017260A1 - Systeme chimio-mecanique d'administration par expansion - Google Patents

Systeme chimio-mecanique d'administration par expansion Download PDF

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Publication number
WO1998017260A1
WO1998017260A1 PCT/US1996/016931 US9616931W WO9817260A1 WO 1998017260 A1 WO1998017260 A1 WO 1998017260A1 US 9616931 W US9616931 W US 9616931W WO 9817260 A1 WO9817260 A1 WO 9817260A1
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Prior art keywords
gel
gel network
polymer
polymer gel
compartment
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PCT/US1996/016931
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English (en)
Inventor
Eyal S. Ron
Matthew E. Schiller
Eric Roos
Michal Orkisz
Ann Staples
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Medlogic Global Corporation
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Publication date
Priority claimed from US08/473,218 external-priority patent/US5651979A/en
Application filed by Medlogic Global Corporation filed Critical Medlogic Global Corporation
Publication of WO1998017260A1 publication Critical patent/WO1998017260A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B31/00—Preparation of derivatives of starch
    • C08B31/003—Crosslinking of starch
    • C08B31/006—Crosslinking of derivatives of starch
    • 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
    • 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
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/145—Hydrogels or hydrocolloids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B15/00—Preparation of other cellulose derivatives or modified cellulose, e.g. complexes
    • C08B15/005—Crosslinking of cellulose derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow

Definitions

  • This invention relates to method and apparatus for delivering a biologically active compound to a biological environment in a controlled fashion.
  • 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.
  • a controlled release oral delivery system is the so-called osmotically-controlled delivery system. See, for example, Wang et al., U.S.
  • Patent No. 5,312,390 Eckenhoff et al., U.S. Patent No. 4,474,575; Place et al., U.S. Patent No. 5,147,654; Eckenhoff et al., U.S. Patent No. 4,539,004; and
  • Magruder et al. U.S. Patent No. 4,777,049.
  • 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 compartment containing the osmotic driving agent and the outside of the device.
  • the prior art osmotic systems are also very sensitive to the size of the delivery orifice. See, Theeuwes et al. , "Elementary Osmotic Pump,” /. 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 al., "Osmotic Pumps in Drug Delivery Devices - Fundamentals and Applications," Praveen Tyle, ed., Marcel Dekker, Inc., pl37 (New York).
  • Pulsncap system 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. Reference is also made to the prior art connection of an osmotic system to a syringe-like system to provide an external continuous IV/IM/SQ infusion. See, U.S. Patent No. 3,604,417 and Urquhart et al, "Rate-Controlled Delivery Systems in Drug and Hormone Research," Ann. Rev. Pharmacol Toxicol, 24(199), 1984.
  • 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.
  • Synthesis of a gel may utilize monomers and/or polymers whose toxicologic hazard characteristics are ill defined (e.g., n- isopropylacrylamide, NIPA and related acrylic monomers, polymers and co- polymers). Further, synthesis of a gel may use crosslinkers known to be toxic (e.g., divinylsulfone (DVS), glutaraldehyde, divinylbenzene, n-n- methylenebisacrylamide, and the like). Harsh and Gehrke (J. Control.
  • a suitable gel material for use in a biological environment is a crosslinked, responsive polymer gel network comprising polymer chains interconnected by way of multifunctional crosslinkers.
  • the polymer chains and crosslinkers have a known acceptable toxicological profile, hereinafter referred to as "KATP.”
  • KATP a known acceptable toxicological profile
  • Another suitable material is a crosslinked, responsive polymer gel network comprising polymer chains interconnected by way of KATP crosslinkages.
  • a further suitable material is a crosslinked, responsive polymer gel network having polymer chains interconnected by way of a crosslinker in which each of the polymer crosslinkers is obtainable from a precursor that is used in a process for making material that has a KATP.
  • the first compartment includes a screen or membrane forming at least a portion of a side of the first compartment.
  • the first compartment contains a polymer gel network which undergoes a volume change in response to an environmental condition which may vary in the biological environment or which may be external to the environment.
  • the second compartment contains an effective amount of a biologically active compound and includes an orifice communicating with the biological environment. When a preselected condition is encountered, the volume of the polymer gel network changes, causing the moveable partition to move to discharge the biologically active compound into the biological environment through the orifice.
  • the selected environmental condition is pH.
  • Preferred responsive polymer gel network materials include polysaccharide chains crosslinked with a multifunctional carboxylic acid obtainable from an acyl halide derivative of the acid.
  • the preferred polymer chains are polysaccharides (e.g., starch or cellulose ethers) and the preferred multifunctional carboxylic acid is selected from the group consisting of adipic acid, sebacic acid, succinic acid, citric acid, 1, 2, 3, 4-butanetetracarboxylic acid, and 1, 10 decanedicarboxylic acid.
  • Particularly preferred polymers are cellulose ethers selected from the group consisting of hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose. It is preferred that the gel exhibit substantially pressure independent volume changes at hydrostatic pressures in the range of 0.30-1.3 atmospheres.
  • the responsive polymer gel networks suitable for use in the apparatus of the invention may be responsive to any of a variety of triggers some of which have been set forth above.
  • the pH-response may be triggered by a change in an environmental condition to which the gel is exposed, such as a change in ion concentration, solvent concentration, electric field, magnetic field, electromagnetic radiation, or mechanical force.
  • Methods for making crosslinked polymer networks include selecting a polymeric starting material capable of being crosslinked, wherein the polymeric starting material selected for the particular use has a known acceptable toxicological profile for the particular use or for a related use; selecting a crosslinker capable of crosslinking the polymeric starting material, wherein the crosslinker selected for the particular use has a known acceptable toxicological profile for the particular use or for a related use; and contacting the crosslinker and polymeric starting material under conditions sufficient to form the three- dimensional, crosslinked polymer network.
  • Another method involves selecting a crosslinker capable of crosslinking the polymeric starting material, so that the resulting network, after formation, contains a crosslinkage that has a known acceptable toxicological profile.
  • Preferred methods include the steps of contacting a crosslinker comprising an acyl halide derivative of a multifunctional carboxylic acid with a polysaccharide under conditions sufficient for the three-dimensional, polymer gel network to form so that the gel network includes polysaccharide chains crosslinked with the acid.
  • Particularly preferred methods use a polysaccharide selected from the group consisting of starch and cellulose ethers, which group includes, for example, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and modified food starch .
  • Preferred methods use a crosslinker that is an acyl halide derivative of a multifunctional carboxylic acid, such as, for example, an acyl halide derivative of adipic acid, sebacic acid, succinic acid, 1,2,3,4- butanetetracarboxylic acid, or 1,10 decanedicarboxylic acid.
  • Other preferred methods use bifunctional crosslinkers such as, for example, divinylsulfone.
  • Still other preferred methods utilize irradiation energy as a crosslinker.
  • the apparatus and system of the invention is thus a chemo-mechanical system in which the driving force is provided by the non-continuous expansion properties of the hydrogel.
  • the hydrogels of the invention expand at a rate independent of water influx.
  • the hydrogels of the invention may be submerged in water or other liquid and either remain collapsed or swell at their own rate but only upon the appropriate trigger.
  • the delivery system of the invention can also be designed to cycle on and off. By first applying and then removing the trigger, the system would release the drug or stop the release by design and in a controlled fashion.
  • the system of the present invention is also, within limits, independent of the hydrostatic pressure of the fluid in which the device is placed.
  • 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 is an illustration of the two moving fronts in a dried gel
  • Figure 6 is a pH response curve for an HPCAA hydrogel at 37 °C
  • Figure 7 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 8 is a plot of swell factor v. time for a hydrated HPCAA disc in SIF at 37 °C;
  • Figure 9 represents the pH response at 37 °C of a hydrogel disc dried at 60 °C;
  • Figure 10 is a plot of swell factor v. log force (ATM) for a series of hydrogel samples measured after equilibration for the noted time;
  • Figure 11 is a response surface plot to optimize delivered volume from an apparatus of the invention
  • Figure 12 is a response surface plot to optimize linearity of delivery from an apparatus of the invention
  • Figure 13 is a schematic illustration of an apparatus of the invention.
  • Figure 14 is a plot of released volume v. time for release of a model substance from the apparatus of the invention.
  • Figure 15 is a plot of cumulative release v. time for release of nifedipine from the apparatus of the invention.
  • a controlled drug delivery device 10 includes a first compartment 12 separated from a second compartment 14 by a moveable partition 16.
  • the first compartment 12 includes a side having a screen or membrane 18.
  • the second compartment 14 includes an orifice 20.
  • First compartment 12 contains hydrogel 22 and the second compartment 14 contains a biologically active material or drug 24.
  • the screen or membrane 18 retains the hydrogel 22 within the compartment 12 but allows communication with fluids in a biological environment (not shown) into which the device 10 is placed.
  • the screen or membrane 18 may be a semipermeable membrane if desired.
  • the hydrogel 22 is selected to undergo a volume change such as an 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 moving the moveable partition 16 to the right in Fig. 1. This movement will decrease the volume in the second compartment 14, causing the biologically active material 24 to exit through the orifice 20 into a biological environment (not shown).
  • a volume change such as an expansion in response to the occurrence of an environmental condition such as pH.
  • the drug delivery device 10 is made of any suitable, biologically inert material, such as polyethylene, polypropylene and polyurethane.
  • a preferred screen or membrane 18 is cellulose acetate.
  • the biologically active material or drug 24 may be any material approved for use in a particular diagnostic or treatment protocol.
  • Fig. 2 there is shown the cumulative release of a viscous hydrophilic material (0.5% Carbopol 934P, neutralized) measured at pH 2.2 (glycine buffer) for 1.5 hours, representing gastric residence time.
  • the apparatus was then placed in a vessel containing Simulated Intestinal Fluid, USP (pH 7.5).
  • This graph shows that there was no release of the material at low pH followed by release after the pH was raised to 7.5.
  • the hydrogel was hydroxypropylcellulose crosslinked with adipic acid.
  • a gel having the response characteristics illustrated in Fig. 2 is suitable for a controlled release of a drug into the intestines.
  • 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 to move the moveable partition 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 (Fig. 2) thereby indicating the ability of the apparatus of the present invention to deliver formulations irrespective of their physiochemical properties.
  • the hydrogel 22 in the compartment 12 is substantially independent of hydrostatic pressure as shown in the curves in Fig. 4.
  • the material used in Fig. 4 is hydroxypropylcellulose (HPC) crosslinked with adipic acid.
  • the device 10 In use, the device 10 would be placed into the mouth and swallowed. The pH of the mouth, 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 screen or membrane 18 causes the hydrogel 22 to expand to move the partition 16 to expel the drug 24 into the intestinal region. It will be recognized and appreciated that following the teachings of this application and application serial number 08/413,409, whose teachings are incorporated herein by reference, permit the design and engineering of hydrogels which undergo a volume change 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.
  • a trigger has application to drug delivery into the gastrointestinal tract.
  • 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, 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, and vaccines.
  • 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 reversible volumetric change in which the gel expands from a less liquid-filled state or a dry state to a more liquid-filled state; or collapses from a more liquid-filled state to a less liquid-filled state.
  • the degree of volumetric change between collapsed 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, or blocked co-polymer, that has a KATP and which meets the volumetric response requirement.
  • the gel may also include two or more polymers, each component polymer having a KATP, 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 KATP polymer maintains its properties.
  • IPN interpenetrating polymer network
  • a "continuous" volume change is marked by a reversible change in volume (i.e., a collapsed or swelling) that occurs over a relatively large change in environmental condition. There exists at least one stable volume near the transition between the swollen and collapsed states.
  • 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 crosslinked gels suitable for use in the invention may undergo a "discontinuous" volume change in which the reversible 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 reversible 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).
  • 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.
  • volumetric changes of gels 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.
  • 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 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 rate of swelling is controlled by the slowest of these processes; however, the relative importance varies at different stages of hydration.
  • the shear modulus is related to the effective crosslink density p ' x and the volume fraction of the polymer ⁇ though,
  • the solutions reach equilibrium exponentially with a time constant r oc 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. q 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.
  • the plastification of the dry gel is a linear (0 th order) process.
  • the rate depends on the area exposed to water.
  • That area remains constant as the hydration front progresses.
  • it is the interaction of all these processes that governs the swelling kinetics. This interaction is governed by the parameter called a diffusional Deborah number, De, defined as,
  • ⁇ xe ⁇ is the characteristic relaxation time and ⁇ D is the characteristic solvent diffusion time:
  • 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 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 whose volume change is governed by hydrophobic interactions will collapse when challenged with an increase in temperature and are exemplified by N-isopropylacrylamide. Gels whose volume change is governed by van der Waals interactions will behave similarly to those governed by hydrophobic interactions.
  • 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). A fuller discussion is included in the above- referenced co-pending application.
  • 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(hydroxypropy ⁇ )cellulose: HPMC); 60° methyl(hydroxyethy ⁇ )cellulose; and 55°-70° (ethyl(hydroxyethy ⁇ )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. While one or more of the 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.
  • N-methyl pyrolidone (Fisher Scientific, Catalog No. 03688-4) was added to 5 grams of hydroxypropyl cellulose (Aqualon, Klucel 99- EF NF). The two materials were mixed on a magnetic stirrer for about 2 hours, while covered, to achieve a clear and colorless solution. This solution was then placed in a refrigerator for about 1 hour in order to achieve a solution temperature of 4-8° C. To this solution, while stirring, 1 mL of cold (2-8° C) adipoyl chloride (Aldrich, Cat. No. 16,521-2) was added, and the resulting solution allowed to stir for 1 minute. After stirring, this solution was allowed to gel for eight hours.
  • a general protocol for forming a KATP polymer network suitable for use in the present invention using a crosslinkable polymer includes the steps of dissolving the KATP 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 hydroxyrpropyl 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 KATP polymer with side groups that can react with a di- or multi-functional 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.
  • 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 al, 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 KATP 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), tetrahydrofuran (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 KATP 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 KATP diamine such as ethylenediamine or hexamethylenediamine (21 C.F.R. 175.300 (b)(3) (xxxii) to produce an amine-terminated amide.
  • KATP diamine such as ethylenediamine or hexamethylenediamine (21 C.F.R. 175.300 (b)(3) (xxxii)
  • 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. After the gel is formed, destruction of any remaining acid chloride groups is carried out by soaking the gel in distilled water for about 12 hours.
  • Solvent is then removed by soaking the gel in an alcohol (e.g. methanol, ethanol, and the like) for at least several hours so that the methanol can diffuse into the gel and the solvent can diffuse out of the gel. After several hours, the wash is drained off. This process is repeated at least 4-5 times. The gel is then washed 4-5 times with distilled water while it is being heated to between about 60-80 °C for about 2 hours. Heating drives off any remaining alcohol, leaving gel and water. The process is repeated at least 3-5 times until the gel appears opaque at the elevated temperature. 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. For HPC, 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.
  • an alcohol e.g. methanol, ethanol, and the like
  • 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 6.
  • 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 7.
  • 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 8 and demonstrates a near zero order swelling rate.
  • a further study of swelling factors using hydrogel discs dried at 60 °C has been undertaken.
  • Dried hydrogel discs are preferably from a manufacturing standpoint and it is desirable to demonstrate similar swelling kinetics from such a system.
  • the pH response of such a disc is shown in Figure 9.
  • 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 10.
  • 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.
  • 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 Fig. 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.
  • 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 11 and Figure 12.
  • a working system may fabricated to have acceptable performance criteria based upon the response surface plots in of Figs. 11 and 12. 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 13. 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 14 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.
  • Example 7 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. 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. Cumulative release normalized to percent of extrapolated nifedipine delivered in 24 hours was plotted against time and is shown in Figure 15 as curve 150. This release kinetics were compared to a release from a commercially available product,
  • Procardia/Adalat table shown as curve 160 in Fig. 15. Similar release profiles were obtained.
  • 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

La présente invention a trait à un système permettant l'apport d'une substance biologiquement active dans un environnement donné. Les première et seconde chambres sont séparées par une cloison mobile. Le première chambre se compose d'un réseau en gel polymère dont le volume subit un changement par réaction à des conditions environnementales telles que le pH. Le premier compartiment se compose d'un écran ou d'une membrane qui sert à confiner le réseau en gel polymère tout en lui permettant de communiquer avec le fluide dans un environnement donné. Quand au second compartiment, il contient un composé biologiquement actif ou un médicament qui est administré à l'environnement à travers un orifice aménagé dans le second compartiment. Lors de la survenue de la condition environnementale déclenchante, le volume du réseau en gel polymère subit un changement qui déplace la cloison mobile expulsant ainsi le médicament à travers l'orifice. L'administration du médicament est amorcée et elle ne se prolonge qu'en présence de la condition environnementale ou le facteur déclenchant approprié.
PCT/US1996/016931 1995-06-07 1996-10-23 Systeme chimio-mecanique d'administration par expansion WO1998017260A1 (fr)

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US08/473,218 US5651979A (en) 1995-03-30 1995-06-07 Apparatus and method for delivering a biologically active compound into a biological environment
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2201938A1 (fr) 2008-12-18 2010-06-30 Koninklijke Philips Electronics N.V. Capsule d'administration de médicaments contrôlable

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Publication number Priority date Publication date Assignee Title
EP0427519A2 (fr) * 1989-11-07 1991-05-15 Merck & Co. Inc. Dispositif polymère de délivrance d'un médicament contrôlé par gonflement
US5226902A (en) * 1991-07-30 1993-07-13 University Of Utah Pulsatile drug delivery device using stimuli sensitive hydrogel
WO1996002276A2 (fr) * 1994-07-18 1996-02-01 Gel Sciences, Inc. Nouveaux reseaux de gel polymere et procedes d'utilisation

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
EP0427519A2 (fr) * 1989-11-07 1991-05-15 Merck & Co. Inc. Dispositif polymère de délivrance d'un médicament contrôlé par gonflement
US5226902A (en) * 1991-07-30 1993-07-13 University Of Utah Pulsatile drug delivery device using stimuli sensitive hydrogel
WO1996002276A2 (fr) * 1994-07-18 1996-02-01 Gel Sciences, Inc. Nouveaux reseaux de gel polymere et procedes d'utilisation

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Title
R. DINARVAND ET AL.: "the use of thermoresponsive hydrogels for on-off release of molecules", JOURNAL OF CONTROLLED RELEASE, vol. 36, no. 3, October 1995 (1995-10-01), AMSTERDAM (NL), pages 221 - 227, XP000529175 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2201938A1 (fr) 2008-12-18 2010-06-30 Koninklijke Philips Electronics N.V. Capsule d'administration de médicaments contrôlable

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