WO2023235298A1 - Procédés et dispositifs pour contrôler la libération d'agents thérapeutiques à partir de dispositifs implantables - Google Patents

Procédés et dispositifs pour contrôler la libération d'agents thérapeutiques à partir de dispositifs implantables Download PDF

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Publication number
WO2023235298A1
WO2023235298A1 PCT/US2023/023836 US2023023836W WO2023235298A1 WO 2023235298 A1 WO2023235298 A1 WO 2023235298A1 US 2023023836 W US2023023836 W US 2023023836W WO 2023235298 A1 WO2023235298 A1 WO 2023235298A1
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Prior art keywords
therapeutic agent
reservoir
release
temperature
implantation
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PCT/US2023/023836
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English (en)
Inventor
Lyle Gordon
Adam Mendelsohn
Lisa Porter
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Nano Precision Medical, Inc.
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Application filed by Nano Precision Medical, Inc. filed Critical Nano Precision Medical, Inc.
Publication of WO2023235298A1 publication Critical patent/WO2023235298A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/01—Introducing, guiding, advancing, emplacing or holding catheters
    • A61M25/06—Body-piercing guide needles or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/01—Introducing, guiding, advancing, emplacing or holding catheters
    • A61M25/06—Body-piercing guide needles or the like
    • A61M25/065—Guide needles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M39/00—Tubes, tube connectors, tube couplings, valves, access sites or the like, specially adapted for medical use
    • A61M39/02—Access sites
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M39/00—Tubes, tube connectors, tube couplings, valves, access sites or the like, specially adapted for medical use
    • A61M39/02—Access sites
    • A61M39/0208—Subcutaneous access sites for injecting or removing fluids

Definitions

  • the disclosure provides a method to reduce a thermal start-up burst release from an implantable device for controlled release of a therapeutic agent, the method comprising: providing the device, the device comprising: a capsule configured for implantation and having a reservoir; a fluid formulation of the therapeutic agent contained within the reservoir; a nanoporous membrane with a plurality of pores attached to the capsule and providing a diffusion path for release of the therapeutic agent out of the reservoir; and prewarming the device pre-implantation; and implanting the device.
  • the disclosure provides a method to reduce thermal start-up burst release from an implantable device for controlled release of a therapeutic agent, wherein the device is prewarmed to a temperature of at least 30°C.
  • the disclosure provides a method to reduce a thermal start-up burst release from an implantable device for controlled release of a therapeutic agent, wherein the device is prewarmed to a temperature of 37°C.
  • the disclosure provides a method to reduce thermal start-up burst release from an implantable device for controlled release of a therapeutic agent, wherein the device is prewarmed to a temperature of no more than 43°C.
  • the disclosure provides a method to reduce a thermal startup burst release from an implantable device for controlled release of a therapeutic agent, the method comprising: providing the device, the device comprising: a capsule configured for implantation and having a reservoir; a fluid formulation of the therapeutic agent contained within the reservoir; a nanoporous membrane with a plurality of pores attached to the capsule and providing a diffusion path for release of the therapeutic agent out of the reservoir; and implanting the device, the device being at a temperature above ambient in an environment of use.
  • the disclosure provides a method to reduce a thermal start-up burst release from an implantable device for controlled release of a therapeutic agent, the device being at a temperature of at least 30°C.
  • the disclosure provides a method to reduce thermal start-up burst release from an implantable device for controlled release of a therapeutic agent, the device being at a temperature of 37°C.
  • the disclosure provides a method to reduce a thermal start-up burst release from an implantable device for controlled release of a therapeutic agent, the device being at a temperature of no more than 43°C.
  • the disclosure provides a method to reduce a thermal start-up burst release from an implantable device for controlled release of a therapeutic agent, the method comprising: providing the device, the device comprising: a capsule configured for implantation and having a reservoir; a fluid formulation of the therapeutic agent contained within the reservoir; a nanoporous membrane with a plurality of pores attached to the capsule and providing a diffusion path for release of the therapeutic agent out of the reservoir; prewarming the device pre-implantation to a temperature suitable to reduce the thermal start-up burst release by at least 50% compared to a thermal start-up burst release at the temperature of an environment of use; and implanting the device.
  • the disclosure provides a method to reduce peak plasma concentration of a therapeutic agent upon implantation of an implantable device for controlled release of the therapeutic agent, the method comprising: providing the device, the device comprising: a capsule configured for implantation and having a reservoir; a fluid formulation of the therapeutic agent contained within the reservoir; a nanoporous membrane with a plurality of pores attached to the capsule and providing a diffusion path for release of the therapeutic agent out of the reservoir; prewarming the device pre-implantation to a temperature suitable to reduce the thermal start-up burst release by at least 50% compared to a thermal start-up burst release at the temperature of an environment of use; and implanting the device.
  • the disclosure provides a method to reduce a thermal start-up burst release from an implantable device for controlled release of a therapeutic agent, wherein temperature control is achieved in an applicator for implantation of the device.
  • the disclosure provides an applicator implanting an implantable device for controlled release of a therapeutic agent, the applicator having a heating capability to prewarm the implantable device pre-implantation.
  • FIG. 1 illustrates an exemplary embodiment of an implantable device of the disclosure.
  • FIG. 2 illustrates an exemplary embodiment of an applicator of the disclosure.
  • FIG. 3 shows the effect of a prewarming treatment on the release rate profile over time of a therapeutic agent from an implantable device of the disclosure.
  • FIG. 4 shows the effect of a prewarming treatment on the release rate profile over time of a therapeutic agent from an implantable device of the disclosure.
  • FIG. 5 shows the effect of a prewarming treatment on plasma levels over time of a therapeutic agent from an implantable device of the disclosure.
  • the disclosure pertains to the field of long-term treatment of subjects with implantable devices providing a sustained delivery of therapeutic agents at a controlled rate.
  • Embodiments of the disclosure include devices, formulations, and methods to control the rate of release of therapeutic agents from such devices.
  • Polypeptides refers to molecules with a backbone chain of 2 or more amino acid residues. Some polypeptides may have additional associated groups, such as metal ions in metalloproteins, small organic molecules such as in heme proteins, or carbohydrate groups such as in glycoproteins.
  • Proteins and “Proteins” refers to subgroups of polypeptides. In this disclosure the definition of peptides and proteins follows the practice of the United States Food and Drug Administration, the FDA, which defines peptides as polypeptides with up to 40 amino acid residues, and proteins as polypeptides with more than 40 amino acid residues.
  • Incretin mimetics refers to agents that act like incretin hormones such as glucagon- like peptide- 1 (GLP-1). They bind to GLP-1 receptors and stimulate glucose dependent insulin release, therefore acting as antihyperglycemics.
  • GLP-1 glucagon- like peptide- 1
  • Exenatide (natural, recombinant and synthetic, also called exendin-4) refers to amino acid sequence His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu Glu Ala Vai Arg Leu Phe He Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser.
  • Formulation of a therapeutic agent refers to the actual state in which a therapeutic agent is present in a product or in a product fabrication intermediate, and includes the therapeutic agent, plus, optionally, any used additional therapeutic agents, any used formulation excipients and any used formulation solvents.
  • Membrane refers to a permeable structure allowing mass transport of molecules from one side of the permeable structure to the other side through the permeable structure.
  • Porous membranes refers to membranes characterized by the presence of a two- phase system, in which membrane matrix material represents one phase, typically a continuous phase, which is permeated by open channels extending from one side of the membrane to the other, and filled with a second phase, often a fluid phase, through which mass transport through the membrane can take place.
  • “Dense” or “non-porous membranes” refers to membranes without fluid filled pores. In such membranes mass transport may take place by a dissolution-diffusion mechanism, in which therapeutic agents permeate the membrane by dissolving in the membrane material itself, and diffusing through it.
  • Nanoporous membrane and “nanopore membrane” are used interchangeably, and refer to porous membranes in which the pores have a smallest diameter of less than 1000 nanometer.
  • Nanotube membrane refers to a nanoporous membrane, wherein pores are formed by an array of nanotubes.
  • Titania nanotube membrane refers to an array of titania nanotubes on a titanium substrate where at least a portion of the titania nanotubes are open at both ends and capable of allowing diffusion from one side of the membrane to the other side through the titania nanotubes.
  • the titania nanotube membrane has two faces or sides. A first face or side having an array of titania nanotubes and a second face or side of a titanium substrate.
  • the array of titania nanotubes is grown on the titanium substrate by electrochemical anodization.
  • Molecular diameter of a polymer refers to the diameter of the sphere of gyration of the polymer, which is a physical measure of the size of a molecule and is defined as two times the mass weighted average distance from the core of a molecule to each mass element in the molecule.
  • Stokes diameter or “hydrodynamic diameter” refers to the dimension of a molecule plus its associated water molecules as it moves through an aqueous solution and is defined as the radius of an equivalent hard sphere diffusing at the same rate as the molecule under observation.
  • Ion exchange resin refers to a polymer comprising acidic or basic groups, or a combination thereof, made insoluble, for instance by cross-linking, and capable of exchanging anions or cations, or a combination thereof, with a medium surrounding it.
  • Fluid and “fluid form” as used in this disclosure refers to flowable states of matter and includes, but is not limited to gases, solutions, suspensions, emulsions, colloids, dispersions, and the like.
  • Fluid contact refers to an entity being in contact with a fluid.
  • Neutral pH refers to a pH between 6 and 8 such as between 6.5 and 7.5.
  • Implantable devices with nanoporous membranes for the release of therapeutic agents have been described previously, e.g. in US Patents Nos. 9814867 and 9770412 and US Patent Publication Nos. US2022/0008345 and US2021/0246271 and US 2017/0136224, each of the foregoing incorporated herein by reference.
  • Some embodiments of the disclosure include a device with a cylindrical capsule encapsulating a reservoir, a nanoporous membrane affixed to one end of the capsule, and a formulation of a therapeutic agent contained within the reservoir. Release of the therapeutic agent from the reservoir after implantation of the device in a subject is controlled by the nanoporous membrane.
  • Some embodiments of the disclosure utilize the pH of the formulation of the therapeutic agent as a further means to control the release rate. Additionally, some embodiments control the duration of release of the therapeutic agent using the orientation of the membrane with respect to the reservoir.
  • devices of the disclosure include a capsule 1000 suitable for implantation, wherein the capsule has a reservoir 1001 suitable for holding a formulation of a therapeutic agent 1005 and, optionally, a pH controlling agent, for instance in the form of resin beads 1006.
  • a reservoir 1001 suitable for holding a formulation of a therapeutic agent 1005 and, optionally, a pH controlling agent, for instance in the form of resin beads 1006.
  • the capsule may be made of any suitable biocompatible material.
  • the capsule is made of a medical grade metal, such as titanium or stainless steel, or of a medical grade polymeric material, such as silicone, polyurethane, polyacrylate, polyolefin, polyester, polyamide and the like.
  • the capsule is made of multiple materials.
  • the capsule is made of titanium.
  • Devices of the disclosure have at least one membrane 1004, attached to the capsule and in fluid contact with the reservoir, wherein the membrane provides a pathway for mass transport of a therapeutic agent included within the reservoir out of that reservoir and into the body of a subject into which the capsule has been implanted.
  • attachment to the capsule refers to a component being fixed in place with respect to the capsule, and connected to the capsule directly or indirectly, by using any suitable means, including by welding, gluing, press-fitting and by using threaded means, or by any combination of these.
  • membranes as described in US Patent No. 9814867, and as illustrated in Fig.
  • the nanotube membranes are part of an array of nanotubes 1003, some of which are still attached to the titanium substrate 1002 from which they were grown, and the substrate may be attached to the capsule. At least some of the nanotubes are open on both sides, to allow for mass transport of a therapeutic agent out of the reservoir.
  • Some devices of the disclosure further have a septum 1007, pierceable with a needle, and suitable as access port to deposit formulation 1005 into the reservoir 1001.
  • aspects of the disclosure include at least one membrane providing a pathway for mass transport of a therapeutic agent out of a reservoir of a device of the disclosure. Once the device is implanted into a mammal such as a human, the transport of the therapeutic agent can be into the interstitial fluid of a human body.
  • Membranes of the disclosure include dense and porous membranes; porous membranes include nanoporous membranes and nanotube membranes.
  • Suitable materials for membranes of the disclosure include organic and inorganic materials, polymers, ceramics, metals, metal oxides and combinations thereof. Other suitable materials for the membrane include silicon, silica, titanium and titania.
  • the membrane is a nanoporous membrane. In some aspects the membrane is a nanotube membrane. In some aspects, the membrane is a titania nanotube membrane.
  • aspects of the disclosure are particularly useful as sustained delivery devices for therapeutic agents, in which the release of the agents is controlled by a nanoporous membrane.
  • Devices of the disclosure include a formulation having at least one therapeutic agent, for instance therapeutic agents such as described in this disclosure.
  • the therapeutic agent may be in solid or fluid form.
  • the therapeutic agent may be present in mixed forms, such a suspension of a solid form of the therapeutic agent in a saturated solution of the therapeutic agent.
  • the formulation is in solid form, in some instances the formulation is in fluid form.
  • Formulations in fluid form for instance, formulations including a solution of at least part of the therapeutic agent in the reservoir, may have a pH value. pH controlling agents
  • Materials to control the pH may be the therapeutic agent itself, low molecular weight stabilizers, such as acidic and basic compounds, including weakly acidic and weakly basic compounds that can be used as buffering agent, or high molecular weight compounds like poly-acids or poly-bases. Many such compounds are known in the literature, and those of ordinary skill in the art of pharmaceutical formulation development will be able to select suitable ingredients for the formulation without undue experimentation.
  • the pH controlling materials are insoluble polymeric stabilizers as described in US patent application publication Nos. US20220008345 and US20210246271, each incorporated herein by reference.
  • Other pH controlling agents suitable for the disclosure can be found in US Patent Nos. 10045943, and 10479868, each incorporated herein by reference.
  • Acid refers to a compound that is capable of donating a proton (H+) under the Bronsted-Lowry definition, or is an electron pair acceptor under the Lewis definition.
  • Acids useful in the present invention are Bronsted-Lowry acids that include, but are not limited to, alkanoic acids or carboxylic acids (formic acid, acetic acid, citric acid, lactic acid, oxalic acid, etc.), sulfonic acids and mineral acids, as defined herein.
  • Mineral acids are inorganic acids such as hydrogen halides (hydrofluoric acid, hydrochloric acid, hydrobromic acid, etc.), halogen oxoacids (hypochlorous acid, perchloric acid, etc.), as well as sulfuric acid, nitric acid, phosphoric acid, chromic acid and boric acid.
  • Sulfonic acids include methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, triflouromethanesulfonic acid, among others.
  • Base refers to a compound capable of accepting a proton (H+) under the Bronsted-Lowry definition, or is an electron pair donor under the Lewis definition.
  • Representative bases include, but are not limited to, hydroxy, alkylhydroxy, amines ( — NRR), alkylamine, arylamine, amide ( — C(O)NRR), sulfonamide ( — S(O)2NRR), phosphonamide ( — P(O)( — NRR)2), carboxylate ( — C(O)O-), and others.
  • the pH adjusting agent is a buffer.
  • the buffer is selected from the group consisting of citrate/citric acid, acetate/acetic acid, phosphate/phosphoric acid, formate/formic acid, propionate/propionic acid, lactate/lactic acid, carbonate/carbonic acid, ammonium/ammonia, edentate/edetic acid, and combinations thereof.
  • therapeutic agents suitable for aspects of the disclosure have been described in US patent application publication Nos. US20220008345 and US20210246271, each incorporated herein by reference.
  • the therapeutic substance is a peptide or protein.
  • the peptide or protein is an incretin mimetic.
  • the incretin mimetic is exenatide.
  • Devices of the disclosure have the capability to release therapeutic agents, contained in the reservoir, through the nanopores of the membrane at a controlled rate.
  • the rate of release of the therapeutic agent is a non-Fickian release rate, or zero order release, i.e. a release rate that is not proportional to the concentration gradient driving the release. Examples of non-Fickian release rates through nanoporous membranes have been described in US Patent No. 9814867, incorporated herein by reference.
  • US patent application publication Nos. US20220008345 and US20210246271, incorporated herein by reference, disclose the use of insoluble polymeric agents with a plurality of pH sensitive stabilizing groups that can be employed to provide buffering capacity at desirable pH levels, such as weakly acidic or weakly basic groups, to provide chemical stabilization for therapeutic agents in devices of the disclosure.
  • pH sensitive stabilizing groups that can be employed to provide buffering capacity at desirable pH levels, such as weakly acidic or weakly basic groups, to provide chemical stabilization for therapeutic agents in devices of the disclosure.
  • These polymeric agents stabilize the therapeutic agents by controlling the pH of formulations of the disclosure. Serendipitously, such chemical stabilizers can now be used to control release rates as well.
  • aspects of the disclosure offer a method of controlling the release rate of a therapeutic agent through a nanoporous membrane by adjusting the pH of the formulation of the therapeutic agent.
  • Some aspects of the disclosure provide methods to control the rate of release of therapeutic agents from a reservoir through a nanotube membrane by controlling the pH of a formulation in the reservoir in which at least part of the therapeutic agent, or therapeutic agents, is dissolved.
  • the release rate is controlled by controlling the pH with polymeric stabilizers such as described in US patent application publication Nos. US20220008345 and US20210246271, each incorporated herein by reference.
  • the release rate is controlled by controlling the pH with soluble pH controlling stabilizers, such as low molecular weight acids or bases.
  • soluble pH controlling stabilizers such as low molecular weight acids or bases.
  • a gradual rise of the release rate of a drug from an implant over time is considered desirable. For instance, with exenatide, a gradual ramp-up of the delivered dose per day has been associated with a reduced incidence of nausea.
  • the initial internal pH of a device is set at a relatively low level, and is allowed to rise over time as the internal pH slowly equilibrates with the external environment of the device, i.e., interstitial fluid. The gradual rise in pH is accompanied by a gradual increase in release rate.
  • a dry formulation of a therapeutic agent may be present in a device at the time of implantation in a subject.
  • a promotor of water uptake may be present in the reservoir, such as a water-soluble gas. After implantation the water- soluble gas may promote the uptake of interstitial fluid into the reservoir through the membrane of the device.
  • aspects of the disclosure may include a dry formulation in the reservoir with a composition that, after uptake of the interstitial fluid, generates a liquid formulation with a pH that provides a desired release rate of the therapeutic agent.
  • formulation 1005 of the therapeutic agent in the device is a liquid formulation.
  • the liquid formulation is an aqueous formulation.
  • Water at 20°C has a volumetric thermal expansion coefficient of 0.000207 /°C.
  • the liquid formulation is a non-aqueous, or mixed aqueous - non-aqueous formulation.
  • liquid formulations suitable for application in the disclosure have greater expansion coefficients than solid materials suitable for manufacture of the capsule of the disclosure.
  • thermal start-up burst release from devices including such materials may occur.
  • the quantity of this burst release, combined with the potency of the therapeutic agent may lead to undesirable side effects in the subject into which the device is implanted.
  • the device is pre-warmed pre-implantation (prior to implantation), to allow for the thermal start-up burst release to occur outside the body of the subject into which the device is to be implanted.
  • aspects of the disclosure include methods and devices to reduce the thermal startup burst release post-implantation into a subject. Aspects of the disclosure further include implantable devices for the delivery of a therapeutic agent that have been brought to a temperature above the ambient temperature of the environment of use, methods to bring implantable devices of the disclosure to a temperature above the ambient temperature of the environment of use, and devices to bring implantable devices of the disclosure to a temperature above the ambient temperature of the environment of use.
  • Environments of use of the disclosure can be any environment in which the device is implanted, including, but not limited to, a clinic, hospital or doctor’s office, veterinary clinic, or, in the case of home care, the home of a subject into which the device is implanted.
  • the implantable devices for the delivery of a therapeutic agent is heated or warmed to a temperature above or equal to the temperature of the body to be implanted such as physiological temperature.
  • thermal start-up burst will vary with the therapeutic agent.
  • the limits on allowed quantities to be released in a brief burst release are known in literature. In cases of novel or experimental therapeutic agents they can be determined in a clinical trial.
  • pre-warming temperature, pre-warming duration and time frame to implantation after prewarming will vary with the specific device design and requirements of the therapeutic agent and can be experimentally determined.
  • the quantities of therapeutic agent released from a device in a thermal start-up release will vary with such parameters as total device volume, materials of construction, designs features like volume to surface ratio of the reservoir, concentration of the therapeutic agent in the formulation and the like.
  • the degree to which devices need to be warmed prior to implantation to avoid a thermal start-up burst release can be based on theoretical calculations and can be measured experimentally. Theoretically, a device being implanted at the body temperature or physiological temperature (e.g., 37°C) of the subject at the time of implantation will not exhibit a thermal burst. In some instances, a limited thermal burst release may be acceptable, and there may be a window of temperatures below body temperature that is acceptable. In some instances, some cooling down of devices may occur between prewarming and implantation and prewarming to temperatures above body temperature may be desired.
  • thermal start-up release While it is possible to calculate the thermal start-up release based on the fundamental physical properties of the components involved, simple and well-understood methods to measure it are available and are well known to those skilled in the art of pharmaceutical product development. (See, for instance US Pharmacopeia chapter 711, Dissolution Testing). In the various tests described herein devices are submerged in a dissolution buffer under controlled conditions and the dissolution buffer is sampled at regular intervals. Typically, for thermal start-up burst release, such interval would be 1 hour, but any desired interval can be chosen. Prewarming or warming before implantation can be done to any desired temperature. In some aspects, the prewarming for a human being is done to a temperature of at least 30°C.
  • the prewarming is done to body temperature or physiological temperature such as 37°C. In some aspects, the prewarming is done to a temperature above 37°C.
  • the warming of the device prior to implantation can be from about 30°C to about 45°C; or about 30°C to about 40°C; or about 32°C to about 38°C; or about 35°C to about 39°C.
  • warming of the device prior to implantation can be about 30 °C, 31 °C, 32 °C, 33 °C, 34 °C, 35 °C, 36 °C, 37 °C, 38 °C, 39 °C, 40 °C, 41 °C, 42 °C, 43 °C, 44 °C, and/or about 45 °C.
  • the device is prewarmed to a higher temperature, such as 50°C.
  • the prewarming is done to a temperature above 43 °C, but, because of a time period between prewarming and implantation, the temperature of the devices does not exceed 43 °C at the time of implantation and contact with tissue of the subject into which the device is implanted.
  • the device is prewarmed pre-implantation to a temperature suitable to reduce the thermal start-up burst release by at least 50% compared to a thermal start-up burst release at the temperature of an environment of use.
  • Prewarming or warming before implantation can be performed by any suitable means, including by traditional warming devices like ovens and incubators, or by dedicated, custom developed prewarming devices, or with any heating device or with light.
  • Peak plasma concentrations are a commonly used indicator for the potential for a therapeutic agent to cause side effects, since the severity of many side effects is directly correlated with plasma levels.
  • aspects of the disclosure can lower or reduce peak plasma levels (concentration) of therapeutic agents after administration to a subject.
  • the Cmax of the therapeutic agent is reduced.
  • the Cmax is reduced by about 10% to about 90% such as about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, and/or about 90%.
  • the peak plasma levels are reduced by at least 10%.
  • the peak plasma levels are reduced by at least 25%. [0092] In some aspects, the peak plasma levels are reduced by at least 50%.
  • the peak plasma levels are reduced by at least 75%.
  • the peak plasma levels are reduced by at least 90%. The above reductions are compared to no prewarming the device and/or therapeutic agent.
  • Some aspects of the disclosure comprise an applicator for implanting the device in a subject.
  • the applicator comprises a hollow needle for piercing the skin of a subject and for implanting the device subcutaneously.
  • Some applicators of the disclosure comprise an obdurator inside the needle, designed to hold the device in a stationary position while the needle is being retracted after insertion under the skin, thus expelling the device from the needle and depositing it in a subcutaneous pocket.
  • Prewarming can be performed on an implantable device separately, or on an entire product package, which may include procedural tools like an applicator to implant the device.
  • the implantable device may be pre-loaded in an applicator.
  • Some applicators of the disclosure comprise a heating element used for prewarming the implantable device pre-implantation inside the applicator.
  • FIG. 2 illustrates an exemplary embodiment of an applicator of the disclosure. General details of a suitable applicator can be found in US application publication No. 20170136224, incorporated herein by reference.
  • the implantable device 4002 is located in the tubular outer member 4001 of the applicator.
  • the heating element 4020 may warm the tubular outer member 4001 and the tubular outer member 4001 may transfer heat to the implantable device 4002, thus prewarming the device.
  • the heating element 4020 may be located in any suitable location of the applicator.
  • a heating element 4020 may be in the form of a heating coil wrapped around the tubular outer member 4001. Additionally or alternatively, a heating element 4022 may be located in a tubular outer member guard 4021 placed over the distal end of the tubular outer member 4001.
  • tubular outer member 4001 which extends from housing 4007 in a distal direction, and is partially disposed within housing 4007 in a slideable manner.
  • Tubular outer member 4001 is configured as a hollow needle with a sharpened distal tip 4014.
  • Tubular obturator 4004 is disposed within outer member 4001 and within housing 4007, and is attached to housing 4007 though posts 4009.
  • Slideable pressure reducer 4003 is partially disposed within obturator 4004.
  • O-ring 4012 forms a sealing mechanism between obturator 4004 and outer member 4001, and O-ring 4013 forms a sealing mechanism between pressure reducer 4003 and obturator 4004.
  • Implantable drug delivery device 4002 is located within outer member 4001 towards sharpened distal tip 4014.
  • Plug 4006 seals the lumen of outer member 4001 distal to implantable drug delivery device 4002.
  • Housing 4007 holds the various components of the apparatus, including outer member slider 4015 attached to outer member 4001. The operator moves slideable pressure reducer in a proximal direction, creating a reduced pressure in lumen 4016 of tubular obturator 4004. Because of the sealing action of O-rings 4012 and 4013, and of plug 4006, the reduced pressure is propagated into the reservoir of drug delivery device 4002 through membrane 4005.
  • the applicator device has a heating element 4020 and/or 4022 configured to be heated by passage of an electrical current.
  • the heating element is connected to a power source such as a battery, to deliver electrical resistance and heat.
  • a power source such as a battery
  • current passes from the power supply (e.g., battery) to a resistive element.
  • the resistive element heats the pharmaceutical agent in the implantable device to the predetermined temperature.
  • the heating element can be a coil, a ribbon (straight or corrugated), a rod, a rack or a strip of wire.
  • the battery can be a lithium-ion battery.
  • the battery can produce a voltage in the range of about 0.5 V to about 9 V.
  • the electrical resistance of the heating element is in the range of about 0.1 to 10 Ohms.
  • the applicator device has a thermostat or sensor to heat the element to a certain predetermined temperature as defined herein.
  • Appropriate controls to regulate prewarming and prevent overheating can be incorporated based on standard electronic techniques.
  • Energy for pre-warming may be derived from an internal source, such as battery, or from an external source, such as a power outlet or a specifically designed charger for an applicator.
  • the heating element can be in a heating block that warms the implantable device.
  • Other methods of heating include irradiation, sonication and chemical heating.
  • Some aspects of the invention include methods to treat a subject in need of treatment with a therapeutic agent. The methods include providing a device of the disclosure, having a fluid formulation of the therapeutic agent contained within its reservoir, prewarming the device pre-implantation and implanting the device.
  • the device is prewarmed 30 °C, 31°C, 32 °C, 33 °C, 34°C, 35 °C, 36 °C, 37 °C, 38 °C, 39 °C, 40 °C, 41 °C, 42 °C, 43 °C, 44 °C, and/or about 45 °C. In some instances, the device is prewarmed to a higher temperature, such as 50°C.
  • the therapeutic agent is an incretin mimetic.
  • the incretin mimetic is exenatide or semaglutide.
  • Some aspects of the invention include methods to treat subjects in need of treatment with therapeutic agents.
  • the therapeutic agents are incretin mimetics.
  • the incretin mimetic is exenatide.
  • the condition of the subject in need of treatment is Type 2 diabetes. In some embodiments the condition of the subject in need of treatment is obesity. In some embodiments the condition of the subject in need of treatment is non-alcoholic steatohepatitis (NASH). In some embodiments the condition of the subject in need of treatment is a neurodegenerative disease.
  • NASH non-alcoholic steatohepatitis
  • the plasma levels of the subject after treatment with methods of the invention are between 50 pg/mL and 500 pg/mL. In some aspects the plasma levels are between 500 pg/mL and 5 ng/mL. In some embodiments the plasma levels are between 5 ng/mL and 50 ng/mL. In some embodiments the plasma levels are between 50 ng/mL and 500 ng/mL.
  • Some aspects, of the invention include methods to treat subjects in need of treatment with exenatide, wherein the plasma levels of exenatide are between 50 ng/mL and 500 ng/mL.
  • the devices that were used included titanium capsules of approximately 25 mm length and 2.25 mm diameter.
  • a titanium substrate with a titanium oxide nanoporous membrane was welded to one end of the device.
  • the nanoporous membrane had a diameter of 0.3 mm and was composed of about 6,000,000 nanopores. The average diameter of the nanopores at the substrate end was approximately 20 nm.
  • a silicone septum was inserted at the other end of the device.
  • About 56 mg of a formulation containing 25% exenati de-acetate (w/w), 0.25% Polysorbate 20, 154 mM Na + and a pH of 5.5 was filled into the device as per methods in PCT/US2021/019559. Briefly, the formulation was loaded into a filler apparatus with a hollow needle to pierce the septum. A vacuum was applied to the membrane of the device to reduce the pressure inside the reservoir, and the formulation was injected through the septum into the reservoir through the needle.
  • 16 devices were prepared and were stored submerged in a storage buffer containing 0.9% NaCl and 0.76% sodium acetate in water for injection at pH 5.5.
  • the release rates are plotted on the Y axis, time on the X-axis.
  • the devices that were left at room temperature with no prewarming exhibited a significant and variable initial burst of drug release, with an average normalized rate of 1301 microgram per day at the 1-hour time point.
  • the devices that were prewarmed to 42°C had an average normalized rate of 161 micrograms per day at the 1 hour time point.
  • the release rates are plotted on the Y axis, time on the X-axis.
  • the devices that were left at room temperature with no prewarming exhibited a significant and variable initial burst of drug release, with an average normalized rate of 1042 micrograms per day at the 1 hour time point.
  • the devices that were prewarmed to 42°C had an average normalized rate of 133 micrograms per day at the 1 hour time point.
  • Devices from the same manufacturing batch as in Example 2 were evaluated in vivo by implantation is Sprague-Dawley rats and measuring the plasma concentration time profiles. 15 devices were prepared and were stored submerged in a storage buffer containing 0.9% NaCl and 0.76% sodium acetate in water for injection at pH 5.5.
  • the plasma concentrations expressed in ng/mL are plotted on the Y axis, time on the X-axis.
  • the devices without prewarming showed a significantly elevated level of exenatide in the plasma (average 47 ng/mL) compared to the devices that were prewarmed (average 1.6 ng/mL), indicating an effective reduction of thermal start-up burst release by the prewarming treatment.

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Abstract

L'invention concerne des procédés pour réduire une libération d'impulsion de démarrage thermique à partir d'un dispositif implantable pour une libération contrôlée d'un agent thérapeutique à partir d'un dispositif comprenant une capsule conçue pour une implantation et ayant un réservoir. L'invention concerne en outre des procédés pour réduire la concentration plasmatique maximale d'un agent thérapeutique à partir d'un dispositif implantable pour une libération contrôlée de l'agent thérapeutique.
PCT/US2023/023836 2022-06-01 2023-05-30 Procédés et dispositifs pour contrôler la libération d'agents thérapeutiques à partir de dispositifs implantables WO2023235298A1 (fr)

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Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4030499A (en) * 1974-12-30 1977-06-21 Louis Bucalo Method and apparatus for providing living beings with absorbable implants
WO2012170700A2 (fr) * 2011-06-07 2012-12-13 Orthocon, Inc. Applicateur avec embout adaptable
US9271926B2 (en) * 2001-09-14 2016-03-01 Delpor, Inc. Microfabricated nanopore device for sustained release of therapeutic agent
US20170136224A1 (en) 2015-01-26 2017-05-18 Nano Precision Medical, Inc. Apparatus and Method for Promoting Fluid Uptake Into an Implant
US9770412B2 (en) 2014-01-23 2017-09-26 Nano Precision Medical, Inc. Implant device for drug delivery
US9814867B2 (en) 2011-12-05 2017-11-14 Nano Precision Medical, Inc. Device having titania nanotube membrane for drug delivery
US10045943B2 (en) 2014-11-02 2018-08-14 Nano Precision Medical, Inc. Implantable medical devices for extended release of therapeutic agents
US10479868B2 (en) 2014-09-04 2019-11-19 Nano Precision Medical, Inc. Polymeric stabilizing formulations
US20210246271A1 (en) 2014-09-04 2021-08-12 Nano Precision Medical, Inc. Polymeric stabilizing formulations
WO2021173770A1 (fr) * 2020-02-28 2021-09-02 Nano Precision Medical, Inc. Agents de stabilisation polymériques pour dispositifs implantables d'administration de médicaments
US20220008345A1 (en) 2020-07-08 2022-01-13 Nano Precision Medical, Inc. Methods to control the rate of release of therapeutic agents from implantable devices

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4030499A (en) * 1974-12-30 1977-06-21 Louis Bucalo Method and apparatus for providing living beings with absorbable implants
US9271926B2 (en) * 2001-09-14 2016-03-01 Delpor, Inc. Microfabricated nanopore device for sustained release of therapeutic agent
WO2012170700A2 (fr) * 2011-06-07 2012-12-13 Orthocon, Inc. Applicateur avec embout adaptable
US9814867B2 (en) 2011-12-05 2017-11-14 Nano Precision Medical, Inc. Device having titania nanotube membrane for drug delivery
US9770412B2 (en) 2014-01-23 2017-09-26 Nano Precision Medical, Inc. Implant device for drug delivery
US10479868B2 (en) 2014-09-04 2019-11-19 Nano Precision Medical, Inc. Polymeric stabilizing formulations
US20210246271A1 (en) 2014-09-04 2021-08-12 Nano Precision Medical, Inc. Polymeric stabilizing formulations
US10045943B2 (en) 2014-11-02 2018-08-14 Nano Precision Medical, Inc. Implantable medical devices for extended release of therapeutic agents
US20170136224A1 (en) 2015-01-26 2017-05-18 Nano Precision Medical, Inc. Apparatus and Method for Promoting Fluid Uptake Into an Implant
WO2021173770A1 (fr) * 2020-02-28 2021-09-02 Nano Precision Medical, Inc. Agents de stabilisation polymériques pour dispositifs implantables d'administration de médicaments
US20220008345A1 (en) 2020-07-08 2022-01-13 Nano Precision Medical, Inc. Methods to control the rate of release of therapeutic agents from implantable devices

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