Implantable and refillable drug delivery reservoir system having a porous metal frit for sustained delivery into the ventricle of the brain and method of use

Abstract

An apparatus for delivering a drug to the cerebrospinal fluid of the brain, comprising a hollow container having a reservoir volume and an outlet, and having an upper surface and a lower surface; a porous structure having a rigid material by sintering for passively regulating the diffusion of the drug from the container at a controlled release rate; and a catheter coupled to the lower end of the container, the catheter having a lumen, a proximal end region, and a distal end region, the lumen being configured to communicate with the reservoir volume of the container through the porous structure. Related systems and methods are also provided.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 357,819, filed on July 1, 2022, which is hereby incorporated by reference in its entirety.

[0002] The present technology relates generally to implantable and refillable drug delivery reservoir systems, and more particularly to a refillable and implantable drug delivery system having a porous metal frit for sustained delivery to the central nervous system.

Background Art

[0003] Delivery of therapeutic agents to the central nervous system (CNS) by general systemic administration, such as oral administration, intravenous administration, subcutaneous administration, etc., presents challenges due to the blood - brain barrier and the blood - cerebrospinal fluid barrier. Delivery of therapeutic agents to the CNS via cerebrospinal fluid (CSF) by intracerebroventricular (ICV) administration, intrathecal - cranial (IT - CM) administration, and intrathecal - lumbar (IT - L) administration is considered a more effective alternative approach.

[0004] Current methods of therapeutic delivery into the brain include direct needle bolus injection, implanted port catheter systems, or implanted reservoirs such as Ommaya reservoirs. Administration can be done by use of continuous administration means such as indwelling catheters and pumps, or can be by implantation, such as implanting a sustained release vehicle into the brain. More specifically, a therapeutic agent can be injected through a long-term implanted cannula, or can be injected long-term with the aid of an osmotic minipump. Subcutaneous pumps that deliver a therapeutic agent into the ventricles through a small tube are also available. Very sophisticated pumps can be refilled through the skin and their delivery rates can be set without the need for surgical intervention. Examples of administration procedures and delivery systems that include continuous intracerebroventricular infusion through subcutaneous pump devices or fully implanted drug delivery systems are those used for the administration of dopamine, dopaminergic agents, and cholinergic agents to Alzheimer's patients and animal models of Parkinson's disease, as described by Harbaugh, J. Neural Transm. Suppl. 24:271, 1987 and DeYebenes et.al., Mov. Disord. 2:143, 1987.

[0005] The limitation of these systems is that they can only enable bolus administration of a therapeutic agent, and this bolus injection method may not be ideal. For example, an Ommaya reservoir includes an injectable reservoir and a catheter that accesses the ventricle. This has been used for CSF sampling and direct administration of therapeutic agents into the ventricle. With bolus injection of a therapeutic agent, the concentration of the therapeutic agent in the patient's ventricle can reach a peak higher than the required therapeutic dose and then decline below the therapeutic dose before the next administration. Brief Description of the Drawings

[0006] Next, these and other aspects will be described in detail with reference to the following drawings. In general, the drawings are not to scale, either absolutely or in comparison, but rather are intended to be useful for explanation. Also, the relative arrangements of features and elements may be changed for the purpose of making the description clearer.

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DETAILED DESCRIPTION OF THE INVENTION

[0018] A therapeutic delivery device is described that continuously delivers a therapeutic agent at an ideal therapeutic dose over a long period of time while controlling it. In particular, an implantable and refillable reservoir device for the ventricle of the brain is provided that has a porous metal frit that enables the controlled and continuous release of the therapeutic agent over time based on the principle of passive diffusion. The device described herein separates the reservoir from the drug delivery catheter using a porous metal frit called a release control element (RCE). The RCE acts as a barrier to diffusion from the reservoir to the catheter. The RCE can be adjusted to achieve a desired release profile and can be controlled by varying the porosity of the frit, the size and molecular weight of the drug, and / or the drug concentration in the reservoir. The devices and systems described herein provide novel treatment strategies for various clinical problems arising from the delivery of chemotherapy for brain cancer or monoclonal antibodies, antisense oligonucleotides, gene therapy, or cell therapy for neurodegenerative diseases by reducing the frequency of administration and the negative side effects from current bolus administration methods. The controlled and continuous delivery of the therapeutic agent provides appropriate dosing to avoid under- or overdosing. The frequency of injections is minimized and the need for clinical visits is reduced, thus minimizing the burden on the patient and the healthcare system.

[0019] In some variations, optionally, one or more of the following may be included in any executable combination in the above methods, instruments, devices, and systems. Further details of the devices, systems, and methods are described in the accompanying drawings and the following description. Other features and advantages will become apparent from the description and drawings.

[0020] Furthermore, it should be understood that the devices and systems described herein can be placed at multiple locations on the body and, in particular, as shown in the figures or as described herein, need not be implanted. Using the devices and systems described herein, therapeutic agents can be delivered intracranially over a long period of time. The devices and systems can be useful in the treatment of any of a variety of neurodegenerative diseases of the brain, including Alzheimer's disease, stroke, Huntington's disease, ALS, Angelman syndrome, Parkinson's disease, motor neuron disease, and brain cancer, Batten disease such as infantile late-onset neuronal ceroid lipofuscinosis type 2 (CLN2) also known as tripeptidyl peptidase 1 (TPP1) deficiency, CNS trauma, and other diseases where direct delivery of drugs to the cerebrospinal fluid is thought to be beneficial. Other medical conditions other than these can also be treated with the devices and systems described herein. For example, the devices and systems can deliver treatments for inflammation, infection, and cancerous growth. Various combinations of drugs can be delivered using any of the devices and systems described herein.

[0021] The materials, compounds, compositions, articles, and methods described herein can be more readily understood by reference to the following detailed description of specific embodiments of the disclosed subject matter and the examples included therein. Prior to the disclosure and description of the materials, compounds, compositions, articles, devices, and methods, it should be understood that the aspects described below are not limited to a particular method or a particular reagent and that such methods or reagents can vary. It should also be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.

[0022] Definitions

[0023] Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, patent applications, published applications and publications, websites, and other published materials referred to throughout this specification are incorporated by reference in their entirety unless otherwise expressly noted. In the case of multiple definitions for terms in this specification, the definitions in this section shall prevail. When a URL or other such identifier or address is referenced, such identifiers may change and particular information on the Internet may move, but it is understood that equivalent information is known and readily accessible, for example, by searching the Internet and / or appropriate databases. Such references are evidence that such information is available and known to the public.

[0024] As used herein, terms indicating relative directions such as front, back, proximal, distal, outside, inside, sagittal, coronal, transverse, etc. are used throughout this disclosure. Such terms are for the purpose of describing the device and features of the device and are not intended to be limiting. For example, as used herein, "proximal" generally means closest to the user implanting the device and farthest from the target location of the implant, and "distal" means farthest from the user implanting the device into the patient and closest to the target location of the implant.

[0025] As used herein, a disease or disorder refers to a pathological condition in an organism that is caused, for example, by an infection or genetic defect and is characterized by identifiable symptoms.

[0026] As used herein, treatment means any way in which the symptoms of a condition, disorder, or disease are improved or otherwise beneficially changed. Treatment also encompasses any pharmaceutical use of the devices described and provided in this specification.

[0027] As used herein, improvement or alleviation of the symptoms of a particular disorder, such as by administration of a particular pharmaceutical composition, refers to a reduction that may be caused by or related to the administration of the composition, and such reduction may be permanent or temporary, persistent or transient.

[0028] As used herein, an effective amount of a compound for treating a particular disease is an amount sufficient to improve the symptoms associated with the disease or to alleviate them in some way. Such an amount can be administered as a single dose or according to an effective dosing regimen. This amount may be able to cure the disease, but typically it is administered to improve the symptoms of the disease. Repeated dosing may be required to achieve the desired improvement in symptoms. The pharmaceutically effective amount, therapeutically effective amount, biologically effective amount, and therapeutic amount are used interchangeably herein to refer to an amount of a therapeutic substance, whether quantitative or qualitative, sufficient to achieve the desired result, i.e., a therapeutic effect. In particular, a pharmaceutically effective amount in the body is an amount that results in a reduction, delay, or elimination of undesirable effects (e.g., pathological, clinical, biochemical, etc.) in a subject.

[0029] As used herein, the release rate index includes (PA / FL), where P includes porosity, A includes effective area, F includes a curve fitting parameter corresponding to the effective length, and L includes the length or thickness of the porous structure. The unit of the release rate index (RRI) includes the unit of mm, unless otherwise indicated, and can be determined by one of ordinary skill in the art according to the teachings described herein.

[0030] As used herein, sustained release includes the release of an active ingredient of a therapeutic agent in an effective amount over an extended period of time. Sustained release may include primary release of the active ingredient, zero-order release of the active ingredient, or other release kinetics such as intermediate between zero-order and primary, or combinations thereof. Sustained release may include controlled release of a therapeutic agent via passive molecular diffusion driven by a concentration gradient across a porous structure.

[0031] As used herein, a subject includes any animal for which diagnosis, screening, monitoring, or treatment is contemplated. Animals include mammals such as primates and domestic animals. An exemplary primate is a human. A patient refers to a subject who is afflicted with a disease state, or in whom a disease state has been determined, or in whom the risk of a disease state has been determined, such as a mammal, primate, human, or domestic animal.

[0032] As used herein, a therapeutic agent referred to by a trade name encompasses one or more of a formulation of a therapeutic agent marketed under that trade name, an active ingredient of a marketed formulation, the generic name of the active ingredient, or a molecule containing the active ingredient. As used herein, a therapeutic substance or therapeutic agent is a substance that ameliorates the symptoms of a disease or disorder or ameliorates the disease or disorder. Therapeutic agents, therapeutic compounds, therapeutic dosing regimens, or chemotherapies are known to those of skill in the art and include conventional drugs and drug therapies, including vaccines, as described elsewhere herein. Therapeutic agents include, but are not limited to, those that allow for controlled and sustained release into the body.

[0033] As used herein, a composition refers to any mixture. A composition can be a solution, suspension, emulsion, liquid, powder, paste, aqueous, non-aqueous, or any combination of such components.

[0034] As used herein, a fluid refers to any composition that can flow. Thus, a fluid encompasses compositions in the form of semi-solids, pastes, solutions, aqueous mixtures, gels, lotions, creams, and other such compositions.

[0035] As used herein, a kit is a packaged combination, optionally including instructions for using the combination and / or other reactions and components for such use.

[0036] As used herein, the term "oligonucleotide" or "therapeutic oligonucleotide" is defined as a molecule comprising two or more covalently linked nucleosides, as generally understood by those of ordinary skill in the art. Such covalently linked nucleosides may also be referred to as nucleic acid molecules, oligonucleotides, or oligomers. Oligonucleotides are generally made in the laboratory by solid-phase chemical synthesis followed by purification. When referring to the sequence of an oligonucleotide, reference is made to the sequence or order of the nucleobase portions of the covalently linked nucleotides or nucleosides, or modifications thereof. The oligonucleotides of the present invention are artificial, chemically synthesized, and typically purified or isolated. The oligonucleotides of the present invention may comprise one or more modified nucleosides or nucleotides, such as, for example, 2'-sugar modified nucleosides.

[0037] As used herein, the term "antisense oligonucleotide" is defined as an oligonucleotide that can regulate the expression of a target gene by hybridizing to a target nucleic acid, particularly a contiguous sequence on the target nucleic acid. Antisense oligonucleotides are not essentially double-stranded and are thus not siRNA or shRNA. Preferably, antisense oligonucleotides are single-stranded. A single-stranded oligonucleotide is understood to be able to form a hairpin or intermolecular double-stranded structure (a double-strand between two molecules of the same oligonucleotide) as long as the degree of internal or intermolecular self-complementarity is less than 50% over the entire length of the oligonucleotide.

[0038] Therapeutic device

[0039] Figures 1A and 2 are exploded cross-sectional views of one embodiment of the drug delivery device 100. Briefly, the device 100 in each embodiment includes a container 105 that defines a reservoir volume, a catheter 110 configured to communicate with the reservoir volume of the container 105, and a frit or drug release control element (RCE) 120 that controls the release of the therapeutic substance held within the reservoir volume of the container 105. The RCE 120, which will be described in more detail later, can be a porous metal material adjusted to adjust the release profile of the therapeutic agent contained within the reservoir based on the surface area, length, and pore size of the RCE 120.

[0040] Figures 1B and 1C are schematic cross-sectional views of the drug delivery device 100 implanted within the brain. The devices described herein can be arranged such that the container 105 remains substantially external to the patient or is covered by a layer of skin (i.e., subcutaneous), and the catheter 110 of the device 100 coupled to the container 105 penetrates the skull until the tip 112 of the catheter 110 is located within, adjacent to, or in communication with the target site. The target site for treatment is preferably within the skull, within the brain, or within the ventricles of the brain. The devices can be used with various therapeutic agents such as one or more chemotherapeutic agents typically delivered by bolus injection for the treatment of cancer. The therapeutic agent can be a peptide, protein, monoclonal antibody, antisense oligonucleotide, gene therapy, cell therapy, or other small molecules particularly for the treatment of neuropathy. Both drug stability and molecular weight are important for the delivery of antisense oligonucleotides (ASO) and cystine knot peptides (CKP), disulfide constrained peptides (DCP), and therapeutic substances that can be delivered from a small reservoir volume to achieve a therapeutic effect. The devices described herein are particularly useful for the delivery of therapeutic substances that can be delivered from a reservoir volume in the range of 0.5 mL to 5 mL.

[0041] The devices described herein are referred to as drug delivery devices, treatment devices, therapeutic devices, port delivery systems, and the like. It should be understood that these terms are used interchangeably herein and are not intended to limit the device to any particular embodiment other than those described. For the sake of brevity, various combinations are considered herein, but explicit descriptions of each of these combinations may be omitted. Further, various methods for implanting and accessing the device are described herein. For various implants, various different devices and systems can be used to perform implantation, filling, refilling, etc. according to various different methods. Some representative descriptions of how implantation and access can be performed for various devices are presented, but for the sake of brevity, explicit descriptions of each method for each implant or system may also be omitted.

[0042] Again, with respect to FIG. 1A, which shows a side cross-sectional view of the device 100, the therapeutic agent as described herein can be injected when the device 100 is implanted.

[0043] The reservoir volume of the container 105 (also referred to herein as a reservoir) can hold an amount of therapeutic agent to be delivered over a period of time. FIG. 1A shows a container 105 having a reservoir volume larger than the reservoir volume of the container 105 in FIG. 2. For example, the reservoir volume can be between 0.5 mL and about 5.0 mL. The overall size of the container 105 can be selected to be relatively thin so that the container 105 can be implanted between the skull and the skin. The lower surface 115 of the container 105 can be positioned against the skull 5, and the upper surface 117 of the container 105 can be covered by the overlying skin 7 (see FIG. 1C). Thus, most of the container 105 is implanted substantially within the patient's body but outside the skull 5. The diameter of the container 105 can be between about 10 mm and about 45 mm. The maximum height of the container 105 between the lower surface 115 and the upper surface 117 configured to be seated against the skull 5 can be between about 3 mm and about 15 mm.

[0044] The container 105 may have an oval, elliptical, or circular peripheral shape. The lower surface 115 may be flat or may have a curved outer shape that substantially conforms to the shape of the skull 5 at a specific location. The upper surface 117 may be substantially convex spherical or annular. In some embodiments, the container 105 has a rounded outer shape that avoids sharp or angular edges that may cause discomfort to the patient during implantation. The material of the container 105 may be a relatively rigid silicone or other polymeric material such that the reservoir volume of the container 105 remains substantially constant regardless of the filling state. Alternatively, or in combination therewith, the material of the container 105 may be relatively flexible or elastic, for example, such that the contour of the container 105 changes as the therapeutic agent 10 enters and exits the container 105. The flexible material of the container 105 can be combined with a rigid material, for example, to provide support.

[0045] The container 105 can be formed by a lower base 114 including the lower surface 115 and an upper cap 116 including the upper surface 117. The base 114 and the cap 116 cooperatively define the reservoir volume of the container 105. At least a portion of the cap 116, including the whole of the cap 116, can be formed of a material configured to be penetrated by a sharp object such as a needle for injecting the therapeutic agent into the reservoir volume. The cap 116 can be joined (such as by epoxy) to the base 114 to seal and form a reservoir volume that does not leak the liquid of the container 105. The base 114 can define an outlet from the container 105.

[0046] The inner surface of the base 114 can include a seat 118 that is sealed by the RCE 120. The seat 118 in FIGS. 1A and 2 is disposed at the bottom of the reservoir 105 away from the penetrable cap 116. The RCE, which is generally porous titanium or stainless steel, is tightly fitted into the seat 118 of the base 114 by press-fitting, heat swaging, epoxy, etc. into the impermeable structure of the container. The tight fit ensures that diffusion occurs through the RCE rather than around it.

[0047] Below the seat 118, there is a diffusion chamber 122 disposed within a protrusion 124 from the lower surface 115 of the base 114. The diffusion chamber 122 can have an inner diameter that is smaller than the inner diameter of the container 105 located above the diffusion chamber 122 and larger than the inner diameter of an outlet channel 125 that extends through a return connector 127 and is located below the diffusion chamber 122. The diffusion chamber 122 is tapered along its length to a smaller inner diameter of the outlet channel 125. The inner diameter of the outlet channel 125 can be smaller than the inner diameter of the diffusion chamber 122 and smaller than the lumen 111 of the catheter 110. The size of the diffusion chamber 122 located below the position of the RCE 120 and above the outlet channel 125 allows for the use of the entire surface area of the RCE 120 positioned above the diffusion chamber 122 before narrowing to the outlet channel 125 for connection with the lumen 111 of the catheter 110.

[0048] As best shown in FIG. 1D, the return connector 127 projects from the lower surface 115 of the base 114 and can have a similarly varying outer diameter from its upper end to its lower end. The upper region 123 of the return connector 127 that defines the diffusion chamber 122 can have a first outer diameter. The first outer diameter can be smaller than the outer diameter of the container 105 and can be larger than the outer diameter of the catheter 110. The upper region 123 of the return connector 127 can be tapered along its length to the lower region 124. The lower region 124 of the return connector 127 can have an outer diameter smaller than that of the upper region 123 and can have an outer diameter smaller than the outer diameter of the catheter 110. The lower region 124 of the return connector 127 can include a return 128 or other surface features near its distal end that ensure a stable connection between the container 105 and the catheter 110 and prevent unintentional disconnection. The return 128 can have an outer diameter slightly larger than the inner diameter of the catheter 110, such that when the return connector 127 is inserted through the proximal opening 108 of the catheter 110, the material of the catheter 110 is slightly deformed to accept the larger outer diameter by interference fit. The flat upper surface 129 and angled edges of the return 128 make it more difficult to withdraw the return 128 from the lumen 111 than to insert the tapered front face 130 of the return 128 into the lumen 111. When the base 114 is connected to the catheter 110, the outlet channel 125 communicates with the lumen 111 of the catheter 110, and the RCE 120 controls the release of the therapeutic substance from the reservoir volume into the lumen 111.

[0049] In the embodiment shown in FIG. 2, the base 114 can be epoxy-attached to the cap 116 to form a pierceable reservoir for containing a therapeutic agent. The return connector 127 can be epoxy-attached to the bottom component 113, and then the subassembly is epoxy-attached to the base 114. This embodiment can form a secondary fluid space that allows for diffusion through the entire surface of the RCE 120. Since the return connector 127 is not directly attached to the base 114, unlike the embodiment shown in FIG. 1A, it has additional degrees of freedom and flexibility. Further, the overall size of the implant can be made smaller so as to be less invasive.

[0050] As shown in FIGS. 1A and 2, an elongate catheter 110 is coupled to the lower end of a container 105. The catheter 110 can be centered with respect to the lower end of the container 105 or can be eccentric. The lumen 111 of the catheter 110 extends from a proximal opening 108 into the catheter 110 to at least one distal opening 109 near the tip 112 of the catheter 110. The catheter 110 has a length dimensioned to extend from outside the skull 5 to a target position for releasing a therapeutic agent into a region of the brain, preferably the superior sagittal sinus or the ventricles. The length can be dimensioned, for example, in the range from about 10 cm to about 20 cm. The length can be less than about 15 cm, can be as short as about 10 cm, about 5 cm, about 3 cm, or can be of sufficient length to extend through a burr hole and into, for example, the ventricles or one or more superior sagittal sinuses. In one embodiment, the length of the catheter can be from 3 cm to 5 cm, up to about 15 cm. Further, a catheter 110 having a length greater than these ranges (e.g., about 30 cm to 50 cm) can be provided and later cut to a predetermined size by the user during implantation to achieve a final preferred length. The catheter 110 can be manufactured to have a single size greater than the length required to reach the target site during implantation so that any of a variety of target positions can be treated with the same modular system. The device can be provided with the catheter separated from the shuttle, and prior to implantation, the proximal end of the catheter can be cut to a predetermined size and then pushed into the shuttle. Cutting the proximal end to adjust the size of the catheter 110 avoids affecting the distal tip 112 which can have a specialized distal opening 109 for delivering a therapeutic agent. The catheter 110 can have one or more markings on the outer surface near the proximal end to guide cutting to a predetermined size and indicate the length to the distal tip 112 depending on where the proximal end is cut.

[0051] The outer cross-sectional diameter of the catheter 110 may be sized to reduce the invasiveness of the device 100, and may have an outer diameter of about 5 mm or less, preferably about 1 mm to about 4 mm. The inner diameter of the catheter 110 can be at least about 0.5 mm, preferably about 0.5 mm to about 3 mm.

[0052] The distal tip 112 of the catheter can be shaped to include one or more outlets including the distal opening 109. The distal tip 112 of the catheter 110 can have one or more outlets that extend through the wall of the catheter 110. The plurality of outlets may be disposed through the wall and may be of various sizes between about 0.0008 inches (0.02 mm) to about 0.08 inches (2.03 mm), preferably about 0.008 inches (0.2 mm) to about 0.05 inches (1.2 mm). The outlets can be of various shapes and numbers, such as one or more rows of about 2 to about 20 holes having a circular, oval, or other shape. The outlets can be positioned at angular intervals of about 90 degrees from each other so as to be circumferentially present around the distal tip 112. The outlets can be positioned at intervals of about 45 degrees, 90 degrees, 120 degrees, or 180 degrees in the circumferential direction.

[0053] The catheter 110 can be formed of silicone or polyurethane, or a combination of materials. One or more regions of the catheter 110 can be reinforced with a tube, cut tube, coil, braid, or other reinforcing structure. The reinforcing structure can be a metallic material or a plastic material having a durometer greater than that of the remainder of the catheter 110. The return 128 and the base 114 can be fabricated from a plastic that is stiffer than the proximal end region of the catheter 110, such as polysulfone or polymethyl methacrylate or other suitable plastic. The more rigid material of the return 128 and / or the base 114 causes these portions of the device to deform the more flexible catheter material and allows for a more secure connection.

[0054] Catheter 110 is preferably kept straight between its proximal and distal ends without any bend between the container 105 and the site to be treated. Thus, when implanted, the container 105 is generally positioned above the distal tip 112 of the catheter 110 disposed within the target site. The vertical orientation of the straight catheter 110 ensures the delivery of the therapeutic substance through the lumen from the container 105 to the target site via the distal tip 112.

[0055] The RCE 120 can be positioned relative to the catheter 110 to release the therapeutic agent from the container 105 over a long period of time. The frit can be adjusted to adjust the release profile of the therapeutic agent. Specifically, all of the parameters including the surface area of the RCE, the length of the RCE, the tortuosity, and the pore size can be adjusted to achieve the desired release profile. The size, molecular weight, and concentration of the therapeutic agent also affect the release profile. The length of the catheter contributes to the tortuosity parameter of the release rate. Thus, the RCE is relatively porous compared to drug delivery devices having substantially shorter catheters or cannulas.

[0056] In many embodiments, the RCE 120 has a porosity, thickness, channel parameter, and surface area configured to release a therapeutic amount over a long period of time. The porosity may have a value within the range of about 1% to about 70%, preferably 15% to 40%. The porosity may have a value within the range of about 3% to about 30%. The porosity may have a value within the range of about 5% to about 10%. The porosity may have a value within the range of about 10% to about 25%. The porosity may have a value within the range of about 10% to about 20%.

[0057] In many embodiments, the channel parameter includes a fit parameter corresponding to the tortuosity of the channel.

[0058] In many embodiments, the channel parameter includes a fit parameter corresponding to the effective length of the interconnecting channel extending from the first side of the RCE120 to the second side of the RCE120. The effective length of the interconnecting channel may correspond to at least about twice the thickness of the RCE120. The effective length of the interconnecting channel may correspond to at least about five times the thickness of the RCE120. The channel parameter may be between 1 and 10, preferably between 2 and 5.

[0059] In many embodiments, the rate of release of at least one therapeutic agent corresponds to the ratio of the porosity to the channel parameter, and the ratio of the porosity to the channel parameter is less than about 0.5 so that the RCE120 releases at least one therapeutic agent over a long period of time. The ratio of the porosity to the channel parameter may be less than about 0.2 so that the RCE120 releases at least one therapeutic agent over a long period of time. The ratio of the porosity to the channel parameter may be less than about 0.1 so that the RCE120 releases at least one therapeutic agent over a long period of time. The ratio of the porosity to the channel parameter may be less than about 0.05 so that the RCE120 releases at least one therapeutic agent over a long period of time. The ratio of the porosity to the channel parameter may be between 0.001 and 0.7, preferably between 0.03 and 0.2.

[0060] In many embodiments, the channel parameter includes a value of at least about 1. The value of the channel parameter may include at least about 2. The channel parameter may include a value of at least about 5. The channel parameter may include a value of at least about 10.

[0061] In many embodiments, RCE120 includes a release rate index (RRI) determined by a ratio of the porosity of RCE120 multiplied by the cross-sectional area of RCE120, divided by the channel parameter multiplied by the thickness extending over the entire cross-sectional area of RCE120. The range of the release rate index may be from 0.01 to 20, although the range of the RRI may vary depending on the molecule and the desired release time. RCE120 may have a release rate index of about 5.0 mm or less. RCE120 may have a release rate index of about 2 mm or less. RCE120 may have a release rate index of about 1.2 mm or less. RCE120 may have a release rate index of about 0.2 mm or less. RCE120 may have a release rate index of about 0.1 mm or less. RCE120 may have a release rate index of about 0.05 mm or less.

[0062] The apparatus 100 described herein can include one or more RCE120s. The RCE120 described herein (also referred to herein as a drug release mechanism, drug release element, release control element, porous structure, or frit) can be positioned adjacent to the outlet channel 125 from the apparatus 100 and / or within the outlet channel 125 from the apparatus 100 so that the delivery of one or more therapeutic agents from the container 105 through the outlet channel 125 can be controlled or regulated by the RCE120. The contents of the container 105 can be delivered by slow diffusion rather than by fluid flow or ejection as a bolus. In some embodiments, the RCE120 can be positioned within the region of the container 105 in communication with the catheter 110. In some embodiments, the RCE120 can be a coating or lining having a particular porosity for the substance being delivered and can be used to provide a particular release rate of the substance.

[0063] The RCE120 can include, but is not limited to, Wick material, permeable silicone, filling floor, small porous structure or porous frit, multiple porous coatings, nano coatings, rate-limiting membrane, matrix material, sintered porous frit, permeable membrane, semi-permeable membrane, capillary or serpentine channel, nanostructure, nanochannel, sintered nanoparticles, etc. The RCE120 can have a porosity, cross-sectional area, and thickness for releasing one or more therapeutic agents from the container 105 over a long period of time. The porous material of the RCE120 can have a porosity corresponding to the proportion of void space formed by channels extending through the material or extending between materials. The formed void space can be about 1% to about 70%, about 5% to about 10%, about 10% to about 25%, or about 15% to about 20%, or any other proportion of void space.

[0064] The osmotic pressure and tonicity of cerebrospinal fluid can be in the range of about 290.5 mOsm / L to about 291.5 mOsm / L (see Akaishi et.al., Neural Regen Res, 2020 May 15(5):944 - 947). For example, a commercially available formulation of a therapeutic agent to be delivered can be diluted to have a formulation with an osmotic pressure and tonicity substantially the same as that of CSF, such as about 290 mOsm / L. The therapeutic agent can have an osmotic pressure and tonicity substantially the same as that of CSF, but the therapeutic agent can also have a solution with a high osmotic pressure (hypertonic) relative to CSF or a solution with a low osmotic pressure (hypotonic) relative to CSF. Those skilled in the art can perform experiments based on the teachings described herein and empirically determine the formulation and osmotic pressure of the therapeutic agent to provide for the release of the therapeutic agent over a long period of time.

[0065] The RCE120 has a first side facing the reservoir volume of the container 105 and a second side facing the proximal opening 108 into the lumen 111 of the catheter. The first side has the first region described herein, and the second side has the second region. The RCE120 has a thickness and a diameter between the first side and the second side. The RCE120 has a release rate exponent, which is described in detail below. The RCE120 includes a fixed serpentine porous material, such as sintered metal, sintered glass, or sintered polymer, having a predetermined porosity and tortuosity that controls the rate of delivery of at least one therapeutic agent to a target site. The rigid body RCE120 provides certain advantages over capillaries, erodible polymers, and membranes as a mechanism for controlling the release of therapeutic agents or substances from a therapeutic device. These advantages include that the rigid body RCE120 is simpler and allows for more cost-effective manufacturing, can be flushed for cleaning or clog removal before or after implantation, provides high-efficiency deep filtration of microorganisms due to the labyrinth of irregular paths within the structure, and is more robust compared to a membrane or erodible polymer matrix due to the high hardness and large size of the structure. In some embodiments, the drug can be injected into the reservoir, flushed, and then refilled with the drug. Flushing can push a first bolus of the drug deeper into the brain tissue, and the second refill of the drug is used for sustained release. Further, when the rigid body RCE120 is manufactured from sintered metal, ceramic, glass, or certain plastics, sterilization and cleaning procedures such as sterilization and depyrogenation based on heat or radiation, which may damage polymers and other membranes, can be performed.

[0066] In certain embodiments, as shown in Example 1, the rigid RCE 120 may be configured to provide a therapeutically effective concentration of a therapeutic agent in the CSF for at least 1 month, at least 2 months, at least 3 months, up to about 6 months, 12 months, 24 months, or up to about 36 months. The treatment time can vary depending on the diffusibility of the therapeutic agent, molecular size / molecular weight, concentration, half-life, stability, and volume, as well as the parameters of the RCE. The release profile can vary from as short as a few days to as long as several months to several years, depending on the specific application, drug efficacy, as well as the characteristics of the device and the physical properties of the RCE. This release profile provided by a particular configuration of the rigid RCE 120 enables a smaller device, which is preferred in intracerebral treatments where larger devices can affect device invasiveness and patient comfort and can cause problems due to infection or leakage.

[0067] The RCE 120 may include a plurality of interconnected channels formed between sintered particles of a material such as titanium or stainless steel. The interconnected material particles define a space through the RCE 120 through which the therapeutic agent can pass and reach from a first side of the RCE 120 to a second side of the RCE 120. The channels may extend around the sintered material particles such that they include interconnected channels that extend through the porous material.

[0068] The rigid RCE 120 can have a hardness parameter in the range of about 160 Vickers to about 500 Vickers. In some embodiments, the rigid RCE 120 is formed from sintered stainless steel. The material of the RCE may have a hardness parameter in the range of about 200 Vickers to about 240 Vickers. In some embodiments, it is preferred to prevent the discharge of the therapeutic agent through the RCE 120 while filling or refilling the container 105 of the treatment device 100 with fluid. In these embodiments, the channels of the rigid RCE 120 have a resistance to the flow of the injected solution or suspension such that the discharge of the solution or suspension through the RCE 120 is substantially prevented when the solution or suspension is injected into the container 105 of the treatment device 100.

[0069] Container 105 and RCE 120 can be configured to release a therapeutically effective amount of a therapeutic agent in many ways. Container 105 and RCE 120 can be configured to release a therapeutically effective amount of a therapeutic agent corresponding to a concentration of at least about 1 mg / mL to about 300 mg / mL over at least about several days to up to about 12 months. The therapeutic agent can be at least an antibody fragment and have a molecular weight of at least about 150 Daltons. For example, the therapeutic agent can be about 8,000 to 200,000 Daltons. Alternatively or in combination, the therapeutic agent can be a small molecule drug suitable for sustained release having a molecular weight of about 100 Daltons to about 100 million Daltons. The therapeutic agent can be one or more different antisense oligonucleotides, CKP, various immunotherapies such as monoclonal antibodies, and thrombolytics and protease inhibitors useful for treating various neurodegenerative disorders, etc.

[0070] The reservoir and RCE 120 can be configured to release a therapeutically effective amount of a therapeutic agent corresponding to a concentration of at least about 1 mg / mL, 100 mg / mL, 200 mg / mL, or 300 mg / mL over several days, 1 month, 2 months, 3 months, 6 months, 12 months, 24 months, up to about 36 months, and any long period in between.

[0071] The rigid body RCE 120 can include a composite porous material that can be easily formed into a wide variety of shapes and configurations. For example, the porous material can be a composite impregnated with a sintered powder or aerogel in the through-holes of a metal, aerogel, or ceramic foam (i.e., a reticulated cell interconnect structure where the internal cells are interconnected to provide a large number of pores passing through the volume of the structure, the walls of the cells themselves are substantially continuous and non-porous, and the volume of the cells relative to the volume of the material forming the cell walls is such that the overall density of the cell interconnect structure is less than about 30% of the theoretical density). The final thickness, density, porosity, and porous properties of the composite porous material can vary to suit the desired release of the therapeutic agent.

[0072] The release rate of a therapeutic agent passing through a porous body such as a sintered porous metal structure or a porous glass structure can be explained by an effective diffusion coefficient equal to the diffusion coefficient of the therapeutic agent in the liquid filling the reservoir multiplied by the porosity of the porous body and the channel parameter, by the diffusion of the therapeutic agent in RCE120 having the channel parameter.

[0073] Release rate = (D P / F)A(C R - Cp) / L wherein,

[0074] C R = concentration in the reservoir

[0075] C p = concentration outside the reservoir or at the target site

[0076] D = diffusion coefficient of the therapeutic agent in the reservoir solution

[0077] P = porosity of the porous structure

[0078] F = channel parameter that can correspond to the tortuosity parameter of the channels of the porous structure

[0079] A = area of the porous structure

[0080] L = thickness (length) of the porous structure

[0081] Cumulative release = 1 - cR / cR0 = 1 - exp((-D PA / FL V R )t) wherein,

[0082] t = time, Vr = reservoir volume

[0083] The release rate index (hereinafter, RRI) can be used to determine the release of a therapeutic agent. The RRI may be defined as (PA / FL), and the RRI values herein have units of mm unless otherwise indicated. Many of the RCE120s used in the therapeutic delivery devices described herein have an RRI between 0.01 and 20, although the RRI range can vary depending on the molecule as well as the desired release time and application.

[0084] The channel parameter can correspond to the length of the path of the therapeutic agent released through the RCE120. The RCE120 may include a number of interconnected channels, and the channel parameter can correspond to the effective length that the therapeutic agent moves from the reservoir side to the patient side along the interconnected channels of the RCE120 during release. Multiplying the channel parameter by the thickness (length) of the RCE120 can determine the effective length that the therapeutic agent moves from the reservoir side to the patient side along the interconnected channels. For example, a channel parameter (F) of about 1.5 corresponds to interconnected channels that result in an increase in the effective length of movement of the therapeutic agent of about 50%. In the case of an RCE120 with a thickness of 1 mm, the effective length that the therapeutic agent moves from the reservoir side to the patient side along the interconnected channels corresponds to about 1.5 mm. A channel parameter (F) of at least about 2 corresponds to interconnected channels that result in an increase in the effective length of movement of the therapeutic agent of about 100%. In the case of an RCE120 with a thickness of 1 mm, the effective length that the therapeutic agent moves from the reservoir side to the patient side along the interconnected channels corresponds to at least about 2.0 mm. Since the RCE120 includes many interconnected channels that provide many alternative paths for the release of the therapeutic agent, even if some of the channels are blocked, alternative interconnected channels are available, so the effective path length through the RCE120 does not substantially change. Thus, even if some of the channels are blocked, the rate of diffusion through the RCE120 and the release of the therapeutic agent are substantially maintained.

[0085] If the reservoir solution is aqueous or has a viscosity similar to water, the value of the diffusion coefficient of the therapeutic agent (TA) in water at the desired temperature can be used. Using the following equation, the diffusion coefficient at 37 °C can be estimated from the measured value of D BSA,20C = 6.1e-7 cm 2 / s for bovine serum albumin in water at 20 °C (Molokhia et al, Exp Eye Res 2008).

[0086] D TA,37C = D BSA,20C (η 20C / η 37C )(MW BSA / MW TA ) 1 / 3 wherein

[0087] MW refers to the molecular weight of either BSA or the test compound, and η is the viscosity of water. Table 1 below lists the diffusion coefficients of the target proteins.

Table 1

[0088] Small molecules have a diffusion coefficient similar to that of fluorescein (MW = 330, D = 4.8 - 6e-6 cm 2 / s (from Stay, MS et al. Pharm Res 2003, 20(1), pp. 96 - 102)). For example, small molecules can include glucocorticoids such as triamcinolone acetonide having a molecular weight of about 435.

[0089] RCE120 has a porosity, thickness, channel parameters, and surface area configured to release a therapeutic dose over a long period of time. The porous material can have a porosity corresponding to the proportion of the void space of the channels extending within the material. The porosity can include values in the range of about 1% to about 70%, preferably 15% to 40%. The porosity can be determined from the weight and macroscopic volume, or can be measured by nitrogen gas adsorption.

[0090] The RCE120 may include a plurality of porous structures, and the area used in the above formula may be the combined area of the plurality of porous structures.

[0091] The channel parameter may include a fitting parameter corresponding to the tortuosity of the channel. For known porosity, surface area, and thickness of the surface parameter, a curve fitting parameter F corresponding to the tortuosity of the channel can be determined based on experimental measurements. Using the parameter PA / FL, a desired sustained release profile can be determined, and the values of P, A, F, and L can be determined. The rate of release of the therapeutic agent corresponds to the ratio of the porosity to the channel parameter, and the ratio of the porosity to the channel parameter can be less than about 0.7 so that the RCE120 releases the therapeutic agent over a long period. For example, the ratio of the porosity to the channel parameter can be less than about 0.1 so that the RCE120 releases the therapeutic agent over a long period, or, for example, less than about 0.2. The channel parameter may include a value of at least about 1, such as at least about 1.2. For example, the value of the channel parameter may include at least about 1.5, for example at least about 2, and may include at least about 5. The channel parameter can be in the range of about 1.1 to about 10, for example in the range of about 2 to about 5. One skilled in the art can perform experiments based on the teachings described herein and empirically determine the channel parameter so as to release the therapeutic agent with respect to the intended release rate profile.

[0092] The area in the model is derived from the description of the mass transported in flow rate units, i.e., the mass transfer rate per unit area. In the case of a simple shape such as a porous disk attached to an impermeable sleeve of the same thickness, the area corresponds to one face of the disk, and the thickness L is the thickness of the disk. In the case of a more complex shape such as a frustum-shaped porous body, the effective area is a value between the area where the therapeutic agent enters the porous body and the area where the therapeutic agent exits the porous body. The porosity of RCE120 can be made sufficiently high so that the length of the catheter does not affect, or only minimally affects, the release rate from the device. The drug release rate is controlled by the porosity of RCE120, the size of the drug molecules to be delivered, and / or the concentration of the drug in the reservoir. The reservoir is preferably placed directly above the catheter, and there is no meandering in the catheter from the reservoir to the target treatment area. This vertical orientation between the distal exit from the catheter and the inlet from the reservoir is preferred to ensure good drug diffusion to the target treatment area.

[0093] By relating the change in concentration in the reservoir to the above-mentioned release rate, a model can be derived that describes the release rate as a function of time. This model assumes a solution of the therapeutic agent in which the concentration in the reservoir is uniform. In addition, the concentration in the receiving fluid is considered negligible (C p = 0). Solving and rearranging the differential equation gives the following equation that describes the concentration in the reservoir as a function of time t and the volume V R of the reservoir for the release of the therapeutic agent from the solution in the reservoir through the porous structure.

[0094] C R = C RO exp((-D PA / FL V R )t)

[0095] And, cumulative release = 1 - C R / C RO

[0096] When the reservoir contains a suspension, the concentration C Ris the dissolution concentration (i.e., the solubility of the therapeutic agent) in equilibrium with the solid. In this case, the concentration in the reservoir is constant with respect to time, the release rate is zero order, and the cumulative release increases linearly with time until the time when the solid is exhausted.

[0097] The therapeutic concentration of many therapeutic agents can be experimentally determined by measuring the concentration at the target site that induces a therapeutic effect. Therefore, it is valuable to extend the prediction of the release rate to the prediction of the concentration at the target site. Most of the cerebrospinal fluid (CSF) is produced by the choroid plexus in the ventricles of the brain, circulates through the ventricles, cisterns, and subarachnoid space, and is absorbed into the blood by the arachnoid villi. CSF circulation involves not only the directed flow of CSF but also the pulsatile reciprocating motion throughout the brain involving local fluid exchange between blood, interstitial fluid, and CSF. CSF has a physiological volume of about 150 - 200 ml in adults, and the metabolic turnover per day is about 500 ml. In the case of a device with long-term release, the concentration in the cerebrospinal fluid (CSF) changes slowly over time. In this situation, a model can be derived from the mass balance that equates the release rate from the device (represented by the above equation) to the removal rate from CSF, k, C p , V v From. By rearrangement, the following equation for the concentration in CSF is obtained.

[0098] C p = Release rate from the device / kV V

[0099] Since the release rate from a device containing a solution of the therapeutic agent decreases exponentially with time, the concentration in CSF decreases exponentially with the same rate constant. In other words, the CSF concentration decreases with a rate constant equal to D PA / FL V R and thus depends on the properties of the porous structure and the volume of the reservoir.

[0100] Since the release rate from a device containing a suspension of the therapeutic agent is zero order, the CSF concentration is also independent of time. The release rate depends on the properties of the porous structure via the specific PA / FL, but does not depend on the volume of the reservoir until the time when the drug is exhausted.

[0101] The channels of the rigid porous structure can be sized in many ways to release the intended therapeutic agent. For example, the channels of the rigid porous structure can be sized to allow passage of a therapeutic agent that includes a molecule having a molecular weight of at least about 100 Daltons, or for example at least about 200 kDa. The channels of the rigid porous structure can be sized to allow passage of a therapeutic agent that includes a molecule having a cross-sectional size of about 10 nm or less. The channels of the rigid porous structure include interconnected channels that are configured to allow passage of the therapeutic agent therebetween. The rigid porous structure includes particles of a rigid material, and the interconnected channels extend at least partially around the particles of the rigid material such that the therapeutic agent passes through the porous material. The particles of the rigid material can be bonded to each other at attachment locations, and the interconnected channels extend at least partially around the attachment locations.

[0102] The porous structure includes a sintered material. The sintered material can include particles of a material having an average size of about 20 μm or less. For example, the sintered material can include particles of a material having an average size of about 10 μm or less, about 5 μm or less, or about 1 μm or less. The channels are sized based on the particle size of the sintered material and processing parameters such as the compression force and the time and temperature in the furnace so that a therapeutic amount of the therapeutic agent passes through the sintered material over a long period of time. The channels can be sized to prevent entry of microorganisms including bacteria and fungal spores through the sintered material.

[0103] The sintered material includes a wettable material to suppress air bubbles within the channels of the material.

[0104] The sintered material includes at least one of metal, ceramic, glass, or plastic. The sintered material may include a sintered composite material, and the composite material may include two or more of metal, ceramic, glass, or plastic. The metal includes at least one of stainless steel including alloys such as Ni, Ti, nitinol, 304, 304L, 316, or 316L, cobalt chrome, Elgiloy, Hastelloy, c-276 alloy, or nickel 200 alloy. The sintered material may include ceramic. The sintered material may include glass. The plastic may include a wettability coating to suppress bubble formation in the channel, and the plastic may include at least one of polyetheretherketone (PEEK), polyethylene, polypropylene, polyimide, polystyrene, polycarbonate, polyacrylate, polymethacrylate, or polyamide. A continuous porous channel system can be formed, and any material that is biocompatible is also considered for the porous structure herein.

[0105] The channel parameter and the effective length from the first side to the second side can be configured in many ways. The channel parameter can be greater than 1, can be in the range of about 1 to about 10, preferably can be between about 2 and about 5.0, and thus the effective length is in the range of about 2 to 5.0 times the thickness, but the channel parameter can also be greater than 5, for example, can be in the range of about 1.2 to 10. For example, the channel parameter can be about 1.3 to about 2.0 such that the effective length is about 1.3 to 2.0 times the thickness. For example, experimental tests have shown that the channel parameter can be about 1.4 to about 1.8 such that the effective length is about 1.4 to 1.8 times the thickness, for example, about 1.6 times the thickness. The channel parameter may include a value of at least about 10. These values correspond to the path of the channel around the sintered particles of the material and can correspond, for example, to the path of the channel around the packing beads of the material.

[0106] The rigid porous structure 120 can be shaped and formed in many ways, for example, by a tubular shape, a conical shape, a disk, and a hemispherical shape. The rigid porous structure may be a rigid porous structure by molding. The rigid porous structure body 120 by molding may be at least one of a disk, a helix, or a tube configured to be coupled to a reservoir and release a therapeutic agent over a long period of time.

[0107] The porous structure 120 may include a plurality of elongated nanochannels extending from a first side of the porous structure to a second side of the porous structure. The porous structure body 120 may be a rigid material with pores formed therein, and the pores may include a maximum lateral dimension such as a diameter. The diameter of the nanochannel may have, for example, a lateral dimension of about 10 nm to about 1000 nm or even larger. The channels can be formed by etching of the material, for example, lithographic etching of the material. The channels may include substantially linear channels such that the channel parameter F can include about 1, and the parameter area A as well as the thickness or length L correspond to the total cross-sectional area of the channels and the thickness or length of the porous structure.

[0108] Mathematical modeling can be promisingly used to predict how the reservoir container 110 incorporating the RCE120 behaves in a manner specific to the molecules and concentrations. Using Fick's law of diffusion and the mass balance equation, the following equation (Equation 1) can be derived. TIFF2025523550000003.tif14170

[0109] D is the diffusion coefficient of the therapeutic agent, RRI is a property determined by the RCE defined in more detail below, C dev,o is the initial concentration in the device, V dev is the volume of the device, t is the time, and m dev is the mass in the device. The following are assumed: (1) The drug is not lost by means other than diffusion, the release of the substance is driven by the concentration gradient, the catheter concentration is much lower than the device concentration, and the rate-limiting step is diffusion across the RCE.

[0110] The RRI described herein can be determined for an RCE120 having a plurality of elongated nanochannels that extend substantially linearly through the RCE120. The RRI can be determined by the formula (Formula 2) described herein: RRI = (P * A) / (F * L), where P = the porosity of the RCE, A = the surface area of the RCE, F = the tortuosity channel parameter of the RCE, and L = the length (thickness) of the RCE120. The channel parameter F corresponds to 1 for a straight channel, and the porosity P corresponds to the ratio of the surface area of the RCE120 having substantially straight nanochannels. For example, for a flat plate with a surface area of 1 mm 2 of surface area, a thickness of 0.5 mm, and pores exceeding 10% of the surface area, the corresponding RRI is determined to be (0.1 * 1) / (1 * 0.5) = 0.2. Based on the teachings described herein, one of ordinary skill in the art can determine the surface area A and thickness L of the RCE120 and the ratio of the surface area of the nanochannels to provide an appropriate RRI for the therapeutic agents and the reservoir volume of the device 100 described herein.

[0111] Initial mass M o is, and integrating Equation 1 under the initial condition that the mass at infinite time is 0 results in the following equation for the mass in the device over time (Equation 3). TIFF2025523550000004.tif12170

[0112] Experiment

[0113] Example 1

[0114] Tests were conducted to determine the feasibility of various RCEs to affect the release of drugs from the reservoir devices described in this specification to the CNS. The tests were conducted using reservoir devices with volume sizes of 4.5 mL and 1 mL. For each reservoir size, the catheter length was 11 cm, and the reservoir was placed above the target treatment site to achieve a vertical or nearly vertical orientation between the reservoir and the target so that drug delivery could be assisted by gravity, and administration was performed into the cerebral ventricle. Table 2 below shows the configuration of the devices tested. The catheter can have an outer diameter of 1 / 8 inch (3.175 mm) and an inner diameter of 1 / 16 inch (1.5875 mm).

[0115]

Table 2

[0116] The reservoirs of the devices were filled with monoclonal antibody (mAb A) as a model macromolecular therapeutic agent or fluorescein as a model small molecule therapeutic agent. Table 3 below shows the list of molecules tested for sustained delivery. Antisense oligonucleotides generally have a size range of 3000 - 7000 m.w., and sustained release is considered beneficial.

[0117]

Table 3

[0118] The RCEs varied in diameter, thickness, porosity, and micron grade. Some devices contained highly porous RCEs (types 334, 011, 012), while other devices contained less porous RCEs (types 014, 627). Still other devices were without RCEs. Table 4 below shows the various RCEs tested.

[0119]

Table 4

[0120] The device was filled with mAb A at approximately 200 mg / mL, and the fill volume was calculated from the difference in the mass of the device before and after filling using the density of the mAb A solution. The initial internal mass of each device was calculated based on the known volume and concentration. The catheter was filled with phosphate buffered saline (PBS) and attached to the reservoir after filling. The device was oriented such that the therapeutic substance was released into a 50 mL PBS sink. The sink was gently stirred at 100 rpm on an orbital shaker at 37 °C to simulate body movement. The sink was sampled over time, and the mAb concentration was determined by UV-visible spectroscopy (UV-Vis) at 278 nm (a standard curve with mAb A was pre-determined at 278 nm to determine the extinction coefficient) using Little Lunatic (Unchained Labs), and the mass of mAb A released over time was tracked. If the mAb concentration in all sink samples exceeded the detection limit, the sink was replaced with fresh PBS if applicable.

[0121] Figure 3 shows the release of mAb from a device with a 4.5 mL reservoir volume and a highly porous RCE, compared to the case without an RCE. Each point is the average of replicate device samples with or without an RCE. Devices without an RCE are shown as open squares, and the dotted line is the curve fit to the data (n = 5). Devices with a highly porous RCE are shown as white circles, and the solid line is the curve fit to the data (n = 4, RCE334). An exponential function model of mAb release from the device was fit to the data. The presence of a highly porous RCE with a diameter of 0.188 inches affected the mAb release profile compared to the case where no RCE was present in the device and sustained the mAb release over time.

[0122] Figure 4 shows the mAb release from an apparatus having a 1 mL reservoir with different types of RCEs attached to illustrate how the properties of the RCE affect the release of mAb A. The apparatus had no RCE attached (open square), a high porosity RCE attached (open upside-down triangle), or a low porosity RCE attached (open triangle). Each RCE had the same diameter and thickness but different micron grades (i.e., porosities). The small pore size of the low porosity RCE slows down the release rate of mAb A. The pore size of the RCE is proportional to the release rate of mAb A.

[0123] Figure 5 shows the release of mAb A from an apparatus having a 1 mL reservoir with no RCE attached (open square) or with RCEs of the same high porosity but different diameters attached. The larger diameter RCE (open upside-down triangle) had a diameter of 0.188 inches and the smaller diameter RCE (open diamond) had a diameter of 0.125 inches. This decrease in the diameter of the RCE slowed down the release rate of mAb A. There is a proportional relationship between the surface area of the RCE and the release rate of mAb A. Since the selection of the RCE was limited, the thickness was not experimentally tested, but from the laws of diffusion, an inverse proportional relationship between the thickness and the release rate can be assumed.

[0124] The tests were repeated with a small molecule model of fluorescein (332 Da). The same trends that were present in the large molecule model with mAb A (≈150 kDa) are also present in the small molecule model. The fluorescein solution was a solution at a concentration of 100 mg / mL diluted with PBS + 0.02% sodium azide (NaN3) to achieve an initial concentration of 25 mg / mL. Since fluorescein has a lower detection ability, the PBS sink volume was adjusted to 200 mL. A standard curve of absorption at 492 nm was determined in advance and this experimental extinction coefficient was used. Figure 6 shows the fluorescein release profiles of devices with a 1 mL reservoir, no RCE attached (open square), or a high porosity RCE (open square) or a low porosity RCE (open hexagon) attached. Further, one of the high porosity RCEs had a small diameter of 0.125 inches compared to a larger diameter of 0.188 inches (open diamond). Similar to the larger molecule model, the small molecule model shows that a decrease in porosity slows the release of fluorescein and a decrease in surface area slows the rate of fluorescein release.

[0125] Figure 7 shows the experimental data points corresponding to various RCEs of a small reservoir device (1 mL) filled with high molecular weight mAb A, along with each fitting curve (according to Equation 3). The fit appears to match the data well, but as time progresses, the assumption that the concentration inside the device is much higher than the concentration inside the catheter breaks down slightly. Further, in ICV delivery, the sink (e.g., CSF) is replenished by CSF production in the ventricle more rapidly than the sink changes experimentally performed. This can cause a larger concentration gradient and result in a faster molecular release rate. Rate constant Using TIFF2025523550000008.tif6170, this fitting parameter can be used to show significance in the molecular release rate. The results show that RCE014 (white upside-down triangle) with low porosity and a larger diameter of 0.188 inches and RCE012 (white diamond) with high porosity and a smaller diameter of 0.125 inches have significantly different mAb A release rates compared to RCE011 (white circle) with high porosity and a larger diameter of 0.188 inches. In this fitting data, to avoid air bubbles, the therapeutic agent was filled in the diffusion region below the RCE, and time = 0 was started 3 hours after the release. After 3 hours, it is assumed that most of the molecules starting below the RCE diffused from the catheter into the sink. This assumption can be confirmed by the rapid release of the therapeutic agent in a device without an RCE.

[0126] Figure 8 shows the experimental data points corresponding to various RCEs of a small reservoir device (1 mL) filled with low molecular weight fluorescein, along with each fitting curve (according to Equation 3). This fit shows a good agreement with the experimental data. All three RCEs showed significantly different release rate constants from each other. The results show that RCE011 (white upside-down triangle) with high porosity and a larger diameter of 0.188 inches and RCE012 (white diamond) with high porosity and a smaller diameter of 0.125 inches have significantly different fluorescein release rates compared to RCE627 (white circle) with low porosity and a larger diameter of 0.188 inches. Since fluorescein can be detected at lower concentrations, the sink size can be larger, and the assumption that diffusion through the RCE is the rate-limiting step and the concentration in the device remains much higher than in the catheter and sink probably fits better.

[0127] Data shows the release of small molecule model therapeutics, namely fluorescein, and macromolecule model therapeutics, namely mAb A, in a controlled manner to achieve sustained delivery over time by incorporation into an implantable and refillable ICV reservoir device with a porous metal frit (RCE). The RCE parameters (surface area, length, and porosity) can be modified to achieve the desired release rate of therapeutics for various clinical applications. The two molecules tested, namely fluorescein and mAb A, are representative of other potential classes of therapeutics such as peptides, proteins, ASOs (antisense oligonucleotides), and Fab fragments (antigen-binding fragments) with respect to molecular size.

[0128] Method of Use

[0129] It should be understood that the treatment devices described herein can be used at various locations and implanted in various ways. The method of implantation and use of the treatment devices described herein can vary depending on the type of treatment device to be implanted and the location and drug intended for treatment. As described in more detail below, the treatment devices described herein can be primed, implanted, filled, refilled, and / or removed using one or more devices.

[0130] In one embodiment of the implantation of the treatment device, a skin flap can be formed in the scalp to expose the area of the skull located directly above the target delivery position. A burr hole can be formed in the skull to expose the area of the dura mater. The burr hole is typically drilled to a depth and diameter that reflects the shape of the lower end of the container. The diameter of the base of the burr hole is sized to accommodate the lower surface 115 of the base 114 so that the device can be retracted and placed. The ideal trajectory for catheter implantation can be executed using neuronavigation software, and the imaging convention is the implantation of devices such as the Ommaya reservoir (see www.cureus.com / articles / 29046-ommaya-reservoir-insertion-a-technical-note).

[0131] The catheter 110, which may be cut to an appropriate size during implantation, can be fixed to the ferrule 128 at the lower end of the device 100. The catheter can be cut slightly shorter than the distance of the planned trajectory, taking into account the depth of the ferrule connector inserted into the burr hole. The container 105 may be filled with the drug to be delivered during implantation or may be provided in a pre-filled state with the drug. The catheter 110 can be primed before attachment to the ferrule 128 so that it is filled with BSA and air bubbles are released. The distal tip 112 of the catheter 110 can be inserted through the burr hole and advanced to a target position such as within the ventricle below the burr hole. The upper region 123 of the ferrule connector 127 can be placed within the burr hole, and the lower surface 115 of the base 114 can be placed against the surface of the skull. The skin flap can be returned to cover the upper surface 117 of the cap 116 and sutured. In this way, the container 105 remains under the scalp and outside the skull so that it can be easily refilled by needle penetration. The implantation procedure of the device may be similar to the procedure for implanting the Ommaya reservoir (see www.cureus.com / articles / 29046-ommaya-reservoir-insertion-a-technical-note).

[0132] Generally, embodiments of the therapeutic devices described herein include a drug solution, a drug suspension, and / or a drug matrix. Additionally, the therapeutic devices described herein can include one or more solid drug cores or pellets formulated to deliver one or more therapeutic agents in a therapeutically effective amount over a long period of time. The period during which the therapeutic device administers a therapeutically effective amount can vary. In some embodiments, the therapeutic device is implanted to provide therapy over the useful life of the device such that refilling of the device is not required.

[0133] The therapeutic devices described herein need not be removed and can remain in place indefinitely, as long as and beyond being therapeutically effective. However, it is also possible to remove the therapeutic device 100 (i.e., remove it from the target location).

[0134] Indications

[0135] The therapeutic devices described herein can be used for the treatment and / or prevention of various neurodegenerative diseases of the brain, including Alzheimer's disease, stroke, Huntington's disease, amyotrophic lateral sclerosis (ALS), Angelman syndrome, Parkinson's disease, motor neuron diseases, and brain cancer, Batten disease such as late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) also known as tripeptidyl peptidase 1 (TPP1) deficiency, CNS trauma, and other diseases.

[0136] Therapeutic Substances

[0137] Examples of therapeutic agents that may be delivered by the treatment device described herein include, but are not limited to, antisense oligonucleotides, CKP, various immunotherapies such as monoclonal antibodies, and thrombolytic agents and protease inhibitors useful for the treatment of various neurodegenerative disorders. Therapeutic agents listed in Bhavna Kumar, et al., ‘‘Recent Patent Advances for Neurodegenerative Disorders and its Treatment’’, Recent Patents on Drug Delivery&Formulation(2017)11(3):158-172 are also contemplated. Other therapeutic agents known to those skilled in the art that enable controlled and sustained release to a patient in the manner described herein are also suitable for use with the embodiments of the device described herein.

[0138] Material

[0139] Generally, the components of the device described herein are made of materials that are biocompatible and preferably insoluble in the body fluids and tissues with which the device comes into contact. The materials generally do not cause irritation to the portions of the tissue with which they come into contact. Examples of materials include various polymers such as silicone elastomers and rubbers, polyolefins, polyurethanes, acrylates, polycarbonates, polyamides, polyimides, polyesters, and polysulfones.

[0140] In various embodiments, the description is made with reference to the drawings. However, a particular embodiment may be practiced without one or more of these specific details, or in combination with other known methods and configurations. The description includes numerous specific details such as specific configurations, dimensions, and processes to provide a complete understanding of the embodiments. In other cases, well-known processes and manufacturing techniques are not described in detail so as not to unnecessarily obscure the description. Throughout this specification, references to "one embodiment", "an embodiment", "one implementation", "an implementation", etc. mean that the particular feature, structure, configuration, or characteristic described is included in at least one embodiment or implementation. Thus, the appearances of the expressions "one embodiment", "an embodiment", "one implementation", or "an implementation" etc. in various places throughout this specification are not necessarily referring to the same embodiment or implementation. Furthermore, the particular features, structures, configurations, or characteristics may be combined in any suitable manner in one or more embodiments.

[0141] The devices and systems described herein can incorporate any of a variety of features. Elements or features of one embodiment of the devices and systems described herein can be incorporated as alternatives to, or in combination with, elements or features of another embodiment of the devices and systems described herein. Although various combinations are contemplated herein, for the sake of brevity, explicit descriptions of each of these combinations may sometimes be omitted. Further, the devices and systems described herein can be placed on a patient and need not be implanted as specifically shown in the figures or described herein. The various devices can be used in a variety of different ways, using a variety of different devices and systems, for example, implanted, placed, and adjusted. The various devices can be adjusted at any time before, during, and after implantation. Although some representative descriptions are provided of how the various devices can be implanted and placed, for the sake of brevity, explicit descriptions of each method for each implant or system may be omitted.

[0142] The use of relative terms throughout the specification may indicate a relative position or direction or orientation and is not intended to be limiting. For example, "distal" may indicate a first direction away from a reference point. Similarly, "proximal" may indicate a position in a second direction opposite the first direction. The use of terms such as "upper", "lower", "top", "bottom", "front", "side", and "back", as well as "anterior", "posterior", "caudal", "cephalad", etc., is used to establish a relative frame of reference and is not intended to limit any use or orientation of the devices described herein in various embodiments.

[0143] The term "about" means a range of values that includes the value specified therein and that would reasonably be considered by one of ordinary skill in the art to be similar to the specified value. In some embodiments, "about" means within the range of standard deviation using measurements generally accepted in the art. In some embodiments, "about" means a range extending from ±10% of the value specified therein. In some embodiments, "about" includes the value specified therein.

[0144] Although this specification contains many details, these should not be construed as limitations on the scope of what is claimed or of what could be claimed, but rather as descriptions of features specific to particular embodiments. The particular features described herein in the context of separate embodiments may be implemented in combination in a single embodiment. Conversely, the various features described in the context of a single embodiment may be implemented separately in multiple embodiments or in any suitable subcombination. Moreover, although features may be described above as acting in certain combinations and initially claimed as such, one or more features from a claimed combination may in some cases be excised from the combination, and the claimed combination may be directed to a subcombination or variation of a subcombination. Similarly, although operations are shown in the drawings in a particular order, this should not be understood as requiring that such operations be performed in the particular order shown or in sequential order, nor that all of the operations shown be performed. Only some examples and embodiments are disclosed. Variations, modifications, and enhancements to the disclosed examples and embodiments, as well as other embodiments, may be made based on the disclosed content.

[0145] In the foregoing description and claims, phrases such as "at least one of" or "one or more of" may appear in connection with a listing of elements or features. Further, the term "and / or" may be used in a listing of two or more elements or features. Such phrases are intended to mean either any of the recited elements or features individually, or any combination of any of the recited elements or features with any of the other recited elements or features, so long as they are not implicitly or explicitly inconsistent in their context of use. For example, the phrases "at least one of A and B", "one or more of A and B", and "A and / or B" are each intended to mean "only A, only B, or A and B together". A similar interpretation is intended for listings that include three or more items. For example, the phrases "at least one of A, B, and C", "one or more of A, B, and C", and "A, B, and / or C" are each intended to mean "only A, only B, only C, A and B together, A and C together, B and C together, or A, B, and C together".

[0146] The use of the term "based on" in the foregoing and the claims means "based at least in part on", and means that features or elements not recited are also admissible.

Claims

1. A device for delivering drugs to the cerebrospinal fluid of the brain, A hollow container having a reservoir volume and an outlet, and having an upper and lower surface, A porous structure comprising a sintered rigid material that passively adjusts the diffusion of the drug from the container to a controlled release rate, A catheter connected to the lower end of the container, having a lumen, a proximal end region, and a distal end region, wherein the lumen is configured to communicate with the reservoir volume of the container via the porous structure. A device equipped with.

2. The apparatus according to claim 1, wherein the container is sized to be embedded between the area of ​​the skull and the skin above it.

3. The apparatus according to claim 1, wherein the container comprises a lower base having the lower surface and an upper cap having the upper surface, and the base and the cap together define the reservoir volume.

4. The apparatus according to claim 3, wherein the base defines the outlet from the container.

5. The apparatus according to claim 3, wherein the base has an inner surface including a seat portion configured to be sealed by the porous structure.

6. The apparatus according to claim 5, further comprising a diffusion chamber located distal to the porous structure within the seat portion, wherein the diffusion chamber comprises an upper region and a lower region.

7. The apparatus according to claim 6, wherein the diffusion chamber is located within a protrusion that protrudes from the lower surface of the base.

8. The apparatus according to claim 6, wherein the porous structure has an upper surface facing the reservoir volume of the container and a lower surface facing the diffusion chamber.

9. The apparatus according to claim 1, wherein the catheter is linear between its proximal and distal ends when implanted, and the container is positioned above the distal end of the catheter when the distal end is located within the target site.

10. The apparatus according to claim 1, wherein the catheter has sufficient length to extend to a target location in the brain.

11. The apparatus according to claim 10, wherein the target location is a dural venous sinus or a ventricle.

12. The apparatus according to claim 1, wherein the distal end region of the catheter has at least one opening from the lumen.

13. The apparatus according to claim 12, wherein the at least one opening in the distal end region of the catheter includes a plurality of outlets located through the wall of the catheter.

14. The apparatus according to claim 1, wherein the porous structure is made of titanium or stainless steel.

15. The apparatus according to claim 1, wherein the porous structure has a porosity of about 1% to about 70%.

16. A method for controlling the delivery of a drug into the body, comprising administering the drug into the body through the apparatus described in claim 1.

17. A method for treating brain diseases in subjects requiring treatment for brain diseases, The aforementioned subject includes administering an effective amount of drug into the cerebrospinal fluid (CSF) using an implantable device. The embeddable device comprises a hollow container having a reservoir volume and an outlet, A porous structure comprising a sintered rigid material that passively adjusts the diffusion of the drug from the container to a controlled release rate, It has a lumen configured to communicate with the reservoir volume of the container via the porous structure, and a catheter connected to the lower end of the container. A method that includes [a certain feature].

18. The method according to claim 17, wherein the brain disease is a neurodegenerative disease.

19. The distal end region of the catheter is positioned in the ventricle or dural venous sinus. The method according to claim 17, further comprising:

20. The method according to claim 17, wherein the porous structure and the container are configured to release the drug from the reservoir volume into the CSF at a predetermined rate profile for the treatment of the brain over a long period of time.

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