Implantable and refillable drug delivery reservoir systems with porous metal frits for sustained intracerebral delivery and methods of use

Abstract

The present disclosure provides a device for delivering a drug into cerebrospinal fluid of a brain, the device comprising: a hollow container having a reservoir volume and an outlet, the container having an upper surface and a lower surface; a porous structure having a sintered rigid material, the porous structure passively modulating diffusion of the medicament from the container at a controlled release rate; and a catheter coupled to a lower end of the container, the catheter having a lumen configured to communicate with the reservoir volume of the container through the porous structure, a proximal end region, and a distal end region. The present disclosure provides related systems and methods.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] 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. Technical Field

[0003] The present technology relates generally to implantable and refillable drug delivery reservoir systems, and more particularly, to a refillable implantable drug delivery system having a porous metal frit for sustained delivery to the central nervous system. Background Art

[0004] Delivery of therapeutic agents to the central nervous system (CNS) via conventional systemic administration (such as oral, intravenous, subcutaneous) is challenging due to the blood-brain barrier and the blood-cerebrospinal fluid barrier. CNS-directed delivery of therapeutic agents via the cerebrospinal fluid (CSF) using intracerebroventricular (ICV), intrathecal cisternal (IT-CM), and intrathecal lumbar (IT-L) administration is considered a more effective alternative approach.

[0005] Current methods of intracerebral delivery of therapeutic agents include direct needle push injection, implantable port catheter systems or implantable reservoirs, such as Ommaya reservoirs. Administration can be performed by using an indwelling catheter and a continuous administration method such as a pump, or can be administered by implanting, for example, an intracerebral implant of a slow-release vehicle. More specifically, the therapeutic agent can be injected through a long-term implanted cannula or infused for a long time with the help of an osmotic mini-pump. A subcutaneous pump can be used to deliver the therapeutic agent to the ventricle through a small tube. A highly complex pump can be refilled through the skin, and its delivery rate can be set without surgical intervention. Examples of administration regimens and delivery systems involving subcutaneous pump devices or continuous intraventricular infusions by fully implanted drug delivery systems are those used to administer dopamine, dopamine agonists, and cholinergic agonists to Alzheimer's patients and Parkinson's disease animal models, such as Harbaugh, J. Neural Transm. Supplement 24:271, 1987; and DeYebenes et al., Mov. Disord. 2:143, 1987.

[0006] A limitation of these systems is that they only allow for bolus administration of the therapeutic agent, and this bolus injection method may be less than ideal. For example, the Ommaya reservoir includes an injectable reservoir and a catheter that enters the ventricle. It has been used to sample CSF and administer the therapeutic agent directly into the ventricle. With a bolus injection of the therapeutic agent, the concentration of the agent within the patient's ventricle may peak (greater than the desired therapeutic dose) and drop below the therapeutic dose before the next administration. BRIEF DESCRIPTION OF THE DRAWINGS

[0007] These and other aspects will now be described in detail with reference to the following drawings. In general, the illustrations are not drawn to absolute or relative scale, but are intended for illustration. In addition, the relative arrangement of features and elements may be modified for the purpose of clarity of illustration.

[0008] FIG1A is a cross-sectional exploded view of a particular implementation of a drug delivery device;

[0009] FIG1B shows the drug delivery device of FIG1A implanted in the brain;

[0010] FIG1C shows the drug delivery device of FIG1A implanted in the brain and the reservoir positioned between the skin and the skull;

[0011] FIG1D is a detailed view of the barbed connector of the device described in FIG1A ;

[0012] FIG2 shows a related implementation of the drug delivery device of FIG1A with a smaller reservoir volume;

[0013] Figure 3 shows the time-dependent release of high molecular weight monoclonal antibody (mAb) (%) using a device with a reservoir volume of 4.5 mL without a release controlling element (RCE) or with a high-porosity RCE;

[0014] Figure 4 shows the mAb (%) released over time using a device with a reservoir volume of 1 mL without RCE, with a high-porosity RCE, or with a low-porosity RCE;

[0015] Figure 5 shows the mAb (%) released over time using a device with a reservoir volume of 1 mL without RCE, with a high-porosity RCE, or with a high-porosity RCE with reduced diameter;

[0016] Figure 6 shows the release of low molecular weight fluorescein (%) over time using a device with a reservoir volume of 1 mL without RCE, with a high porosity RCE, with a high porosity RCE with a reduced diameter, or with a low porosity RCE;

[0017] Figure 7 shows the exponential fit of the mass of mAb A in the device over time using a device with a reservoir volume of 1 mL in the case of a high porosity RCE, a high porosity RCE with a reduced diameter, or a low porosity RCE;

[0018] Figure 8 shows the exponential fit of the mass of fluorescein in the device as a function of time using a device with a reservoir volume of 1 mL with a high porosity RCE, a high porosity RCE with a reduced diameter, or a low porosity RCE. DETAILED DESCRIPTION

[0019] Described is a therapeutic agent delivery device that provides controlled and sustained delivery of a therapeutic agent at an ideal therapeutic dose over an extended period of time. Specifically, an intraventricular implantable and refillable reservoir device with a porous metal frit is provided that is capable of controlled and sustained release of a therapeutic agent over time based on the principle of passive diffusion. The device described herein separates the reservoir from a drug delivery catheter having a porous metal frit known as a release control element (RCE). The RCE acts as a barrier to diffusion from the reservoir into the catheter. The RCE can be customized to achieve the desired release profile and can be controlled by changing the porosity of the frit, the size and molecular weight of the drug, and / or the drug concentration in the reservoir. The device and system described herein provide new therapeutic strategies for various clinical problems such as delivering chemotherapeutic agents to brain cancer or providing monoclonal antibodies, antisense oligonucleotides, gene therapy or cell therapy for neurodegenerative diseases by reducing the frequency of administration and the negative side effects of current bolus administration methods. The controlled and sustained delivery of therapeutic agents provides appropriate doses to avoid underdosing or overdosing. Since the frequency of injections is minimized, the burden on patients and healthcare systems can be minimized.

[0020] In some variations, one or more of the following may be optionally included in any feasible combination of the above methods, devices, apparatuses, and systems. Further details of the apparatuses, systems, and methods are set forth in the accompanying drawings and the following description. Other features and advantages will be apparent from the description and drawings.

[0021] It should also be understood that the device and system described herein can be positioned in many positions of the body and do not need to be implanted specifically as shown in the figure or as described herein.The device and system described herein can be used for the intracranial delivery of therapeutic agents for a period of time that continues to extend.The device and system can be used for treating the neurodegenerative diseases of any multiple brains, including Alzheimer's disease, stroke, Huntington's disease, ALS, Angelman syndrome, Parkinson's disease, motor neuron disease and other brain diseases, including brain cancer, such as late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) (also referred to as tripeptidyl peptidase 1 (TPP1) deficiency) Batten disease, CNS trauma and other diseases that will be beneficial by direct delivery of drugs to the cerebrospinal fluid.Other medical conditions except these diseases can be treated with the device and system described herein.For example, the device and system can provide treatment for inflammation, infection and cancer growth.Any device and system described herein can be used to deliver any number of drug combinations.

[0022] The materials, compounds, compositions, articles and methods described herein can be more easily understood by reference to the following detailed description of specific aspects of the disclosed subject matter and the examples included therein. Before disclosing and describing the materials, compounds, compositions, articles, devices and methods of the present invention, it should be understood that the aspects described below are not limited to specific methods or specific reagents, and therefore they can vary. It should also be understood that the terms used herein are only for the purpose of describing specific aspects and are not intended to be limiting.

[0023] definition

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as generally understood by a technician in the technical field to which the present invention belongs. Unless otherwise stated, all patents, patent applications, disclosed applications and publications, websites and other disclosed materials cited in the entire disclosure of this article are incorporated by reference in their entirety. If there are multiple definitions of terms in this article, the definitions in this section shall prevail. In the case of citing URLs or other such identifiers or addresses, it should be understood that such identifiers can be changed, and specific information on the Internet can change, but equivalent information is known and can be easily accessed, such as by searching the Internet and / or appropriate databases. Reference to this proves the availability and public dissemination of such information.

[0025] As used herein, relative directional terms such as anterior, posterior, proximal, distal, lateral, medial, sagittal, coronal, transverse, etc. are used throughout this disclosure. Such terms are for the purpose of describing the device and the features of the device, and are not intended to be limiting. For example, as used herein, "proximal" generally means closest to the user of the implanted device and farthest from the target location of implantation, while "distal" means farthest from the user of the implanted device in the patient's body and closest to the target location of implantation.

[0026] As used herein, a disease or disorder refers to a pathological condition in an organism caused by, for example, an infection or a genetic defect, and is characterized by recognizable symptoms.

[0027] As used herein, treatment means any manner in which the symptoms of a condition, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the devices described and provided herein.

[0028] As used herein, amelioration or alleviation of the symptoms of a particular condition, such as by administration of a particular pharmaceutical composition, refers to any permanent or temporary, lasting or transient relief attributable to or associated with administration of the composition.

[0029] As used herein, the effective amount of a compound for treating a specific disease is an amount sufficient to improve or in some way reduce the symptoms associated with the disease. Such an amount can be administered as a single dose or can be administered according to a protocol, whereby it is effective. The amount can cure the disease, but is usually administered to improve the symptoms of the disease. Repeated administration may be required to achieve the desired symptom improvement. Pharmaceutically effective amount, therapeutically effective amount, biologically effective amount, and therapeutic amount are used interchangeably herein to refer to the amount of therapeutic agent sufficient to achieve the desired result, i.e., whether it is a quantitative or qualitative therapeutic effect. Specifically, the pharmaceutically effective amount in vivo is an amount that causes adverse effects (such as pathological, clinical, biochemical, etc.) in the subject to be reduced, delayed, or eliminated.

[0030] As used herein, the release rate index encompasses (PA / FL), where P includes porosity, A includes effective area, F includes curve fitting parameters corresponding to effective length, and L includes the length or thickness of the porous structure. Unless otherwise specified, the units of the release rate index (RRI) include mm units and can be determined by one of ordinary skill in the art according to the teachings described herein.

[0031] As used herein, sustained release encompasses the release of an effective amount of an active ingredient of a therapeutic agent for an extended period of time. Sustained release can encompass the first order release of an active ingredient, the zero order release of an active ingredient, or other release kinetics, such as intermediate to zero order and first order or a combination thereof. Sustained release can encompass the controlled release of a therapeutic agent via passive molecular diffusion driven by a concentration gradient across a porous structure.

[0032] 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, such as a mammal, primate, human or domestic animal subject, who suffers from a disease condition or for whom a disease condition or risk of a disease condition is to be determined.

[0033] As used herein, a therapeutic agent referred to by a trade name encompasses one or more of the following: a preparation of a therapeutic agent commercially available under that trade name, an active ingredient of a commercially available preparation, a common name of an active ingredient, or a molecule comprising an active ingredient. As used herein, a therapeutic agent or therapeutic agent is an agent that improves the symptoms of a disease or condition or improves a disease or condition. Therapeutic agents, therapeutic compounds, treatment regimens, or chemotherapeutic agents include conventional drugs and drug therapies, including vaccines, which are known to those skilled in the art and described elsewhere herein. Therapeutic agents include, but are not limited to, portions capable of controlled, sustained release into the body.

[0034] As used herein, a composition refers to any mixture. It can be a solution, a suspension, an emulsion, a liquid, a powder, a paste, aqueous, non-aqueous, or any combination of such ingredients.

[0035] As used herein, fluid refers to any composition that can flow. Thus, fluid encompasses compositions in the form of semisolids, pastes, solutions, aqueous mixtures, gels, lotions, creams, and other such compositions.

[0036] As used herein, a kit is a packaged combination, optionally including instructions for use of the combination and / or other reactions and components for such use.

[0037] The definition of the term "oligonucleotide" or "therapeutic oligonucleotide" as used herein is generally understood by the skilled artisan to refer to a molecule comprising two or more covalently linked nucleosides. Such covalently linked nucleosides may also be referred to as nucleic acid molecules, oligonucleotides or oligomers. Oligonucleotides are typically prepared in a laboratory by solid phase chemical synthesis followed by purification. When referring to the sequence of an oligonucleotide, reference is made to the covalently linked nucleotide or nucleoside core base portion or its modified sequence or order. The oligonucleotides of the present invention are artificial, and are chemically synthesized, and are typically purified or isolated. The oligonucleotides of the present invention may comprise one or more modified nucleosides or nucleotides, such as 2' sugar-modified nucleosides.

[0038] As used herein, the term "antisense oligonucleotide" is defined as an oligonucleotide that can regulate the expression of a target gene by hybridizing with a target nucleic acid, particularly with a contiguous sequence on the target nucleic acid.Antisense oligonucleotide is not double-stranded substantially, and is therefore not siRNA or shRNA.Preferably, antisense oligonucleotide is single-stranded.It should be understood that single-stranded oligonucleotide can form a hairpin or intermolecular duplex structure (duplex between two molecules of the same oligonucleotide), as long as its internal or mutual self-complementarity is less than 50% of the total length of the oligonucleotide.

[0039] Treatment Devices

[0040] 1A and 2 are cross-sectional exploded views of implementations of the drug delivery device 100. Briefly, the device 100 in each implementation includes a container 105 defining a reservoir volume, a conduit 110 configured to be in fluid communication with the reservoir volume of the container 105, and a frit or drug release controlling element (RCE) 120 that controls the release of a therapeutic agent contained within the reservoir volume of the container 105. The RCE 120 may be a porous metal material that is tailored 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, which will be described in detail below.

[0041] Figures 1B to 1C are cross-sectional schematic diagrams of a drug delivery device 100 implanted in the brain. The device described herein can be positioned so that the container 105 remains substantially outside the patient's body or is covered by the skin layer (i.e., subcutaneous), and the catheter 110 of the device 100 connected to the container 105 pierces the skull until the tip 112 of the catheter 110 is positioned within, adjacent to, or in communication with the target site. The target site for treatment is preferably intracranial, intracerebral, or intraventricular. The device can be used with a variety of therapeutic agents, including one or more chemotherapeutic agents for cancer treatment, which are usually delivered in the form of a bolus injection. 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 neurological diseases. Drug stability and molecular weight are important therapeutic agents for the delivery of antisense oligonucleotides (ASOs) and cystine knot peptides (CKPs), disulfide bond restricted peptides (DCPs), and 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 agents that can be delivered from reservoir volumes ranging from 0.5 mL to 5 mL.

[0042] Devices described herein are referred to as drug delivery devices, therapeutic devices, therapeutic agent devices, port delivery systems, etc. It should be understood that these terms are used interchangeably herein and are not intended to limit specific implementations beyond other specific implementation devices. For the sake of brevity, although various combinations will be considered herein, the explicit description of each of these combinations can be omitted. In addition, different methods for implanting and accessing devices are described herein. Various implants can be implanted, filled, and refilled, etc. according to various different methods and using various different devices and systems. Some representative descriptions of how various devices can be implanted and accessed are provided, however, for the sake of brevity, the explicit description of each method for each implant or system can be omitted.

[0043] Referring again to FIG. 1A , which shows a cross-sectional view of device 100 , when device 100 is implanted, a therapeutic agent as described herein may be injected.

[0044] The reservoir volume of the container 105 (which may also be referred to herein as a reservoir) can accommodate a certain amount of therapeutic agent delivered over a period of time. FIG. 1A shows a container 105 having a larger reservoir volume than the reservoir volume of the container 105 of 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 a relatively low profile so that the container 105 can be implanted between the skull and the skin. The lower surface 115 of the container 105 can be placed against the skull 5, and the upper surface 117 of the container 105 can be covered by the overlying skin 7 (see FIG. 1C ). Therefore, the majority of the container 105 is substantially implanted in 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 rest against the skull 5 can be between about 3 mm and about 15 mm.

[0045] The peripheral shape of the container 105 can be oval, elliptical or circular. The lower surface 115 can be flat or have a curved profile that substantially conforms to the shape of the skull 5 at a specific location. The upper surface 117 can be substantially convex spherical or complex. In some specific implementations, the container 105 has a circular profile to avoid sharp or square edges that may cause discomfort to the patient during implantation. The material of the container 105 can be relatively rigid silicone or other polymeric materials so that the reservoir volume of the container 105 remains substantially constant regardless of the filling state. Alternatively or in combination, the material of the container 105 can be relatively soft or elastic, for example, so that when the therapeutic agent 10 is removed from the container 105 or introduced into the container, the profile of the container 105 changes. The soft material of the container 105 can be combined with, for example, a rigid material to provide support.

[0046] The container 105 can be formed by a lower base 114 including a lower surface 115 and an upper cover 116 including an upper surface 117. The base 114 and the cover 116 together define a reservoir volume of the container 105. At least a portion of the cover 116, including the entire cover 116, can be formed of a material configured to be pierced by a sharp object such as a needle to inject a therapeutic agent into the reservoir volume. The cover 116 can be coupled to the base 114 (such as by epoxy) and sealed to form a liquid-tight reservoir volume of the container 105. The base 114 can define an outlet of the container 105.

[0047] The inner surface of the base 114 may include a seat 118 for sealing with the RCE 120. The seat 118 in Figures 1A and 2 is located in the bottom of the reservoir 105 away from the penetrable cover 116. The RCE is generally porous titanium or stainless steel, and fits tightly into the impermeable structure of the container, such as by pressure fitting, hot swaging, epoxy, within the seat 118 of the base 114. The tight fit ensures that diffusion occurs in the RCE, rather than around the RCE.

[0048] Below the seat 118 is a diffusion chamber 122 located within a protrusion 124 of 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 and larger than the inner diameter of the outlet channel 125 located below the diffusion chamber and extending through the barb connector 127. The diffusion chamber 122 tapers along its length to the smaller inner diameter of the outlet channel 125. The inner diameter of the outlet channel 125 can have a smaller inner diameter than the diffusion chamber 122 and can also have a smaller inner diameter than the lumen 111 of the catheter 110. The size of the diffusion chamber 122 located below the location of the RCE 120 and above the outlet channel 125 allows the entire surface area of ​​the RCE 120 located above it to be used before narrowing to the outlet channel 125 to connect with the lumen 111 of the catheter 110.

[0049] As best shown in FIG. 1D , the barb connector 127 protrudes from the lower surface 115 of the base 114 and the outer diameter may similarly change from the upper end to the lower end. The upper region 123 of the barb connector 127 defining the diffusion chamber 122 may have a first outer diameter. The first outer diameter may be smaller than the outer diameter of the container 105 and larger than the outer diameter of the catheter 110. The upper region 123 of the barb connector 127 may taper along the length to the lower region 124. The lower region 124 of the barb connector 127 may have a smaller outer diameter than the upper region 123 and also have an outer diameter smaller than the outer diameter of the catheter 110. The lower region 124 of the barb connector 127 may incorporate a barb 128 or other surface feature near its distal end that ensures that the connection between the container 105 and the catheter 110 is snug and will not be unintentionally displaced. The barb 128 may have an outer diameter slightly larger than the inner diameter of the catheter 110, so that when the barb connector 127 is inserted through the proximal opening 108 of the catheter 110, the material of the catheter 110 deforms slightly to accommodate the larger outer diameter through an interference fit. The flat upper surface 129 and square edge of the barb 128 are more difficult to withdraw from the cavity 111 than the tapered front surface 130 of the barb 128 when inserted into the cavity 111. When the base 114 is connected to the catheter 110, the outlet channel 125 is placed in fluid communication with the cavity 111 of the catheter 110, wherein the RCE 120 controls the release of the therapeutic agent from the reservoir volume into the cavity 111.

[0050] In the embodiment shown in FIG2 , the base 114 can be epoxied to the cap 116, forming a pierceable reservoir to contain the therapeutic agent. The barb connector 127 can be epoxied to the bottom member 113 and then epoxied to the base 114 along with the subassembly. This embodiment can create a secondary fluid space to allow diffusion through the entire surface of the RCE 120. The barb connector 127 has greater freedom and flexibility because it is not directly attached to the base 114 as in the embodiment shown in FIG1A . The implant can also have a smaller overall size to make it less invasive.

[0051] An elongated catheter 110 is coupled to the lower end of the container 105, as shown in FIGS. 1A and 2 . The catheter 110 may be centered relative to the lower end of the container 105 or may be eccentric. A 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 length of the catheter 110 is set to extend from the outside of the skull 5 to a target location to release the therapeutic agent into an area of ​​the brain, preferably within a dural sinus or ventricle of the brain. The length may be, for example, in the range of about 10 cm up to about 20 cm. The length may be less than about 15 cm to as short as about 10 cm, about 5 cm, about 3 cm, or a length sufficient to extend through a craniotomy hole into one or more dural sinuses, such as within a ventricle or dural sinus of the brain. In a specific implementation, the catheter length may be between 3 cm and 5 cm, up to about 15 cm. The catheter 110 may also be provided with a length greater than these ranges (e.g., between about 30 cm and 50 cm) and then cut to size by the user at the time of implantation to obtain the final preferred length. The catheter 110 may be manufactured to a single size greater than the length required to reach the target site at the time of implantation, so that any of a plurality of target locations may be treated with the same modular system. The device may be provided with a catheter separated from the barb so that the proximal end of the catheter may be cut to size and then pressed onto the barb before implantation. Cutting the proximal end to adjust the size of the catheter 110 avoids impacting the distal tip 112, which may have a dedicated distal opening 109 to deliver the therapeutic agent. The catheter 110 may have one or more markings on its outer surface near the proximal end to guide trimming to size and indicate the length to the distal tip 112 depending on the location where the proximal end is cut.

[0052] The cross-sectional outer diameter of catheter 110 can be sized to reduce the invasiveness of device 100 and can include an outer diameter of no more than about 5 mm, preferably about 1 mm to about 4 mm. The inner diameter of catheter 110 can be at least about 0.5 mm, preferably about 0.5 mm to about 3 mm.

[0053] The catheter distal tip 112 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 extending through the wall of the catheter 110. Multiple outlets can be positioned through the wall, and their size can vary between about 0.0008 inches (0.02 mm) and about 0.08 inches (2.03 mm), preferably between about 0.008" (0.2 mm) and about 0.05" (1.2 mm). The shape and number of outlets can also vary, including one or more rows of about 2 to about 20 holes having circular, oval or other shapes. The outlets can be spaced apart at an angle of about 90 degrees from each other so as to appear circumferentially around the distal tip 112. The outlets can be spaced apart circumferentially by about 45 degrees, 90 degrees, 120 degrees, or 180 degrees.

[0054] The catheter 110 may be formed of silicone or polyurethane or a combination of materials. One or more regions of the catheter 110 may be reinforced, such as with a tube, cut tube, coil, braid, or other reinforcing structure. The reinforcing structure may be a metal material or a plastic material having a greater hardness than the rest of the catheter 110. The barbs 128 and base 114 may be made of a more rigid plastic than the proximal region of the catheter 110, including polysulfone or polymethyl methacrylate or other suitable plastics. The more rigid material of the barbs 128 and / or base 114 allows these portions of the device to deform and more fully connect to the softer catheter material.

[0055] The catheter 110 preferably remains straight between its proximal and distal ends, without any turns between the container 105 and the site being treated. Therefore, the container 105 is generally positioned above the distal tip 112 of the catheter 110 positioned within the target site when implanted. The vertical orientation of the straight catheter 110 ensures that the therapeutic agent is delivered from the container 105 through the lumen and enters the target site from outside the distal tip 112.

[0056] The RCE 120 can be positioned relative to the catheter 110 so as to release the therapeutic agent from the container 105 over an extended period of time. The frit can be customized to adjust the release profile of the therapeutic agent. Specifically, parameters including the surface area, length, tortuosity of the RCE, and the pore size of the RCE can all be customized to achieve the desired release profile. The size, molecular weight, and concentration of the therapeutic agent can also affect the release profile. The length of the catheter affects the tortuosity parameter of the release rate. Therefore, the RCE is relatively porous compared to drug delivery devices having substantially shorter catheters or cannulas.

[0057] In many embodiments, the RCE 120 comprises a porosity, thickness, channel parameters, and surface area configured to release a therapeutic amount over an extended period of time. The porosity may include values ​​in the range of about 1% to about 70%, preferably 15% to 40%. The porosity may include values ​​in the range of about 3% to about 30%. The porosity may include values ​​in the range of about 5% to about 10%. The porosity may include values ​​in the range of about 10% to about 25%. The porosity may include values ​​in the range of about 10% to about 20%.

[0058] In many embodiments, the channel parameters include fitting parameters corresponding to the tortuosity of the channel.

[0059] In many embodiments, the channel parameter includes a fitting parameter corresponding to an effective length of an interconnecting channel extending from a first side of the RCE 120 to a second side of the RCE 120. The effective length of the interconnecting channel may correspond to at least about 2 times the thickness of the RCE 120. The effective length of the interconnecting channel may correspond to at least about 5 times the thickness of the RCE 120. The channel parameter may be between 1 and 10, preferably between 2 and 5.

[0060] In many embodiments, the release rate of the 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, such that the RCE 120 releases the at least one therapeutic agent over an extended period of time. The ratio of the porosity to the channel parameter may be less than about 0.2, such that the RCE 120 releases the at least one therapeutic agent over an extended period of time. The ratio of the porosity to the channel parameter may be less than about 0.1, such that the RCE 120 releases the at least one therapeutic agent over an extended period of time. The ratio of the porosity to the channel parameter may be less than about 0.05, such that the RCE 120 releases the at least one therapeutic agent over an extended 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.

[0061] In many embodiments, the channel parameter comprises a value of at least about 1. The value of the channel parameter may comprise at least about 2. The channel parameter may comprise a value of at least about 5. The channel parameter may comprise a value of at least about 10.

[0062] In many embodiments, the RCE 120 comprises a release rate index (RRI) determined by the ratio of the porosity times the cross-sectional area of ​​the RCE 120 divided by the channel parameter times the thickness of the RCE 120, the thickness extending across the cross-sectional area. Although the RRI range may vary depending on the molecule and the desired release time, the release rate index range may be 0.01 to 20. The RCE 120 may comprise a release rate index of no more than about 5.0 mm. The RCE 120 may comprise a release rate index of no more than about 2 mm. The RCE 120 may comprise a release rate index of no more than about 1.2 mm. The RCE 120 may comprise a release rate index of no more than about 0.2 mm. The RCE 120 may comprise a release rate index of no more than about 0.1 mm. The RCE 120 may comprise a release rate index of no more than about 0.05 mm.

[0063] The device 100 described herein may include one or more RCEs 120. The RCE 120 (also referred to herein as a drug release mechanism, drug release element, release control element, porous structure, or frit) as described herein may be positioned near and / or within the outlet channel 125 of the device 100 such that the RCE 120 may control or regulate the delivery of one or more therapeutic agents from the container 105 through the outlet channel 125. The contents of the container 105 may be delivered according to slow diffusion rather than being discharged as a fluid stream or bolus. In some implementations, the RCE 120 may be disposed in a region of the container 105 that is in communication with the conduit 110. In some implementations, the RCE 120 may be a covering or lining having a specific porosity for the substance to be delivered and may be used to provide a specific release rate of the substance.

[0064] The RCE 120 may include, but is not limited to, wicking materials, permeable silicones, packed beds, small porous structures or porous frits, multiple porous coatings, nanocoatings, rate-limiting membranes, matrix materials, sintered porous frits, permeable membranes, semipermeable membranes, capillaries or tortuous channels, nanostructures, nanochannels, sintered nanoparticles, and the like. The RCE 120 may have a porosity, cross-sectional area, and thickness to release one or more therapeutic agents from the container 105 for an extended period of time. The porous material of the RCE 120 may have a porosity corresponding to the portion of the void space formed by the channels extending through or between the material. The void space formed may be between about 1% and about 70%, between about 5% and about 10%, between about 10% and about 25%, or between about 15% and about 20%, or any other portion of the void space.

[0065] The osmolarity and tonicity of the cerebrospinal fluid can range from about 290.5 mOsm / L to about 291.5 mOsm / L (see Akaishi et al., Neural Regen Res, May 2020 15(5):944-947). For example, a commercially available formulation of the therapeutic agent to be delivered can be diluted to obtain a formulation having an osmolarity and tonicity substantially similar to the osmolarity and tonicity of the CSF, e.g., about 290 mOsm / L. Although the therapeutic agent can have an osmolarity and tonicity substantially similar to that of the CSF, the therapeutic agent can have a high osmolarity (hypertonic) solution relative to the CSF or a low osmolarity (hypotonic) solution relative to the CSF. A person skilled in the art or ordinary skill can conduct experiments based on the teachings described herein to empirically determine the formulation and osmolarity of the therapeutic agent to provide release of the therapeutic agent for an extended period of time.

[0066] The RCE 120 has a first side facing the reservoir volume of the container 105 and a second side facing the proximal opening 108 into the catheter lumen 111. The first side has a first region as described herein, and the second side has a second region. The RCE 120 has a thickness and a diameter between the first side and the second side. The RCE 120 has a release rate index, which will be described in detail below. The RCE 120 includes a fixed tortuous porous material, such as a sintered metal, sintered glass, or sintered polymer with a defined porosity and tortuosity, which controls the rate at which at least one therapeutic agent is delivered to a target site. As a mechanism for controlling the release of one or more therapeutic agents from a therapeutic device, the rigid RCE 120 provides certain advantages over capillaries, easily eroded polymers, and membranes. These advantages include the ability of the rigid RCE 120 to be simpler and more cost-effective to manufacture, flushability for cleaning or clearing blockages before or after implantation, efficient deep filtration of microorganisms provided by the labyrinth of irregular pathways within the structure, and greater robustness of the structure due to greater stiffness and thickness compared to membranes or easily eroded polymer matrices. In a specific implementation, a drug can be injected into the reservoir, flushed, and then refilled with the drug. The flushing can deliver a first bolus of drug deeper into brain tissue, and the second fill of drug for extended release. Additionally, when the rigid RCE 120 is made of sintered metal, ceramic, glass, or certain plastics, it may be subjected to sterilization and cleaning procedures, such as heat or radiation-based sterilization and depyrogenation, which may damage polymers and other membranes.

[0067] In certain embodiments, as shown in Example 1, the rigid RCE 120 can be configured to provide therapeutically effective concentrations of the 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 diffusion rate, molecular size / weight, concentration, half-life, stability, and volume of the therapeutic agent and the RCE parameters. The release profile can vary from as short as a few days to as long as several months or even years, depending on the specific application, drug potency, and the characteristics of the device and the physical properties of the RCE. Such release profiles provided by certain configurations of the rigid RCE 120 enable the use of smaller devices, which are preferred in intraventricular treatments where larger devices may affect device invasiveness, patient comfort, and may cause infection or leakage issues.

[0068] The RCE 120 may include a plurality of interconnected channels formed between sintered grains of a material such as titanium or stainless steel. The interconnected grains of material define a space through the RCE 120 through which a therapeutic agent may pass to pass from a first side of the RCE 120 to a second side of the RCE 120. The channels may extend around the sintered grains of material such that the channels include interconnected channels extending through the porous material.

[0069] The rigid RCE 120 may have a hardness parameter in the range of about 160 Vickers to about 500 Vickers. In some embodiments, the rigid RCE 120 is formed of sintered stainless steel. The material of the RCE may have a hardness parameter in the range of from about 200 Vickers to about 240 Vickers. In some embodiments, it is preferred to inhibit ejection of the therapeutic agent through the RCE 120 during filling or refilling of the container 105 of the therapeutic device 100 with a fluid. In these embodiments, the channel of the rigid RCE 120 has a resistance to the flow of the injected solution or suspension, so that when the solution or suspension is injected into the container 105 of the device 100, ejection of the solution or suspension through the RCE 120 is substantially inhibited.

[0070] The container 105 and the RCE 120 can be configured to release therapeutic amounts of the therapeutic agent in a variety of ways. The container 105 and the RCE 120 can be configured to release therapeutic amounts of the therapeutic agent corresponding to a concentration of at least about 1 mg / mL up to about 300 mg / mL for at least about multiple days up to about 12 months. The therapeutic agent can be at least a fragment of an antibody and have a molecular weight of at least about 150 Daltons. For example, the therapeutic agent can be about 8,000 Daltons to about 200,000 Daltons. Alternatively or in combination, the therapeutic agent can be a small molecule drug with a molecular weight of about 100 Daltons to about 10,000 Daltons suitable for sustained release. The therapeutic agent can be one or more different antisense oligonucleotides, CKPs, various immunotherapies such as monoclonal antibodies, as well as thrombolytic agents, protease inhibitors, and other therapeutic agents that can be used to treat various neurodegenerative diseases.

[0071] The reservoir and RCE 120 can be configured to release therapeutic amounts of the therapeutic agent corresponding to a concentration of at least about 1 mg / mL, 100 mg / mL, 200 mg / mL, or 300 mg / mL over an extended period of several days, 1 month, 2 months, 3 months, 6 months, 12 months, 24 months, up to about 36 months, and any time therebetween.

[0072] The rigid RCE 120 may comprise a composite porous material that can be readily formed or formed into a variety of different shapes and configurations. For example, the porous material may be a composite of metal, aerogel, or ceramic foam (i.e., a reticular intercellular structure in which the internal cells are interconnected to provide a plurality of pores through the volume of the structure, the walls of the cells themselves being substantially continuous and non-porous, and the volume of the pores relative to the volume of the material forming the cell walls such that the total density of the intercellular structure is less than about 30% of the theoretical density) wherein the through-pores are impregnated with a sintered powder or aerogel. The thickness, density, porosity, and porous properties of the final composite porous material may be varied to conform to the desired release of the therapeutic agent.

[0073] The release rate of the therapeutic agent through a porous body (such as a sintered porous metal structure or a porous glass structure) can be described by the diffusion of the therapeutic agent within the RCE 120, and the effective diffusion coefficient is 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:

[0074] ,in:

[0075] C R = concentration in reservoir

[0076] C p= concentration outside the reservoir or at the target site

[0077] D = diffusion coefficient of the therapeutic agent in the reservoir solution

[0078] P = porosity of porous structure

[0079] F = channel parameter which may correspond to the tortuosity parameter of the channels of the porous structure

[0080] A = Porous structure area

[0081] L = thickness (length) of the porous structure

[0082] ,in

[0083] t = time, Vr = reservoir volume

[0084] The release rate index (hereinafter RRI) can be used to measure the release of a therapeutic agent. The RRI can be defined as (PA / FL), and unless otherwise specified, the RRI values ​​herein are in mm. Many of the RCE 120 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 and the desired release and application time.

[0085] The channel parameter may correspond to the elongation of the path of the therapeutic agent released through the RCE 120. The RCE 120 may include a number of interconnected channels, and the channel parameter may correspond to the effective length of the therapeutic agent traveling along the interconnected channels of the RCE 120 from the reservoir side to the patient side when released. The channel parameter multiplied by the thickness (length) of the RCE 120 may determine the effective length of the therapeutic agent traveling along the interconnected channels from the reservoir side to the patient side. For example, a channel parameter (F) of about 1.5 corresponds to an interconnected channel that effectively increases the length of the therapeutic agent traveling by about 50%, and for a 1 mm thick RCE 120, the effective length of the therapeutic agent traveling along the interconnected channels from the reservoir side to the patient side corresponds to about 1.5 mm. A channel parameter (F) of at least about 2 corresponds to an interconnected channel that provides an effective increase of about 100% in the length of the therapeutic agent traveling, and for a 1 mm thick RCE 120, the effective length of the therapeutic agent traveling along the channel from the reservoir side to the patient side corresponds to at least about 2.0 mm. Because the RCE 120 includes many interconnecting channels that provide many alternative pathways for release of the therapeutic agent, blockage of some channels does not substantially change the effective path length through the RCE 120 because alternative interconnecting channels are available, such that the diffusion rate and release of the therapeutic agent through the RCE 120 is substantially maintained when some channels are blocked.

[0086] If the reservoir solution is aqueous or has a viscosity similar to that of water, then the value of the diffusion coefficient of the therapeutic agent (TA) in water at the temperature of interest can be used. The following formula can be used based on the diffusion coefficient of bovine serum albumin in water at 20°C: The diffusion coefficient at 37°C was estimated using the measured value of (Molokhia et al., Exp Eye 2008):

[0087] ,in

[0088] MW refers to the molecular weight of BSA or the test compound, and η is the viscosity of water. Table 1 below lists the diffusion coefficients of the proteins of interest.

[0089] Table 1

[0090]

[0091] Small molecules have diffusion coefficients similar to fluorescein (MW = 330, D = 4.8 to 6 e-6 cm 2 / s, from Stay, MS et al., Pharm Res 2003, 20(1), pp. 96-102). For example, the small molecule may comprise a glucocorticoid, such as acetonide, which has a molecular weight of about 435.

[0092] The RCE 120 has a porosity, thickness, channel parameters, and surface area configured to release a therapeutic amount over an extended period of time. The porous material can have a porosity that corresponds to the portion of the void space of the channels extending within the material. The porosity includes values ​​ranging from about 1% to about 70%, preferably 15% to 40%. The porosity can be determined based on weight and macroscopic volume, or can be measured via nitrogen adsorption.

[0093] The RCE 120 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.

[0094] 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 that may correspond to the tortuosity of the channel may be determined based on experimental measurements. The parameter PA / FL may be used to determine the desired sustained release profile and determine the values ​​of P, A, F, and L. The release rate 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 may be less than about 0.7, such that the RCE 120 releases the therapeutic agent over an extended period of time. For example, the ratio of the porosity to the channel parameter is less than about 0.1 or, for example, less than about 0.2, such that the RCE 120 releases the therapeutic agent over an extended period of time. 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, such as at least about 2, and may include at least about 5. The channel parameter may be in the range of about 1.1 to about 10, such as in the range of about 2 to about 5. One of ordinary skill in the art can perform experiments based on the teachings described herein to empirically determine the channel parameters to release the therapeutic agent to achieve a desired release rate profile.

[0095] The area in the model is derived from the description of mass transfer in units of flux; that is, the mass transfer rate per unit area. For simple geometries, such as a porous disk mounted in an impermeable sleeve of equal thickness, the area corresponds to one face of the disk, and the thickness L is the thickness of the disk. For more complex geometries, such as a porous body in the shape of a truncated cone, the effective area is the value between the area where the therapeutic agent enters the porous body and the area where the therapeutic agent leaves the porous body. The porosity of the RCE 120 can be high enough so that the length of the catheter does not affect or minimally affects the release rate from the device. The drug release rate is controlled by the porosity of the RCE 120, the size of the drug molecules being delivered, and / or the concentration of the drug in the reservoir. Preferably, the reservoir is positioned directly above the catheter and there are no tortuosity in the catheter from the reservoir to the target treatment area. This vertical orientation between the distal outlet of the catheter and the inlet of the reservoir is preferred to ensure good diffusion of the drug to the target treatment area.

[0096] By correlating the change in concentration in the reservoir with the above release rate, a model can be derived to describe the release rate over time. The model assumes that the concentration of the therapeutic agent solution in the reservoir is uniform. In addition, the concentration in the receiving fluid is considered to be negligible (C p =0). Solving the differential equation and rearranging yields the following equation, which describes the volume V of the reservoir over time t and the volume V of the reservoir R The varying concentrations are used to release the therapeutic agent from the solution in the reservoir through the porous structure.

[0097]

[0098] and

[0099] When the reservoir contains a suspension, the concentration C in the reservoir R is the dissolved concentration (i.e., the solubility of the therapeutic agent) in equilibrium with the solid. In this case, the concentration in the reservoir is constant over time, the release rate is zero order, and the cumulative release rate increases linearly with time until the solid is exhausted.

[0100] The therapeutic concentration of many therapeutic agents can be determined experimentally by measuring the concentration in the target site where the therapeutic effect is elicited. Therefore, it is valuable to extend the prediction of release rate to the prediction of concentration in the target site. Most of the cerebrospinal fluid (CSF) is produced by the choroid plexus within the ventricles of the brain and flows through the ventricles, cisterns, and subarachnoid space to be absorbed into the blood by the arachnoid villi. CSF circulation includes not only the directional flow of CSF, but also the pulsatile back and forth movement throughout the brain, and local fluid exchange between blood, interstitial fluid, and CSF. The physiological volume of CSF is approximately 150 ml to 200 ml, with a daily turnover of approximately 500 ml. For extended release devices, the concentration in the cerebrospinal fluid (CSF) changes slowly over time. In this case, a model can be derived from a mass balance that relates the release rate of the device (described by the equation above) to CSF, k, C p 、V v The elimination rates of α and β are equal. Rearranging gives the following equation for the concentration in CSF:

[0101] .

[0102] Since the release rate of the device with the solution of therapeutic agent decreases exponentially with time, the concentration in the CSF decreases exponentially with the same rate constant. In other words, the CSF concentration decreases at a rate equal to The rate constant for the decrease therefore depends on the characteristics of the porous structure and the volume of the reservoir.

[0103] Since the release rate from the device with a suspension of therapeutic agent is zero order, the CSF concentration will also be independent of time. The release rate will depend on the properties of the porous structure through the ratio PA / FL, but will be independent of the volume of the reservoir until the drug is exhausted.

[0104] The size of the channels of the rigid porous structure can be adjusted in a variety of ways to release the intended therapeutic agent. For example, the size of the channels of the rigid porous structure can be designed to allow a therapeutic agent to pass through, the therapeutic agent comprising a molecule having a molecular weight of at least about 100 Daltons or, for example, at least about 200 k Daltons. The size of the channels of the rigid porous structure can be designed to allow a therapeutic agent to pass through, the therapeutic agent comprising a molecule having a cross-sectional dimension of no more than about 10 nm. The channels of the rigid porous structure include interconnecting channels that are configured to allow the therapeutic agent to pass between the interconnecting channels. The rigid porous structure includes grains of rigid material, and wherein the interconnecting channels extend at least partially around the grains of the rigid material to allow the therapeutic agent to pass through the porous material. The grains of the rigid material can be connected together at an attachment site, and wherein the interconnecting channels extend at least partially around the attachment site.

[0105] The porous structure comprises a sintered material. The sintered material may include grains of material, wherein the grains include an average size of no more than about 20 μm. For example, the sintered material may include grains of material, wherein the grains include an average size of no more than about 10 μm, an average size of no more than about 5 μm, or an average size of no more than about 1 μm. Based on the grain size of the sintered material and processing parameters (such as compaction force and time and temperature in the furnace), the size of the channel is designed to allow a therapeutic amount of the therapeutic agent to pass through the sintered material for an extended period of time. The size of the channel can be designed to inhibit the penetration of microorganisms, including bacteria and fungal spores, through the sintered material.

[0106] The sintering material includes a wettable material to inhibit air bubbles within the channels of the material.

[0107] 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 includes two or more of metal, ceramic, glass or plastic. The metal includes at least one of Ni, Ti, Nitinol, stainless steel including alloys such as 304, 304L, 316 or 316L, cobalt-chromium alloy, Elkiloy, 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 wettable coating to suppress the formation of bubbles in the channel, and the plastic may include at least one of polyetheretherketone (PEEK), polyethylene, polypropylene, polyimide, polystyrene, polycarbonate, polyacrylate, polymethacrylate or polyamide. Any material capable of forming a continuous porous channel system and being biocompatible is also considered herein for porous structure.

[0108] The channel parameter and the effective length from the first side to the second side can be configured in a variety of ways. The channel parameter can be greater than 1 and in the range of about 1 to about 10, preferably between about 2 to about 5.0, so that the effective length is in the range of about 2 to 5.0 times the thickness, although the channel parameter can be greater than 5, such as in the range of about 1.2 to 10. For example, the channel parameter can be about 1.3 to about 2.0, so that the effective length is about 1.3 to 2.0 times the thickness. For example, experimental testing has shown that the channel parameter can be about 1.4 to about 1.8, so that the effective length is about 1.4 to 1.8 times the thickness, such as about 1.6 times the thickness. The channel parameter can include a value of at least about 10. These values ​​correspond to the path of the channel around the sintered grains of the material, and can correspond to, for example, the path of the channel around the filling beads of the material.

[0109] The rigid porous structure 120 can be shaped and molded in a variety of ways, such as tubular, conical, disc-shaped, and hemispherical. The rigid porous structure can be a molded rigid porous structure. The molded rigid porous structure 120 can be at least one of a disc, spiral, or tube connected to a reservoir and configured to release the therapeutic agent over an extended period of time.

[0110] 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 120 may be a rigid material having holes formed thereon, and the holes may include a maximum dimension across, such as a diameter. The diameter of the nanochannel may include a dimension across, such as from about 10 nm across to about 1000 nm across or greater. The channel may be formed by etching of the material, such as photolithographic etching of the material. The channel may include a substantially straight channel such that the channel parameter F includes about 1, and the parameters area A and thickness or length L correspond to the combined cross-sectional area of ​​the channel and the thickness or length of the porous structure.

[0111] Mathematical models can potentially be used to predict how a storage container 110 with incorporated RCE 120 will behave in a molecule and concentration specific manner. Using Fick's diffusion laws and mass balance equations, the following equation (Eq. 1) can be derived:

[0112] Equation 1

[0113] D is the diffusion coefficient of the therapeutic agent, RRI is the RCE definition property which will be defined in 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 The following assumptions were made: (1) no drug is lost by any means other than diffusion, release of the drug is driven by a concentration gradient, the catheter concentration is much lower than the device concentration, and the rate-limiting step is diffusion across the RCE.

[0114] The RRI described herein can be determined for an RCE 120 having a plurality of elongated nanochannels extending substantially straight through the RCE 120. The RRI can be determined by the following formula (Equation 2) as described herein , where P = RCE porosity, A = RCE surface area, F = RCE tortuosity channel parameter, and L = length (thickness) of RCE 120. For straight channels, the channel parameter F corresponds to 1, and the porosity P corresponds to the percentage of the surface area of ​​RCE 120 having substantially straight nanochannels. For example, a surface area of ​​1 mm 2For a plate with a thickness of 0.5 mm and pores occupying more than 10% of the surface area, the corresponding RRI is Based on the teachings described herein, one of ordinary skill in the art can determine the surface area A and thickness L of RCE 120, percentage of the surface area of ​​the nanochannels, to provide an appropriate RRI for the therapeutic agent and reservoir volume of device 100 described herein.

[0115] The initial condition is the initial mass M o Integrating Equation 1, which states that the mass is zero at infinite time, yields the following formula for the mass of the device as a function of time (Equation 3):

[0116]

[0117] experiment

[0118] Example 1

[0119] Tests were conducted to determine the feasibility of different RCE effects on drug release from the reservoir devices described herein into the CNS. Reservoir devices with 4.5 mL volumetric size and 1 mL volumetric size were used for testing. The catheter length for each reservoir size was 11 cm, and the administration was intraventricular, with the reservoir positioned above the target treatment site to achieve a vertical or near-vertical orientation between the reservoir and the target, so that the delivery of the drug can be assisted by gravity. Table 2 below shows the device configurations tested. The outer diameter of the catheter can be 1 / 8" (3.175 mm OD), and the inner diameter is 1 / 16" (1.5875 mm ID).

[0120] Table 2: Tested device configuration

[0121]

[0122] The reservoir of the device was filled with either a monoclonal antibody (mAb A) as a model macromolecular therapeutic or fluorescein as a model small molecule therapeutic. Table 3 below shows a list of molecules tested for sustained delivery. Antisense oligonucleotides are typically in the 3000 mw to 7000 mw size range and would benefit from sustained release.

[0123] Table 3: List of molecules tested for sustained delivery

[0124]

[0125] The diameter, thickness, porosity, and micron size of the RCEs varied. Some devices contained high porosity RCEs (types 334, 011, 012), and other devices contained lower porosity RCEs (types 014, 627). Some devices also did not include RCEs. Table 4 below shows the different RCEs tested.

[0126] Table 4: List of RCEs

[0127]

[0128] The devices were filled with approximately 200 mg / mL of mAb A, and the fill volume was calculated from the difference in mass of the unfilled and filled devices using the density of the mAb A solution. The initial internal mass of each device was calculated from the known volume and concentration. The catheter was filled with phosphate buffered saline (PBS) and attached to the fill reservoir. The device was designed to release the therapeutic agent into a 50 mL PBS reservoir. The reservoir was gently shaken at 100 rpm on an orbital shaker at 37°C to simulate body movement. Over time, the reservoir was sampled and the mAb concentration was measured by UV-visible spectroscopy (UV-Vis) at 278 nm on a Little Lunatic (Non-chain Laboratories) (a standard curve of mAb A was previously measured at 278 nm to determine the extinction coefficient), and the mass of mAb A released over time was tracked. If the mAb concentration in all reservoir samples was above the detection limit, the reservoir was replaced with fresh PBS when applicable.

[0129] Figure 3 shows mAb release from devices with 4.5 mL reservoir volume and high porosity RCE compared to no RCE. Each point is the average of replicate device samples with or without RCE. Devices without RCE are shown in open squares with dashed lines fitted to the data (n=5). Devices with high porosity RCE are shown in open circles with solid lines fitted to the data (n=4, RCE 334). An exponential model for mAb release from the devices was fit to the data. The presence of a high porosity RCE with a diameter of 0.188" affected the release profile of the mAb and sustained the release of the mAb over time compared to devices without RCE.

[0130] Figure 4 shows mAb release from devices with 1 mL reservoirs and fitted with different RCE types to determine how RCE properties affect the release of mAb A. Devices were fitted with no RCE (open squares), high porosity RCE (open inverted triangles), or low porosity RCE (open triangles). Each RCE had the same diameter and thickness but differed in micrometer size (i.e., porosity). Decreasing pore size of the low porosity RCE slowed the release rate of mAb A. The pore size of the RCE is proportional to the release rate of mAb A.

[0131] Figure 5 shows the release of mAb A from devices with a 1 mL reservoir and no RCE fit (open squares) or with the same high porosity but RCEs of different diameters. The larger diameter RCE (open inverted triangles) has a diameter of 0.188" and the smaller diameter RCE (open diamonds) has a diameter of 0.125". This reduction in RCE diameter slows 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. Due to the limited RCE selection, thickness was not experimentally tested, but based on the laws of diffusion, an inverse relationship between thickness and release rate can be assumed.

[0132] The test was repeated with a small molecule model of fluorescein (332 Da). The small molecule model was present with mAb A ( The fluorescein solution was a 100 mg / mL solution diluted with PBS + 0.02% sodium azide (NaN3) to achieve an initial concentration of 25 mg / mL. The PBS reservoir volume was adjusted to 200 mL due to the low detectability of fluorescein. A standard curve for absorbance at 492 nm was previously determined and used for this experimental extinction coefficient. Figure 6 shows the fluorescein release profiles for devices with a 1 mL reservoir and no RCE (open squares) or RCEs with high porosity (open inverted triangles) or low porosity (open hexagons). One of the high porosity RCEs also has a reduced diameter of 0.125" (open diamonds) compared to the larger 0.188" diameter. Like 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 release rate of fluorescein.

[0133] Figure 7 shows the experimental data points and each fitted curve (following Eq. 3) consistent with different RCEs for a small reservoir device (1 mL) filled with high molecular weight mAbA. The fit appears to match the data well, however, it is slightly disrupted by the fact that over time the concentration in the device is much greater than the concentration in the catheter. Additionally, in ICV delivery, the CSF produced in the ventricle replenishes the sink (e.g., CSF) faster than the sink changes performed in the experiment. This would result in a larger concentration gradient and lead to a faster rate of release of the molecule. Using the rate constant , this fitting parameter can be used to show the significance of the molecular release rate. The results show that the mAb A release rate of RCE014 with low porosity and a larger diameter of 0.188" (hollow inverted triangles) and RCE 012 with high porosity and a smaller diameter of 0.125" (hollow diamonds) is significantly different from that of RCE 011 with high porosity and a larger diameter of 0.188" (hollow circles). For this fitted data, the time is equal to zero at the start of 3 hours of release because the therapeutic agent is filled into the diffusion area under the RCE to avoid bubbles. It is assumed that after 3 hours, most of the molecules starting under the RCE diffuse out of the catheter and into the sink. The rapid release of the therapeutic agent in the device without RCE confirms this assumption.

[0134] Figure 8 shows the experimental data points on each fitted curve (following Eq. 3) consistent with different RCEs of a small reservoir device (1 mL) filled with low molecular weight fluorescein. The fits agree well with the experimental data. All three RCEs show release rate constants that are significantly different from each other. The results show that the fluorescein release rates of RCE 011 (open inverted triangles) with high porosity and a larger diameter of 0.188" and RCE 012 (open diamonds) with high porosity and a smaller diameter of 0.125" are significantly different from RCE 627 (open circles) with low porosity and a larger diameter of 0.188". Since fluorescein can be detected at lower concentrations, the sink size may be larger and may better fit the assumption that diffusion through the RCE is the rate limiting step and the concentration in the device is still much higher than that in the catheter and sink.

[0135] Data show that by incorporating a porous metal frit (RCE) into an implantable and refillable ICV reservoir device, a small molecule model therapeutic agent, fluorescein, and a large molecule model therapeutic agent, mAb A, were released in a controlled manner to achieve sustained delivery over time. RCE parameters (surface area, length, and porosity) can be modified to achieve the desired therapeutic release rates for different clinical applications. The two molecules tested, fluorescein and mAb A, span other potential classes of therapeutic agents in terms of molecular size, such as peptides, proteins, ASOs (antisense oligonucleotides), and Fab agents (antigen binding fragments).

[0136] How to use

[0137] It should be understood that the therapeutic devices described herein can be used in a variety of locations and implanted in a variety of ways. The methods of implantation and use of the therapeutic devices described herein can vary depending on the type of therapeutic device implanted and the intended location and drug for treatment. As will be described in more detail below, the therapeutic devices described herein can be infused, implanted, filled, refilled, and / or explanted using one or more devices.

[0138] In one specific implementation of therapeutic device implantation, a flap can be formed in the scalp to expose an area of ​​the skull directly above the target delivery location. A burr hole can be formed in the skull to expose an area of ​​the dura mater. The burr hole is typically drilled to a depth and diameter that mirrors 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 to allow recessed positioning of the device. An ideal trajectory for catheter implantation, which can be performed using neuronavigation software and imaging routines, is to implant a device such as an Ommaya reservoir (see www.cureus.com / articles / 29046-ommaya-reservoir-insertion-a-technical-note).

[0139] The catheter 110 can be cut to size at the time of implantation and can be secured to the barbs 128 on the lower end of the device 100. The catheter can be cut shorter than the distance of the planned trajectory to account for the depth of the barb connector inserted into the burr hole. The container 105 can be filled with the drug to be delivered at the time of implantation or pre-filled with the drug. The catheter 110 can be primed before being connected to the barbs 128 to fill with BSA and release any bubbles. The distal tip 112 of the catheter 110 can be inserted through the burr hole and advanced to the target location, such as within the ventricle below the burr hole. The upper region 123 of the barb connector 127 can be positioned within the burr hole, and the lower surface 115 of the base 114 is positioned against the skull surface. The flap can be positioned back over the upper surface 117 of the cover 116 and sutured. Thus, the container 105 remains outside the skull and below the scalp for easy refilling by needle penetration. The device implantation procedure may be similar to the procedure for implanting an Ommaya reservoir (see www.cureus.com / articles / 29046-ommaya-reservoir-insertion-a-technical-note).

[0140] Typically, embodiments of the therapeutic devices described herein include drug solutions, drug suspensions, and / or drug matrices. The therapeutic devices described herein may also contain a therapeutic agent formulated as one or more solid drug cores or pellets that are formulated to deliver one or more therapeutic agents in a therapeutically effective amount for an extended period of time. The time period over which the therapeutic device delivers the therapeutically effective amount may vary. In some embodiments, the therapeutic device is implanted to provide treatment during the useful life of the device, such that refilling of the device is no longer necessary.

[0141] The therapeutic devices described herein need not be removed and may remain in place indefinitely, as long as the treatment is effective or exceeds the therapeutic effect. However, the therapeutic device 100 may be explanted (ie, removed from the target site).

[0142] Indications

[0143] The therapeutic devices described herein can be used to treat and / or prevent a variety of neurodegenerative diseases of the brain, including Alzheimer's disease, stroke, Huntington's disease, amyotrophic lateral sclerosis (ALS), Angelman syndrome, Parkinson's disease, motor neuron disease, and other brain diseases, including 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.

[0144] Therapeutic agents

[0145] Examples of therapeutic agents that can be delivered by the therapeutic device described herein include, but are not limited to, antisense oligonucleotides, CKP, various immunotherapies such as monoclonal antibodies, and thrombolytic agents, protease inhibitors, and other drugs that can be used to treat various neurodegenerative diseases. Also contemplated are the 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. Other therapeutic agents known to those skilled in the art that can be controlled and sustained released into the patient's body in the manner described herein are also suitable for use according to the embodiments of the device described herein.

[0146] Material

[0147] Typically, the components of the devices described herein are made of materials that are biocompatible and preferably insoluble in the body fluids and tissues that the devices contact. These materials generally do not cause irritation to the tissue portions that they contact. For example, the materials may include various polymers, including, for example, silicone elastomers and rubbers, polyolefins, polyurethanes, acrylates, polycarbonates, polyamides, polyimides, polyesters, and polysulfones.

[0148] In various specific implementations, description is made with reference to the drawings. However, certain specific implementations may be practiced without one or more of these specific details or in combination with other known methods and configurations. In the description, many specific details, such as specific configurations, sizes and processes, are described to provide a thorough understanding of the specific implementation. In other cases, known processes and manufacturing techniques are not particularly described to avoid unnecessarily obscuring the description. References throughout this specification to "one embodiment", "embodiment", "one specific implementation", "specific implementation" etc. mean that the specific features, structures, configurations or characteristics described are included in at least one embodiment or specific implementation. Therefore, phrases "one embodiment", "embodiment", "one specific implementation", "specific implementation" etc. appearing in different positions throughout the specification do not necessarily refer to the same embodiment or specific implementation. In addition, specific features, structures, configurations or characteristics may be combined in any suitable manner in one or more specific implementations.

[0149] Device and system described herein may include any one of a variety of features.Alternatively or in combination with another specific implementation of device and system described herein, an element or feature of a specific implementation of device and system described herein may be included.For the sake of brevity, although various combinations will be considered herein, the explicit description of each of these combinations may be omitted.Additionally, device and system described herein may be positioned in the patient and may not be specifically implanted as shown or as described herein.Various devices may be implanted, positioned and adjusted, etc., according to various different methods and using various different devices and systems.Various devices may be adjusted at any time before implantation, during implantation and after implantation.Some representative descriptions of how to implant and position various devices are provided, however, for the sake of brevity, the explicit description of each method of each implant or system may be omitted.

[0150] Relative terms used throughout the description may indicate relative positions or directions or orientations and are 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 to the first direction. The terms "upper," "lower," "top," "bottom," "front," "side," and "rear," as well as "front," "rear," "tail," "head," and the like may be used to establish a relative reference frame and are not intended to limit the use or orientation of any of the devices described herein in various specific implementations.

[0151] The word "about" means a range of values ​​including the specified value, and one of ordinary skill in the art would reasonably consider values ​​similar to the specified value. In the embodiments, about means within the standard deviation (using measurements generally accepted in the art). In the embodiments, about means a range extending to + / - 10% of the specified value. In the embodiments, about includes the specified value.

[0152] Although this specification contains many details, these should not be interpreted as limiting the scope of the content that is claimed or may be claimed, but as a description of features specific to a particular embodiment. Certain features described in the context of independent embodiments in this specification may also be implemented in combination in a single embodiment. On the contrary, the various features described in the context of a single embodiment may also be implemented individually or in any suitable sub-combination in multiple embodiments. In addition, although the features may be described above as working in certain combinations, and even initially claimed as such, in some cases, one or more features from the claimed combination may be deleted from the combination, and the claimed combination may be for a sub-combination or a variant of the sub-combination. Similarly, although operations are depicted in a particular order in the drawings, this should not be understood as requiring such operations to be performed in the particular order shown or in sequence, or requiring all illustrated operations to be performed to obtain the desired result. Only a few examples and specific implementations are disclosed. The described examples and specific implementations and other specific implementations may be changed, modified and improved based on the disclosed content.

[0153] In the above description and claims, phrases such as "at least one" or "one or more" may appear, followed by a list of combinations of elements or features. The term "and / or" may also appear in a list of two or more elements or features. Unless otherwise implicitly or explicitly contradicted by the context in which it is used, the phrase is intended to represent any element or feature listed alone, or any other described element or feature in combination with any other described element or feature. For example, the phrases "at least one of A and B"; "one or more of A and B"; "A and / or B" are each intended to represent "A alone, B alone, or A and B together". A similar interpretation also applies to lists including three or more items. For example, the phrases "at least one of A and B"; "one or more of A, B, and C" and "A, B, and / or C" are each intended to represent "A alone, B alone, C alone, A and B together, A and C together, B and C together, or A and B and C together".

[0154] Use of the term "based on" above and in the claims is intended to mean "based, at least in part, on" such that non-recited features or elements are also permissible.

Claims

1. A device for delivering a drug into the cerebrospinal fluid of the brain, the device comprising: a hollow container having a reservoir volume and an outlet, the container comprising an upper surface and a lower surface; a porous structure comprising a sintered rigid material, the porous structure passively regulating diffusion of the drug from the reservoir at a controlled release rate; as well as A conduit is coupled to a lower end of the container, the conduit 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.

2. The device of claim 1, wherein the container is sized to be implanted between an area of ​​the skull and the overlying skin.

3. The device according to claim 2, wherein: When implanted, the lower surface of the container is positioned against the skull and the overlying skin covers the upper surface of the container.

4. The device of claim 3, wherein the lower surface of the container is flat or has a curved contour that substantially conforms to the shape of the skull at the region.

5. The device of claim 1, wherein the container has a diameter of about 10 mm to about 45 mm.

6. The device of claim 1, wherein a maximum height of the container between the lower surface and the upper surface is about 3 mm to about 15 mm.

7. The device according to claim 1, wherein the peripheral shape of the container is oval, elliptical or circular.

8. The device of claim 1, wherein the reservoir volume is about 0.5 mL to about 5.0 mL.

9. The device of claim 1, wherein the container comprises a lower base having the lower surface and an upper cover having the upper surface, the base and the cover together defining the reservoir volume.

10. The device of claim 9, wherein at least a portion of the cover is formed of a material configured to be pierced by a needle for injection of the drug.

11. The device of claim 9, wherein the base defines the outlet from the container.

12. The device of claim 9, wherein the base has an inner surface including a seat configured to seal with the porous structure.

13. The device of claim 12, further comprising a diffusion chamber located distally of the porous structure within the seat, the diffusion chamber comprising an upper region and a lower region.

14. The device of claim 13, wherein the diffusion chamber is located in a protrusion protruding from the lower surface of the base.

15. The device of claim 13, wherein the porous structure has an upper surface facing the reservoir volume of the container and a lower surface facing the diffusion chamber.

16. The device of claim 13, wherein the upper region of the diffusion chamber has an inner diameter that is smaller than an inner diameter of the container.

17. The apparatus of claim 16, wherein an outlet passage is located below the lower region of the diffusion chamber, the outlet passage having an inner diameter that is smaller than an inner diameter of the lower region.

18. The device of claim 17, wherein the lower region of the diffusion chamber tapers from the inner diameter of the upper region to the inner diameter of the outlet passage.

19. The device of claim 17, wherein the outlet passage is positioned within a barbed connector of the container, the barbed connector being configured to couple the conduit to the container.

20. The device of claim 19, wherein the barbs of the barbed connector mitigate unintentional displacement between the catheter and the container.

21. The device of claim 20, wherein the barb of the barbed connector has an outer diameter that is greater than an inner diameter of the lumen of the catheter.

22. The device of claim 19, wherein the barbed connector and the base are formed of a more rigid material than the proximal end region of the catheter.

23. The device of claim 21, wherein the barbed connector positioned within the lumen of the catheter is positioned inside the skull and the container is positioned outside the skull when the device is implanted in a patient.

24. The device of claim 1, wherein the catheter is straight between a proximal end and a distal end after implantation such that the reservoir is positioned above the distal end of the catheter when the distal end is positioned within a target site.

25. The device of claim 1, wherein the catheter has a length sufficient to extend to a target location in the brain.

26. The device of claim 25, wherein the length is about 3 cm to about 15 cm.

27. The device of claim 25, wherein the length of the catheter is no greater than 11 cm.

28. The device of claim 25, wherein the target location is a dural sinus or a ventricle of the brain.

29. The device of claim 25, wherein the length of the catheter is longer than the distance between the skull and the target location.

30. The apparatus of claim 29, wherein the proximal end region of the catheter is configured to be cut to size prior to implantation in the container.

31. The device of claim 30, wherein the length of the conduit is between 30 cm and 50 cm, and the distance is between about 3 cm and about 15 cm.

32. The device of claim 30, wherein an outer surface of the catheter at the proximal end region includes one or more markings indicating the length of the catheter to a distal-most end of the catheter.

33. The device of claim 1 wherein the distal end region of the catheter has at least one opening from the lumen.

34. The apparatus of claim 33, wherein the at least one opening of the distal end region of the catheter comprises a plurality of outlets positioned through a wall of the catheter.

35. The device of claim 34, wherein the plurality of outlets have a diameter of about 0.02 mm to about 2 mm.

36. The device of claim 34, wherein each of the plurality of outlets are spaced apart at an angle of approximately 90 degrees from one another so as to occur circumferentially around the distal end region of the catheter.

37. The device of claim 34, wherein each of the plurality of outlets are spaced apart by approximately 45 degrees, 90 degrees, 120 degrees, or 180 degrees.

38. The device of claim 1, wherein the conduit has a cross-sectional outer diameter of no greater than 5 mm.

39. The device of claim 38, wherein the cross-sectional outer diameter of the conduit is approximately 1 / 8" (3.175 mm) and the inner diameter of the conduit is approximately 1 / 16" (1.5875 mm).

40. The device of claim 1, wherein the porous structure is made of titanium or stainless steel.

41. The device of claim 1, wherein the porous structure has a porosity of about 1% to about 70%.

42. The device of claim 1, wherein the drug is released from the reservoir for at least 1 month to about 36 months.

43. The device of claim 1, wherein the drug has a molecular weight of at least about 100 Daltons up to about 200,000 Daltons.

44. The device of claim 1, wherein the drug is a peptide, a protein, an antisense oligonucleotide, or an antigen binding fragment.

45. The device of claim 1, wherein the drug is for treating a neurodegenerative disease of the brain.

46. ​​The device of claim 1, wherein the drug is used to treat Alzheimer's disease, stroke, Huntington's disease, amyotrophic lateral sclerosis (ALS), Angelman syndrome, Parkinson's disease, motor neuron disease, brain cancer, neuronal ceroid lipofuscinosis, tripeptidyl peptidase 1 (TPP1) deficiency, or central nervous system trauma.

47. A method of controlling the delivery of a drug to an internal part of the body, the method comprising administering the drug to the internal part via the device of claim 1.

48. A method of treating a disease of the brain in a subject in need thereof, the method comprising: administering an effective amount of a drug to the subject into cerebrospinal fluid (CSF) using an implantable device, the implantable device comprising: a hollow container having a reservoir volume and an outlet; a porous structure comprising a sintered rigid material, the porous structure passively regulating diffusion of the drug from the reservoir at a controlled release rate; and A conduit is coupled to a lower end of the container, the conduit having a lumen configured to communicate with the reservoir volume of the container through the porous structure.

49. The method of claim 48, wherein the disease of the brain is a neurodegenerative disease.

50. The method of claim 49, wherein the neurodegenerative disease is Alzheimer's disease, stroke, Huntington's disease, amyotrophic lateral sclerosis (ALS), Angelman syndrome, Parkinson's disease, or motor neuron disease.

51. The method of claim 48, wherein the disease is brain cancer.

52. The method of claim 48, wherein the drug is an antisense oligonucleotide, a cysteine ​​knot peptide, or a Fab antibody fragment.

53. The method of claim 48, further comprising positioning a distal end region of the catheter within a ventricle or a dural sinus of the brain.

54. The method of claim 48, wherein the sintered rigid material comprises at least one of a metal, a ceramic, and a glass.

55. The method of claim 48, wherein the porous structure and the container are adapted to release the drug from the reservoir volume into the CSF at a predetermined rate profile to treat the brain for an extended period of time.

56. The method of claim 55, wherein the porous structure comprises porosity, thickness, channel parameters, and surface area configured to release a therapeutic amount of the drug for the extended period of time.

57. The method of claim 56, wherein the channel parameters include fitting parameters corresponding to effective lengths of a plurality of irregularly shaped channels extending from a first side of the porous structure to a second side of the porous structure.

58. The method of claim 57, wherein the release rate of the drug through the porous structure corresponds to a ratio of the porosity to the channel parameter, and wherein the ratio of the porosity to the channel parameter is between 0.03 and 0.2, enabling the porous structure to release the therapeutic agent over an extended period of time.

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