Biodegradable Fuse-Reservoir System for Intermittent Delivery of Bioactive Agents

Abstract

A device for delivering one or more bioactive agents is disclosed. The device comprises: a first layer comprising a first biodegradable polymer, the first layer having a first side and a second side, with a plurality of reservoirs containing one or more bioactive agents present on the first side; a second layer comprising a second biodegradable polymer adjacent to the first side of the first layer; and a third layer comprising a third biodegradable polymer, the third layer sealing the first and second layers and including an exposed second layer where at least one surface of the device is not covered by the third biodegradable polymer. In one embodiment, the first and third biodegradable polymers are poly-ε-caprolactone, and the second biodegradable polymer is a mixture of cellulose acetate phthalate and poloxamer. A method for manufacturing the device is also disclosed.

Description

[Technical Field]

[0001] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under Grant No. R21EB031454-01A1 awarded by the National Institutes of Health. The government has certain rights in this invention.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 425,344, filed November 15, 2022, the disclosure of which is incorporated herein by reference. [Background technology]

[0003] Most implantable drug delivery devices release drugs continuously (e.g., contraceptive implants). However, for applications such as cancer and hormonal disorders, cyclical or intermittent drug release is more desirable. A known intermittent release device, commercially available from Microchips Biotech, is expensive, large (4.5 cm x 5.5 cm), and requires a surgical procedure for implantation. After the full dose has been delivered, the device must be removed. For treatments lasting months or years, multiple surgical procedures may be required, increasing the potential risks to the patient.

[0004] Delivery devices capable of delivering bioactive agents over a period of several months are an attractive therapeutic approach for certain medical conditions. Depression, for example, represents a significant public health burden both nationally and globally. Treatment options for patients with major depressive disorder (MDD) primarily consist of psychotherapy and pharmacotherapy. Especially in the latter category, treatment options have seen only incremental advances until the recent approval of esketamine, a form of ketamine given in the form of an intranasal spray.

[0005] A major challenge to the treatment of MDD is the relatively low success rate of pharmacological treatment, as well as the high relapse rate in many patients. The most comprehensive study of MDD to date was the National Institute of Mental Health-funded Alternative Continuing Treatments for Depression Reduction (STAR) study. * D) Trials. Trials outline an algorithmic sequential treatment approach, allowing for estimation of the likelihood of antidepressant success in subsequent trials. The acute remission rate decreased with each additional trial (Trial 1: 37%, Trial 2: 31%, Trial 3: 14%, Trial 4: 13%). Similarly, the probability of achieving and maintaining remission at 1 year decreased with each additional trial (Level 1: 26%, Level 2: 14%, Level 3: 5%, Level 4: 3%). Unfortunately, this applies to over 43% of patients who failed the first two trials.

[0006] Microdosing is one approach to treating depression and other illnesses, but it also has limitations. For example, the use of 5-HT agonists, such as LSD or psilocybin, to treat depression is not yet widespread. 2A A major obstacle to advancing agonist research is their current status as Schedule I drugs. Due to strict restrictions on distribution of these compounds as well as potential concerns regarding diversion or abuse, dosing is restricted to supervised settings. This requires patients to present for dosing on a 2-day (Q48) or 3-day (Q72) schedule for several weeks, potentially limiting patient participation and treatment.

[0007] What is needed is a device that allows for intermittent delivery of a bioactive agent to a patient so that the patient does not have to bear the responsibility of administering the bioactive agent. The bioactive agent is delivered to the patient automatically at desired intervals. An ideal device and / or technique would not require repeated patient visits, leading to improved patient compliance and achieving the desired therapeutic outcome. Additionally, the device would be biodegradable, eliminating the need for surgical removal and ideally allowing administration with a single injection. These and other needs are met by the present disclosure. Summary of the Invention

[0008] In accordance with the purposes of the disclosure as embodied and broadly described herein, the disclosure relates, in one aspect, to a device for delivering one or more bioactive agents to a subject, the device comprising: (a) a first layer comprising a first biodegradable polymer, the first layer having a first side and a second side, with a plurality of reservoirs comprising one or more bioactive agents present on the first side of the first layer; (b) a second layer comprising a second biodegradable polymer adjacent the first side of the first layer; and (c) a third layer comprising a third biodegradable polymer, the third layer sealing the first and second layers, with at least one surface of the device comprising an exposed second layer not covered by the third biodegradable polymer. In one embodiment, the first and third biodegradable polymers are poly-ε-caprolactone (PCL), polysebacic acid, polylactic acid, or any combination thereof, and the second biodegradable polymer is a mixture of cellulose acetate phthalate (CAP) and poloxamer. Methods of manufacturing this device are also disclosed.

[0009] Other systems, methods, features, and advantages of the present disclosure will become apparent to one of ordinary skill in the art upon examination of the following drawings and detailed description. All such additional systems, methods, features, and advantages are intended to be included within this specification, be within the scope of the present disclosure, and be protected by the accompanying claims. In addition, all alternative and preferred features and variations of the described embodiments can be used in all aspects of the present disclosure taught herein. Furthermore, all alternative and preferred features and variations of the described embodiments, as well as individual features of the dependent claims, are combinable and interchangeable with each other. [Brief explanation of the drawings]

[0010] Many aspects of the present disclosure can be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale, emphasis instead being placed upon clearly illustrating the principles of the present disclosure. Moreover, in the drawings, like reference characters indicate corresponding parts throughout the several views. [Figure 1A] FIG. 1A illustrates the assembly and construction of the micro fuse device described herein. [Figure 1B] FIG. 1B illustrates the assembly and construction of the micro fuse device described herein. [Figure 2] FIG. 2 shows the direct correlation established between the mass of polymer and the thickness of the resulting film (volume constant). [Figure 3A] Figures 3A to 3C show the release of Rhodamine B dye from eroding polymer films. Drug release time slows with increasing film thickness. Figure 3A shows erosion time versus thickness of CAPP films. [Figure 3B] Figure 3B shows the cumulative release of rhodamine from 0.1–0.4 mm films. Error bars are included, but may be invisible if the error is small. [Figure 3C] Figure 3C shows the erosion time of 70:30 to 90:10 CAPP films at each thickness (0.1, 0.2, 0.3, and 0.4 mm). [Figure 4A] Figures 4A to 4D show an overview of the mold making process according to the present disclosure: Figure 4A is a schematic diagram of the stamping die design. [Figure 4B] FIG. 4B is a silicon master with features made from an epoxy-based photoresist (SU-8). [Figure 4C] Figure 4C is a polydimethylsiloxane (PDMS) replica of the silicon master. [Figure 4D] FIG. 4D is an epoxy resin mold made from the prototype shown in FIG. 4C. [Figure 5A]FIG. 5A shows a polycaprolactone / polyvinyl alcohol (PCL / PVA) film ready to be hot embossed with the mold shown in FIG. 4D. [Figure 5B] FIG. 5B shows an example of a first layer of a micro fuse device that has undergone hot embossing, according to one embodiment of the present disclosure. [Figure 6A] FIG. 6A shows an SEM image of a fluorescein (FITC)-loaded device coated with cellulose acetate phthalate-Pluronic F-127 (CAPP). [Figure 6B] FIG. 6B shows an SEM image of a reservoir loaded with one drug. [Figure 6C] FIG. 6C shows an image of a FITC-loaded microdevice sealed with PCL and coated with CAPP. [Figure 7] Preliminary fluorescein release curves are shown in Figure 7. Fluorescence intensity over time shows that all devices exhibit an intermittent release profile, with five out of six devices demonstrating the same release timing. [Figure 8] 8 shows a cross-sectional view of the disclosed device in operation. One end is uncoated, allowing the surrounding environment to access the at least one second biodegradable polymer. Surface erosion of the at least one second biodegradable polymer sequentially exposes each reservoir, thereby allowing drug release. [Figure 9A] 9A and 9B show a micro fuse device design according to one embodiment of the present disclosure: Figure 9A is a cross-sectional view of a micro fluidic fuse. [Figure 9B] Figure 9B shows a side view of a microfabricated device for prolonged intermittent drug release, illustrating the μ-fuse concept. The proposed approach results in implantable devices that are smaller and have more drug reservoirs than previously published devices. [Figure 10A] Figures 10A to 10F show the fabrication and structural characterization of a μFuse-based device (MDI): Figure 10A shows a process schematic outlining the soft lithography of a μFuse-based MDI. [Figure 10B] FIG. 10B shows a representative image of the stamp. [Figure 10C] FIG. 10C shows the stamped PCL base. [Figure 10D] FIG. 10D shows PCL filled with FITC. [Figure 10E] FIG. 10E shows a cross-sectional view (top) and a side view (bottom) of a CAPP fuse placed on PCL filled with FITC. [Figure 10F] FIG. 10F shows a cross section (right side) of the final trimmed MDI at the reservoir. [Figure 11] Figure 11 shows precisely timed drug release from a μfuse-based MDI. MDIs manufactured by the process shown in Figures 10A through 10F reliably release FITC pulses every 3 days when kept in 40% FBS. [Figure 12A] Figures 12A to 12G show the in vivo delivery of DOI of a 5-HT2A agonist from monolayer and multilayer CAPP films. Figure 12A shows the in vitro cumulative release of DOI from a 0.1 mm CAPP film. [Figure 12B] FIG. 12B shows a schematic diagram of the subcutaneous implantation of a 0.1 mm DOI-loaded CAPP film and the time course of the experiment. [Figure 12C] FIG. 12C shows the pharmacokinetics in plasma (n=4) of DOI released from subcutaneously implanted monolayer CAPP films. [Figure 12D] FIG. 12D shows the pharmacokinetics in the brain (n=4) of DOI released from subcutaneously implanted monolayer CAPP films. [Figure 12E] FIG. 12E shows a schematic diagram of the subcutaneous implantation of multilayered CAPP films and the time course of the experiment. [Figure 12F] FIG. 12F shows the pharmacokinetics in plasma (n=4) of DOI released from multilayer CAPP films. [Figure 12G] FIG. 12G shows the pharmacokinetics in the brain (n=4) of DOI released from multilayer CAPP films.

[0011] Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. DETAILED DESCRIPTION OF THE INVENTION

[0012] Many variations and other embodiments of what is disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. It is to be understood, therefore, that the disclosure is not limited to the particular embodiments disclosed, and that variations and other embodiments are intended to be included within the scope of the appended claims. Those skilled in the art will recognize many variations and adaptations of the aspects described herein. These variations and adaptations are within the teachings of the present disclosure and are intended to be encompassed by the scope of the claims herein.

[0013] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0014] As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has individual components and features that may be readily separated from or readily combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure.

[0015] Any recited method may be carried out in the order of events recited or in any other order that is logically possible. That is, unless expressly stated otherwise, it is in no way intended that the methods or aspects described herein be construed as requiring that its steps be performed in a specific order. Accordingly, method claims are in no way intended to imply any order unless the claims or specification specifically recite that the steps are limited to a particular order. This also applies to all possible implicit bases of interpretation, including logical matters regarding the arrangement of steps or operational flow, the apparent meaning derived from grammatical construction and punctuation, or the number and type of aspects described in the specification.

[0016] All publications mentioned herein are incorporated by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein should be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein may be different from the actual publication dates, which may require independent confirmation.

[0017] Although aspects of the present disclosure may be described and claimed in terms of particular statutory classes, such as the statutory class of systems, this is for convenience only, and those skilled in the art will understand that each aspect of the present disclosure may be described and claimed in any statutory class.

[0018] It should also be understood that the terminology used herein is for the purpose of describing particular embodiments and is not intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compositions and methods belong. Furthermore, it will be understood that terms as defined in commonly used dictionaries should be interpreted as having a meaning consistent with the meaning in the context of this specification and related art, and should not be interpreted in an idealized or overly formal sense unless explicitly defined herein.

[0019] Prior to describing the various aspects of this disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in this disclosure.

[0020] definition As used herein, "comprising" is interpreted as specifying the presence of the stated features, integers, steps, or components as referenced, but does not exclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Furthermore, the terms "by," "comprising," "comprises," "comprised of," "including," "includes," "included," "involving," "involves," "involved," and "such as" are each used in an open and non-limiting sense and may be used interchangeably. Furthermore, the term "comprising" is intended to include examples and embodiments encompassed by the terms "consisting essentially of" and "consisting of." Similarly, the term "consisting essentially of" is intended to include examples encompassed by the term "consisting of."

[0021] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "bioactive agent," a "polymer," or a "time interval" includes, but is not limited to, mixtures, combinations, or ranges of two or more such bioactive agents, polymers, or time intervals, etc.

[0022] It should be noted that ratios, concentrations, amounts, and other numerical data may be expressed herein in a range format. It is further understood that the endpoints of each range are significant in relation to the other endpoint, and independently of the other endpoint. Also, certain values ​​are disclosed herein, and it is understood that each value is also disclosed herein as "about" that particular value in addition to the value itself. For example, if the value "10" is disclosed, then "about 10" is also disclosed. Ranges can be expressed herein as from "about" one particular value and / or to "about" another particular value. Similarly, when values ​​are expressed as approximations by use of the antecedent "about," it is understood that the particular value forms a further aspect. For example, if the value "about 10" is disclosed, then "10" is also disclosed.

[0023] When ranges are expressed, a further aspect includes from the one particular value and / or to the other particular value. For example, when the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure; for example, the phrase "from x to y" includes ranges from "x" to "y," as well as ranges from greater than "x" to less than "y." Ranges can also be expressed as upper limits, e.g., "about x, y, z, or less," and should be interpreted to include the specific ranges of "about x," "about y," and "about z," as well as ranges of "less than x," "less than y," and "less than z." Similarly, the phrase "about x, y, z, or more" should be interpreted to include the specific ranges of "about x," "about y," and "about z," as well as ranges of "greater than x," "greater than y," and "greater than z." Additionally, the phrase "about 'x' to 'y'" (where 'x' and 'y' are numerical values) includes "about 'x' to about 'y'."

[0024] It should be understood that such range formats are used for convenience and brevity and, thus, should be interpreted flexibly to include not only the numerical values ​​explicitly recited as the limits of the range, but also all individual numerical values ​​or subranges subsumed within that range, as if each numerical value and subrange were explicitly recited. As an example, a numerical range of "about 0.1% to 5%" should be interpreted not only to include the explicitly recited value of about 0.1% to about 5%, but also to include individual values ​​(e.g., about 1%, about 2%, about 3%, and about 4%) and subranges (e.g., about 0.5% to about 1.1%, about 5% to about 2.4%, about 0.5% to about 3.2%, and about 0.5% to about 4.4%, as well as other possible subranges) within the indicated range.

[0025] As used herein, the terms "about," "approximate," "at or about," and "substantially" mean that the quantity or value in question may be an exact value or a value that will provide an equivalent result or effect as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and / or may be larger or smaller, if desired, to reflect tolerances, conversion factors, rounding, measurement errors, and the like, as well as other factors known to those skilled in the art, so as to provide an equivalent result or effect. In some circumstances, a value that will provide an equivalent result or effect may not be reasonably determinable. In such cases, as used herein, "about" and "at or about" are generally understood to mean a ±10% variation from the nominal value stated, unless otherwise indicated or implied. In general, an amount, size, formulation, parameter, or other quantity or characteristic is "about," "approximate," or "at or about," whether or not expressly stated as such. When "about," "approximate," or "at or about" is used before a quantitative value, it is understood that the parameter also includes the particular quantitative value itself, unless otherwise specified.

[0026] As used herein, the term "effective amount" refers to an amount sufficient to achieve a desired modification of a physical property of a composition or material. For example, an "effective amount" of poly(lactic-co-glycolic acid) (PLGA) refers to an amount sufficient to achieve a desired improvement in a property controlled by a formulation component, e.g., to achieve a desired release timing of a bioactive agent upon dissolution of a PLGA reservoir cap. The specific wt% level in a composition required as an effective amount, or the thickness of a layer containing the same, will depend on various factors, including the amount of PLGA in the reservoir cap, the amount and type of other polymers present in the cap, and the desired bioactive agent dosing level and timing.

[0027] As used herein, the term "microfuse" or "μfuse" refers to the disclosed surface-erodible microfluidic fuse device for the intermittent delivery of pharmaceutical agents to a subject. In one aspect, the μfuse device consists of or includes a biodegradable polymer and can be implanted in a subject.

[0028] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances in which the event or circumstance occurs and instances in which it does not occur.

[0029] Unless otherwise indicated, temperatures referred to herein are based on atmospheric pressure (ie, 1 atmosphere).

[0030] Delivery Device Described herein are devices that provide intermittent delivery of a bioactive agent to a subject upon administration of the device to the subject. The devices are composed of a biodegradable polymer such that, upon administration to a subject, the polymer in the second layer erodes, releasing the bioactive agent at specific time intervals. The term "microdosing" refers to the administration of small amounts (e.g., micrograms) of a bioactive agent every 3 to 7 days to treat or prevent a disease or its symptoms. In some embodiments, the second layer can further comprise an additional bioactive agent, separate from the bioactive agent in the reservoir, that is to be released at a constant rate over time.

[0031] An example of a delivery device described herein is provided in FIGS. 1A and 1B and is referred to herein as a microfuse 10. Referring to FIG. 1A, a first layer 1 composed of a first biodegradable polymer has multiple reservoirs 2 containing a bioactive agent. The number, shape, and size of the reservoirs vary depending on the amount of bioactive agent to be delivered to a subject. A second layer 4 comprising at least one second biodegradable polymer is attached to the reservoir-bearing side of the first layer such that the second layer is adjacent to (i.e., abuts) the first side 3 of the first layer, forming a layered structure 5. Finally, the layered structure 5 is sealed with a third biodegradable polymer to form device 6. The layered structure 5 is sealed such that all but one surface of the layered structure is covered with the third biodegradable polymer. In one embodiment, the device has a longitudinal axis, and the reservoirs are arranged in one or more rows parallel to the longitudinal axis. One surface of the layered structure not covered by the third biodegradable polymer can be perpendicular to the longitudinal axis, exposing a portion of the second layer to the surrounding medium. In some embodiments, the longitudinal axis will span the length of the longest side of the disclosed device and be parallel to that side. In some embodiments, when the reservoirs are arranged in parallel rows, the reservoirs in each row can contain different bioactive agents. This allows the device to release two drugs simultaneously.

[0032] A schematic of the disclosed device in use is provided in Figure 8. In one embodiment, the third layer coating is absent on one side perpendicular to the longitudinal axis of the device (left side of the top image of Figure 8), exposing at least one second biodegradable polymer. When the second biodegradable polymer erodes to the point where the reservoir is exposed (see bottom image of Figure 8), the drug contained in the reservoir is released.

[0033] In one embodiment, the device further includes multiple distances between the reservoirs, the multiple distances being measured parallel to the longitudinal axis. In a further embodiment, each of the multiple distances can be the same. In an alternative embodiment, at least one of the multiple distances can be different from at least one other of the multiple distances. In yet another embodiment, equal distances between the reservoirs can lead to equal intervals between drug releases, while different distances between the reservoirs can lead to longer or shorter intervals between drug releases. A longer distance between the reservoirs will mean less frequent drug release, while a shorter distance between the reservoirs will mean more frequent drug release.

[0034] In any of these embodiments, the overall length of the device (i.e., the dimension parallel to the longitudinal axis) is not limited. In one embodiment, longer devices may incorporate more reservoirs, or greater distances between reservoirs, or both, to tailor the number and timing of doses to a particular application.

[0035] In one embodiment, the exposed second layer is only surface eroded and not bulk eroded. In a further embodiment, the second layer is comprised of a polymer capable of surface erosion, although not all polymers are surface erodible. Surface eroding polymers are further characterized as follows: In any of these embodiments, the surface eroding dissolvable polymer layer can be fabricated with different distances between reservoirs, allowing for control of the timing of release of bioactive agents in different reservoirs, as discussed further below.

[0036] In one embodiment, each reservoir can have the same volume. In alternative embodiments, each reservoir can have a different volume. For example, in one embodiment, it may be desirable to provide a high initial dose of drug followed by decreasing doses, or it may be desirable to gradually decrease the dose of drug by delivering successively smaller amounts over time.

[0037] In one embodiment, each of the multiple reservoirs contains a different bioactive agent. In another embodiment, each of the multiple reservoirs contains the same bioactive agent. In yet another embodiment, combinations of these possibilities are contemplated—for example, two reservoirs containing the same bioactive agent combined with a third reservoir containing a different bioactive agent. Furthermore, in this embodiment, as the surface of the second layer erodes, reservoirs further from the exposed surface release their bioactive agent more slowly, while reservoirs closer to the exposed surface release their bioactive agent more quickly. In this manner, two, three, four, or more reservoirs, each at different distances from the exposed surface, can be included in the same device, allowing for intermittent delivery of the bioactive agent contained in the reservoir, i.e., at regular intervals, without the need for any action by the patient or healthcare professional. Multiple rows of reservoirs containing different bioactive agents at the same distance from the exposed surface are also contemplated, allowing for simultaneous release of two or more bioactive agents. In alternative embodiments, the array of reservoirs can be covered by or adjacent to different second layer polymers that erode at different rates, thereby providing different release timing for each array. In another embodiment, the array of reservoirs can be covered by the same second layer polymer, with either the same or different distances from the exposed surface as outlined above.

[0038] The selection of the at least one second biodegradable polymer, as well as the distance of the reservoir from the exposed surface, determines the release rate of the one or more bioactive agents, since the second polymer layer erodes (i.e., biodegrades) over time after the device is administered to a subject. In one embodiment, the first biodegradable polymer and the third biodegradable polymer are the same or different polymers. Furthermore, in this embodiment, the first and third layers are biodegradable, eliminating the need to remove the delivery device from the body after a dosage is completed. In another embodiment, the first biodegradable polymer and the at least one second biodegradable polymer are different.

[0039] In some embodiments, the at least one second biodegradable polymer can be mixed with or otherwise include a bioactive agent, which can be the same as one of the one or more bioactive agents in the reservoir or can be a different bioactive agent.

[0040] In one embodiment, the first layer 1 of the device shown in Figure 1A is composed of a polymer that biodegrades at a slower rate than the polymer in the second layer 4. In another embodiment, the first layer 1 of the device shown in Figure 1A is composed of a polymer that biodegrades at half, one-third, or one-quarter the rate of the at least one second biodegradable polymer in the second layer 4. In one embodiment, the first biodegradable polymer is poly-ε-caprolactone (PCL), polysebacic acid, polylactic acid, polyester, polyanhydride, polyurethane, polyphosphazine, polyalkylcyanoacrylate, polypeptide, block copolymer comprising polyethylene glycol (PEG), or any combination thereof. In another embodiment, the first layer has a thickness of about 0.1 mm to about 2 mm, or about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2 mm, any combination of the foregoing values, or a range encompassing any of the foregoing values ​​(where either value can be the upper or lower endpoint of the range).

[0041] In one embodiment, the at least one second biodegradable polymer in the second layer 4 is a polymer that biodegrades faster than the first polymer in the first layer 1. In one embodiment, the at least one second biodegradable polymer can comprise a mixture of two or more different polymers. In one embodiment, the at least one second biodegradable polymer comprises a mixture of cellulose acetate phthalate (CAP) and poloxamer, a polyanhydride, a polyorthoester, or any combination thereof. In one embodiment, the CAP has a molecular weight of about 1,000 g / mol to about 5,000 g / mol, or about 2,000 g / mol to about 3,000 g / mol.

[0042] In one embodiment, a poloxamer is a non-ionic triblock copolymer composed of a central hydrophobic chain of polyoxypropylene (e.g., polypropylene oxide) flanked by two hydrophilic chains of polyoxyethylene (e.g., polyethylene oxide). In one embodiment, the poloxamer has the following composition: HO(C2H4O) b (C3H6O) a (C2H4O) b OH wherein a is 10-100, 20-80, 25-70, or 50-70, and b is 5-250, 10-225, 20-200, 50-200, 100-200, or 150-200. In another embodiment, the poloxamer has a molecular weight of 2,000-15,000, 3,000-14,000, or 4,000-12,000. Poloxamers useful herein are sold by BASF under the trade name "Pluronic®." Non-limiting examples of poloxamers useful herein include, but are not limited to, those listed in Table 1. In one embodiment, the poloxamer is F-127.

[0043] [Table 1]

[0044] In one embodiment, the at least one second biodegradable polymer comprises a mixture of cellulose acetate phthalate (CAP) in an amount of about 50 mol% to about 90 mol% and poloxamer in an amount of about 10 mol% to about 50 mol%. In another embodiment, the at least one second biodegradable polymer comprises cellulose acetate phthalate (CAP) in an amount of about 50 mol%, 55 mol%, 60 mol%, 65 mol%, 70 mol%, 75 mol%, 80 mol%, 85 mol%, or 90 mol%. Any value can be the lower or upper endpoint of a range (e.g., 60 mol% to 80 mol%, etc.). In another embodiment, the at least one second biodegradable polymer comprises poloxamer in an amount of about 10 mol%, 15 mol%, 20 mol%, 25 mol%, 30 mol%, 35 mol%, 40 mol%, 45 mol%, or 50 mol%. Any value can be the lower or upper endpoint of a range (e.g., 20 mol% to 40 mol%, etc.). In one embodiment, second layer 4 has a thickness of about 0.1 mm to about 2 mm, or about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or about 2 mm, any combination of the foregoing values, or a range encompassing any of the foregoing values ​​(where any value can be the upper or lower endpoint of the range). In one embodiment, second layer 4 is a surface-eroding polymeric mesh having a known erosion rate of about 1 μm / h to about 10 μm / h, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 μm / h, any combination of the foregoing values, or a range encompassing any of the foregoing values ​​(either value can be the upper or lower endpoint of the range).

[0045] The device shown in Figures 1A and 1B can be manufactured using the following non-limiting process. In one embodiment, the biodegradable polymer poly-ε-caprolactone (PCL) forms the body of the device, which contains the drug and fuse (i.e., the first and third layers). The drug reservoir is created in the first layer by hot embossing using a Carver heated press and a micro-machined die. PCL can be molded at relatively low temperatures (e.g., a melting point of 60°C) without damaging the bioactive agent with high heat. Additionally, the first and third polymers degrade slowly in the body, creating a device that can last for more than a year in the body.

[0046] After the first layer 1 is hot-embossed, a powdered bioactive agent can be loaded into reservoir 2 without heating using a Carver press. This drug reservoir loading method is particularly attractive because it can be used with a variety of bioactive agents and does not require the use of heat or solvents for loading. The loaded device is then inverted and briefly immersed in a solution of at least one second biodegradable polymer (e.g., CAP and poloxamer) dissolved in a solvent such as acetone. The solvent quickly evaporates, leaving behind a thin film of at least one second biodegradable polymer that seals the drug reservoir and forms a fuse. Multiple dipping steps can be performed to adjust the thickness of second polymer layer 4 depending on the application. Finally, a third biodegradable polymer (e.g., PCL) is melted and poured over the layered structure 5, sealing it. The final device is then ready for cutting and use.

[0047] After the above-described cutting step is performed, the second layer 4 is exposed on one or more sides of the device. Referring to FIG. 1B, face 7 has the exposed second layer 4. The exposed second layer 4 on face 7 functions as a fuse. As the fuse dissolves along the exposed surface, the reservoirs containing the bioactive agent are periodically exposed to the intracellular space and release their contents. The distance between the reservoirs 2 beneath the microfluidic fuse (i.e., second layer 4) governs the release schedule. This spacing is determined at the time of fabrication and tailored to the specific application. While FIGS. 1A and 1B show a single fuse (i.e., a single second layer 4), multiple fuses, each with its own unique erosion rate, on a single device can be used to achieve extremely long-term implantable drug release. In other embodiments, multiple fuses can be used for the sustained release of multiple, mutually exclusive drugs and / or for responding to various environmental cues.

[0048] The devices and methods of manufacture described herein allow for the incorporation of a variety of different types of bioactive agents, hi one aspect, the bioactive agent comprises an antibiotic, an analgesic, an immunomodulatory component, a growth factor, an enzyme inhibitor, a hormone, a messenger molecule, a cell signaling molecule, a receptor agonist, an oncolytic virus, a chemotherapeutic agent, a receptor antagonist, a nucleic acid, a nanoparticle, a drug conjugate, or an antibody drug conjugate, or any combination thereof.

[0049] In another embodiment, the bioactive agent is a 5-HT agonist such as 2,5-dimethoxy-4-iodoamphetamine (DOI), 1-acetyl-N,N-diethyllysergamide (ALD-52), O-acetylpsirosine (4-AcO-DMT), lysergic acid diethylamide (LSD), or psilocybin. 2A The devices described herein contain trace amounts of 5-HT 2AThe agonist can be delivered consistently over a long period of time, which may overcome barriers to compliance, cost, and abuse. The microfuse devices described herein are an effective and safe method of microdosing by delivering a bioactive agent every about 48 to about 96 hours, or about every 72 hours, for months. The devices described herein can be administered to a subject using conventional techniques. In one embodiment, the device is implanted in the subject. In one embodiment, a healthcare professional can inject the device subcutaneously instead of performing a minor surgical procedure. This streamlined implantation procedure saves time and money and may further improve patient compliance. In another embodiment, the devices described herein can be formulated with pharmaceutically acceptable additives suitable for injection.

[0050] Stimuli-responsive devices Stimulus-responsive devices are also contemplated herein. In further embodiments, stimuli-responsive devices according to the present disclosure degrade only in the presence of specific types of molecules in the surrounding fluid. In one embodiment, reactive oxygen species (ROS)-responsive devices could be made from polysulfides or polythioketals. In another embodiment, reduction-responsive devices could be made from disulfide-bonded polymers, acid-cleavable devices could be made from acid-cleavable polymers such as ketals or imines, and enzyme-cleavable devices could be made from enzyme-cleavable polymers such as enzyme-cleavable peptide crosslinks.

[0051] Methods for manufacturing a delivery device In one aspect, a method of making the disclosed device is disclosed, the method comprising at least: (a) creating a mold defining the negative shapes of a plurality of devices; (b) depositing a first biodegradable polymer into the mold to form a first layer; (c) loading at least one of the plurality of reservoirs with a bioactive agent to form a plurality of loaded device substrates; (d) depositing at least one second biodegradable polymer onto the plurality of loaded device substrates to form a second layer attached to the first layer to form a plurality of loaded devices; (e) encapsulating the plurality of filled devices with a third biodegradable polymer to form a third layer, the third layer encapsulating the first and second layers, and at least one surface of each of the plurality of devices comprising an exposed second layer that is not covered by the third biodegradable polymer.

[0052] In any of the above embodiments, "depositing" can refer to any method of incorporating a polymer into a device, including, but not limited to, hot embossing, 3D printing, spray coating, spin coating, dip coating, vacuum deposition, or other methods known in the art.

[0053] In some embodiments, in step (b), the first biodegradable polymer is deposited by hot embossing, injection molding, or 3D printing with a biodegradable resin. In some embodiments, in step (d), the at least one second biodegradable polymer can be spin coated, spray coated, or hot embossed to form the second layer.

[0054] Exemplary materials and processes useful in fabricating the devices are provided in the Examples.

[0055] 3D printing In one embodiment, a 3D printing process can be used in place of the disclosed hot embossing process. In an alternative embodiment, the 3D printing process can be used in combination with other techniques and polymers disclosed herein. In one embodiment, some biocompatible polymers suitable for 3D printing may have different release profiles for bioactive agents, and layer thickness, cross-linking or lack thereof, and other methods and parameters can be manipulated to provide devices according to the present disclosure.

[0056] In another embodiment, any biodegradable monomer, oligomer, or polymer compatible with digital light processing (DLP) 3D printing processes can be used to fabricate all or a portion of the disclosed devices. In one embodiment, DLP 3D printing involves contacting one or more monomers and / or oligomers with a photoinitiator and exposing them to ultraviolet light, which causes polymerization of the monomers and / or oligomers.

[0057] In some embodiments, biodegradable fillers can also be used in combination with one or more polymers in the disclosed devices. In further embodiments, the filler can be composed largely of starch, for example, obtained from common foods such as potato, sweet potato, and / or yam.

[0058] Having described aspects of the present disclosure, the following examples generally describe some additional aspects of the present disclosure. While aspects of the present disclosure will be described in conjunction with the following examples and corresponding text and figures, it is not intended to limit the aspects of the present disclosure to this description. On the contrary, it is intended to cover all alternatives, modifications, and equivalents that are included within the spirit and scope of the present disclosure.

[0059] Aspects The present disclosure can be described according to the following numbered aspects, which should not be confused with the claims.

[0060] Embodiment 1. A device for delivering one or more bioactive agents to a subject, comprising: a first layer comprising a first biodegradable polymer, the first layer having a first side and a second side, wherein a plurality of reservoirs comprising one or more bioactive agents are present on the first side of the first layer; a second layer comprising at least one second biodegradable polymer adjacent to the first side of the first layer; and a longitudinal axis; a third layer comprising a third biodegradable polymer that seals the first and second layers, and at least one surface perpendicular to the longitudinal axis of the device comprising an exposed second layer surface that is not covered by the third biodegradable polymer.

[0061] Embodiment 2. The device of embodiment 1, wherein the first biodegradable polymer and the at least one second biodegradable polymer are different polymers.

[0062] Embodiment 3. The device of embodiment 1 or 2, wherein the first biodegradable polymer and the third biodegradable polymer are the same polymer.

[0063] Embodiment 4. The device of any one of embodiments 1 to 3, wherein the first biodegradable polymer comprises poly-ε-caprolactone (PCL), polysebacic acid, polylactic acid, polyester, polyanhydride, polyurethane, polyphosphazine, polyalkyl cyanoacrylate, polypeptide, a block copolymer comprising polyethylene glycol (PEG), or any combination thereof.

[0064] Embodiment 5. The device of any one of embodiments 1 to 4, wherein the first layer has a thickness of about 0.1 mm to about 2 mm.

[0065] Embodiment 6 The device of any one of embodiments 1 to 5, wherein the at least one second biodegradable polymer erodes from the exposed second layer surface.

[0066] Embodiment 7. The device of any one of embodiments 1 to 6, wherein the at least one second biodegradable polymer comprises a mixture of cellulose acetate phthalate (CAP) and poloxamer, a polyanhydride, a polyorthoester, or any combination thereof.

[0067] Embodiment 8. The device of any one of embodiments 1 to 7, wherein the at least one second biodegradable polymer comprises a mixture of cellulose acetate phthalate (CAP) in an amount of about 50 mol% to about 90 mol% and poloxamer in an amount of about 10 mol% to about 50 mol%.

[0068] Embodiment 9. The device of any one of embodiments 1 to 8, wherein the second layer has a thickness of about 0.1 mm to about 2 mm.

[0069] Embodiment 10. The device of any one of embodiments 1 to 9, wherein the third biodegradable polymer comprises poly-ε-caprolactone (PCL), polysebacic acid, polylactic acid, polyester, polyanhydride, polyurethane, polyphosphazine, polyalkyl cyanoacrylate, polypeptide, a block copolymer comprising polyethylene glycol (PEG), or any combination thereof.

[0070] Embodiment 11. The device of any one of embodiments 1 to 10, wherein the third layer has a thickness of about 0.1 mm to about 2 mm.

[0071] Embodiment 12. The device of any one of embodiments 1 to 11, wherein the one or more bioactive agents comprise an antibiotic, an analgesic, an immunomodulatory component, a growth factor, an enzyme inhibitor, a hormonal agent, a messenger molecule, a cell signaling molecule, a receptor agonist, an oncolytic virus, a chemotherapeutic agent, a receptor antagonist, a nucleic acid, a nanoparticle, a drug conjugate, an antibody drug conjugate, or any combination thereof.

[0072] Embodiment 13. The device of any one of embodiments 1 to 12, wherein each of the plurality of reservoirs comprises a different bioactive agent.

[0073] Embodiment 14. The device of any one of embodiments 1 to 12, wherein each of the multiple reservoirs contains the same bioactive agent.

[0074] Embodiment 15. The device of any one of embodiments 1 to 14, wherein the plurality of reservoirs are arranged in one or more rows parallel to the longitudinal axis.

[0075] Embodiment 16 The device of embodiment 15, comprising at least two rows of reservoirs, each row of reservoirs comprising a different bioactive agent.

[0076] Embodiment 17. The device of embodiment 15, comprising at least two rows of reservoirs, each row of reservoirs containing the same bioactive agent.

[0077] Embodiment 18. The device of any one of embodiments 1 to 17, further comprising a plurality of distances between the reservoirs, the plurality of distances being measured parallel to the longitudinal axis.

[0078] Embodiment 19. The device of embodiment 18, wherein each distance of the plurality of distances is the same.

[0079] Embodiment 20. The device of embodiment 18, wherein at least a first distance of the plurality of distances is different from at least a second distance of the plurality of distances.

[0080] Embodiment 21. The device of any one of embodiments 1 to 20, wherein at least a first reservoir of the plurality of reservoirs is adjacent to a second biodegradable polymer that is different from at least a second reservoir of the plurality of reservoirs.

[0081] Embodiment 22 The device of any one of embodiments 1 to 20, wherein each of the plurality of reservoirs is adjacent to the same second biodegradable polymer.

[0082] Embodiment 23. The device of any one of embodiments 1 to 22, wherein each of the plurality of reservoirs has the same volume.

[0083] Embodiment 24. The device of any one of embodiments 1 to 22, wherein at least a first reservoir of the plurality of reservoirs has a different volume than at least a second reservoir of the plurality of reservoirs.

[0084] Embodiment 25 The device of any one of embodiments 1 to 24, wherein the at least one second biodegradable polymer comprises an additional bioactive agent.

[0085] Embodiment 26 The device of embodiment 25, wherein the additional bioactive agent is the same as one or more bioactive agents in the plurality of reservoirs.

[0086] Embodiment 27 The device of embodiment 25, wherein the additional bioactive agent is different from one or more bioactive agents in the plurality of reservoirs.

[0087] Embodiment 28 A method for intermittent delivery of one or more bioactive agents to a subject, comprising implanting in the subject a device according to any one of embodiments 1 to 27.

[0088] Embodiment 29. The method of embodiment 28, wherein the device is implanted by injection. [Example]

[0089] The following examples are presented to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices, and / or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the disclosure and are not intended to limit the scope of what the inventors regard as their disclosure. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperatures, etc.), but some errors or deviations should be accounted for. Unless otherwise indicated, parts are parts by weight, temperature is in ° C. or is at ambient temperature, and pressure is at or near atmospheric.

[0090] Example 1: Device optimization and drug release profile

[0091] Correlation between polymer mass and polymer film thickness Optimal conditions for the formation of surface-eroding cellulose acetate phthalate-Pluronic F-127 (CAPP) films of various thicknesses were determined. After screening various conditions (different molar ratios of CAP to P, solvent selection, evaporation conditions, and polymer weight percentage), it was found that the CAP:P mixture dispersed well in acetone at a concentration of 7% (w / v), and CAP:P films at a 70:30 molar ratio formed uniform, hard films upon acetone removal at 4 °C. Using uniform-diameter Teflon (PTFE)-coated dishes, films composed of 300, 600, 900, and 1,200 mg of the CAPP polymer mixture were produced. This resulted in films approximately 0.1, 0.2, 0.3, and 0.4 mm thick, respectively (Figure 2). There was a strong linear correlation between polymer mass and film thickness, enabling the fabrication of homogeneous films.

[0092] Set erosion time of polymer films and correlation between film thickness and erosion time Having found that film thickness was predictable based on polymer mass, the next goal was to establish some correlation between film thickness and erosion time. First, it was confirmed that CAPP films degrade via surface erosion. As degradation occurred, they maintained similar mechanical properties but decreased in size. Furthermore, erosion time depended on film thickness; films 0.1, 0.2, 0.3, and 0.4 mm thick were completely eroded in 36, 48, 66, and 84 hours, respectively.

[0093] Quantifying drug release from films of various thicknesses (using fluorescent dye as a drug surrogate) Finally, we quantified drug release from 0.1-, 0.2-, 0.3-, and 0.4-mm-thick monolayer CAPP films. The erosion time depended on the film thickness; the 0.1-, 0.2-, 0.3-, and 0.4-mm-thick films were completely eroded in 8, 24, 36, and 48 hours, respectively (Figure 3A). Drug release, measured by encapsulating a rhodamine fluorescent dye within the film, closely matched the erosion times described above. Release from the 0.1-mm-thick film was complete in approximately 8 hours (Figure 3B). Release from the 0.2-mm-thick film was complete in approximately 20 hours (Figure 3B). Release from the 0.3-mm-thick film was complete in approximately 28 hours (Figure 3B). Release from the 0.4-mm-thick film was complete in approximately 44 hours (Figure 3B). Surprisingly, the films eroded uniformly via surface erosion. The release times were generally comparable for the 70:30 CAP:P and 80:20 CAP:P films, but were slightly longer for the 90:10 CAP:P film (Figure 3C).

[0094] Example 2: Device Fabrication The μFuse device mold design is shown in Figure 4A. Fabrication began with the creation of a photolithographically defined mold. Briefly, SU-8 photoresist was applied to a silicon wafer, and a high-resolution photomask was used to define the negative shape of the μFuse device. The outer edges of the μFuse device mold were taller than the three central reservoir pillars to allow for successful polymer molding later in the process. Therefore, the fabrication of the prototype required two layers of photoresist and two exposure steps, lengthening the time required for successful process optimization and device fabrication. The three central square pillars each have dimensions of 200 μm × 200 μm × 200 μm. The outer walls are 100 μm thick and 400 μm high. Figure 4B shows the completed SU-8 negative mold on a 3-inch silicon wafer. Next, a replica of the mold was fabricated using the two-component elastomer polydimethylsiloxane (PDMS). PDMS monomer and curing agent were mixed in a 10:1 ratio and poured into an SU-8 mold and allowed to cure (Figure 4C). The final mold fabrication step was to use the PDMS replica as a mold for RenCast4037, a two-component, thermally conductive epoxy resin. After some optimization, an epoxy mold (Figure 4D) was successfully fabricated. The epoxy mold was relatively robust and expected to withstand multiple cycles, which is necessary for the subsequent hot-embossing step.

[0095] Once an epoxy mold suitable for hot embossing was prepared, parameters were optimized to fabricate thin films of polyvinyl alcohol (PVA) and polycaprolactone (PCL). These polymers will form the base layer of the final μFuse drug delivery device. First, PVA pellets were compressed in a heated press at 1,200 PSI and 154 °C for 360 seconds and then cooled under pressure for 2 hours. This produced a PVA film approximately 1 mm thick. The pressure was then released on the PVA film, and a PCL pellet was placed on top. The pellet and film were then subjected to 200 PSI at 71 °C for 120 seconds and cooled under pressure for 30 minutes. This procedure produced reproducible films of appropriate thickness for the fabrication of fuse devices (approximately 400 μm thick PCL and approximately 1 mm thick PVA) (Figure 5A). After the film was fabricated, the hot embossing conditions were optimized. During optimization, issues such as air bubbles, mold adhesion to the thin film, and poor shape reproduction were addressed. μFuse devices were successfully hot-embossed by combining a PCL / PVA film with an epoxy mold in a heated press and applying 55 PSI of pressure at 57°C for 5 minutes. The mold and film were then cooled to 4°C and carefully removed from the mold. Initial experiments yielded approximately 10% usable μFuse devices after hot-embossing.

[0096] Figures 6A to 6C show devices completely filled with fluorescein (FITC) as a model drug compound, coated with a CAPP film, and sealed to an outer layer of PCL on all sides. Figure 6A shows a scanning electron microscope (SEM) image of a single device with three FITC-loaded drug reservoirs before the application of CAPP fuses. Figure 6B shows the same image, but zoomed in on one reservoir, revealing that the FITC completely fills it. Figure 6C shows an array of multiple devices coated with CAPP fuses and final sealing in PCL to form a fully functional device.

[0097] Figure 7 shows release studies (FITC from reservoirs shown in Figures 6A to 6C) for six separate devices. Measurements were taken every 8 hours until all three reservoirs released their loaded FITC. The fluorescence intensity observed during the initial reading did not represent the desired release profile. This was the result of FITC remaining on and in the device. This residue is the result of an imperfect loading procedure, which is currently under optimization. However, the devices demonstrated a clear and fairly precise punctuated release of FITC dye, with an average time between reservoir releases of approximately 20 hours.

[0098] Example 3: 5-HT 2A Microfabrication and in vitro validation of a μFuse device enabling agonist delivery

[0099] Manufacturing and structural characterization A first-generation prototype for interval microdosing of hallucinogens was developed using a layered CAPP film. While multilayered CAPP films provided the first proof-of-concept for biomaterial-based MDIs, they suffer from several major deficiencies that limit their clinical translation. Therefore, a second-generation biomaterial-based MDI was developed and further pursued in research (Figures 9A and 9B). The primary innovation that distinguishes this technology is the use of surface-erodible, biodegradable μFuses, which are used to program the interval of drug release from the reservoir beneath the fuse. Figures 10A to 10F illustrate the microfabrication process by which μFuse-based devices are fabricated. Briefly, a high-resolution Phrozen8K digital light processing (DLP) 3D printer is used to create a UV-crosslinkable resin mold. The mold is placed on a glass slide coated with a poly-ε-caprolactone (PCL) film, and the assembly is clamped and placed in an oven at 87°C for 2 minutes. After the assembly was removed and allowed to cool, the mold was removed and FITC powder was manually packed into the reservoir using a measuring spatula. The device was then mounted on a spin coater, and successive thin layers of CAPP were spun over the device at high speed until a sufficiently thick layer of CAPP covered the reservoir. Finally, the device was pressed CAPP-side down onto the molten PCL film, sealing the fuse and coating the device with PCL. After cooling, one end of the device was trimmed to expose the μ-fuse, allowing for unidirectional erosion of the fuse. SEM images demonstrate the successful fabrication of a second-generation MDI: the male mold (Figure 10B), the molded PCL (Figure 10C), the FITC-filled PCL (Figure 10D), the CAPP-coated PCL (Figure 10E), and a cross-section of the final sealed drug reservoir (Figure 10F).

[0100] In vitro precisely spaced drug delivery from μ-fuse-based MDIs Once the microfabrication of μFuse-based implants was achieved, testing was performed to confirm the ability to precisely time drug delivery from the implants. Fluorescein (FITC) was loaded into the reservoirs of a three-dose implant designed to release drug every three days (Q72). μFuse degradation was then monitored via imaging and FITC release on a microplate reader. Linear degradation of the CAPP μFuse was observed over time. μFuse degradation "unmasks" the reservoirs, ensuring sequential, timed release. Importantly, FITC release also coupled with μFuse degradation, resulting in rapid, comparable release from all three reservoirs, with each pulse equally spaced by three days as designed (Figure 11).

[0101] Trace amounts of 5-HT 2A In vivo release of agonist-loaded μFuse devices 5-HT 2ATo confirm that agonists can be effectively delivered in vivo from an implantable drug delivery system, the encapsulation and release of DOI (2,5-dimethoxy-4-iodoamphetamine) by CAPP films was investigated. DOI release was first observed from monolayer CAPP films. Importantly, the release kinetics of DOI closely mimicked those of rhodamine and FITC, model drugs used in earlier studies (Figure 12A). DOI-loaded monolayer films were then implanted subcutaneously into CD-1 mice (50:50 male / female ratio), and the pharmacokinetics and biodistribution of DOI after implantation were monitored (Figures 12B to 12D). DOI was found to be rapidly absorbed from the subcutaneous films, with peak plasma concentrations 2 hours after implantation and subsequently cleared from the circulation, closely mimicking the published pharmacokinetic profile of the drug (Figure 12C). Furthermore, DOI rapidly accumulated in the brain and was subsequently cleared with kinetics similar to that in plasma (Figure 12D). Following this initial optimization, multilayer CAPP films with DOI encapsulated in the "release" layer were produced and implanted subcutaneously into CD-1 mice (50:50 male / female ratio, Figure 12E). Again, rapid absorption of DOI from the first "release" layer and accumulation in the brain (as well as kidney and liver) were observed (Figures 12F to 12G). After DOI levels returned to baseline, a second clear pulse of DOI was observed in plasma and organs approximately 20 hours after the first pulse. These results represent the first successful interval dosing of a hallucinogen from a biomaterial and support the ability to evaluate encapsulation and interval release of hallucinogens from implantable drug delivery systems.

[0102] It should be emphasized that the above-described embodiments of the present disclosure are merely possible examples of implementations, set forth for a clear understanding of the principles of the disclosure. Many variations and modifications may be made to the above-described embodiments without substantially departing from the spirit and principles of the disclosure. All such modifications and variations are intended to be included within the scope of the disclosure and are protected by the following claims.

[0103] References 1.Hossain M, et al. Interval delivery of 5HT(2A) agonists using multilayered polymer films. J Biomed Mater Res A. Jun 2023;111(6):790-800. doi:10.1002 / jbm.a.37497 2.de la Fuente Revenga M, et al. Fully automated head-twitch detection system for the study of 5-HT(2A) receptor pharmacology in vivo. Sci Rep. Oct 3 2019;9(1):14247. doi:10.1038 / s41598-019-49913-4

Claims

1. 1. A device for delivering one or more bioactive agents to a subject, comprising: (a) a first layer comprising a first biodegradable polymer, the first layer having a first side and a second side, wherein a plurality of reservoirs comprising the one or more bioactive agents are present on the first side of the first layer; (b) a second layer comprising at least one second biodegradable polymer, the second layer adjacent to the first side of the first layer; (c) a longitudinal axis; (d) a third layer comprising a third biodegradable polymer, the third layer sealing the first layer and the second layer, and at least one surface perpendicular to the longitudinal axis of the device comprising an exposed second layer surface not covered by the third biodegradable polymer; and 1. A device comprising:

2. The device of claim 1 , wherein the first biodegradable polymer and the at least one second biodegradable polymer are different polymers.

3. The device of claim 1 , wherein the first biodegradable polymer and the third biodegradable polymer are the same polymer.

4. 10. The device of claim 1, wherein the first biodegradable polymer comprises poly-ε-caprolactone (PCL), polysebacic acid, polylactic acid, polyester, polyanhydride, polyurethane, polyphosphazine, polyalkylcyanoacrylate, polypeptide, a block copolymer comprising polyethylene glycol (PEG), or any combination thereof.

5. The device of claim 1 , wherein the first layer has a thickness of about 0.1 mm to about 2 mm.

6. The device of claim 1 , wherein the at least one second biodegradable polymer erodes from the exposed surface of the second layer.

7. 10. The device of claim 1, wherein the at least one second biodegradable polymer comprises a mixture of cellulose acetate phthalate (CAP) and poloxamer, a polyanhydride, a polyorthoester, or any combination thereof.

8. 10. The device of claim 1, wherein the at least one second biodegradable polymer comprises a mixture of cellulose acetate phthalate (CAP) in an amount of about 50 mol% to about 90 mol% and poloxamer in an amount of about 10 mol% to about 50 mol%.

9. The device of claim 1 , wherein the second layer has a thickness of about 0.1 mm to about 2 mm.

10. 10. The device of claim 1, wherein the third biodegradable polymer comprises poly-ε-caprolactone (PCL), polysebacic acid, polylactic acid, polyester, polyanhydride, polyurethane, polyphosphazine, polyalkylcyanoacrylate, polypeptide, a block copolymer comprising polyethylene glycol (PEG), or any combination thereof.

11. The device of claim 1 , wherein the third layer has a thickness of about 0.1 mm to about 2 mm.

12. 10. The device of claim 1, wherein the one or more bioactive agents comprise an antibiotic, an analgesic, an immunomodulatory component, a growth factor, an enzyme inhibitor, a hormonal agent, a messenger molecule, a cell signaling molecule, a receptor agonist, an oncolytic virus, a chemotherapeutic agent, a receptor antagonist, a nucleic acid, a nanoparticle, a drug conjugate, an antibody drug conjugate, or any combination thereof.

13. The device of claim 1 , wherein each of the plurality of reservoirs contains a different bioactive agent.

14. The device of claim 1 , wherein each of the multiple reservoirs contains the same bioactive agent.

15. The device of claim 1 , wherein the plurality of reservoirs are arranged in one or more rows parallel to the longitudinal axis.

16. 16. The device of claim 15, comprising at least two rows of reservoirs, each row of reservoirs containing a different bioactive agent.

17. 16. The device of claim 15, comprising at least two rows of reservoirs, each row of reservoirs containing the same bioactive agent.

18. The device of claim 1 , further comprising a plurality of distances between reservoirs, said plurality of distances being measured parallel to said longitudinal axis.

19. 20. The device of claim 18, wherein each distance of the plurality of distances is the same.

20. 20. The device of claim 18, wherein at least a first distance of the plurality of distances is different from at least a second distance of the plurality of distances.

21. 10. The device of claim 1, wherein at least a first reservoir of the plurality of reservoirs is adjacent to a second biodegradable polymer that is different from at least a second reservoir of the plurality of reservoirs.

22. The device of claim 1 , wherein each of the plurality of reservoirs is adjacent to the same second biodegradable polymer.

23. The device of claim 1 , wherein each of the plurality of reservoirs has the same volume.

24. The device of claim 1 , wherein at least a first reservoir of the plurality of reservoirs has a different volume than at least a second reservoir of the plurality of reservoirs.

25. The device of claim 1 , wherein the at least one second biodegradable polymer comprises an additional bioactive agent.

26. 26. The device of claim 25, wherein the additional bioactive agent is the same as the one or more bioactive agents in the multiple reservoirs.

27. 26. The device of claim 25, wherein the additional bioactive agent is different from the one or more bioactive agents in the plurality of reservoirs.

28. 28. A method for intermittent delivery of one or more bioactive agents to a subject, comprising implanting in said subject a device according to any one of claims 1 to 27.

29. 30. The method of claim 28, wherein the device is implanted by injection.

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