Biodegradable implants for zero order release of solid drug formulations

Abstract

An implantable device for delivery of a hydrophobic compound to a subject, the device including: at least one tablet including the hydrophobic compound in a compressed form, wherein the tablet is configured to exhibit a sustained release profile via surface-mediated dissolution when implanted into the subject.

Description

BWH 2025-313-02Quarles 129319.01147 BIODEGRADABLE IMPLANTS FOR ZERO ORDER RELEASE OF SOLID DRUG FORMULATIONSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application is based on and claims priority from U.S. Patent Application Ser. No. 63 / 776,837, filed on March 24, 2025, the entire disclosure of which is incorporated herein by reference.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0002] N / A.BACKGROUND

[0003] Reversible contraceptives empower women to prevent unintended pregnancies and enable family planning, however the need for frequent dosing of contraceptive pills or injections often leads to suboptimal medication adherence and reduced effectiveness, a challenge which is mirrored across various chronic conditions. Among college women in the United States, adherence to daily oral contraceptive pills is estimated at only -52%, resulting in a drop in effectiveness from 99.7% under perfect use conditions to 91% in typical use conditions.Similarly, low adherence rates are observed for a range of other chronic drug therapies including for hyperlipidemia, diabetes, obesity, hypertension, asthma, depression, epilepsy, human immunodeficiency virus (HIV), and tuberculosis. As a result, suboptimal medication adherence severely compromises treatment effectiveness, leading to high discontinuation rates, poorer health outcomes, and increased healthcare costs.SUMMARY

[0004] It would be advantageous to provide improved delivery mechanisms for substances such as contraceptives or other compounds including other drugs. Accordingly, embodiments disclosed herein provide implants that exhibit numerous advantages including zero-order drug release kinetics, longer duration than current products, and / or reduced or no excipients. These implants can be used to deliver a variety of compounds including contraceptive1QB\101545652.4BWH 2025-313-02Quarles 129319.01147 compounds.

[0005] This disclosure provides embodiments of implant devices, which in various embodiments are not limited to administering contraceptives. Instead, the implant devices can be used to administer a number of hydrophobic compounds such as drugs. In various embodiments the term "monolithic" indicates that the implant is entirely solid and dry as opposed to using injectable liquid or suspension systems and in situ forming implants or liquid formulations.

[0006] Embodiments of the disclosure introduce designs of implants that are fully bioresorbable, eliminating the need for end-of-life surgical removal. The disclosure also introduces compacted formulations of hydrophobic drugs and implant architectures (including one or multiple layers) that enable higher drug loading efficiencies compared to existing implants, zero order drug release kinetics which are not seen with existing implants, and tunable formulation surface areas and formulation thickness, which govern the drug release rate and drug release duration, respectively. Together, these innovations enable the current implant design to provide therapeutic coverage beyond what is offered by existing implants (i.e., > 5years) and in a smaller device. The tunability of this system also enables delivery of different hydrophobic drugs for a variety of therapeutic applications.

[0007] While the disclosure provides for numerous embodiments, exemplary embodiments include:

[0008] 1 One 2-layer rod-shaped device (with length = 27.9 mm, width = 2.4 mm, thickness = 2.1mm) that is loaded with compacted levonorgestrel formulations and is inserted into the body using a trocar and can provide up to an estimated about 5 years of contraceptive coverage.

[0009] 2. Two 1-layer devices ( 27.9 mm x 2.4 mm x 2.0 mm) that are loaded with compacted levonorgestrel formulations and are inserted into the body using a trocar which can provide up to an estimated about 10 years of contraceptive coverage.

[0010] 3 Two 3-layer devices (40.4 mm x 0.84 mm x 0.64 mm) that are loaded with compacted levonorgestrel formulations and are inserted into the body using an 18-gauge hypodermic needle which can provide up to an estimated about 1 year of contraceptive coverage.

[0011] 4 Three 2-layer devices ( 40.4 mm x 0.84 mm x 0.64 mm) that are loaded with compacted levonorgestrel formulations and are inserted into the body using an 18-gauge hypodermic needle which can provide up to an estimated about 1.5 years of contraceptive2QB\101545652.4BWH 2025-313-02Quarles 129319.01147 coverage.

[0012] 5. Instead of levonorgestrel, each of the above implant designs can be loaded with compacted formulations of Ivermectin, Quinestrol, or any other hydrophobic small molecule drugs and can provide sustained zero-order drug release of these compounds.

[0013] 6. The disclosure is exemplified using levonorgestrel, Ivermectin, and Qinestrol, but other drugs can be used; a non-limiting list is provided below.

[0014] Various advantages and characteristics of the disclosed embodiments include that they:

[0015] 1. Leverage a highly space efficient formulation made up of substantially 90 — 100% compacted hydrophobic drug that can provide more than 6 months of sustained drug release via a surface-mediated dissolution mechanism. This formulation has several attributes that make it useful including:

[0016] a. It has very high drug loading efficiency (as much as 100% by mass and volume), and / or

[0017] b. provides sustained drug release via a surface dissolution / erosion mechanism over for 6 months to greater than 1 year. This dissolution / erosion occurs predominantly at the surface of the compacted formulation rather than in the internal porosity and is useful because drug release rate and duration can be predicted as function of the gross geometry and size of the formulation. The large size of these formulations, with characteristic length scales ranging between 0.1 mm to over 10 cm, enables sustained release for months to years. Implications of this design include:

[0018] i. One implication of this phenomenon is that the compacted formulation will exhibit a sustained or "zero-order" drug release profile so long as the exposed surface area of the formulation is maintained / held constant as the formulation slowly dissolves / erodes. This can be achieved by incorporating the solid formulation(s) into a device, and / or

[0019] ii. A second implication is that large micron to millimeter, or larger, sized formulations that exhibit the surface-mediated dissolution phenomenon can be manufactured by physical compaction of micron or smaller sized drug crystals (i.e., powders), rather than growing large micron to millimeter-sized drug crystals. This allows easy manufacturing and scalable manufacturing using established industry processes; and / or

[0020] c. The formulations themselves can be implanted into the body to provide3QB\101545652.4BWH 2025-313-02Quarles 129319.01147 sustained drug release.

[0021] 2 introduce a flexible implant architecture that houses the compacted formulations that:

[0022] i. modulates dissolution and drug release from one or more surfaces of the compacted formulation. This can be leveraged to maintain a constant exposed surface area of the incorporated compacted drug formulations to achieve zero order drug release kinetics as the formulation dissolves;

[0023] ii. allows fortuning of the thickness and total exposed surface area of the compacted formulations through arrangement on one or more layers separated by a hydrogel that swells following insertion into the body such that drug release from opposed formulation surfaces is relatively unimpeded. This allows for modulation / control of the total drug release rate from the implant and the duration of drug release. This can be used to create implants for different therapeutic use cases (i.e., different drugs and indications, different durations of drug release, different drug release rates, loading and delivery of combinations of drugs);

[0024] iii. is space efficient with respect to drug loading (showing drug loading by total weight or volume > 70%);

[0025] iv. has a narrow form factor that allows for minimally invasive insertion into the body using a trocar or a standard gauge hypodermic needle (e.g., 16G, 18G, 21G, or 23 G needles);

[0026] v. enhances the mechanical integrity of the formulations to enable easy handling and prevent fracturing of the compacted formulations, which are prone to cracking and shattering; and / or

[0027] vi. is fully biodegradable. The time it takes for the polymer implant casing can be modulated by the use of different polymer chemistries and molecular weights. The casing can also be composed of alternative materials such as biodegradable and biocompatible metals (e g., zinc, molybdenum, tungsten, magnesium, iron, calcium, or alloys of these materials)

[0028] 3 are smaller and / or longer lasting compared to existing contraceptive implants, and / or

[0029] 4. provide a platform system that can be loaded with compacted formulations of multiple drugs. The duration and drug release rate of each can be controlled as described above.

[0030] Accordingly, in one aspect, the disclosure provides an implantable device for 4QB\101545652.4BWH 2025-313-02Quarles 129319.01147 delivery of a hydrophobic drug to a subject. The device includes a highly compacted formulation of the drug with no excipients and in tablet form.

[0031] Exemplary hydrophobic drugs that can be formulated into the device of the disclosure include, without limitation:

[0032] For HIV prophylaxis: cabotegravir, ilpivirine, lenecapavir, and MK 8527 for example.

[0033] For malaria: tafenoquine and ivermectin, for example.

[0034] For tuberculosis: ganfeborole, TBAJ-876, and pretomanid for example.

[0035] For hormone therapy (e.g., contraception, hormone replacement therapy, reproductive disorders etc.): testosterone enanthate, estradiol benzoate, estradiol valerate, zoledronate, and medroxyprogesterone acetate for example.

[0036] For pain management: dinalbuphine sebacate, sufentanil, and fentanyl for example.

[0037] For mental disorders (schizophrenia, tourette's syndrome, depression, biopolar disorder etc.): pimozide, brexpiprazole, paliperidone palmitate, olanzapine pamoate, aripiprazole, aripiprazole lauroxil, and haloperidol decanoate for example.

[0038] For cancer: Fulvestrant, testosterone enanthate, paclitaxel, and docetaxel for example.

[0039] In another aspect, the device further includes a partial encasement composed of a biocompatible and biodegradable / bioresorbable (which includes a material that can be broken down and cleared by the body over time) polymeric material. Poly-lactic acid (PLA) is exemplified. The tablet is partially encased in the polymer, but two opposing surfaces of the tablet, typically the top and bottom, are left exposed and not encased in the polymer. Encasing the tablet in this manner provides a predictable and steady release of the drug over time.

[0040] The encasement material is not limited to poly lactic acid (PLA; or more specifically poly-L Lactic acid, PLLA; or poly D lactic acid, PLDA) of various molecular weights and end caps (acid or ester end caps, but may also be poly lactic-co-glycolic acid (PLGA) of various molecular weights, lactic acid to glycolic acid rations and end caps (acid or ester end caps) and Poly( E-caprolactone) (PCL) of various molecular weights. The encasement material may also include additives within the polymer matrix or structure including imaging contrast agents (e.g., iodine-based contrast agents such as lohexal, iopamidol, iopromide, or 5QB\101545652.4BWH 2025-313-02Quarles 129319.01147 others; gadolinium-based contrast agents such as gadobutrol, gadopentetate dimeglumine, or others; manganese-based contrast agents such as Mn-EDTA, MD-DPDP, or others; iron nanoparticles; fluorescent nanoparticles and quantum dots; fluorescent molecules) to enable non-invasive imaging of the implant in the body using modalities such as x-ray, microCT, MRI, and others.

[0041] Further, the tablet can be formed into layers separated by a hydrogel or xerogel. The xerogel takes up less space (when dried) and then once in the body it rehydrates into the hydrogel. Chemically, hydrogels and xerogels are the same material. The design requirement for these materials is that they are biocompatible and swell as is expected for a hydrogel. Exemplary hydrogels that would work include hydrogels made from the following (or derivatives of these, or combinations / copolymers of these), without limitation: hyaluronic acid, alginate, chitosan, gelatin and derivatives thereof (one derivative is gelatin methacrylate (GeLMA), poly(vinyl pyrrolidone), and poly(ethylene glycol). These can all be of various molecular weights, cross linking densities, cross linking agents, chemical modifications, and densities as is well known in the art.

[0042] Thus, in one embodiment the disclosure provides an implantable device for delivery of a hydrophobic compound to a subject, the device including: at least one tablet including the hydrophobic compound in a compressed form, wherein the tablet is configured to exhibit a sustained release profile via surface-mediated dissolution when implanted into the subject.

[0043] In another embodiment the disclosure provides a method of manufacturing an implantable device for delivery of a hydrophobic compound to a subject, the method including: compacting crystals of the hydrophobic compound to form at least one tablet, wherein the tablet is configured to exhibit a sustained release profile via surface-mediated dissolution when implanted into the subject.

[0044] In still another embodiment the disclosure provides a method of delivering a hydrophobic compound to a subject, the method including: implanting in the subject a device including at least one tablet including the hydrophobic compound, wherein the tablet is configured to exhibit a sustained release profile via surface-mediated dissolution, and maintaining the device in the subject for a period of at least one month.

[0045] In yet another embodiment the disclosure provides a method of treating a6QB\101545652.4BWH 2025-313-02Quarles 129319.01147 condition in a subject in need thereof, the method including: implanting in the subject a device including at least one tablet including a hydrophobic compound, wherein the tablet is configured to exhibit a sustained release profile via surface-mediated dissolution, and maintaining the device in the subject for a period sufficient to treat the condition.BRIEF DESCRIPTIONS OF THE DRAWINGS

[0046] Figure 1. Figure 1A) Schematic illustrating the dosing regimen and therapeutic duration of current reversible long-acting contraceptive systems compared to the proposed bioresorbable MoSAIC system. Figure IB) Schematic illustrating the effect of size and geometry of four different LNG formulations on the drug release profile and therapeutic duration. Figure 1C) Photograph showing the tablet compression of lyophilized LNG to form compacted LNG formulations. Figure ID) Photograph of compacted LNG formulations of three different sizes: l x l mm, 2 x 2 mm, and 4 x 4 mm. Figure IE) In vitro drug release profile for the three different compacted LNG formulations in pH 7.4 PBS supplemented with 3%SDS at 37°Cunder sink conditions and constant agitation. Data plotted as mean ± SD ( n > 4). Figure IF) In vitro drug release rate for the three different compacted LNG formulations. Data plotted as mean ± SD ( n > 4).

[0047] Figure 2. In vivo characterization of compacted LNG formulations. Panel A) Experimental timeline. The formulations were implanted into the subcutaneous tissue on the dorsal region of Sprague Dawley rats. Blood was sampled over the course of a 53-week period. Animals were euthanized and the compacted LNG formulations were retrieved 15 months post implantation. Panel B) Plasma concentration-time curves showing plasma LNG levels of 3 different formulation sizes over a 53-week period. Data plotted as mean ± SD ( n = 4). Panel C) Normalized plasma concentration-time curves showing plasma LNG levels of 3 different formulation sizes that are normalized to the initial surface area of the formulations over a 53 -week period. Data plotted as mean ± SD ( n = 4). Panel D) Photograph of explanted4 x 4 mmcompacted LNG formulation. Inset: formulation was extracted from the subcutaneous tissue. Panel E) H&E-stained tissue section showing the cross section of the compacted LNG formulation within the subcutaneous tissue. Panel F) SEM image showing the top-down view of a 4 X 4 mmcompacted LNG formulation prior to implantation. Panel G) SEM image showing the surface of a 4 x 4 mmcompacted LNG formulation prior to implantation. Panel H) SEM 7QB\101545652.4BWH 2025-313-02Quarles 129319.01147 image showing the top-down view of a 4 x 4 mmcompacted LNG formulation 15 months post implantation. Panel I) SEM image showing the surface of a 4 x 4 mmcompacted LNG formulation 15 months post implantation.

[0048] Figure 3. Monolithic LNG implants. Figure 3 A) Schematic and photograph of LNG-loaded MoSAIC implants. Figure 3B) Photograph showing loading of a MoSAIC implant in a trocar for subdermal insertion. Figure 3C) Photograph showing the ability to insert MoSAIC implants through an 8G trocar. Figure 3D) Plasma LNG concentration-time curves of four different MoSAIC device designs over a 120 -day period following subcutaneous implantation into the dorsal region of Sprague Dawley rats. Full-thickness devices were evaluated with 5 replicates (n = 5). End-of-life devices were evaluated with 4 replicates (n = 4). Data plotted as mean ± SD. Figure 3E) Daily drug release rates for four different MoSAIC device designs over a 120 -day period. Data plotted as mean ± SD. Figure 3F) Photograph a MoSAIC device loaded with 2 mm thick compacted LNG formulations 6-months after implantation in the subcutaneous tissue of a rat. Figure 3G) Photograph a MoSAIC device loaded with 0.05 mm thick compacted LNG formulations 6-months after implantation in the subcutaneous tissue of a rat. Figure 3H) Body weights of the rats receiving an implant over the course of the 120 -day implantation period. Data plotted as mean ± SD (n > 4). Figure 31) H&E-stained tissue section showing the cross section of the LNG-loaded MoSAIC devices within the subcutaneous tissue. Figure 31) Optical profilometry image of the top surface of a retrieved MoSAIC device, which was initially loaded with 2 mm thick compacted LNG formulations, 6 months after implantation in the subcutaneous tissue of a rat. The white line denotes the location of the measured cross-sectional profile. Figure 3K) The measured profile along the length of the compacted LNG formulation. The distance along the length of device and the vertical height of the device, measured with respect to the top surface of the device, is plotted on the x-axis and y-axis, respectively.

[0049] Figure 4. Space-efficient shape-changing monolithic LNG implant designs. Figure 4A) Schematic showing the cross section of a MoSAIC implant design with one, two, or three layers. The compacted LNG formulation and PLLA casing are shown in pink and grey respectively. The exposed formulation surface area is denoted in blue, and the characteristic formulation thickness is denoted in green. Two- and three-layer designs are separated with a crosslinked xerogel that expands upon exposure to interstitial fluid to physically separate the layers. Figure 4B) Photograph showing a two-layer shape changing MoSAIC design prior to 8QB\101545652.4BWH 2025-313-02Quarles 129319.01147 (dry) and after (swollen) incubation in pH 7.4 PBS. Figure 4C) In vitro drug release profdes for two MoSAIC device designs with equivalent exposed formulation surface area (i.e., two discrete a single-layer MoSAIC devices and a single 2-layer shape-changing device). Devices were incubated in pH 7.4 PBS supplemented with 3%SDS at 37°Cunder sink conditions and constant agitation. Data plotted as mean ± SD (n = 5). Figure 4D) Experimental timeline for in vivo pharmacokinetic evaluation of three different LNG-loaded MoSAIC device designs. Devices were individually implanted into the subcutaneous tissue on the dorsal region of Sprague Dawley rats. Each device design was evaluated with n = 5 replicates. Blood was sampled over a 175-day period. Figure 4E) Plasma LNG concentration-time curves for 3 different MoSAIC device designs over a 175-day. Data obtained from n > 4replicates and plotted as Mean ±SD. Figure 4F) Daily drug release rates for 3 different MoSAIC device designs over a 175-day period. Data obtained from n > 4replicates and plotted as Mean ± SD. Figure 4G) AUC for the 3 different MoSAIC device designs following subcutaneous implantation in rats. Data obtained from n > 4replicates and plotted as Mean ± SD. Figure 4H) Models of four different MoSAIC implant designs and the commercial Jadelie® system for long-term reversible contraception. Estimated therapeutic durations are calculated from the measured in vivo dissolution rates of compacted LNG formulations in rats. Figure 41) Photograph showing the relative size of 2 different MoSAIC device designs, the commercial Nexplanon® system, and a model of the commercial Jadelle® system for long-term reversible contraception. Figure 4J) Photographs showing loading of a 2-layer MoSAIC contraceptive device into a trocar for subsequent subcutaneous placement. Figure 4K) Photographs showing the procedure for minimally invasive subcutaneous placement of a 2-layer MoSAIC contraceptive implant into the rear flank of an anesthetized pig. Figure 4L) Photographs showing the procedure for minimally invasive retrieval of a 2-layer MoSAIC contraceptive implant from the rear flank of an anesthetized pig 2-weeks post insertion.

[0050] Figure 5. In vitro characterization of compacted LNG formulations. Figure 5 A) Effect of compaction force on the density of the solid LNG formulations. Formulations were 2.0 mm in diameter, 1.26 ± 0.22 mm in height, and 4.57 ± 0.16mg in weight. Compaction forces evaluated were 500 N, 1500 N, and 3500 N, which corresponds to compaction pressures of 159.16 MPa, 477.47 MPa, and 1114.11 MPa, respectively. Data presented as mean ± SD (n = 3). Figure 5B) In vitro drug release kinetics of compacted LNG formulations. The cylindrical formulations were incubated in 40 mL of pH 7.4 PBS supplemented with 10% B-CD at 37°C 9QB\101545652.4BWH 2025-313-02Quarles 129319.01147 with constant agitation. Drug concentrations in the samples were measured using HPLC. Data presented as mean ± SD ( n = 3).

[0051] Figure 6. Quinestrol formulations. Figure 6A) Quinestrol stability following incubation of solubilized drug at 37°C and 60°C for up to 2 weeks. Quinestrol was dissolved at a concentration of 0.551 + 0.078mg / mL in pH 7.4 PBS supplemented with 10% B-CD. Data presented as mean ±SD (n = 3). Figure 6B) In vitro drug release kinetics of compacted LNG formulations. The cylindrical formulations weighing 26.73 + 3.95mg were incubated in 20 ml of pH 7.4 PBS supplemented with 10%B-CD at 37°C with constant agitation. 10 ml of release medium was sampled at each timepoint and replaced with 10 ml of fresh medium. Drug concentrations in the samples were measured using HPLC. Data presented as mean ± SD. Data presented as mean ± SD ( n = 3).

[0052] Figure 7. Ivermectin formulations. Figure 7A) Ivermectin stability following incubation of solubilized drug at 37°C and 60°C for up to 2 weeks. Ivermectin was dissolved at a concentration of 1.047 + 0.287mg / mL in pH 7.4 PBS supplemented with 10%SDS. Data presented as mean ±SD ( n = 3). Figure 7B) In vitro drug release kinetics of compacted LNG formulations. The cylindrical formulations weighing 28.22 + 1.75mg were incubated in 20 mL of pH 7.4 PBS supplemented with 10% SDS at 37°Cwith constant agitation. 10 mL of release medium was sampled at each timepoint and replaced with 10 mL of fresh medium. Drug concentrations in the samples were measured using HPLC. Data presented as mean ± SD. Data presented as mean ± SD (n = 3).

[0053] Figure 8. Photograph of manipulation of a retrieved compacted 4 mm x 4 mm cylindrical LNG formulation.

[0054] Figure 9. Representative HPLC chromatograms of solid LNG formulations before (top) and after (bottom) heating at 200°C. Retention time and purity remained consistent at 3.174 minutes and 100% respectively, suggesting that LNG remained stable following heat treatment.

[0055] Figure 10. Photographs showing structural integrity of MoSAIC implants. Figure 10A) The MoSAIC implant was inserted into a 1 -inch-thick section of porcine skin tissue mounted on a rigid support. A 60 N point load was applied overtop of the center of the device using a 1 / 8" diameter steel plunger at a rate of 15 mm / min. Figure 10B) Photograph of the intact MoSAIC device following force application.

[0056] Figure 11. Chemical purity of LNG within monolithic implants that were10QB\101545652.4BWH 2025-313-02Quarles 129319.01147 implanted into the SC tissue of rats and retrieved after 1 year. Chemical purity is normalized to LNG within control monolithic implants that were not implanted into animals. Data presented as mean ±SD (n = 3).

[0057] Figure 12. Photograph showing the concept of an 18 G monolithic implant design. The implant is loaded with a compacted LNG formulation and fitted within the body of an 18-gauge hypodermic needle.

[0058] Figure 13 shows Table 1 which provides specifications of compacted formulations and MoSAIC devices.

[0059] Figure 14 shows Table 2 which provides a detailed comparison of contraceptive MoSAIC designs with Jadelie® and Nexplanon®.

[0060] Figure 15 shows pharmacokinetics of pimozide-loaded MoSAIC implants in rats. The graph shows plasma pimozide concentrations in rats implanted with pimozide-loaded MoSAIC devices. Data presented as n=4. Error bars represent standard deviation.

[0061] Figure 16 shows self-injectable monolithic implants which can be delivered via a hypodermic needle, including aspects of the manufacture of such injectable monolithic implants which are compatible with self-administration using 21G-23G hypodermic needles. Panel A) Photograph showing the manufacture injectable monolithic implants via laser engraving of biodegradable metal sheets followed by compaction of hydrophobic drug (levonorgestrel) into the casing. Panel B) Photograph of individual monolithic implants. Panel C) Injection of an array of monolithic implants into the subcutaneous tissue of ex vivo pig tissue using a 21G hypodermic needle. Panel D) Photograph of two monolithic implants, one on top of a US penny, and the second in the bore of a 21G hypodermic needle. Panel E) Photograph of a monolithic implant in the bore of a 21G hypodermic needle. Panel F) x-ray imaging of the deposited depot of monolithic implants in the ex vivo pig tissue.

[0062] Figure 17 shows various implant configurations and designs, including schematics showing MoSAIC designs containing the monolithic formulation of compressed hydrophobic drug contained within a rigid casing. Formulation shown in orange and labeled 'API'. Rigid casing shown in blue. Panel A) Cross section of a rigid device with multiple formulations.Formulations are exposed to the external environment through the top and bottom formulation surfaces. Panel B) Cross section of a rigid device with multiple formulations. Formulations are exposed to the external environment through the top formulation surface only. Panel C) Cross 11QB\101545652.4BWH 2025-313-02Quarles 129319.01147 section of an array of rigid devices, each containing a formulation contained within a casing. Formulations are exposed to the external environment through the top and bottom formulation surfaces. Panel D) Cross section of a rigid device with one formulation. Formulation is exposed to the external environment through the top formulation surface only. Panel E) Cross section of a device with multiple formulations, each formulation within its own rigid casing and connected with a flexible member. Formulations are exposed to the external environment through the top and bottom formulation surfaces. Flexible members may be constructed of a flexible material (e.g., silicone, rubber) and / or may have geometries that enable deformation under load (e.g., serpentine geometry, thin geometry, suture, filament, thin film). Flexible member show in pink. Panel F) Cross section of a device with multiple formulations, each formulation within its own rigid casing and connected with a flexible thin-film member. Flexible member show in pink. Panel G) Cross section of a rigid device with multiple formulations and two layers, separated by a hydrogel or xero gel (shown in green). Formulations are exposed to the external environment through the top and bottom formulation surfaces. Panel H) Cross section of a rigid device with multiple formulations and two layers, separated and encased by a hydrogel or xero gel (shown in green). Formulations are exposed to the external environment through the top and bottom formulation surfaces. Panel I) Cross section of a rigid device with multiple formulations integrated onto the surface of a larger implant (e.g., intrauterine device, ingestible capsule, intrabladder device).

[0063] Figure 18 shows plasma ivermectin concentrations in rats implanted with ivermectin-loaded MoSAIC devices. Devices had a total exposed formulation surface area of 172.8 mm2(orange, lower trace) or 345.6 mm2(blue, upper trace). Data presented as n=4. Error bars represent standard deviation.DETAILED DESCRIPTION

[0064] Reversible contraceptives empower women to prevent unintended pregnancies and enable family planning. However, the need for frequent dosing with pills or injections often leads to suboptimal medication adherence and reduced effectiveness-an issue common to many chronic conditions. Long-acting drug delivery implants offer a compelling alternative by enabling autonomous, multi-year drug release, thereby improving real-world adherence and treatment outcomes. However, user acceptability and access are limited by need for invasive 12QB\101545652.4BWH 2025-313-02Quarles 129319.01147 insertion and surgical end-of-life removal, particularly in low-resource settings, as well as by limited drug loading and suboptimal drug utilization efficiency, which constrain both the duration of therapy and the range of drugs that can be effectively delivered.

[0065] To address these limitations, we developed the Monolithic Shape-shifting Absorbable Implants for Chronic Care (MoSAIC) platform-a minimally invasive, fully bioresorbable system that integrates compacted drug formulations with a space-efficient device architecture. This approach reduces implant size, eliminates the need for surgical removal, and prolongs therapeutic duration compared to existing implants. We develop compacted formulations of the contraceptive drug levonorgestrel (LNG), and other poorly water-solubility drugs, demonstrating exceptional drug loading ( 100%w / w) and multi-year sustained drug release via surface-mediated dissolution in rats. When incorporated into MoSAIC devices, these formulations enable high-efficiency drug loading and zero-order drug release kinetics with geometrically tunable rates and durations. As a result, MoSAIC systems can be designed to be smaller, less invasive, and / or longer lasting than current contraceptive implants such as Jadelle® and Nexplanon®.

[0066] The MoSAIC platform expands access to reversible contraception and supports long-term medication adherence, with the potential to improve health outcomes and quality of life. More broadly, it provides a flexible approach for delivering other potent, low-solubility therapeutics and lays the foundation for a "dose it and forget it" paradigm in chronic disease management, where adherence is designed into the therapy itself.

[0067] Despite significant advances in pharmaceutical development that have transformed the management of chronic health conditions, medication non-adherence remains a major barrier to realizing the full benefits of these therapies. For instance, while reversible contraceptives enable women to prevent unintended pregnancies, the necessity for repeated dose administration over extended periods contributes to low adherence and high discontinuation rates. Among college women in the United States, adherence to daily oral contraceptive pills is estimated at only -52%, resulting in a drop in effectiveness from 99.7% under perfect use conditions to 91% in typical use conditions. Similarly, low adherence rates are observed for a range of other chronic drug therapies including for hyperlipidemia, diabetes, obesity, hypertension, asthma, depression, epilepsy, human immunodeficiency virus (HIV), and tuberculosis. As a result, suboptimal medication adherence severely compromises treatment 13QB\101545652.4BWH 2025-313-02Quarles 129319.01147 effectiveness, leading to high discontinuation rates, poorer health outcomes, and increased healthcare costs.

[0068] Medication adherence can be improved by developing and adopting new treatment regimens that require fewer and less frequent dose administration events. As a result, extended-release drug delivery systems with progressively longer dosing intervals have been the focus of intense development over the past two decades. Injectable polymer microspheres, crystalline suspension drug depots, oil-based formulations, and in situ forming polymer implants are promising extended-release technologies; however, the therapeutic duration achievable with these systems is largely limited to 1 — 6 months. Furthermore, these systems are generally nonretrievable, precluding the possibility of discontinuing therapy if patients develop adverse reactions or change their family planning goals.

[0069] Implantable drug delivery devices also offer extended drug release profiles, with the added benefit of being easily retrievable and providing substantially longer therapeutic coverage compared to injectable formulations. For instance, the Nexplanon® and Jadelle® subdermal implants can provide 3 or 5 years of contraception, respectively, and are the most effective form of reversible contraceptives available today. A prospective cohort study showed that 75% of women in the St. Louis area (USA) preferred long-acting reversible contraceptive systems such as implants and intrauterine devices over shorter-acting self-administrable systems (i.e., daily oral pills, long-acting injectables, vaginal rings, patches, and diaphragms) when the barriers of cost, knowledge and access were removed. Thus, long-acting drug delivery implants can offer unique advantages for the management of chronic conditions by leveraging their ultralong therapeutic durations to shift the treatment paradigm from frequent patient selfadministration, which is prone to low adherence rates, to a dose-it-and-forget it strategy where near-perfect adherence is engineered into the system (Figure 1 A).

[0070] Despite the improved adherence, effectiveness, and convenience offered by long-acting drug delivery implants, patient adoption and access to these systems can be limited by the need for subcutaneous insertion into the arm using a trocar, and end-of-life surgical removal (Figure 1A). These procedures can be painful, increase risk of infection, and require access to a clinic. Furthermore, the limited volume available for drug loading within these minimally invasive devices drastically restricts the type of drugs that can be delivered, the list of clinical indications that can be targeted, and the achievable therapeutic durations.14QB\101545652.4BWH 2025-313-02Quarles 129319.01147

[0071] To address these challenges, we report the development of the Monolithic Shapeshifting Absorbable Implants for Chronic Care (MoSAIC) platform - a minimally invasive and fully biodegradable implant architecture that maximizes the efficiency of drug loading, drug utilization, and drug release of low solubility drugs to enable smaller, less invasive, and / or longer-lasting implants. We focus on the development of MoSAIC for the delivery of levonorgestrel (LNG), a potent progesterone used for long-term contraception but also demonstrate its applicability towards other chronic conditions which face analogous long-term adherence challenges and technical limitations preventing improved long-term treatment options.

[0072] Thus, various embodiments of the disclosure relate to implantable devices for delivery of hydrophobic compounds to a subject, methods of manufacturing such devices, methods of delivering hydrophobic compounds, and / or methods of treating conditions using such devices.

[0073] Implantable Device

[0074] The implantable device of the present invention includes at least one tablet including a hydrophobic compound, wherein the tablet is configured to exhibit a sustained release profile via surface-mediated dissolution when implanted into the subject. In some embodiments the sustained release profile is a zero-order drug release profile. So-called "zeroorder" release indicates that the drug release rate remains substantially constant over time, rather than decreasing as is typical with conventional diffusion-controlled or erosion-controlled dosage forms. In other embodiments, the sustained release profile is a tapered drug release profile. In other embodiments, the sustained release profile is escalating drug release profile. In other embodiments, the sustained release profile is a combination of escalating, zero-order, and / or tapering drug release profile.

[0075] In various embodiments, the device is implanted subcutaneously / dermally, subdermally in a subject, for example under the skin in the arm, abdomen, leg, thigh, scalp, or other region of the body.

[0076] In additional embodiments, the device is implanted in or near various portions of the body and / or organs, e.g., to treat particular conditions, including for example in muscle, the brain, the kidney, the prostate, tumor, the eye, the vagina, the uterus, the ovary, the breast, the bladder , the bone, gastrointestinal tract, and / or intraperitoneal space.

[0077] Tablet Composition and Structure15QB\101545652.4BWH 2025-313-02Quarles 129319.01147

[0078] The tablet includes the hydrophobic compound in a compressed form. The tablet is formed by applying pressure to crystals of the compound, typically in a range of 20 MPa to 1200 MPa, preferably at least 150 MPa, and more preferably about 208 MPa. The crystals of the compound are typically one micron or smaller in size. In some embodiments, the crystals of the hydrophobic compound are 150 micron or smaller in size and in particular embodiments the crystals of the hydrophobic compound are in a range of 0.3 to 20 micron in size. The tablet is formed by compaction of these micron-sized or smaller drug crystals without the use of magnesium stearate or other lubricants.

[0079] The tablet is substantially non-porous, having a porosity of less than about 5%. The tablet has a density approximately equal to the true crystal density of the compound. For levonorgestrel, this density is about 1.13±0.02 mg / mm3. The tablet includes substantially no excipients, with the concentration of the hydrophobic compound in the tablet being at least 90%, and preferably about 100%.

[0080] In some embodiments, the tablet comprises a drug loading (i.e., a weight percentage of active pharmaceutical ingredient (API) relative to a total weight of the tablet, excluding optional coatings or external structures) of at least 80% by weight, at least 90% by weight, at least 95% by weight, at least 98% by weight, or approximately 100% by weight.

[0081] The tablet exhibits limited water penetration into a core of the tablet due to the absence of interconnected porosity. Drug partitioning occurs predominantly at an external surface of the tablet rather than at internal porosity. This surface-mediated dissolution mechanism enables predictable zero-order drug release kinetics.

[0082] The tablet has a characteristic length scale in a range of 0.1 mm to 10 cm. The tablet exhibits a surface erosion rate of about 100 pm per year, with uniform surface erosion characterized by a peak-to-trough surface roughness variation of about 15 pm. The tablet maintains chemical purity of at least 95% after one year of subcutaneous implantation.

[0083] The tablet can be made in a number of different forms which may depend on the particular use and / or delivery mechanism. In various embodiments, the device is configured in a form factor suitable for implantation or insertion into a subject via a minimally invasive or non-surgical delivery route, for example in an elongated form for delivery via a trocar or needle. In some embodiments, the tablet can be formed to fit within a microneedle to facilitate transdermal delivery, for example with a tablet contained within a separable or non-separable microneedle 16QB\101545652.4BWH 2025-313-02Quarles 129319.01147 such that insertion of the needle into the skin exposes the tablet to the dermal / subdermal tissue to enable sustained drug release via surface-mediated dissolution.

[0084] In various embodiments, the device has a largest dimension between 50 microns and about 50 millimeters. In some embodiments, the device has a largest dimension less than about 1 millimeter. In other embodiments, the device has a largest dimension less than about 500 microns.

[0085] In some embodiments, the device is configured as one or more of: a rod, cylinder, pellet, filament, millimeter scale particle, microscale particle, or array. In some embodiments, a plurality of tablets may be contained within a single casing. In other embodiments, the device may be made up of a plurality of separate / discrete devices, where each device includes one or more tablets. In still other embodiments, the device may be configured as part of a larger device. In some embodiments, the device is configured as part of a microneedle array, where the tablet is positioned within a microneedle structure comprising the casing.

[0086] In some embodiments, the device is configured as part of an ingestible device. In particular embodiments, the ingestible device is configured to be retained within the gastrointestinal tract for a prolonged period of time (e.g., days / weeks / months). In other embodiments, the device is configured as part of an intrauterine device. In still other embodiments, the device is configured as part of an intravaginal device. In yet other embodiments, the device is configured as part of an intrabladder device.

[0087] In various embodiments, the device is configured for delivery using a trocar. In certain embodiments, the device is configured for delivery through a hypodermic needle where the hypodermic needle is between 16 gauge and 23 gauge (e.g., 16G, 18G, 21G, or 23G). In some embodiments, the device is configured for delivery using a catheter. In other embodiments, the device is configured for delivery using an endoscope. In particular embodiments, the device is configured for delivery via oral ingestion. In some embodiments, the device is configured for delivery via vaginal placement. In other embodiments, the device is configured for delivery via intrauterine placement.

[0088] In various embodiments, the device is configured for administration to one or more of subcutaneous tissue, intramuscular tissue, dermal tissue, brain tissue, kidney tissue, ovary tissue, prostate tissue adipose tissue, intratumoral tissue, ocular tissue, oral tissue, vaginal tissue, breast tissue, bladder tissue, bone tissue, gastrointestinal tissue, or intraperitoneal space.17QB\101545652.4BWH 2025-313-02Quarles 129319.01147 In particular embodiments, the device is configured to be retained within the placement site for a prolonged period of time (e g., days / weeks / months).

[0089] Multi-Layer Configurations

[0090] In some embodiments, the tablet includes a plurality of layers. A space between adjacent layers of the plurality of layers includes a xerogel or a hydrogel. The xerogel or hydrogel includes a material selected from the group consisting of hyaluronic acid, methacrylated hyaluronic acid, alginate, chitosan, dextran, agarose, carrageenan, gelatin, collagen, fibrin, silk fibroin, and derivatives thereof, gelatin methacrylate (GelMA), poly(vinyl pyrrolidone), poly(ethylene glycol) (PEG), poly(ethylene glycol) diacrylate (PEGDA), poly(acrylamide) (pAAM), poly(vinyl alcohol (PVA), poly(N-isopropylacrylamide (PNIPAM), poly(2-hydroxyethyl methacrylate) (HEMA), poly(lactic-co-glycolic acid) (PLGA)-PEG, poloxamers including Pluronic F127, and combinations, networks, or copolymers thereof. In such embodiments, the tablet itself may be flexible.

[0091] The xerogel takes up less space when dried and then rehydrates into the hydrogel once implanted in the body. The hydrogel or xerogel swells upon exposure to interstitial fluid to physically separate the adjacent layers, thereby enabling unimpeded drug release from opposed tablet surfaces.

[0092] In some embodiments, the device includes at least one compliant region and at least one rigid region, where the compliant region exhibits greater deformation under an applied force than the rigid region. In some embodiments, a difference in deformation is based on at least one of (i) a difference in material properties between the compliant region and the rigid region, or (ii) a difference in a geometric configuration between the compliant region and the rigid region. In various embodiments, the compliant region has a lower relative flexural rigidity than the rigid region. In certain embodiments, the compliant region includes a material with lower relative Young's modulus than the rigid region. In particular embodiments, the compliant region includes at least one of a filament, fiber, thread, suture, or serpentine or reduced-thickness structure. In other embodiments, the compliant region includes an elongated portion having a cross-sectional dimension configured to permit bending under physiological forces.

[0093] In some embodiments, the hydrophobic compound includes a compound having an aqueous solubility of less than about 1 mg / mL. In various embodiments, the hydrophobic compound includes a compound having an aqueous solubility of less than about 0.1 mg / mL. In 18QB\101545652.4BWH 2025-313-02Quarles 129319.01147 certain embodiments, the hydrophobic compound comprises a compound having a logP of greater than about 2.

[0094] Implantation Configurations

[0095] The tablet is configured to be implanted subcutaneously. In one embodiment, the tablet is configured to be implanted using a trocar, with the tablet including a width of 2.4 mm and a thickness of 2.0 mm. In another embodiment, the tablet is configured to be implanted using a needle having a diameter of 16G, 18G, 21G, or 23G, with the tablet including a width of 0.84 mm and a thickness of 0.64 mm. The device is configured for insertion at a depth of about 0.5 cm from a skin surface.

[0096] Device Configurations

[0097] The device may include a plurality of tablets including the hydrophobic compound. In one embodiment, the device includes a plurality of discrete tablets arranged in a linear configuration, thereby reducing risk of mechanical fracture due to bending compared to a single high-aspect-ratio tablet. The device may include 2-6 discrete tablets or more, depending on factors including the release rate, desired dosage, desired duration / lifetime of the device, and / or placement location. In some embodiments, a plurality of discrete tablets (e.g., with each having its own rigid coating) are arranged in a linear configuration and are interconnected by relatively compliant regions. The compliant regions may be due to use of a material and / or elongated member having a cross-sectional dimension sufficiently small to permit bending under physiological forces. The compliant help avoid issues related to lack of flexibility of a larger, entirely rigid device. The use of multiple tablets arranged longitudinally helps give the device flexibility. In some embodiments, a group of separate tablets (e.g., with each having its own coating but not being joined to one another) may be delivered, which can provide the same dosage as a linked group of tablets, thereby avoiding issues related to lack of flexibility of a larger device. In some embodiments, the tablets may be incorporated into a larger device (e g., an intrauterine device, a gastrointestinal-retentive device, a bladder retentive device, a vaginal ring).

[0098] The device is configured to withstand an axial force of at least 60 N without mechanical failure when implanted subcutaneously. The device is configured to withstand the axial force without tablet fracture or tablet displacement from the biodegradable casing.

[0099] Biodegradable Casing

[0100] The device may further include a casing surrounding at least a portion of the 19QB\101545652.4BWH 2025-313-02Quarles 129319.01147 tablet, where the casing may be a biodegradable casing. The biodegradable casing surrounds an outer edge of the tablet, while one face or two opposing faces of the tablet are not surrounded by the biodegradable casing and thus are exposed to tissue. Drug release from the device occurs through exposed top and / or bottom surfaces of the tablet, with the surrounding casing providing structural support.

[0101] The biodegradable casing may include a biodegradable polymer selected from the group consisting of poly(-lactic acid) (PLA), poly(-L-lactic acid) (PLLA), poly(-D-lactic acid) (PDLA), poly(-lactic-co-glycolic acid) (PLGA), poly(s-caprolactone) (PCL), and combinations or copolymers thereof. In one embodiment, the biodegradable casing includes poly-L-lactic acid (PLLA) having a molecular weight of about 197,641 Da. In some embodiments, the biodegradable casing is formed by at least one of vacuum compression molding, injection molding (particularly for industrial-scale manufacturing), machining, electrical discharge machining, metal stamping, laser engraving (particularly on smaller devices), and / or 3D printing / additive manufacturing (particularly for materials such as PLA). In some embodiments, a casing may be made first and then powder may be compressed into the casing to form the tablet or tablets directly in the casing. In other embodiments, the tablets and casing may be made separately and then the pre-formed tablets may be press fitted or pushed into the casing.

[0102] In certain embodiments, the biodegradable polymer further includes one or more additives configured to reduce the rate of hydrolysis and / or autocatalytic degradation of the polymer. In some embodiments the one or more additives may include an acid scavenger, a chain extender or end-group modifying agent, and / or a hydrolysis inhibitor. In various embodiments, the one or more additives are selected from the group consisting of carbodiimides, aziridines, epoxy-functionalized compounds, oxazoline or oxazole-containing compounds, isocyanates, hydrotalcites, magnesium oxide, calcium oxide, silicon dioxide, and combinations thereof.

[0103] Alternatively, the biodegradable casing may include a biodegradable metal selected from the group consisting of zinc, molybdenum, tungsten, magnesium, iron, calcium, and alloys thereof.

[0104] The biodegradable casing may further include one or more imaging contrast agents selected from the group consisting of iodine-based contrast agents, gadolinium-based contrast agents, manganese-based contrast agents, iron nanoparticles, fluorescent nanoparticles, quantum dots, and fluorescent molecules.20QB\101545652.4BWH 2025-313-02Quarles 129319.01147

[0105] Biocompatible (Non-Biodegradable) Casing

[0106] The device may include a biocompatible (non-biodegradable) casing surrounding at least a portion of the tablet. The casing surrounds an outer edge of the tablet, while one face or two opposing faces of the tablet are not surrounded by the casing and thus are exposed to tissue. Drug release from the device occurs through exposed top and / or bottom surfaces of the tablet, with the surrounding casing providing structural support.

[0107] The biocompatible casing may include a biocompatible polymer selected from the group consisting of fluoropolymers (PTFE, FEP, PF A, ETFE), polyurethanes (polyurethane (PU), polycarbonate urethanes (PCU)), silicones (PDMS), polyolefins (polyethylene, polypropylene), non-degradable polyesters (polyethylene terephthalate (PET), acrylics / methacrylates (polymethyl methacrylate (PMMA)), polyether-based polymers (Polyether ether ketone (PEEK)) and / or biocompatible metals selected from the group consisting of titanium, stainless steel, nitinol, and their alloys, and combinations thereof. In one embodiment, the biocompatible casing includes medical-grade 316L stainless steel. In another embodiment, the biocompatible casing includes Bionate polycarbonate urethane (PCU). The biocompatible casing is formed by injection molding, CNC machining, additive manufacturing (e g., 3D printing), and / or laser engraving / cutting.

[0108] Therapeutic Duration

[0109] The tablet exhibits the zero-order drug release profile for a period of at least six months and may exhibit the zero-order drug release profile for a period of at least one year, at least five years, or at least ten years, although other durations are also possible. The device provides rapid cessation of drug release at an end-of-life timepoint.

[0110] Biocompatibility and Storage[OHl] The device induces formation of a fibrous capsule having a thickness of about 10-300 pm (or 20.8 pm to about 130.84 pm) when implanted subcutaneously, indicating good biocompatibility.

[0112] The device is stored at 4°C and protected from moisture prior to implantation.

[0113] Hydrophobic Compounds

[0114] The tablet may include a single hydrophobic compound or a plurality of hydrophobic compounds. As used herein, the term “compound” includes the recited chemical entity as well as all pharmaceutically acceptable forms thereof, including but not limited to salts,21QB\101545652.4BWH 2025-313-02Quarles 129319.01147 prodrugs, solvates, hydrates, polymorphs, stereoisomers, tautomers, crystalline forms, amorphous forms, and derivatives that retain substantially similar biological activity.

[0115] Exemplary hydrophobic compounds include levonorgestrel, ivermectin, quinestrol, cabotegravir, rilpivirine, lenacapavir, MK 8527, tafenoquine, ganfeborole, TBAJ-876 and analogs or derivatives thereof, pretomanid, testosterone enanthate, estradiol benzoate, estradiol valerate, zoledronate, medroxyprogesterone acetate, kisspeptin and analogs and derivatives thereof, dinalbuphine sebacate, sufentanil, fentanyl, pimozide, brexpiprazole, paliperidone palmitate, olanzapine pamoate, aripiprazole, aripiprazole lauroxil, haloperidol decanoate, fulvestrant, paclitaxel, and docetaxel, and combinations thereof. In a preferred embodiment, the hydrophobic compound is levonorgestrel.

[0116] Method of Manufacturing

[0117] The method of manufacturing the implantable device includes compacting crystals of the hydrophobic compound to form at least one tablet, wherein the tablet is configured to exhibit a zero-order drug release profile via surface-mediated dissolution when implanted into the subject.

[0118] Compacting includes applying a pressure in a range of 20 MPa to 1200 MPa, preferably greater than about 120 MPa and less than about 1200 MPa, more preferably greater than about 150 MPa and less than about 1200 MPa, to the crystals, and most preferably at least about 150 MPa. The tablet is compacted to a density approximately equal to a true crystal density of the compound. The tablet includes substantially no excipients.

[0119] The method may further include forming a biodegradable casing around at least a portion of the tablet, wherein the biodegradable casing surrounds an outer edge of the tablet while leaving one or more faces (e.g., two opposing faces) of the tablet exposed. Forming the biodegradable casing includes vacuum compression molding a biodegradable polymer around the tablet.

[0120] The method may further include inserting a plurality of tablets into the biodegradable casing. The method may further include disposing a xerogel or a hydrogel between adjacent layers of a plurality of tablets within the biodegradable casing. The xerogel or the hydrogel may include various materials and in one particular embodiment includes methacrylated hyaluronic acid.

[0121] Method of Delivering22QB\101545652.4BWH 2025-313-02Quarles 129319.01147

[0122] The method of delivering a hydrophobic compound to a subject includes implanting subcutaneously in the subject a device including at least one tablet including the hydrophobic compound, wherein the tablet is configured to exhibit a zero-order drug release profile via surface-mediated dissolution and maintaining the device in the subject for a period of at least six months.

[0123] The tablet includes the hydrophobic compound in a compressed form at a concentration of at least 90%. Implanting may include inserting the device using a trocar or using a needle having a diameter of 16G, 18G, 21G, or 23 G.

[0124] The device may further include a biodegradable casing surrounding at least a portion of the tablet, wherein the biodegradable casing maintains a substantially constant exposed surface area of the tablet during the period. The device may be fully bioresorbable such that the method does not include or require surgically removing the device from the subject at an end of the period.

[0125] The device may include a plurality of layers of tablets separated by a xerogel or a hydrogel, wherein the xerogel or the hydrogel swells upon exposure to interstitial fluid to physically separate the layers.

[0126] The period during which the device is implanted and releasing compound may be at least one year, at least five years, or at least ten years. The method may further include retrieving the device from the subject prior to an end of the period if needed or desired.

[0127] Method of Treating

[0128] The method of treating a condition in a subject in need thereof includes implanting subcutaneously in the subject a device including at least one tablet including a hydrophobic compound, wherein the tablet is configured to exhibit a zero-order drug release profile via surface-mediated dissolution, and maintaining the device in the subject for a period sufficient to treat the condition.

[0129] The condition includes a condition treatable by administration of a hydrophobic compound and may be selected from the group consisting of contraception, dysmenorrhea, menorrhagia, endometriosis, polycystic ovary syndrome, HIV, malaria, tuberculosis, onchocerciasis, scabies, menopausal hormone deficiency or other hormone therapy, pain, schizophrenia, bipolar disorder, Tourette syndrome, breast cancer, prostate cancer or other cancer, and / or inflammatory or autoimmune disorders. The condition is generally one in which 23QB\101545652.4BWH 2025-313-02Quarles 129319.01147 the condition requires sustained systemic or local delivery of the compound over a prolonged period of time

[0130] The device may further include a biodegradable casing surrounding at least a portion of the tablet, and the method does not include surgically removing the device from the subject. The device maintains a plasma concentration of the hydrophobic compound above a therapeutic threshold throughout the period.

[0131] EXAMPLES

[0132] Example 1 - Compacted levonorgestrel formulations exhibit sustained drug release kinetics

[0133] The MoSAIC platform employs millimeter-sized, compacted formulations of potent, poorly water-soluble drugs to achieve higher drug loading capacities than polymer-drug matrix systems (e.g., Jadelle®, Nexplanon®) and to enable prolonged therapeutic durations compared to injectable microcrystalline suspension drug depots (e.g., Depo-Provera®, Sayana Press®, Apretude®). This approach draws inspiration from injectable aqueous crystalline suspension depot formulations, which provide extended drug release through the gradual partitioning of drug molecules from the surfaces of micron-sized particles, with release duration proportional to particle size (Figure IB). For instance, Depo-Provera Cl®is formulated as an aqueous suspension containing medroxyprogesterone acetate particles approximately ll / i min diameter, which dissolve slowly following intramuscular injection to provide ~ 3 months of sustained drug release. While extending drug release beyond this 3-month window by increasing particle size is a potential strategy, manufacturing large, millimeter-scale crystalline drug particles for multiyear efficacy is impractical. We therefore hypothesize that a millimeter-scale monolithic formulation, created by mechanically compacting micron-sized drug crystals, could enable surface-mediated dissolution similar to that of individual particles, thereby facilitating multi-year drug release durations (Figure IB).

[0134] Cylindrical compacted monolithic LNG formulations with diameters of1 mm, 2 mm, and 4 mm and heights of 1 mm, 2 mm, and 4 mm, respectively, were fabricated by tablet compression (Figures 1C, ID, Table 1 / Figure 13). The tablets were composed entirely of drug (i.e., 100%wt.) and had an apparent density of 1.13 ± 0.02mg / mm3, closely approximating the predicted density of pure LNG (Figure 5 A). To determine whether the compacted LNG formulations exhibit sustained release profiles, we characterized their in vitro 24QB\101545652.4BWH 2025-313-02Quarles 129319.01147 release kinetics under accelerated conditions-pH 7.4 phosphate-buffered saline supplemented with 3%w / wSDS surfactant, at 37°C and constant agitation (Figures IE, IF). Surfactant supplementation enhanced the solubility of LNG in the release medium, enhancing and accelerating dissolution due to LNG's poor water solubility.

[0135] The in vitro drug release profiles revealed rapid dissolution of the l x l mm cylindrical formulations within 1 day, whereas the larger 2 x 2 mmand 4 x 4 mm formulations exhibited sustained release over 200 days (Figure IE). The drug release rates for the 2 x 2 mm and 4 x 4 mm formulations were proportional to the formulation surface area, with the 4 x 4 mm formulations exhibiting a ~ 4-fold greater initial surface area and a corresponding ~ 4-fold higher daily release rate (Figure IF). Notably, the release rates remained consistent throughout the experiment. These observations suggest that drug release from the compacted LNG formulations is governed by a surface area-controlled dissolution mechanism, and that increasing the formulations size can extend the release duration. Compacted monolithic LNG formulations manufactured using different tablet compression pressures, ranging from 159.2 MPa to 1114.1 MPa, had comparable bulk densities (Figure 5A) and in vitro drug release rates (Figure 6B), indicating that the formulations were fully compacted across all pressures tested.

[0136] We further investigated whether compacted formulations of other poorly water-soluble drugs exhibit similar release kinetics. Using the same approach, we fabricated compacted formulations of quinestrol, an estrogen used in menopausal hormone therapy, and ivermectin, an antiparasitic for onchocerciasis and scabies. These formulations demonstrated excellent chemical stability when incubated at simulated physiological conditions (pH 7.4 PBS at 37°C and 60°C supplemented with surfactant) for up to 2 weeks and exhibited sustained drug release under accelerated physiological conditions (Figure 6, 7). These results suggest that compacted monolithic formulations of various low-solubility small molecules drugs also undergo surface-mediated dissolution under physiological conditions, resulting in sustained drug release.

[0137] Compacted levonorgestrel formulations provide sustained drug release for over 1 year following subcutaneous implantation in rats

[0138] To evaluate in vivo drug release kinetics of the compacted LNG formulations, cylindrical formulations of three different sizes ( l x l mm, 2 x 2 mm, and 4 x 4 mm, corresponding to surface areas of 4.71 mm2, 18.85 mm2, and 75.4 mm2, respectively) were individually implanted into the subcutaneous tissue of healthy Sprague Dawley rats (Table 25QB\101545652.4BWH 2025-313-02Quarles 129319.01147 1 / Figure 13). Plasma drug concentrations were measured weekly over a period exceeding one year (Figure 2A). Pharmacokinetic profiles for animals implanted with the largest(4 x 4 mm)formulation demonstrated consistent plasma drug levels with no discernible Cmaxor Tmax. Plasma drug concentrations were maintained above the equivalent human therapeutic drug level of Ing / mLin rats throughout the 53-week study (Figure 2B). In contrast, plasma LNG concentrations in animals implanted with the l x l mmor 2 x 2 mmformulations remained above the limit of quantification (LLOQ of 25pg / mL) for up to 3 months. Normalization of plasma drug concentrations to the initial surface area of each formulation revealed a clear correlation between formulation surface area and systemic drug levels (Figure 2C). Together, these results indicated that drug release from the monolithic formulations is primarily governed by the bulk surface area, consistent with in vitro observations, and suggest that a formulation with a surface area greater than 75.4 mm2is sufficient to achieve and maintain human therapeutic drug levels in Sprague Dawley rats (~ Ing / mL).

[0139] The 4 x 4 mmcompacted LNG formulations remained intact, solid, and structurally stable within the subcutaneous tissue after 15 months. The formulations retained sufficient mechanical integrity to allow for physical extraction and manipulation (Figure 2D, Figure 8). Histological analysis of the implantation site showed no evidence of active inflammation and revealed the formation of a defined fibrous capsule, ranging from 20.8 / zm to 130.84iJ.m min thickness, surrounding the formulation-indicating good biocompatibility (Figure 2E).

[0140] Detailed SEM analysis comparing the monolithic LNG formulation before implantation (Figure 2F, 2G) and after 15 months in vivo (Figure 2H, 21) revealed a reduction in diameter from 3920.3 ± 0.3 / zm to 3664.8 ± 35.6 / zm, and a mass loss of 5.14 ± 0.83mg, corresponding to an estimated surface erosion rate of 102.2 ± 14.3 / z mper year. SEM imaging of the formulation surface prior to implantation (Figure 2G) and following retrieval (Figure 21) demonstrated that the tablet remained densely compacted with no significant development of enlarged internal porosity, supporting the hypothesis that drug partitioning occurs predominantly at the external surface rather than the internal porosity of the compacted meso-crystalline structure.

[0141] Design of monolithic absorbable implant architectures

[0142] A common limitation in dissolution-controlled solid formulations-including 26QB\101545652.4BWH 2025-313-02Quarles 129319.01147 aqueous crystalline suspensions and the compacted monolithic systems described above-is the gradual tapering of drug release rates over time, as the formulation size and surface area decreases during dissolution (Figure IB). To achieve sustained therapeutic levels over a target duration, this tapering necessitates initially elevated drug release rates, resulting in supratherapeutic plasma drug levels early in the treatment. This phenomenon also results in a prolonged subtherapeutic phase after the treatment period. For instance, users of Sayana Press® injectable contraceptive may experience delayed return to fertility lasting over a year, likely due to unpredictable pharmacologic effects of prolonged subtherapeutic drug exposure. Analogously, prolonged subtherapeutic exposure to antibiotics, anti-parasitics, anti-retrovirals, and chemotherapeutics may promote drug resistance and treatment failure. Moreover, this release profile leads to inefficient drug utilization, reducing the achievable therapeutic duration of space-constrained dosage forms. An optimal long-acting drug delivery system would therefore provide consistent zero-order release, maintaining plasma drug levels at or slightly above the therapeutic threshold throughout the implant's lifetime, followed by a rapid and complete cessation of drug release.

[0143] Drug release modulation from solid dosage forms have been extensively studied, particularly in oral extended-release polymer matrix tablets. Several systems capable of zeroorder drug release over several hours in the gastrointestinal tract have been developed by combining insights in drug diffusion, polymer matrix erosion, and clever geometric designs. Building on these principles, we adapted this strategy for overcoming inefficient drug utilization and dose tapering of compacted monolithic formulations for long-acting parenteral delivery by embedding them into space-efficient biodegradable devices. These devices modulate the exposed formulation surface area over multi-year timeframes, enabling precise tuning of drug release kinetics, including zero-order drug release and rapid end-of-life termination (Figure IB).Additionally, orthogonal modulation of formulation thickness provides a mechanism to adjust the total duration of drug release. Unlike prior systems reported in the literature, our device designs aim to be fully bioresorbable and highly space-efficient to maximize therapeutic lifetime while enabling minimally invasive insertion using a hypodermic needle or trocar, and providing orthogonal control over drug release rates and duration. To our knowledge, this is the first demonstration of this approach in the parenteral environment, and using polymer-free extended-release drug formulations over multi-month to multi-year timescales.27QB\101545652.4BWH 2025-313-02Quarles 129319.01147

[0144] Accordingly, we designed biodegradable monolithic implants to address three major challenges hindering the clinical translation of compacted LNG formulations: (1) Tapering drug release due to shrinking surface area, leading to prolonged subtherapeutic periods and requiring initial supratherapeutic exposure; (2) poor mechanical integrity of the compacted formulations, which are brittle and prone to fracturing during handling and residence in the body; and (3) the need for integration of multiple tablets into a single, mechanically robust, and compact device for minimally invasive insertion, if needed, retrieval should users choose to discontinue therapy.

[0145] The rod-shaped monolithic implant includes a biodegradable casing encasing the perimeter of six discrete compacted LNG formulations, each rectangular in shape and measuring 1.8 mm x 4 mm x 2 mm (Figure 3 A, 3B, Table 1 / Figure 13). The solid LNG formulations remained stable throughout the vacuum compression molding process used to manufacture the implants (Figure 9). Use of multiple discrete tablets, rather than a single high-aspect-ratio tablet, reduces the risk of mechanical fracture due to bending and allows the device to be flexible. Drug release from the device occurs through the exposed top and bottom surfaces of each compacted tablet, with the surrounding casing providing structural support.

[0146] These trocar-compatible device designs achieve an overall drug loading efficiency > 68% by volume (Table 1 / Figure 13), surpassing those of Jadelie® (~ 35.5% by weight) and Nexplanon® (-54.1% by weight). The overall implant diameter of 2.4 mm supports minimally invasive insertion via trocar, in line with Jadelie®, to ensure patient acceptability (Figure 3C). The device architecture ensures a constant exposed formulation surface area throughout the therapeutic lifetime of the system, facilitating consistent drug release. Construction using high molecular weight poly-L-lactic acid (PLLA), an FDA-approved biodegradable polyester, facilitates retrieval during use and complete degradation, erosion, and clearance from the body following depletion of encapsulated drug, eliminating the need for end-of-life surgical removal.

[0147] To demonstrate mechanical durability under simulated use conditions, implants were inserted subcutaneously into ex vivo porcine tissue at a depth of 0.5 mm to mimic the clinical placement of Nexplanon®. An axial force of 60 N was applied to the skin surface directly above the implant to simulate maximum finger force encountered during routine use (Figure 10A). Post-loading inspection revealed no evidence of implant damage, tablet fracture, or tablet displacement, confirming the implant's structural integrity (Figure 10B).28QB\101545652.4BWH 2025-313-02Quarles 129319.01147

[0148] Monolithic absorbable implants maintain consistent plasma drug levels following subcutaneous implantation in rats

[0149] To characterize in vivo drug release kinetics from monolithic LNG implants, 20 healthy Sprague Dawley rats were randomized into 4 experimental groups. Animals in the first three groups received 1, 2, or 3 devices, each containing 3 compacted monolithic tablets, corresponding to total exposed formulation surface areas of 43.2 mm2, 86.4 mm2, or 129.6 mm2, respectively. These 'full-duration' devices contained tablets that were 2 mm thick and are estimated to provide sustained drug release for ~10years based on previously determined erosion rates (Figure IF, 1H). To evaluate end-of-life drug release kinetics, animals in the fourth group received 2 "end-of-life duration" devices loaded with 50 / z mthick tablets, designed to release drug for ~ 3 months. Plasma drug levels (Figure 3D) and drug release rates (Figure 3E) were measured weekly over a 4-month period.

[0150] In rats implanted with full-duration devices, plasma LNG levels remained stable throughout the study, consistent with zero-order release kinetics. Interestingly, despite previous results suggesting that an exposed formulation surface area of 75.4 mm2was sufficient to maintain plasma LNG levels above the therapeutic threshold of Ing / mL, devices with86.4 mm2and 129.6 mm2surface area exhibited subtherapeutic plasma concentrations (Figure 3D) and drug release rates at approximately half of the 30 / rg / day target (Figure 3E). This discrepancy may stem from the presence of comers on the cylindrical compacted monolithic formulations, which may dissolve at a faster rate compared to flat surfaces, resulting in higher drug release rates. In the "end-of-life duration" implant group, plasma LNG levels remained similar to the "full-duration" for 3 months, followed by a rapid decline to undetectable levels (Figure 3D, 3E). These results show a rapid cessation of drug release at the expected 3-month timepoint, supports the hypothesis that the system can deliver rapid return to fertility without a protracted sub-therapeutic phase.

[0151] To assess local tissue response, implants were retrieved 6 months post implantation. Gross inspection of the implants showed that full-duration devices remained intact with a substantial amount of drug remaining (Figure 3F), while end-of-life devices were complete depletion of drug, leaving empty polymer casings (Figure 3G), consistent with in vivo drug release data. Animals in all groups gained weight at a comparable rate over the study period, indicating good systemic tolerability (Figure 3H). Histological analysis of the29QB\101545652.4BWH 2025-313-02Quarles 129319.01147 implantation site revealed formation of a well-defined 30 — 260j m-thick fibrous capsule and a resolved inflammatory response, indicating good biocompatibility (Fig 31).

[0152] To verify the compacted LNG formulation erosion rate within the monolithic implants, devices were retrieved after 6 months, and their geometry was characterized using laser profilometry (Figure 3J). A cross-sectional profile of the tablets (Figure 3K) revealed uniform surface erosion with an average depth of ~ 50 / zm, closely matching previous estimates. Surface roughness analysis revealed a peak-to-trough variation of lS^m, further supporting a uniform and consistent surface erosion mechanism.

[0153] LNG stability within the implants was also confirmed. Compacted LNG formulations from devices explanted after ~1 year were extracted and analyzed for chemical purity. A ~ 4% reduction in chemical purity was observed relative to freshly drug, indicating excellent long-term in vivo stability (Figure 11).

[0154] Collectively, these results demonstrate that two full-duration, human-sized devices, with a combined exposed formulation surface area of 172.8 mm2, can be co-implanted in a manner analogous to the well -tolerated Jadelle® system to provide approximately 10 years of contraceptive protection. This system offers 2-3.3 fold longer coverage compared to Jadelle® and Nexplanon®, with the added advantage of smaller device size, full bioresorbability (eliminating the need for surgical retrieval), and rapid end-of-life drug release termination to support improved patient acceptability, adoption, and access.

[0155] Importantly, the monolithic implant architecture allows precise orthogonal control over drug release rate and duration by independently tuning formulation surface area and thickness. This capability enables a customizable family of implant designs tailored to a range of contraceptive durations aligned with individual user needs. For example, monolithic implants fitted with 0.1 mm, 0.2 mm, 1 mm, or 2 mm -thick compacted LNG formulations could provide coverage for 1,2,5, or 10 years, respectively.

[0156] Design of monolithic shape-changing absorbable implant architectures which enable space-efficient tuning of drug release rates and therapeutic duration

[0157] The need for two separate implants to achieve therapeutic efficacy may limit patient acceptability and adoption. To address this, we developed a space-efficient, in-situ shapechanging monolithic implant architecture capable of providing therapeutic LNG release rates (i.e., 30^ g / day, corresponding to an exposed formulation surface area of 172.8 mm2) from a 30QB\101545652.4BWH 2025-313-02Quarles 129319.01147 single device (Figure 4A). These designs increase the exposed formulation surface area multiple folds by dividing the original rod-shaped architecture into multiple planar sections or layers, at the cost of reducing formulation thickness, and thus, reduced therapeutic duration. Critically, this strategy preserves the constant exposed formulation surface area throughout the lifetime of the device, supporting consistent drug release rates and plasma drug levels.

[0158] To overcome impeded drug release from opposed formulation surfaces, a dehydrated hyaluronic acid hydrogel layer was incorporated between the layers. Upon subcutaneous implantation, interstitial fluid induces hydrogel swelling, physically separating the layers and enabling unimpeded drug release (Figure 4B). This design is highly space-efficient since the hydrogel layer increases the implant's dry-state volume by < 5% while preserving its narrow geometry, allowing for minimally invasive trocar-based insertion.

[0159] To evaluate whether the hydrogel layer affects drug release from the compacted formulations, we compared in vitro release kinetics from two systems with equivalent exposed formulation surface areas (Figure 4C, Table 1 / Figure 13). The first, a shape-changing MoSAIC device, includes two 1 mm -thick planar sections separated by a swollen hydrogel layer, such that half the formulation surfaces oppose the hydrogel. The second control group includes two discrete, free-floating 2 mm-thick monolithic devices with all surfaces exposed to the release medium. Both systems exhibited identical drug release profiles, indicating that neither erosion nor drug release from the compacted LNG formulation surfaces was impeded by the presence of the hydrogel (Figure 4C).

[0160] To compare in vivo performance, healthy Sprague Dawley rats were randomized into three experimental groups. The first group received four 1 -layer "half-length" monolithic devices with a total exposed formulation surface area of 172.8 mm2(design 13, Table 1 / Figure 13). The second group received four 2-layer "half-length" devices with a total exposed formulation surface area of 345.6 mm2(design 15, Table 1 / Figure 13) and where the two layers were either separated by a 0.1 mm hydrogel. The third group also received 2 -layer "half-length" devices with a total exposed formulation surface area of 345.6 mm2(design 13, Table 1 / Figure 13), however these layers were fully encapsulated with a 0.1 mm hydrogel layer on all sides (design 14, Table 1 / Figure 13). Plasma LNG levels were measured weekly for 6 months (Figure 4D). All groups maintained plasma LNG concentrations above Ing / mLand drug release rates in excess of 30 / rg / day throughout the study (Figure 4E, 4F), confirming that the extrapolated 31QB\101545652.4BWH 2025-313-02Quarles 129319.01147 compacted formulation surface area of 172.8 mm2is sufficient to achieve human-equivalent therapeutic levels in rats (Figure 3G, 3H). Notably, shape changing MoSAIC groups showed ~ 2-fold higher plasma LNG levels, daily release rates, and AUC o-4 wks compared to the standard monolithic group, consistent with their doubled exposed formulation surface area (Figure 4G). These findings support a surface-erosion based release mechanism and indicate that the hydrogel layer does not significantly impeded drug release.

[0161] Together, these results demonstrate a space-efficient, orthogonal method to independently modulate LNG release rates and therapeutic duration. Importantly, the shapechanging, multilayer MoSAIC design enables therapeutic LNG delivery from a single rodshaped 2-layer implant for a projected ~ 5 years (Figure 4H, 41, Table 1 / Figure 13, Table 2 / Figure 14). The same principle can be extended to smaller-diameter designs suitable for insertion via standard 18-gauge hypodermic needles, enabling 1-1.5 years of contraceptive (Figure 4H, 41, Figure 12, Table 1 / Figure 13). Recognizing that the physicochemical properties, target therapeutic drug levels, and desired therapeutic durations of other long-acting drug therapies (e.g., ivermectin, quinestrol) differ from LNG, this generalized shape-changing approach offers a versatile platform for developing minimally invasive, biodegradable long-acting drug delivery implants for a wide range of chronic indications.

[0162] We further demonstrate the feasibility of minimally invasive insertion and retrieval of the full-length (human-sized) 2-layer MoSAIC contraceptive implant in a large animal porcine model, which better approximates human skin anatomy compared to rodents. The implant was loaded into a trocar and temporarily secured in place using a plunger (Figure 4 J) . Placement into the subcutaneous tissue of the rear flank proceeded via trocar insertion and advancement (along with the implant), followed by trocar retraction while stabilizing the implant within the tissue with the plunger (Figure 4K). The plunger was then withdrawn from the tissue, and the incision closed using bandages (i.e., Tegaderm®) or surgical adhesive. We further demonstrate the feasibility of removing the implant (Figure 4L). At two weeks post-implantation, the device was retrieved by identifying and securing the implant through the skin, making a small incision at one end, and withdrawing the implant as a single intact, rigid object using forceps. The incision was then closed using bandaging or surgical glue.

[0163] Discussion

[0164] Contraceptive drugs empower women to prevent unintended pregnancies and to 32QB\101545652.4BWH 2025-313-02Quarles 129319.01147 space planned ones. Their effectiveness, however, hinges on the maintenance of consistent drug levels over time, making adherence to dosing regimens essential. To reduce the burden of frequent dose administration, long-acting implantable contraceptives have been developed and approved. These systems are among the most effective reversible contraceptive options available under real -use conditions, yet their requirement for surgical implantation and removal limits accessibility, particularly in low-resource settings. Each year, an estimated 257 million women who wish to avoid pregnancy are not using modern contraceptive methods, underscoring the need for next-generation systems that are more accessible and acceptable.

[0165] In response, we developed the MoSAIC system, which is a monolithic, shapechanging contraceptive implant that is smaller, less invasive, and / or longer lasting than current available systems such as Jadelie®. MoSAIC was specifically designed to overcome key barriers to user acceptability and treatment access. To improve user acceptability and discretion, we developed and employed space-efficient compacted LNG formulations and shape-changing device architectures to minimize overall implant size, thereby reducing subdermal palpability and visibility. This approach also minimizes invasiveness by enabling device insertion using standard 18 G hypodermic needle for shorter-duration coverage (1 — 1.5 years), and reducing the number trocar-inserted devices needed for longer-term use. For example, MoSAIC enables 5-year contraception with a single device, compared to the two-device Jadelie® system. Critically, the system is constructed entirely from bioresorbable, FDA-approved materials, which eliminates the need for end-of-life surgical removal-improving treatment access, particularly in low-resource settings where trained medical personnel and clinical facilities are limited.

[0166] MoSAIC's unique drug release kinetics minimizes risk of side effects and enables longer-term coverage compared to existing systems. The system's zero-order drug release profile maximizes drug utilization, enabling up to 10 years of coverage and significantly reducing the lifetime number of devices and procedures a user might require compared to Jadelie®. It also minimizes plasma concentration fluctuations (i.e., large peak to trough plasma drug levels), although LNG's broad therapeutic window makes it less susceptible to such variation. The absence of dose tapering and sharp end-of-life cessation of drug delivery mitigates the risk of long-term subtherapeutic drug exposure that often leads to delayed return to fertility-a concern with extended-release formulations like Depo-Provera® and Sayana Press®.

[0167] These capabilities were enabled by two key advances: the development of33QB\101545652.4BWH 2025-313-02Quarles 129319.01147 compacted, extended-release LNG formulations with exceptionally high drug loading efficiency, and the design of a flexible, space-efficient, structurally robust multilayer shape-changing device architecture that enables independent control of both drug release rate and duration. We demonstrated that compacted monolithic formulations of LNG and other low-solubility drugs exhibit gradual surface-mediated dissolution in aqueous environments, even in the presence of internal porosity. This behavior, reminiscent of the micronized drug particles used in long-acting injectable crystalline suspensions, likely arises from limited water penetration into the formulation core due to the hydrophobic nature of LNG (i.e., low surface energy limits wetting), poorly connected internal pores, and / or slow transport of solubilized drug from within the tortuous internal pore network leading to saturation-limited partitioning of LNG in the core. While further mechanistic studies are needed, this behavior enables the scalable, low-cost manufacturing of millimeter-scale formulations with both extremely high drug loading (~ 100% w / w) and multi-year release durations-well beyond the capacity of injectable aqueous suspensions and conventional polymer-matrix systems.

[0168] By incorporating these formulations into the MoSAIC platform, we created a system in which drug release is confined to two planar surfaces. This architecture allows for independent tuning of drug release rate and duration by adjusting surface area and formulation thickness, respectively. Because the exposed surface area remains constant, dissolution proceeds with predictable zero-order kinetics. The layered, shape-changing design further allows for flexible control of these parameters within a prescribed implant footprint. Using this strategy, we demonstrate three versions of the MoSAIC implant capable of providing therapeutic LNG delivery for different durations: one capable of providing up to 10 years of contraception using 2 devices; another capable of delivering up to 5 years of coverage with a single device; and a third, ultrathin two-device system compatible with 18 G needle insertion and capable of sustaining drug release for 1 year.

[0169] Overall, the MoSAIC contraceptive system represents a significant advancement over existing long-acting reversible contraceptive implants. It is smaller, less invasive, and / or longer lasting compared to existing implants and offer users enhanced access and user experience, particularly in low resource settings. More broadly, the exceptional drug loading efficiency, ultralong drug release profiles, and fully bio-resorbable nature of the MoSAIC platform has the potential to shift the current standard of chronic drug therapy from a paradigm 34QB\101545652.4BWH 2025-313-02Quarles 129319.01147 of frequent and repeated dose administration, which is associated with suboptimal adherence, to a "dose it and forget it" approach where dose adherence is engineered into the system.

[0170] While this study focused on the delivery of LNG for long-acting contraception, the same system (and drug formulation) may support non-contraceptive indications such as dysmenorrhea, menorrhagia, endometriosis, and polycystic ovary syndrome (PCOS). The MoSAIC platform is also generalizable to other long-acting therapeutic applications. The modular nature of the device allows for tuning of layer count, formulation thickness, and formulation surface area to accommodate the dissolution and drug release kinetics of compacted formulations of otherpotent, low-solubility drugs. Potential indications include menopausal hormone therapy, breast or prostate cancer (e.g., quinestrol and estradiol), mass drug administration campaigns for parasitic infections such as onchocerciasis or malaria (e.g., ivermectin), HIV pre-exposure prophylaxis (PrEP), and chronic psychiatric conditions such as schizophrenia and bipolar disorder (e.g., pimozide and aripiprazole). Interestingly, the modular nature of this platform further enables easy delivery of drug combinations (e.g., contraception and HIV PrEP). In each case, treatment-specific drug release rates and durations could be achieved through appropriate structural modifications.

[0171] Despite its promise, the MoSAIC platform has important limitations. It is best suited for the delivery low-solubility, high-potency, and chemically stable active pharmaceutical ingredients. Drug selection must carefully consider both the limited volume available in the minimally invasive implants and the intended therapeutic duration. Candidate compounds must also remain stable under physiological conditions (37°C, interstitial fluid) for the full duration of delivery. Moreover, while the MoSAIC architecture affords flexibility in geometry and release kinetics, successful implementation requires the drug be compacted into solid monolithic formulations and capable of achieving therapeutic partitioning rates from the exposed surface area. These constraints pose challenges for the delivery of biologies, water-soluble drugs, or drugs requiring large doses. Finally, although we demonstrated minimally invasive insertion, retrieval, biocompatibility, and sustained delivery of LNG at human-equivalent levels in animal models, additional preclinical and clinical studies will be essential to support translation into human use.

[0172] Materials and Methods35QB\101545652.4BWH 2025-313-02Quarles 129319.01147

[0173] Dulbecco's Phosphate-Buffered Saline (PBS) was purchased from Gibco by Life Technologies (Woburn, USA). Levonorgestrel (LNG, CAS# 797-63-7) was purchased from Austin Chemical, Inc. (sourced from Biosynth Carbosynth, COO, China). Ivermectin (CAS# 70288-86-7) was purchased from MedChemExpress. Quinestrol (CAS# 152-43-2) was purchased from Santa Cruz Biotechnology, USA. Sodium dodecyl sulfate (SDS, CAS# 151-21- 3) was purchased from Thermo Fisher Scientific (28312). 2-hydroxypropyl beta cyclodextrin (HP- ?-CD, CAS 128446-35-5) was purchased from Sigma, USA (778966). Poly (L-lactic acid) (PLLA, Mn 197,641, PDI 1.69) was purchased from Akina Inc., USA (AP008). Hyaluronic acid (300-500 kDa MW, 600-01-07) was purchased from Contipro a.s. (Czech Republic).

[0174] Development of compacted drug formulations

[0175] Solid formulations composed of 100%w / wdrug was manufactured by tablet compaction of as-received lyophilized product using an RDlOANatoli Tablet press (St. Charles, MO, USA). In a typical experiment compacted LNG formulations were formed using a compaction pressure of 208.3 MPa , although a broader range of pressures ranging between 39.7 MPa and 636.6 MPa were also explored. Magnesium stearate, a common lubricant used in tableting, was excluded from this process. The solid formulations were stored at 4°Cand protected from moisture until use. Tablet density was calculated by dividing the gross weight of the formulation by its volume, as determined using optical profilometry.

[0176] In vitro LNG release kinetics of compacted formulations

[0177] To characterize the drug release profile of compacted drug formulations, formulations were individually incubated in pH 7.4 PBS supplemented with 3%SDS or10%HP — — CDat 37°C, sink conditions, and under constant agitation. At predetermined timepoints, 1.0 mL of release medium was sampled and replaced. Drug concentrations within the samples were analyzed using an Agilent 1260 Infinity I HPLC equipped with a UV detector, and an Agilent Poroshell 120 EC-C 182.7 / zm 3.0 x 50 mm column (Agilent 699975-302). 5 zL of sample was loaded onto the column, heated at 50° C, using a mobile phase consisting of 5% acetonitrile and 95% of 0.1% formic acid. Gradient elution was carried out over a 4.5-minute period with a flow rate of 1.0 mL / min starting at 5% of acetonitrile and 95%of 0.1%formic acid and ending at 95% of acetonitrile and 5% of 0.1% formic acid. LNG was detected using a UV absorbance of 250 nm. LNG concentration was determined as the area under the main peak.

[0178] Synthesis of methacrylated hyaluronic acid36QB\101545652.4BWH 2025-313-02Quarles 129319.01147

[0179] 2 g of hyaluronic acid was dissolved in 100 mL of water and stirred at 500 rpm for 2 hours at room temperature. 1.6 mL of methacrylic anhydride was added dropwise to the solution. 5 M NaOH was added dropwise to the solution to adjust the final pH to 8.5. The solution was protected from light and stirred at 4 °C for 24 hours. 2.92 g of NaCl was added to the solution followed by precipitation of the polymer in ethanol. The resulting product was then isolated by centrifugation and washed in ethanol. The product was then redissolved in DI water and dialyzed against DI water for 3 days at 4°C.

[0180] Manufacturing of monolithic and MoSAIC implants

[0181] Monolithic implants were fabricated using a vacuum compression molder. First, a positive implant casing mold was designed using SolidWorks and printed out of Rigid 10K resin and HTL resin using a Form 3 printer (Formlabs, USA) or BMF printer (Boston Micro Fabrication, USA), respectively. These were then used to cast a two-part separable negative PDMS mold for subsequent vacuum compression molding. PLLA was introduced into the PDMS molds and heated at 120°C for 10 minutes while under vacuum. The PLLA casing was cooled to room temperature and separated from the PDMS mold. Compacted drug formulations were manually inserted into the PLLA casing, heated at 120°C for 10 minutes while under vacuum, and cooled to room temperature. The monolithic devices were stored at 4°C and protected from moisture and light until use.

[0182] MoSAIC implants were constructed by stacking two or more monolithic implants alongside each other in a silicone mold and separated 0.1 mm apart. A stock photo-initiator solution was prepared by dissolving 60 mg of Irgacure 12959 in 3.6 mL of DI water and heated at 65°C for 12 hours while protected from light. A polymer stock solution was prepared by dissolving 200 mg of methacrylated hyaluronic acid and 4 mg of N, N'-methylenebisacrylamide in 1.6 mL of pH 7.4 PBS. The solution was heated at 37°C for 4 hours. To this stock, 2.4 mL of photo-initiator stock was added, vortexed, and incubated at 37°Cfor 15 minutes. 4 / zL of 25% glutaraldehyde solution was added to the solution and vortexed. The homogenous solution was then centrifuged at 1000 rpm for 3 minutes to remove air bubbles. IOOJUL of this polymer solution was dispensed into each mold, between the monolithic devices, and allowed to dry overnight at room temperature. The devices were subsequently exposed to UV irradiation in a UV oven for 15 minutes to facilitate UV-initiated hydrogel crosslinking. The MoSAIC devices were stored at 4°C and protected from moisture and light until use.37QB\101545652.4BWH 2025-313-02Quarles 129319.01147

[0183] In vitro characterization of LNG stability

[0184] The in vitro stability of levonorgestrel formulations was evaluated prior to and after integration into the MoSAIC implants using reverse phase HPLC. The samples were subjected to vacuum compression molding process whereby formulations are heated at 200°Cfor 30 minutes. LNG was physically extracted from the devices, weighed, and dissolved in 50%acetonitrile and 50% water at a concentration of 0.5mg / mL. The chemical purity of LNG within the samples was measured using RP HPLC. Samples were analyzed using an Agilent 1260 Infinity I HPLC equipped with a UV detector, and an Agilent Poroshell 120 EC-C-18 2.7 / zm 3.0 x 50 mmcolumn (Agilent 699975-302). 5^zL of sample was loaded onto the column, heated at 50°C, using a mobile phase consisting of 5% acetonitrile and 95% of 0.1% formic acid. Gradient elution was carried out over a 4.5-minute period with a flow rate of1.0 mL / minstarting at 5% of acetonitrile and 95% of 0.1% formic acid and ending at 95% of acetonitrile and 5% of 0.1% formic acid. LNG was detected using a UV absorbance of 250 nm. LNG concentration was determined as the area under the main peak. LNG purity was determined as the ratio of the area under the main LNG peak and the total area under all peaks.

[0185] Mechanical characterization of MoSAIC implants

[0186] The structural integrity of MoSAIC implants under simulated use conditions was evaluated in ex vivo porcine tissue. A freshly excised 1 -inch-thick porcine tissue section was harvested from the flank and mounted to a rigid steel support. Full length devices were inserted into the tissue at a depth of 0.5 cm from the skin surface. A 60 N point load, which is the estimated maximum force that can be exerted by a finger, was applied overtop of the center of the device using a 1 / 8” diameter steel plunger fastened to the upper gripper of an Instron testing machine equipped with a 500 N load cell. Displacement was applied to the specimen at a rate of 15 mm / minuntil a force of 60 N was achieved. Following loading, the device was retrieved from the ex vivo tissue and examined for mechanical failure.

[0187] In vitro characterization of LNG release kinetics from MoSAIC implants

[0188] To characterize the drug release profile of compacted LNG formulations, formulations were individually incubated in pH 7.4 PBS release medium supplemented with 10%HP- ?-CD at 37°C, sink conditions, and under constant agitation. At predetermined timepoints, 1.0 mL of release medium was sampled and replaced. Release medium was exchanged at regular intervals to maintain physiological pH. Drug concentrations within the 38QB\101545652.4BWH 2025-313-02Quarles 129319.01147 samples were analyzed using an Agilent 1260 Infinity I HPLC equipped with a UV detector, and an Agilent Poroshell 120 EC-C-182.7 / zm 3.0 x 50 mm column (Agilent 699975-302). 5 / zL of sample was loaded onto the column, heated at 50° C, using a mobile phase consisting of 5% acetonitrile and 95% of 0.1% formic acid. Gradient elution was carried out over a 4.5 -minute period with a flow rate of 1.0 mL / min starting at 5% of acetonitrile and 95%of 0.1%formic acid and ending at 95% of acetonitrile and 5% of 0.1% formic acid. LNG was detected using a UV absorbance of 250 nm. LNG concentration was determined as the area under the main peak.

[0189] Pharmacokinetics of compacted LNG formulations in rats

[0190] All animal experiments were approved by and performed in accordance with the Committee on Animal Care at MIT. 200-225 g female Sprague Dawley (SAS SD strain 400) were purchased from Charles River. Compacted LNG formulations and LNG-loaded MoSAIC implants were implanted into the subcutaneous tissue of rats using a trocar. At predetermine timepoints, blood was sampled from the lateral tail vein and collected in EDTA microtainer capillary blood collection tubes (Becton Dickinson, BD365974-MI). Plasma samples were extracted via centrifugation at 2000 g and stored at — 80°C. LNG concentrations within the plasma samples were measured by triple quadrupole liquid chromatography-tandem mass spectrometry (LC-MS / MS).

[0191] Non-compartmental pharmacokinetic analysis was used to calculate the daily drug release rates from each system (equation 1). Significant changes in the body weight of the rats were observed over the course of the experiment resulting in a change in drug clearance over time (Figure 3H). The predicted LNG clearance in the rats was calculated by bodyweightdependent allometric scaling based on clearance values reported by Ko et al.22(i.e., CLIV = 1.01 L / hrin 305 g Sprague Dawley rats).

[0192] Equation 1: Release rate =LNG concentration xPredicted clearancef L lOOOmL 24hr lug \I _ x _ X _ X 1\hr L day lOOOngJ

[0193] Equation 2: Predicted Clearance =Estimated Clearance X / ■ Body weight (g) \\ Average body weight (g)J

[0194] Biocompatibility of compacted LNG formulations and MoSAIC devices in rats

[0195] Compacted LNG formulations and LNG-loaded MoSAIC devices were implanted 39QB\101545652.4BWH 2025-313-02Quarles 129319.01147 into the subcutaneous tissue of 200 — 225 g female Sprague Dawley rats for up to 15 months. The implants and the surrounding tissue were subsequently excised, grossed, and fixed in 10% neutral buffered formalin for 24 hours, and stored in 70% ethanol. Tissue was embedded within paraffin blocks, sectioned into 5-micron tissue sections, and stained with hematoxylin and eosin. The inflammatory response and degree of fibrosis surrounding the implants was reviewed by a veterinary pathologist (Dr. Bronson, The Hope Babette Tang Histology Facility, Swanson Biotechnology Center, MIT).

[0196] Minimally invasive implant insertion and retrieval in pigs

[0197] All animal experiments were approved by and performed in accordance with protocols approved by the Committee on Animal Care at the Massachusetts Institute of Technology. We demonstrate minimally invasive insertion and retrieval of the MoSAIC implants in a large animal model (75-kg Yorkshire swine; Cummings School of Veterinary Medicine at Tufts University, Grafton, MA). This model was used because its skin and subcutaneous tissue anatomy is similar to that of humans. Animals were fasted overnight before procedures to ensure safe anesthesia and to avoid aspiration. Pigs were sedated with Telazol ( 5mg / kg; tiletamine / zolazepam) and xylazine (2mg / kg) or dexmedetomidine (0.03mg / kg) and midazolam (0.25mg / kg), intubated, and maintained on 1 to 3%isoflurane in oxygen. Their heart rate, respiratory rate, end tidal C02, SpO2, and temperature were monitored while anesthetized.

[0198] Sterile full-length 2 -layer LNG-loaded MoSAIC devices were loaded into 10-gauge stainless steel trocars and inserted into the subcutaneous tissue at the rear flank of the pigs, along a superficial plane beneath the skin, on day 0 and day 7. A steel plunger was used to maintain the location of the implant within the subcutaneous tissue while the trocar was retracted. The plunger was then retracted, and the small incision was closed using surgical glue and bandaged using Tegaderm® transparent film dressing. On day 14, the implants were retrieved by forming a small surgical incision at one of the MoSAIC devices, grasping the exposed device end using forceps, and extraction of the entire device from the subcutaneous tissue.

[0199] Ex vivo characterization of LNG formulations and MoSAIC implants

[0200] The weight and geometry of compacted LNG formulations and MoSAIC implants was measured using a Mettler Toledo XSR205 analytical balance and a Keyence VK-X30003D surface profiler, respectively. Formulation density was calculated as p = mass(m<g) / volume 40QB\101545652.4BWH 2025-313-02Quarles 129319.01147 (mm3). The in vivo erosion rate for the compacted LNG formulations were calculated from the dv vl — vOchange in formulation thickness over the total time of implantation (i.e., — = where y isthe formulation thickness at a specified timepoint). The surface morphology of the compacted LNG formulations, before and after subcutaneous implantation in rats, was evaluated using a Hitachi FlexSEM TM-1000 II (SU1000, Tokyo, Japan) scanning electron microscope. The chemical stability of LNG within MoSAIC implants prior to and following implantation in the subcutaneous tissue of rats for a period of 1 year was evaluated using RP HPLC in an analogous manner described above.

[0201] SEM Sample Preparation and Imaging Conditions

[0202] Prior to vacuum pump down, the LNG formulations and MoSAIC implants were coated with approximately 15 nm of gold using JEOL USA's Smart Coater (Peabody, MA USA). This conductive coating prevented excessive surface charging artifacts in images. The samples were mounted using double sided carbon tape (Ted Pella Inc) and imaged in high vacuum mode using the secondary electron (SE) detector from Hitachi FlexSEM TM-1000 II (Tokyo, Japan). Low voltage imaging (3kV) was used to prevent damage from electron bombardment, but 3 kV also provided high surface detail. Typical imaging conditions would also include a spot intensity of 50 (based unitless scale from 1-100) and a working distance between 6.5-8 mm.

[0203] Statistical analysis

[0204] Unpaired two-sided Student's t-tests and one-way analysis of variance (ANOVA) with Tukey's multiple comparisons tests were performed using GraphPad Prism (Version 9.4.1). A value of P < 0.05 was considered statistically significant. Figure captions and text describe the number of replicates used in each study. Figure captions define the center line, and error bars presented in the plots.

[0205] Example 2 - Pharmacokinetics of Pimozide-Loaded MoSAIC Implants in Rats

[0206] Figure 15 shows plasma pimozide concentrations in rats implanted with pimozide-loaded MoSAIC devices. Data presented as n=4. Error bars represent standard deviation.

[0207] Methods

[0208] Compacted monolithic formulations composed of 100% pimozide were loaded into MoSAIC implants, with a total exposed formulation surface area of 345.6 mm2. The41QB\101545652.4BWH 2025-313-02Quarles 129319.01147 implants were surgically placed into the subcutaneous tissue of Sprague Dawley rats (-300 g at the time of implantation). Blood samples were collected intermittently over the course of 9.5 months. Plasma pimozide levels were measured using mass spectrometry.

[0209] Results

[0210] These results demonstrate the ability of Pimozide-loaded MoSAIC implants to provide sustained drug release over a period of 9.5 months. The release profde decreases from -10 ng / mL down to a steady state level of -1 ng / mL from 0 to 134 days, due to residual pimozide particles on the surface of the implant introduced during lab-scale manufacturing. Zero-order drug release and steady state plasma drug concentrations persisted out to 285 days.

[0211] Example 3 - Self-Injectable Monolithic Implants Delivered Via Hypodermic Needle

[0212] Figure 16 shows self-injectable monolithic implants which can be delivered via a hypodermic needle, including aspects of the manufacture of such injectable monolithic implants which are compatible with self-administration using 21G-23G hypodermic needles (see Table 3). Figure 16A provides a photograph showing the manufacture of injectable monolithic implants via laser engraving of biodegradable metal sheets followed by compaction of hydrophobic drug (levonorgestrel) into the casing. Figure 16B provides a photograph of individual monolithic implants. Figure 16C shows the injection of an array of monolithic implants into the subcutaneous tissue of ex vivo pig tissue using a 21G hypodermic needle. Figure 16D provides a photograph of two monolithic implants, one on top of a US penny and the second in the bore of a 21G hypodermic needle. Figure 16E shows a photograph of a monolithic implant in the bore of a 21G hypodermic needle. Figure 16F shows an image acquired by x-ray imaging of the deposited depot of monolithic implants in the ex vivo pig tissue.Hypodermic liilii liiilii Exposed Formulation Needle Gauge (pm) liiilii Surface Area (mm2)23G 300 260 100 0.10621G 484 444 100 0.310

[0213] Table 3. Geometry of Self-Injectable Monolithic Implants

[0214] Example 4 - Various Implant Configurations and Designs.42QB\101545652.4BWH 2025-313-02Quarles 129319.01147

[0215] Figure 17 shows various implant configurations and designs, including schematics showing MoSAIC designs containing the monolithic formulation of compressed hydrophobic drug contained within a rigid casing. Formulation shown in orange and labeled 'API'. Rigid casing shown in blue. Figure 17A shows a cross section of a rigid device with multiple formulations. Formulations are exposed to the external environment through the top and bottom formulation surfaces. Figure 17B shows a cross section of a rigid device with multiple formulations. Formulations are exposed to the external environment through the top formulation surface only. Figure 17C shows a cross section of an array of rigid devices, each containing a formulation contained within a casing. Formulations are exposed to the external environment through the top and bottom formulation surfaces. Figure 17D shows a cross section of a rigid device with one formulation. Formulation is exposed to the external environment through the top formulation surface only which may be referred to herein as a ‘cup’ configuration. Figure 17E shows a cross section of a device with multiple formulations, each formulation within its own rigid casing and connected with a flexible member. Formulations are exposed to the external environment through the top and bottom formulation surfaces. Flexible members may be constructed of a flexible material (e.g., silicone, rubber) and / or may have geometries that enable deformation under load (e.g., serpentine geometry, thin geometry, suture, filament, thin film). Flexible member show in pink. Figure 17F shows a cross section of a device with multiple formulations, each formulation within its own rigid casing and connected with a flexible thin-film member. Flexible member show in pink. Figure 17G shows a cross section of a rigid device with multiple formulations and two layers, separated by a hydrogel or xero gel (shown in green). Formulations are exposed to the external environment through the top and bottom formulation surfaces. Figure 17H shows a cross section of a rigid device with multiple formulations and two layers, separated and encased by a hydrogel or xero gel (shown in green). Formulations are exposed to the external environment through the top and bottom formulation surfaces. Figure 171 shows a cross section of a rigid device with multiple formulations integrated onto the surface of a larger implant (e.g., intrauterine device, ingestible capsule, intrabladder device).

[0216] Example 5 - Pharmacokinetics of Ivermectin-Loaded Mosaic Implants in Rats

[0217] Figure 18 shows plasma ivermectin concentrations in rats implanted with ivermectin-loaded MoSAIC devices. Devices had a total exposed formulation surface area of 172.8 mm2(orange, lower trace) or 345.6 mm2(blue, upper trace). Data presented as n=4. Error 43QB\101545652.4BWH 2025-313-02Quarles 129319.01147 bars represent standard deviation.

[0218] Methods

[0219] Compacted monolithic formulations composed of 100% ivermectin were loaded into MoSAIC implants, with a total exposed formulation surface area of 172.8 mm2(orange, lower trace) or 345.6 mm2(blue, upper trace). The implants were surgically placed into the subcutaneous tissue of Sprague Dawley rats (-300 g at the time of implantation). Blood samples were collected intermittently over the course of 10 months. Plasma ivermectin levels were measured using mass spectrometry.

[0220] Results

[0221] These results demonstrate the ability of Ivermectin-loaded MoSAIC Implants to provide sustained drug release over a period of 9.5 months. The release profile decreases from -200-300 ng / mL down to a steady state level of -50 and 100 ng / mL from 0 to 72 days, due to residual ivermectin particles on the surface of the implant introduced during lab-scale manufacturing. Zero-order drug release and steady state plasma drug concentrations persisted out to 285 days.

[0222]

[0223] References - Each of the following references is incorporated by reference in its entirety

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[0269]

[0270] Thus, while the invention has been described above in connection with particular embodiments and examples, the invention is not necessarily so limited, and that numerous other embodiments, examples, uses, modifications and departures from the embodiments, examples and uses are intended to be encompassed by the claims attached hereto.48QB\101545652.4

Claims

BWH 2025-313-02Quarles 129319.01147 CLAIMSWhat is claimed is:

1. An implantable device for delivery of a hydrophobic compound to a subject, the device comprising:at least one tablet comprising the hydrophobic compound in a compressed form, wherein the tablet is configured to exhibit a sustained release profile via surface- mediated dissolution when implanted into the subject.

2. The implantable device of claim 1, wherein the tablet is formed by applying pressure to the hydrophobic compound.

3. The implantable device of claim 2, wherein the applied pressure is in a range of 20 MPa to 1200 MPa.

4. The implantable device of claim 2, wherein the applied pressure is at least 150 MPa.

5. The implantable device of claim 1, wherein the hydrophobic compound comprises crystals.

6. The implantable device of claim 5, wherein the crystals of the hydrophobic compound are 150 micron or smaller in size.

7. The implantable device of claim 5, wherein the crystals of the hydrophobic compound are in a range of 0.3 to 20 micron in size.

8. The implantable device of claim 1, wherein the tablet is substantially non-porous.

9. The implantable device of claim 8, wherein the tablet has a porosity of less than about 5%.49QB\101545652.4BWH 2025-313-02Quarles 129319.0114710. The implantable device of claim 1, wherein the tablet has a density approximately equal to a true crystal density of the hydrophobic compound.

11. The implantable device of claim 10, wherein the tablet has a density of about 1.13±0.02mg / mm3.

12. The implantable device of claim 1, wherein the tablet comprises a drug loading of at least 80% by weight.

13. The implantable device of claim 12, wherein the drug loading is at least about 90% by weight.

14. The implantable device of claim 13, wherein the drug loading is at least about 95% by weight.

15. The implantable device of claim 13, wherein the tablet comprises at least about 98% by weight.

16. The implantable device of claim 13, wherein the drug loading is approximately 100% by weight.

17. The implantable device of claim 1, wherein the tablet is configured to be implanted subcutaneously.

18. The implantable device of claim 17, wherein the tablet is configured to be implanted using a trocar.

19. The implantable device of claim 18, wherein the tablet includes a width of 2.4 mm and a thickness of 2.0 mm.50QB\101545652.4BWH 2025-313-02Quarles 129319.01147 20. The implantable device of claim 17, wherein the tablet is configured to be implanted using a needle.

21. The implantable device of claim 20, wherein the needle has a diameter of 16G, 18G, 21G, or 23G.

22. The implantable device of claim 20, wherein the tablet includes a width of 0.84 mm and a thickness of 0.64 mm.

23. The implantable device of claim 20, wherein the tablet includes a width of 0.30 mm and a thickness of 0.10 mm.

24. The implantable device of claim 1, wherein the device comprises a plurality of tablets comprising the hydrophobic compound.

25. The implantable device of claim 1, wherein the tablet comprises a plurality of different hydrophobic compounds.

26. The implantable device of claim 1, wherein the sustained release profde comprises a zero-order drug release profile.

27. The implantable device of claim 26, wherein the tablet exhibits the zero-order drug release profile for a period of at least six months.

28. The implantable device of claim 27, wherein the tablet exhibits the zero-order drug release profile for a period of at least one year, at least five years, or at least ten years.

29. The implantable device of claim 1, wherein the device further comprises a casing surrounding at least a portion of the tablet,wherein the casing is configured to modulate an exposed surface area of the tablet to control a rate of release of the hydrophobic compound from the tablet.51QB\101545652.4BWH 2025-313-02Quarles 129319.0114730. The implantable device of claim 29, wherein the casing is a biodegradable casing.

31. The implantable device of claim 30, wherein the biodegradable casing surrounds an outer edge of the tablet.

32. The implantable device of claim 31, wherein two opposing faces of the tablet are not surrounded by the biodegradable casing.

33. The implantable device of claim 31, wherein one face of the tablet is not surrounded by the biodegradable casing.

34. The implantable device of claim 33, wherein the device comprises a cup configuration.

35. The implantable device of claim 30, wherein the biodegradable casing comprises a biodegradable polymer selected from the group consisting of polyflactic acid) (PLA), poly(L-lactic acid) (PLLA), poly(D-lactic acid) (PDLA), poly(lactic-co-glycolic acid) (PLGA), poly(s-caprolactone) (PCL), and combinations or copolymers thereof.

36. The implantable device of claim 35, wherein the biodegradable polymer further comprises one or more additives configured to reduce the rate of hydrolysis and / or autocatalytic degradation of the polymer.

37. The implantable device of claim 36, wherein the one or more additives comprise an acid scavenger.

38. The implantable device of claim 36, wherein the one or more additives comprise a chain extender or end-group modifying agent.

39. The implantable device of claim 36, wherein the one or more additives comprise a hydrolysis inhibitor.52QB\101545652.4BWH 2025-313-02Quarles 129319.0114740. The implantable device of claim 36, wherein the one or more additives are selected from the group consisting of carbodiimides, aziridines, epoxy-functionalized compounds, oxazoline or oxazole-containing compounds, isocyanates, hydrotalcites, magnesium oxide, calcium oxide, silicon dioxide, and combinations thereof.

41. The implantable device of claim 30, wherein the biodegradable casing comprises a biodegradable metal selected from the group consisting of zinc, molybdenum, tungsten, magnesium, iron, calcium, and alloys thereof.

42. The implantable device of claim 30, wherein the biodegradable casing comprises one or more imaging contrast agents selected from the group consisting of iodine-based contrast agents, gadolinium-based contrast agents, manganese-based contrast agents, iron nanoparticles, fluorescent nanoparticles, quantum dots, and fluorescent molecules.

43. The implantable device of claim 29, wherein the device is configured in a form factor suitable for implantation or insertion into a subject via a minimally invasive or non-surgical delivery route.

44. The implantable device of claim 43, wherein the device has a largest dimension between 50 microns and about 50 millimeters.

45. The implantable device of claim 43, wherein the device has a largest dimension less than about 1 millimeter.

46. The implantable device of claim 43, wherein the device has a largest dimension less than about 500 microns.

47. The implantable device of claim 43, wherein the device is configured as one or more of: a rod, cylinder, pellet, filament, millimeter scale particle, microscale particle, or array.53QB\101545652.4BWH 2025-313-02Quarles 129319.01147 48. The implantable device of claim 43, comprising a plurality of tablets contained within a single casing.

49. The implantable device of claim 43, comprising a plurality of discrete devices, each device comprising one or more tablets.

50. The implantable device of claim 43, wherein the device is configured as part of a larger device.

51. The implantable device of claim 43, wherein the device is configured as part of a microneedle array.

52. The implantable device of claim 51, wherein the tablet is positioned within a microneedle structure comprising the casing.

53. The implantable device of claim 43, wherein the device is configured as part of an ingestible device.

54. The implantable device of claim 53, wherein the ingestible device is configured to be retained within the gastrointestinal tract for at least one week.

55. The implantable device of claim 43, wherein the device is configured as part of an intrauterine device.

56. The implantable device of claim 43, wherein the device is configured as part of an intravaginal device.

57. The implantable device of claim 43, wherein the device is configured as part of an intrabladder device.54QB\101545652.4BWH 2025-313-02Quarles 129319.01147 58. The implantable device of claim 43, wherein the device is configured for delivery using a trocar.

59. The implantable device of claim 43, wherein the device is configured for delivery through a hypodermic needle.

60. The implantable device of claim 59, wherein the hypodermic needle is 16G-23G.

61. The implantable device of claim 43, wherein the device is configured for delivery using a catheter.

62. The implantable device of claim 43, wherein the device is configured for delivery using an endoscope.

63. The implantable device of claim 43, wherein the device is configured for delivery via oral ingestion.

64. The implantable device of claim 43, wherein the device is configured for delivery via vaginal placement.

65. The implantable device of claim 43, wherein the device is configured for delivery via intrauterine placement.

66. The implantable device of claim 43, wherein the device is configured for administration to one or more of: subcutaneous tissue, intramuscular tissue, dermal tissue, brain tissue, kidney tissue, ovary tissue, prostate tissue adipose tissue, intratumoral tissue, ocular tissue, oral tissue, vaginal tissue, breast tissue, bladder tissue, bone tissue, gastrointestinal tissue, or intraperitoneal space.

67. The implantable device of claim 66, wherein the device is configured to be retained within the subject for at least one week.55QB\101545652.4BWH 2025-313-02Quarles 129319.0114768. The implantable device of claim 29, wherein the device comprises a plurality of layers.

69. The implantable device of claim 68, wherein a space between adjacent layers of the plurality of layers comprises a xerogel or a hydrogel.

70. The implantable device of claim 69, wherein the xerogel or the hydrogel comprises a material selected from the group consisting of hyaluronic acid, methacrylated hyaluronic acid, alginate, chitosan, dextran, agarose, carrageenan, gelatin, collagen, fibrin, silk fibroin, and derivatives thereof, gelatin methacrylate (GelMA), poly(vinyl pyrrolidone), poly(ethylene glycol) (PEG), poly(ethylene glycol) diacrylate (PEGDA), poly(acrylamide) (pAAM), poly(vinyl alcohol (PVA), poly(N-isopropylacrylamide (PNIPAM), poly(2-hydroxyethyl methacrylate) (HEMA), poly(lactic-co-gly colic acid) (PLGA)-PEG, pol oxamers including Pluronic Fl 27, and combinations, networks, or copolymers thereof.

71. The implantable device of claim 1, wherein the device comprises at least one compliant region and at least one rigid region,wherein the compliant region exhibits greater deformation under an applied force than the rigid region, andwherein a difference in deformation is based on at least one of (i) a difference in material properties between the compliant region and the rigid region, or (ii) a difference in a geometric configuration between the compliant region and the rigid region.

72. The implantable device of claim 71, wherein the compliant region has a lower relative flexural rigidity than the rigid region.

73. The implantable device of claim 71, wherein the compliant region comprises a material with lower relative Young's modulus than the rigid region.

74. The implantable device of claim 71, wherein the compliant region comprises at least one of a filament, fiber, thread, suture, or serpentine or reduced-thickness structure.56QB\101545652.4BWH 2025-313-02Quarles 129319.0114775. The implantable device of claim 71, wherein the compliant region comprises an elongated portion having a cross-sectional dimension configured to permit bending under physiological forces.

76. The implantable device of claim 29, wherein the casing comprises a non-biodegradable casing.

77. The implantable device of claim 76, wherein the non-biodegradable casing comprises a biocompatible polymer selected from the group consisting of a fluoropolymer, a polyurethane a silicone, a polyolefin, a non-degradable polyester, an acrylic or methacrylate, a polyether-based polymer.

78. The implantable device of claim 76, wherein the non-biodegradable casing comprises a biocompatible polymer selected from the group consisting of PTFE, FEP, PFA, ETFE, PU, PCU, PDMS, polyethylene, polypropylene, PET, PMMA, and PEEK.

79. The implantable device of claim 76, wherein the non-biodegradable casing comprises a biocompatible metal selected from the group consisting of titanium, stainless steel, nitinol, and their alloys, and combinations thereof.

80. The implantable device of claim 76, wherein the non-biodegradable casing comprises a medical-grade 316L stainless steel.

81. The implantable device of claim 76, wherein the non-biodegradable casing comprises Bionate polycarbonate urethane (PCU).

82. The implantable device of claim 76, wherein the non-biodegradable casing is formed by at least one of injection molding, CNC machining, additive manufacturing, or laserengr avi ng / cutti ng .57QB\101545652.4BWH 2025-313-02Quarles 129319.01147 83. The implantable device of any one of claims 1-82, wherein the hydrophobic compound comprises a compound having an aqueous solubility of less than about 1 mg / mL.

84. The implantable device of any one of claims 1-82, wherein the hydrophobic compound comprises a compound having an aqueous solubility of less than about 0.1 mg / mL.

85. The implantable device of any one of claims 1-82, wherein the hydrophobic compound comprises a compound having a logP of greater than about 2.

86. The implantable device of any one of claims 1-82, wherein the hydrophobic compound comprises a compound selected from the group consisting of levonorgestrel, ivermectin, quinestrol, cabotegravir, rilpivirine, lenacapavir, MK 8527, tafenoquine, ganfeborole, TBAJ-876 and analogs or derivatives thereof, pretomanid, testosterone enanthate, estradiol benzoate, estradiol valerate, zoledronate, medroxyprogesterone acetate, kisspeptin and analogs and derivatives thereof, dinalbuphine sebacate, sufentanil, fentanyl, pimozide, brexpiprazole, paliperidone palmitate, olanzapine pamoate, aripiprazole, aripiprazole lauroxil, haloperidol decanoate, fulvestrant, paclitaxel, docetaxel, and combinations thereof.

87. The implantable device of claim 86, wherein the hydrophobic compound comprises one or more pharmaceutically acceptable salts, prodrugs, solvates, hydrates, polymorphs, stereoisomers, or crystalline or amorphous forms of the hydrophobic compound.

88. The implantable device of claim 86, wherein the hydrophobic compound is levonorgestrel.

89. A method of manufacturing an implantable device for delivery of a hydrophobic compound to a subject, the method comprising:compacting crystals of the hydrophobic compound to form at least one tablet, wherein the tablet is configured to exhibit a sustained release profile via surface- mediated dissolution when implanted into the subject.58QB\101545652.4BWH 2025-313-02Quarles 129319.01147 90. The method of claim 89, wherein compacting comprises applying a pressure in a range of 20 MPa to 1200 MPa to the crystals.

91. The method of claim 90, wherein the pressure is at least 150 MPa.

92. The method of claim 89, wherein the tablet is compacted to a density approximately equal to a true crystal density of the compound.

93. The method of claim 89, wherein the tablet comprises substantially no excipients.

94. The method of claim 89, further comprising forming a biodegradable casing configured to surround at least a portion of the tablet.

95. The method of claim 94, wherein the biodegradable casing surrounds an outer edge of the tablet.

96. The method of claim 95, wherein two opposing faces of the tablet are exposed.

97. The method of claim 95, wherein one face of the tablet is exposed.

98. The method of claim 94, wherein forming the biodegradable casing comprises at least one of vacuum compression molding, injection molding, machining, electrical discharge machining, metal stamping, laser engraving, or additive manufacturing.

99. The method of claim 94, wherein, prior to compacting the crystals of the hydrophobic compound to form the at least one tablet, the method includes:forming the biodegradable casing, andcompressing the crystals of the hydrophobic compound into the biodegradable casing to form the at least one tablet.

100. The method of claim 94, wherein forming the biodegradable casing further comprises:59QB\101545652.4BWH 2025-313-02Quarles 129319.01147 forming the biodegradable casing without the at least one tablet, and inserting the at least one tablet into the biodegradable casing.

101. The method of claim 94, further comprising inserting a plurality of tablets into the biodegradable casing.

102. The method of claim 94, further comprising disposing a xerogel or a hydrogel between adjacent layers of a plurality of tablets within the biodegradable casing.

103. The method of claim 102, wherein the xerogel or the hydrogel comprises methacrylated hyaluronic acid.

104. The method of claim 89, wherein the sustained release profile comprises a zero-order drug release profile.

105. A method of delivering a hydrophobic compound to a subject, the method comprising:implanting in the subject a device comprising at least one tablet comprising the hydrophobic compound, wherein the tablet is configured to exhibit a sustained release profile via surface-mediated dissolution, andmaintaining the device in the subject for a period of at least one month.

106. The method of claim 105, wherein the tablet comprises the hydrophobic compound in a compressed form at a concentration of at least 80%.

107. The method of claim 105, wherein implanting comprises inserting the device using a trocar.

108. The method of claim 105, wherein implanting comprises inserting the device using a needle having a diameter of 16G, 18G, 21G, or 23G.60QB\101545652.4BWH 2025-313-02Quarles 129319.01147 109. The method of claim 105, wherein the device further comprises a biodegradable casing surrounding at least a portion of the tablet, andwherein the biodegradable casing maintains a constant exposed surface area of the tablet during the period.

110. The method of claim 105, wherein the device is fully bioresorbable and the method does not comprise surgically removing the device from the subject at an end of the period.

111. The method of claim 105, wherein the device comprises a plurality of layers of tablets separated by a xerogel or a hydrogel, and wherein the xerogel or the hydrogel swells upon exposure to interstitial fluid to physically separate the layers.

112. The method of claim 105, wherein the period is at least three months, at least six months, at least one year, at least five years, or at least ten years.

113. The method of claim 105, further comprising retrieving the device from the subject prior to an end of the period.

114. The method of claim 105, wherein the sustained release profile comprises a zero-order drug release profile.

115. The method of claim 105, wherein implanting the at least one tablet in the subject further comprises implanting a plurality of separate tablets comprising the hydrophobic compound.

116. The method of claim 105, wherein the implanting in the subject the device comprises implanting into at least one of subcutaneous tissue, intramuscular tissue, dermal tissue, brain tissue, kidney tissue, ovary tissue, prostate tissue adipose tissue, intratumoral tissue, ocular tissue, oral tissue, vaginal tissue, uterine tissue, breast tissue, bladder tissue, bone tissue, gastrointestinal tissue, or intraperitoneal space of the subject.

117. A method of treating a condition in a subject in need thereof, the method comprising:61QB\101545652.4BWH 2025-313-02Quarles 129319.01147 implanting in the subject a device comprising at least one tablet comprising a hydrophobic compound,wherein the tablet is configured to exhibit a sustained release profile via surface- mediated dissolution, andmaintaining the device in the subject for a period sufficient to treat the condition.

118. The method of claim 117, wherein the condition comprises a condition treatable by administration of a hydrophobic compound comprising at least one of contraception, hormone therapy, dysmenorrhea, menorrhagia, endometriosis, polycystic ovary syndrome, HIV, malaria, tuberculosis, onchocerciasis, scabies, menopausal hormone deficiency, pain, schizophrenia, bipolar disorder, Tourette syndrome, breast cancer, prostate cancer, a cancer, inflammatory or autoimmune disorders.

119. The method of claim 117, wherein the hydrophobic compound is selected from the group consisting of levonorgestrel, ivermectin, quinestrol, cabotegravir, rilpivirine, lenacapavir, MK 8527, tafenoquine, ganfeborole, TBAJ-876 and analogs or derivatives thereof, pretomanid, testosterone enanthate, estradiol benzoate, estradiol valerate, zoledronate, medroxyprogesterone acetate, kisspeptin and analogs and derivatives thereof, dinalbuphine sebacate, sufentanil, fentanyl, pimozide, brexpiprazole, paliperidone palmitate, olanzapine pamoate, aripiprazole, aripiprazole lauroxil, haloperidol decanoate, fulvestrant, paclitaxel, docetaxel, and combinations thereof.

120. The method of claim 119, wherein the hydrophobic compound comprises one or more pharmaceutically acceptable salts, prodrugs, solvates, hydrates, polymorphs, stereoisomers, or crystalline or amorphous forms of the hydrophobic compound.

121. The method of claim 119, wherein the hydrophobic compound is levonorgestrel.

122. The method of claim 117, wherein the device further comprises a biodegradable casing surrounding at least a portion of the tablet, and wherein the method does not comprise surgically removing the device from the subject.62QB\101545652.4BWH 2025-313-02Quarles 129319.01147123. The method of claim 117, wherein the tablet comprises a plurality of hydrophobic compounds.

124. The method of claim 117, wherein the device maintains a plasma concentration of the hydrophobic compound above a therapeutic threshold throughout the period.

125. The method of claim 117, wherein implanting the at least one tablet in the subject comprises at least one of implanting the at least one tablet in a tissue of the subject, wherein the tissue comprises at least one of subcutaneous tissue, intramuscular tissue, dermal tissue, brain tissue, kidney tissue, ovary tissue, prostate tissue adipose tissue, intratumoral tissue, ocular tissue, oral tissue, vaginal tissue, uterine tissue, breast tissue, bladder tissue, bone tissue, gastrointestinal tissue, or intraperitoneal space.

126. The method of claim 117, wherein the sustained release profile comprises a zero-order drug release profile.

127. The method of claim 117, wherein implanting the at least one tablet in the subject further comprises implanting a plurality of separate tablets comprising the hydrophobic compound.63QB\101545652.4

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