Control release implants and uses thereof

Abstract

Disclosed is a medical agent delivery implant comprising a non-swellable casing having an internal bore in which a swellable solid core is positioned and wherein the swellable solid core has a maximum swollen state diameter, Ds, and the internal bore of the non-swellable casing has an internal diameter, Db, wherein Db < Ds, such that when the swellable solid core swells in use, the internal bore of the non-swellable casing exerts inward pressure on the swellable solid core that assists to restrict release of the medical agent loaded in the swellable solid core into surrounding tissue, as well as uses of the implant, methods of medical treatment using the implant, and methods of making the implant.

Description

[0001] CONTROL RELEASE IMPLANTS AND USES THEREOF

[0002] Cross-Reference

[0003]

[0001] The present application claims the benefit of Australian Provisional Patent Application No. 2024902380 filed on 31 July 2024, the entire contents of which are incorporated herein by crossreference.

[0004] Technical Field

[0005]

[0002] The invention relates to implants associated with controlled medical agent release in vivo.

[0006] Background

[0007]

[0003] Cancers such as pancreatic ductal adenocarcinoma (PDAC) and triple-negative breast cancer (TNBC) have a poor prognosis. Most cases of PDAC are unresectable, prompting the need for alternative treatment approaches. Neither personalised medicine nor immunotherapy have delivered major positive results in the treatment of PDAC. Indeed, the application of T-cell immune checkpoint inhibitors (ICIs) (e.g. anti-PD1 and anti-PDL1 therapy) in PDAC has not been beneficial due to the immunosuppressive tumour microenvironment and the dense stroma around the pancreas that inhibits the delivery of chemotherapeutics and infiltration of immune cells. Similarly, TNBC has long eluded improvements of more effective targeted therapies, as it is not responsive to hormone or HER2- directed treatments. Consequently, immunotherapy is the mainstay of treatment, to which only 20- 30% of patients respond. TNBC is also typically associated with a more aggressive disease course and a higher rate of regional and distant metastasis. Further, there is no cure for metastatic TNBC, which carries a median overall survival of 13-18 months. Development of more targeted and effective treatments for these cancers is therefore desirable.

[0008]

[0004] Clinical studies involving immunotherapy to treat TNBC as a monotherapy or in tandem with chemotherapy have increased exponentially over the past decade, as elevated levels of tumourinfiltrating lymphocytes (TILs) in the tumour microenvironment are conducive to a favourable prognosis. Programmed cell death protein-1 (PD-1), expressed on immune cells, and its ligand programmed cell death ligand-1 (PD-L1), expressed on tumour cells, are increasingly emerging targets of interest in TNBC. The interaction between PD-1 and PD-L1 initiates downstream signalling pathways that inhibit T-cell activation, proliferation, and cytokine production, and effectively promotes tumour survival and progression. The PD-1 / PD-L1 signalling axis can be inhibited by ICIs, which have demonstrated remarkable response rates and extended survival in numerous cancer types. Treatment response is typically more pronounced in patients where PD-L1 expression is upregulated, including in TNBC, where approximately 38% of tumours exhibit high PD-L1 expression.

[0009]

[0005] Immune-priming agents that are agonists of CD40 are being explored in combination with ICIs to elicit a more robust and durable anti-tumour immune response. In terms of efficacy, a locally delivered anti-CD40 agonist antibody has previously been shown to be superior to systemic treatment in preclinical murine models. In a localised delivery setting, anti-CD40 in combination with anti-PDL1 , delivered by a nanofluidic seed paired with external radiation therapy, has shown a 19-day survival advantage compared to radiation alone, and a two-fold decrease in lung metastasesin a 4T 1 model of TNBC. There are no reports of chemotherapy + ICI ± anti-CD40 using a one-time localised treatment approach.

[0010]

[0006] While the synergistic effects of immunotherapy and chemotherapy have markedly improved treatment response rates in TNBC, dose-limiting toxicities remain a significant barrier to effective treatment. Further, a major barrier of immunotherapy is the occurrence of autoimmunity, such as cytokine release syndrome and hepatotoxicity, which leads to adverse effects on the patient and limit the allowable administered doses. Conventional chemotherapeutics often possess low selectivity for malignant cells, which limits the therapeutic window of the drug and subjects healthy tissues to cytotoxic effects. Moreover, a substantial proportion of patients are not eligible to receive immunotherapy or do not respond to it.

[0011]

[0007] Accordingly, there is a need to develop new combinations and delivery strategies to improve survival and quality of life for cancer patients, particularly for poor prognosis cancers. Development of an effective delivery method for targeted and controlled release of chemotherapy and immunotherapy treatments to a desired site and with minimal off-target effects is desirable.

[0012]

[0008] A reference herein to a patent document or any other matter identified as prior art, is not to be taken as an admission that the document or other matter was known or that the information it contains was part of the common general knowledge as at the priority date of any of the claims.

[0013] Statements of the Invention

[0014]

[0009] In a first aspect, the invention provides a medical agent delivery implant, the implant comprising: a non-swellable casing having an internal bore in which a swellable solid core is positioned, wherein the swellable solid core comprises a hydrogel polymer matrix composed of one or more crosslinked hydrogel polymers loaded with at least one medical agent, and wherein the swellable solid core has a maximum swollen state diameter, Ds, and the internal bore of the non- swellable casing has an internal diameter, Db, and wherein Db < Ds, such that when the swellable solid core swells in use, the internal bore of the non-swellable casing exerts inward pressure on the swellable solid core that assists to restrict release of the at least one medical agent loaded in the swellable solid core into surrounding tissue.

[0015]

[0010] In one embodiment, medical agent delivery implant, the implant comprising: a non-swellable casing having an internal bore in which a swellable solid core is positioned, wherein the non-swellable casing comprises pores in one or more wall(s) thereof that extend through the casing; wherein the swellable solid core comprises a hydrogel polymer matrix composed of one or more crosslinked hydrogel polymers loaded with at least one medical agent, and wherein the swellable solid core has a maximum swollen state diameter, Ds, and the internal bore of the non-swellable casing has an internal diameter, Db, and wherein Db < Ds, such that when the swellable solid core swells in use, the internal bore of the non-swellable casing exerts inward pressure on the swellable solid core that assists to restrict release of the medical agent loaded in the swellable solid core into surrounding tissue.

[0011] The non-swellable casing may be a mechanically rigid non-swellable casing for structurally protecting the swellable solid core during implantation by injection through tissue. The swellable solid core may be positioned in close-fitting arrangement in the non-swellable casing when the hydrogel polymer matrix is partially dehydrated, or when fully dehydrated. The non-swellable casing may have modular strength of at least 70 mPa, as tested by compression testing using a mechanical tester to determine the amount of force required to compress the casing vertically until it bends. The non- swellable casing may have a wall thickness not deviating from an average wall thickness by more than ±5%. The non-swellable casing may comprise one or more polymers. The non-swellable casing may comprise one or more thermoplastic, extrudable polymers, selected from polycaprolactone, poly(lactic acid), poly(lactic-co-glycolic acid), polypropylene glycol), a silicone, and a poly(l-amino acid). In one embodiment, the casing comprises polycaprolactone (PCL). The internal bore diameter, Db, may be 1 .45 mm or less. In one embodiment, Db is about 0.15 mm to 1.45 mm. In another embodiment, Db is about 0.90 mm. The solid core may have a maximum swollen state diameter, Ds, that is at least 1.1xDb. In one embodiment, Ds is at least 2xDb. In another embodiment, Ds is from 1.1x to 10x Db. The swellable solid core may comprise a single fibre. In one embodiment, the solid core comprises a single extruded or 3D printed fibre. In one embodiment, the single fibre has a generally elongate shape. The one or more hydrogel polymers of the swellable solid core may comprise a hydrophilic polymer or copolymer thereof. In one embodiment, the hydrophilic polymer is selected from the group consisting of: alginate, chitosan, gelatin, collagen, carboxymethyl cellulose, poly(vinyl alcohol), hyaluronic acid and polyethylene glycol), preferably, alginate, or a copolymer thereof. The non- swellable casing may comprise one or more medical agents. The pores may be provided as a plurality of apertures along at least part of the length of the casing in spaced apart arrangement.

[0016]

[0012] The medical agent may be a chemotherapeutic. In one embodiment, the chemotherapeutic is irinotecan, 5-flurouracil, oxaliplatin, doxorubicin, gemcitabine, nab-paclitaxel, cyclopamine, paclitaxel, camptothecan, everolimus, epothilone, curcumin, and / or docetaxel. The medical agent may be an immunotherapeutic agent. In one embodiment, the immunotherapeutic agent is an immune checkpoint inhibitor, an immune priming agent, an agonistic CD40 antibody (anti-CD40 mAb), a B7.1 or B7.2 costimulatory agent, a chemokine receptor, or any combination thereof. In one embodiment, the immune checkpoint inhibitor is an anti-PD1 or anti-PDL1 antibody. In one embodiment, the immune priming agent is a cancer vaccine (GVAX). In one embodiment, the chemokine receptor is CCR2 or CCR5. The at least one medical agent may be a combination of one or more Tceii immune checkpoint inhibitors (ICIs) such as an anti-PD1 or anti-PDL1 antibody, or a combination of both an anti-PD1 and anti-CD40 antibody, or a combination of an anti-PD1 and an anti-CD40 antibody and gemcitabine and nab-pax, or a combination of an anti-PD1 and an antiCD40 antibody and nab-pax and dox. The implant may be biodegradable. The implant may further comprise locating means for use in locating the implant during and after implantation into a subject, optionally wherein the locating means is a dye or pigment, such a coloured dye or fluorescent dye; and / or an echogenic material, coating and / or nanoparticles in or on the core and / or casing.

[0013] In a second aspect, the invention provides a method of preparing a medical agent delivery implant, the method comprising: providing a swellable solid implant core comprising a hydrogel polymer matrix composed of one or more at least partially hydrated cross-linked hydrogel polymers loaded with at least one medical agent; at least partially dehydrating the hydrogel polymer(s) of the implant core; positioning the at least partially dehydrated core within an internal bore of a non-swellable casing, wherein the implant core has a maximum swollen state diameter, Ds, and the internal bore has an internal diameter, Db, and wherein Db < Ds, such that when the at least partially dehydrated implant core swells, the internal bore of the non-swellable casing exerts inward pressure on the implant core.

[0017]

[0014] In one embodiment of the second aspect, the method comprises fully dehydrating the hydrogel polymer(s) of the implant core. In one embodiment, fully dehydrating the hydrogel polymer(s) of the implant core comprises drying the hydrogel polymer(s) such that they comprise less than 5 wt% water, or less than 4 wt% water, or less than 3 wt% water, or less than 2 wt% water, or less than 1 wt% water, or of from 0 wt% to 5 wt% water, or of from 0 wt% to 4 wt% water, or of from 0 wt% to 3 wt% water, or of from 0 wt% to 2 wt% water, or of from 0 wt% to 1 wt% water when fully dehydrated.

[0018]

[0015] In one embodiment of the second aspect, the non-swellable casing is provided for the at least partially dehydrated core to be positioned within an internal bore thereof in implant-ready form, that is, already comprising one or more of a medical agent (if being used), pores, dye or pigment (if used), and / or echogenic locating means (if used). In one embodiment, the at least partially dehydrated solid core has a friction fit with the wall of the internal bore. The friction fit may be achieved using hand pressure and without deforming the solid core.

[0019]

[0016] In a third aspect, the invention provides an implant obtained by the method of preparing an implant of the invention (e.g., the second aspect).

[0020]

[0017] In a fourth aspect, the invention provides a use of the implant of the first aspect in localised treatment and / or localised prevention of a disease in a subject. Advantages of localised treatment may include avoidance of immune related adverse effects and reduction of impact to healthy tissues, compared to systemic delivery of combined immunotherapy and / or chemotherapy modalities.

[0021]

[0018] In a fifth aspect, the invention provides for use of the implant according to the first or second aspects, to treat or prevent a condition, wherein the use involves combinations of one or more medical agents, for example, selected from the group consisting of: chemotherapeutic agents, biologies including immune modulating agents, particularly immune-oncology agents, radioactive or radioisotope materials, contrast agents, fluorescent dyes, steroids, fatty acids, nucleic acids, vitamins, and any combination thereof.

[0022]

[0019] In a sixth aspect the invention provides a method of treating and / or preventing a disease or condition in a subject in need thereof, comprising implanting the device in the subject in one or more tissue areas to be subjected to localised delivery of one or more medical agents. In one embodiment, the disease or condition is a cancer, or is a solid cancer, or is a pancreatic cancer or a breast cancer, or is PDAC or TNBC.

[0023] Brief Description of the Drawings

[0020] Notwithstanding any other forms which may fall within the scope of the present invention, preferred embodiments of the invention will now be described, by way of example only, with reference to the accompanying drawings in which:

[0024]

[0021] Figure 1 illustrates: A-D) photographs of a comparative example implant in which Db > Ds (“Formulation 1” (F1)) and an implant according to one embodiment of the present invention (“Formulation 2”, (F2)); E) Recovered pancreas with a dyed green implant of F2; F) Recovered implant with a non-dyed implant of F2. Arrow indicating presence of implant;

[0025]

[0022] Figure 2 illustrates that (A) the presence of the PCL casing in the F2 implant (bottom line) better restricts drug release than comparative example implants comprising bare alginate fibres (top line) and F1 (middle line); and (B) comparative drug release profiles for F2 with 4x sets of holes vs 2x sets of holes against bare alginate fibres (top line). Each data point is mean of n=3-4 ±SD. Statistical analysis via 2-way ANOVA. ****P<0.0001 ;

[0026]

[0023] Figure 3 illustrates that there is a significant increase in the dry state alginate core diameter of F2, compared to F1 where a coaxial combined core and shell fibre is simultaneously coextruded, for an otherwise identical inner bore (internal shell) diameter. Diameters were measured using a light microscope, analysed using Image J. Data is the mean of n=7-9 measurements ± SD. Statistical analysis via an unpaired f-test. ****P<0.0001 ;

[0027]

[0024] Figure 4 illustrates photographs of coaxially extruded fibre F1 and embodiment of the invention herein F2: A) The coaxial fibre with exposed alginate core (left arrow) and PCL shell (right arrow) of F1 ; B) Bare alginate core of the coaxial fibre of F1 with PCL shell removed (arrow); C) the much larger diameter of the bare alginate core of F2 for the same size PCL casing as F1 ; D) Cross section of dehydrated F1 showing the shrunken alginate core (angled arrow) and substantial space gap between the core and PCL coaxially extruded shell. PCL shell denoted by upper arrow.

[0028]

[0025] Figure 5 illustrates that there was a significance decrease in final external (sheath) implant diameter of F2 compared to F1 enabled due to higher drug loading capacity in the larger F2 core. Diameters were measured using a light microscope, analysed using Image J. Data is the mean of n=17-20 measurements ± SD. 4-5 measurements taken per individual sample. Statistical analysis via an unpaired f-test. ****P<0.0001 ;

[0029]

[0026] Figure 6 illustrates F2 with separately extruded PCL casing having mechanical strength necessary for implantation into human tissue. A) Force vs. strain compression test of 4 x F2 samples (see Talaei et al. J Biomed Mater Res. 2023; 111 (3): 526); B) F1 implant, consisting of an alginate core and a PCL shell (co-axial structure) inserted into a 10% gelatin gel (comparable to the stiffness of human tissue) showing the coaxially extruded PCL shell of F1 has lower mechanical strength than F2. C) Three F2 implants (1 xwith dye, 1 cm length, (left) and 2 x without dye, 0.5 cm length (2 x right) in the casing) having an alginate core and extruded PCL casing and inserted into the same gel as B);

[0027] Figure 7 illustrates a schematic outlining the fabrication of the F2 implant;

[0030]

[0028] Figure 8 illustrates Cy-IgG delivered via an F2 implant had greater tumour uptake and was retained longer in vivo compared to systemic delivery: A) IVIS Spectrum CT was used to image 4T1 tumour bioluminescence of live animals prior to treatment, and the fluorescence of the Cy7-lgG at 10 min, 4 h, and 24 h; B) the average radiance of each mouse treated with either Cy7-IMP or CY7-SYS was calculated at 10 min, 4 h, and 24 h; C) At the conclusion of the study, ex vivo tissues were imaged; D) the average radiance of the tumours at study conclusion was calculated. Data is presented as the mean of 3-5 animals ± SD. *P < 0.05; CY7-IMP = Cy7-lgG loaded implant, CY7-SYS = systemic, IV administered Cy7-lgG;

[0031]

[0029] Figure 9 shows that fatal xenogeneic hypersensitivity reaction correlated with increased neutrophil accumulation in the lungs, and increased lymphocyte aggregation in the liver. H&E stains of lung and liver tissue was compared between mice that experienced a fatal hypersensitivity reaction (SYS3) to that of untreated (CONT1) and implant treated (IMP3) mice. Drugs in SYS3 and IMP3 were doxorubicin, nab-paclitaxel, anti-PD1 Ab and anti-CD40 agonist Ab. A) Lungs of SYS3 (iii, vi, viii) showed increase neutrophil accumulation (inset; iii) and alveolar congestion, which was not observed in the CONT (i, iv, vii) or IMP3 (ii, v, vii). Sections are from three representative mice from each treatment cohort. B) Livers of SYS3 at 20* and 100* magnification (iii, vi respectively) show increase in lymphocyte aggregation (black arrow) and cholestasis (yellow arrow), not observed in CONT 1 (i, iv) or IMP3 (ii, v) at 20* and 100* respectively. Sections are from one representative mouse from each treatment cohort;

[0032]

[0030] Figure 10 illustrates flow cytometric analysis of T-cell and myeloid populations in the spleen for the nab-paclitaxel and anti-PD1 and anti-CD40 (SYS4 = systemically delivered, IMP4 = implant delivered) or nab-paclitaxel and anti-PD1 (SYS5 = systemically delivered, IMP5 = implant delivered) vs control (CONT2). Spleens were mechanically dissociated and filtered using a 70 pm strainer to form a single cell suspension. Single cell suspensions were halved and labelled with appropriate fluorochrome-conjugated mAbs for T-cell or myeloid immunophenotyping. The proportions of CD3+of CD45+cells, CD4+and CD8+T-cells of CD3+T-cells, CD4+CD25+T-cells of CD4+T-cells and, CD8+PD1+and CD8+Ki67+T-cells of CD8+T-cells were determined by flow cytometry. The proportion of dendritic cells of CD45+Thy1.2'NK1.T cells, M1 macrophages (M<t>s), M2 M<t>s / monocytes, neutrophils, mature neutrophils, and immature neutrophils of CD45+Thy1.2'NK1.TCD11 b+ / 'CD40+ / ' cells were also determined by flow cytometry. CD11 b and CD40 were used to exclude B cells (CD11 b' CD40+) in the absence of B cell lineage antibodies. Data represents groups means ± SD; symbols represent individual mice; * P < 0.05, ** p < 0.01 , *** P < 0.001 , **** P < 0.0001 ; ordinary one-way ANOVA with Tukey’s multiple comparisons test;

[0033]

[0031] Figure 11 illustrates flow cytometric analysis of T-cell and myeloid populations in the nondraining lymph nodes for nab-paclitaxel and anti-PD1 and anti-CD40 (SYS4 = systemically delivered, IMP4 = implant delivered) or nab-paclitaxel and anti-PD1 (SYS5 = systemically delivered, IMP5 = implant delivered) vs control (CONT2). NDLNs were mechanically dissociated and filtered using a 70 pm strainer to form a single cell suspension. Single cell suspensions were halved and labelled with appropriate fluorochrome-conjugated mAbs forT-cell or myeloid immunophenotyping. The proportions of CD3+of CD45+cells, CD4+and CD8+T-cells of CD3+T-cells, CD4+CD25+T-cells of CD4+T-cells and, CD8+PD1+and CD8+Ki67+T-cells of CD8+T-cells were determined by flow cytometry. The proportion of dendritic cells of CD45+Thy1.2'NK1.T cells, M1 macrophages (M<t>s), M2 Mcbs / monocytes, neutrophils, mature neutrophils, and immature neutrophils of CD45+Thy1 .2 NK1 .T cells were also determined by flow cytometry. Data represents groups means ± SD; symbols represent individual mice; * P < 0.05, ** P < 0.01 ; ordinary one-way ANOVA with Tukey’s multiple comparisons test;

[0034]

[0032] Figure 12 illustrates flow cytometric analysis of T-cell and myeloid populations in the tumour draining lymph nodes for nab-paclitaxel and anti-PD1 and anti-CD40 (SYS4 = systemically delivered, IMP4 = implant delivered) or nab-paclitaxel and anti-PD1 (SYS5 = systemically delivered, IMP5 = implant delivered) vs control (CONT2). TDLNs were mechanically dissociated and filtered using a 70 pm strainer to form a single cell suspension. Single cell suspensions were halved and labelled with appropriate fluorochrome-conjugated mAbs forT-cell or myeloid immunophenotyping. The proportions of CD3+of CD45+cells, CD4+and CD8+T-cells of CD3+T-cells, CD4+CD25+T-cells of CD4+T-cells and, CD8+PD1+and CD8+Ki67+T-cells of CD8+T-cells were determined by flow cytometry. The proportion of dendritic cells of CD45+Thy1.2'NK1.T cells, M1 macrophages (M<t>s), M2 Mct>s / monocytes, neutrophils, mature neutrophils, and immature neutrophils of CD45+Thy1 .2 NK1 .1’ cells were also determined by flow cytometry. Data represents groups means ± SD; symbols represent individual mice; *P< 0.05, **p< 0.01 , *** P< 0.001 ; ordinary one-way ANOVA with Tukey’s multiple comparisons test;

[0035]

[0033] Figure 13 illustrates flow cytometric analysis of myeloid populations in the tumour for nab- paclitaxel and anti-PD1 and anti-CD40 (SYS4 = systemically delivered, IMP4 = implant delivered) or nab-paclitaxel and anti-PD1 (SYS5 = systemically delivered, IMP5 = implant delivered) vs control (CONT2). Tumours were mechanically and enzymatically dissociated, then filtered using a 70 pm strainer to form a single cell suspension. Single cell suspensions were halved and labelled with appropriate fluorochrome-conjugated mAbs for T-cell or myeloid immunophenotyping. The proportion of dendritic cells, M1 macrophages (M<t>s), M2 M<t>s / monocytes and neutrophils of CD45+Thy1.2- NK1 .1- cells were also determined by flow cytometry. Data represents groups means ± SD; symbols represent individual mice; * P < 0.05, ** P < 0.01 , *** P < 0.001 ; ordinary one-way ANOVA with Tukey’s multiple comparisons test;

[0036]

[0034] Figure 14 illustrates A) scanning electron microscopy images of 2% alginate without loaded drug (left) or loaded with doxorubicin, nab-paclitaxel and anti-PD1 (right) at 400 x magnification. B) Photographs of identical dry diameter rehydrated alginate cores with (top image) and without (bottom image) PCL casing (labelled “capsule”) in its hydrated state. The size difference is notable. B) Release of toluidine blue dye from 2% alginate encased in a PCL casing and according to an embodiment of the present invention vs without casing over 120 h. Data is presented as the mean of n=2 ± SD. Dox=doxorubicin, nab-ptx=nab-paclitaxel. Yellow scale bar = 100 pm. The release behaviour for the encased alginate core is not only lower in terms of dose across the time period tested, but is more consistent over time than release from the uncased alginate fibre; and

[0037]

[0035] Figure 15 illustrates that chemo-immunotherapy was tolerated better when delivered via an implant vs a subcutaneous injection. Mice were injected subcutaneously with chemo (Doxorubicin, nab-paclitaxel) ± immunotherapy (anti-CD40, anti-PD1) as a bolus liquid dose, or were injected with an implant (no casing) containing both. A) Injection site was monitored over 7 days for SC treated mice, implant (no casing mice) over 7 days. Mice treated with implant with casing (from efficacy study) was imaged at 28 days for comparison. B) AST / ALT was assessed at the conclusion of the study. C) Spleen weights were measured at the conclusion of the study. D,E) Animal weight was monitored over a 7-day period. Data is presented as the mean of 2-3 animals ± SEM. * P < 0.05, ** P < 0.01. SC = subcutaneous.

[0038] Detailed Description

[0039]

[0036] The invention herein provides a superior controlled release implant that involves a simple manufacturing process and gives highly stable release of medical agents into local tissue at the implantation site. The release profile of the implants herein results in lower systemic toxicity than previously known implants and allows new combinations of different classes of medical agents to be used locally, e.g., chemotherapy and / or immunotherapy treatment combinations. The implant of the invention may be implanted surgically, but in some preferred examples, the device is better suited to implantation by injection. A further advantage of the improved implants herein is that they can hold, in some embodiments, much higher amounts of the medical agents of interest through use of an increased core size without sacrificing desirable size and shape characteristics of the implant or negatively impacting implant injectability.

[0040]

[0037] The present invention provides a medical agent delivery implant, wherein the implant comprises a non-swellable casing having an internal bore in which a swellable solid core is positioned. The swellable solid core comprises a hydrogel polymer matrix composed of one or more crosslinked hydrogel polymers loaded with at least one medical agent. The swellable solid core has a maximum swollen state diameter, Ds, and the internal bore of the non-swellable casing has an internal diameter, Db, wherein Db < Ds. In this arrangement, when the swellable solid core swells in use, the internal bore of the non-swellable casing exerts inward pressure on the swellable solid core that assists to restrict release of the medical agent loaded in the swellable solid core into surrounding tissue. Use of a swellable solid core having a maximum swollen state diameter, Ds, and a non-swellable casing having an internal bore diameter, Db, wherein Db < Ds, offers surprising advantages over previous implants.

[0041]

[0038] Previous work by the present inventors identified an implantable wet-spun coaxial fibre device comprising an alginate core and a PCL shell, wherein the core and / or shell were loaded with gemcitabine (Gem) and / or paclitaxel (Ptx). In this device, the coaxial polymeric fibres were formed by wet-spinning coaxial extrusion methods, whereby the wet-state swollen alginate core was wet-spun simultaneously with the PCL shell such that on coextrusion, the maximum swollen state diameter of the alginate core, Ds, and the PCL shell having an internal bore internal diameter, Db, were always such that Db > Ds. Indeed, it will be appreciated that the alginate core in this previous work was coaxially spun in its maximally swollen state, by virtue of the processing method used, such that there was close contact between the PCL shell and the maximally swollen core during extrusion to produce a coaxial pseudo-single fibre. For mechanical strength, these coaxial fibres were dried and then placed within an additional PCL sheath or envelope to increase the rigidity for implantation, as the coaxial fibres alone were not sufficiently rigid to undergo implantation by injection. The PCL shell was loaded with Ptx, while the alginate core was loaded with Gem, by inclusion of the respective drugs in the polymer spin solutions. The Gem encapsulating efficiency (EE) in the alginate core of the coextruded coaxial fibre device was reported as 48.5% (8.1 mg per meter of fibre), while the Ptx loading in the protective PCL shell had an EE of 89.3% (14.5 mg per meter of fibre). Gem release from the core was assessed in simulated body fluid (SBF), while Ptx release from the shell was assessed in PBS. A total of 2.43 mg of Gem was released from the coaxial fibre over a 14 d period. The majority of Gem, 2.31 mg (94.3%), was released from the alginate core in the first 10 h in an initial burst release manner. For Ptx, 0.83 mg (19.3%) was released from the PCL shell of the coaxial fibre in the first 10 h, followed by a sustained release over a 21 d period, releasing a total of 1.67 mg (38.4%).

[0042]

[0039] It was not until testing of these devices that the burst release characteristics were identified, and the present inventors subsequently discovered that a substantial space gap between the reswelled alginate core and the PCL shell was likely responsible for the strong initial burst release characteristics from the core of the implant. The present inventors have therefore devised a new implant wherein the non-swellable polymer casing has an internal bore diameter smaller than the maximum swollen state diameter of its solid swellable core. In other words, the core dimensions and the casing dimensions, particularly diameters, are selected such that for any rehydrated core, the core on unrestrained maximum swelling will always be greater than diameter of the internal bore of the casing. This means that in use, on swelling, the core will be at least partially restricted by the casing, and it is this confinement that plays a significant part in controlling the medical agent release from the core, that is, slowing agent release due to at least partial restriction of core swelling. In order to produce the implant described herein, the present inventors had to overcome the prejudice in the art towards use of coextrusion and electrospinning to fabricate coaxial fibres and move to a separate, two-step fabrication method. In addition to enabling production of this previously undescribed implant structure, the two-step method introduces additional advantages in terms of functionalising the implants herein for use in vivo.

[0043] Definitions

[0044]

[0040] Unless the context implies otherwise, where any or all of the terms "comprise", "comprises", "comprised" or "comprising" are used in this specification (including the claims) they are to be interpreted as specifying the presence of the stated features, integers, steps or components, but not precluding the presence of one or more other features, integers, steps or components.

[0045]

[0041] As used herein, the term “non-swellable” refers to the polymer casing not absorbing water or other molecules and thereby expanding in size / volume. In one embodiment, “non-swellable” means that the polymer casing stays within 0.5%, or 1%, or 2%, or 3%, or 4% or 5% of its original pre-implant volume during use. In one embodiment, the casing may be non-swellable and mechanically rigid, and in particular, mechanically rigid under the stresses of a swelling core, meaning that the casing does not expand when the swellable core swells. In one embodiment, non-swellable and mechanically rigid means that the polymer casing stays within 0.5%, or 1%, or 2%, or 3%, or 4% or 5% of its original preimplant volume during use.

[0046]

[0042] As used herein, the term “swellable” refers to the solid core absorbing water and / or other molecules and expanding in size / volume. In one embodiment, “swellable” means that the solid core can increase to up to 500%, 400%, 300%, 200% or 100% of its original volume (in other words, can expand up to 6x, 5x, 4x, 3x or 2x larger than its original pre-implant volume) on absorption of water and / or other molecules, such as during use in a subject’s body.

[0047]

[0043] As used herein, the term “inward pressure” refers to pressure being exerted by one or all wall(s) of the internal bore of the non-swellable casing on the swellable solid core on swelling. It will be appreciated that this comprises an equal and opposite “outward pressure” being exerted by the swellable solid core on the internal bore of the casing. The term “inward pressure” therefore refers to more than simply friction between the core and the casing, such as would be present in a close-fitting arrangement where the solid core touches the internal walls of the casing on swelling, and implies a more active arrangement, whereby the solid core can, such as may be osmotically or otherwise driven, to expand beyond the volume of the casing but is prevented from doing so by the non-swellable casing. Casing

[0048]

[0044] The casing herein is non-swellable and may be any suitable non-swellable casing. The casing is multifunctional in that it contains and protects the solid core, such as protects the solid core from implantation and / or injection forces, as well as assisting in control of release of medical agents loaded in the solid core, but in certain embodiments may also be loaded with, and act as a reservoir for, the delivery of one or more hydrophobic medical agents.

[0049]

[0045] In some embodiments, the non-swellable casing is a mechanically rigid non-swellable casing. The mechanically rigid casing may have sufficient rigidity and / or strength to protect the swellable solid core from damage from forces experienced during implantation of the device, during surgery and / or by injection through one or more tissues / tissue types.

[0050]

[0046] In some embodiments, the non-swellable casing has modular strength of at least 70 mPa, at least 100 mPa, at least 120 mPa, at least 140 mPa, or at least 150 mPa, or of from 100 mPa to 180 mPa, or of from 70 mPa to 160 mPa, or of from 120 mPa to 170 mPa, e.g., as tested by compression testing (such as force vs. strain tests) using a mechanical tester to determine the amount of force required to compress the casing vertically until it bends. Such rigidity has been achieved for certain extruded polycaprolactone (PCL) casings.

[0051]

[0047] The casing may have any suitable wall thickness, and the thickness may depend on the overall diameter of the casing as dictated by the implantation means. In this context, “wall thickness” refers to the difference between the outer diameter of the casing and the diameter of the inner bore. The casing may have a wall thickness of up to about 1 mm, or up to about 1 .5 mm, or of from 0.5 mm to 1 .5 mm, or of 0.1 mm to 1 .0 mm, or of 0.1 mm to 0.5 mm, or of 0.25 mm to 1 .25 mm, or of 0.5 mm to 1.0 mm. In some embodiments, the polymer casing has a constant wall thickness, such as a wall thickness not deviating from an average wall thickness by more than ±10%, ±7.5%, ±5%, ±2.5%, or ±1 %.

[0048] The non-swellable polymer casing may be formed using any suitable forming means. In one embodiment, the non-swellable polymer casing is formed from extrusion of a polymer melt, or is 3D printed. Advantages of forming a casing from an extruded polymer melt and / or by 3D printing include any one or more of better control over thickness, homogeneity and / or dimensions, avoiding the use of crosslinking chemicals, greater achievable mechanical strength than chemically cross-linked PCL, including PCL cross-linked in a wet-spinning process, and / or the option to further functionalise the casing through use of dyes or other locating means to impart colour or visibility to the implant to assist with implantation. In some examples, extruded casings and / or 3D printed casings may be used to achieve wall diameter consistency as well as a suitable thickness and strength to withstand outward forces caused by swelling of the core and to withstand forces experienced on injection through one or more tissue types.

[0052]

[0049] Preferably, the casing is a hollow casing, suitable for surrounding at least a majority of the core, or in some embodiments, a majority of the core, or at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% of the volume of the solid core, or in some embodiments the whole solid core, such as about 100% of the solid core. In these embodiments, the solid core may be swollen or may be fully or partially dehydrated at the time of measurement but is preferably measured when the solid core is substantially fully or fully dehydrated.

[0053]

[0050] Although the shape of the casing is not particularly limited, in one embodiment, the casing has a cylindrical shape. In other embodiments, other prismatic shapes may be suitable, such as rectangular prismatic, square prismatic, or a distorted cylinder having an oval cross-section. In one embodiment, the casing has one or more pointed or sharpened end(s), such as to facilitate insertion of the implant into tissue during injection.

[0054]

[0051] The casing may, in some embodiments, have a constant internal cross-sectional shape along the length of the implant. Such shaping advantageously simplifies manufacture of the swellable core. In such embodiments, the internal diameter, Db, is thus constant or substantially constant along the length of the casing. In this embodiment, the swellable solid core must have a maximum swollen state diameter, Ds, that is greater than the internal diameter of the casing, Db. In one embodiment, the casing has an internal diameter that is consistent through the casing, that is, does not deviate in diameter between two locations by more than ±10%, ±7.5%, ±5%, ±2.5%, or ±1%.

[0055]

[0052] However, in other embodiments, the casing may have a non-constant internal cross-sectional shape. In such embodiments, the internal diameter, Db, may vary along the length of the casing, and the core used will have a substantially or completely corresponding profile matching that of the internal diameter of the casing such that at all relevant points (that is, all points excepting end regions where crimping, sharpened points, or other closure of the implant casing may be required) along the length of the casing, the swellable solid core has a maximum swollen state diameter, Ds, that is greater than the internal diameter of the casing, Db.

[0056]

[0053] In one embodiment, the casing has an internal shape that mirrors, or is the same as, the external shape. By way of non-limiting example, the casing may have an externally cylindrical shape and an internal bore also having a cylindrical shape. In other embodiments, the casing can have an internal shape that is different to the external shape. By way of non-limiting example, the casing may have an externally square prismatic shape and an internal bore having a cylindrical shape.

[0057]

[0054] That Db < Ds along the implant is an important feature of the implants described herein, as this ensures that after implantation in a subject’s tissues, on swelling, the solid core expands such that inner walls of the internal bore of the non-swellable casing exerts inward pressure against the solid core to assist in restricting release of the loaded medical agent into surrounding tissue. The importance of avoiding the problem of unrestricted agent release was not appreciated until coextruded coaxial implants having Db > Ds were tested in vivo found to exhibit faster release rates I profiles than were anticipated. The present inventors solved the initial unrestricted release problem with design of an implant as described herein that restricts swelling of the core in vivo.

[0058]

[0055] As described herein, and without wishing to be bound by theory, the inward pressure exerted by the internal bore walls against the swelling solid core may assist in restricting release of the one or more medical agents therein on implantation in a subject’s body by controlling the amount of fluid able to enter the implant and dissolve out the medical agent(s) in the solid core, and / or by controlling swelling of the solid core and thereby restrict its disintegration, and release of medical agents, in fluid.

[0056] In some examples, the casing may comprise an opening at one or each end to aid core positioning, such as core insertion in the internal bore, which in some embodiments is or are then closed off during manufacture to ensure the core remains positioned within the casing during insertion into a subject and during use. It will be understood that closed ends of the implant are not included for the purposes of working out whether Db < Ds, as typically, the ends will not comprise swellable solid core if they are to be closed, such as by crimping, forming into a point, or the like. In other embodiments, the casing comprises an opening at one or both ends that is not closed off during manufacture, as because Db < Ds within the casing, the implant in use is less susceptible to the solid core becoming loose and / or falling out of the casing.

[0059]

[0057] The dimensions of the casing, and therefore of implants as described herein, are not particularly limited. However, for implants intended for implantation via injection, the non-swellable casing preferably has an external wall-to-wall diameter of 1 .4 mm or less, or an average external wall- to-wall diameter from about 0.50 to 1 .45 mm, or of about 1 .20 mm. These external diameters may be preferred when the implant is to be injected through needles of gauge 21 and wider. In other embodiments, such as where endoscopic ultrasound-guided fine-needle injection is desired, non- swellable casings having an average external wall-to-wall diameter from about 0.15 to 0.42 mm, such as compatible with needles of 22 gauge or finer, may be used.

[0060]

[0058] The casing may comprise any suitable materials that are non-swellable, and in some embodiments, that are also mechanically rigid. In some embodiments, the casing comprises one or more polymers. Polymers are advantageously light, inexpensive, non-reactive in the body, easy to process and shape, and, in preferred cases, are biodegradable. Although the polymer is not particularly limited, the polymer may in some embodiments be a biodegradable polymer. In one embodiment, the biodegradable polymer is poly(lactic acid), poly(glycolic acid), poly(caprolactone), polycyanoacrylate, a polyanhydride, polypropylene fumarate, or a copolymer thereof. In one embodiment, the biodegradable polymer is a biodegradable polyester. In one embodiment, the polymer is polycaprolactone. In one embodiment, the polymer comprises polycaprolactone, such as is a co-polymer thereof. In one embodiment, the polymer may be a silicone (polysiloxane) polymer or elastomer. Monomers and / or polymer melts or filaments suitable for forming the non-swellable casing are known in the art, and may be purchased commercially from suppliers such as Sigma Aldrich® and the like.

[0061]

[0059] In one embodiment, the polymer is extrudable. The polymer may be capable of being extruded, such as using commercial extrusion apparatus, including screw extruders, having dies that enable continuous melting and extrusion of a polymer melt. Accordingly, in one embodiment, the polymer is a thermoplastic polymer. Suitable thermoplastic polymers for extrusion include poly(lactic acid), poly(glycolic acid), poly(caprolactone), polycyanoacrylate, polypropylene fumarate, silicones, and copolymers thereof. In one embodiment, the polymer is non-swellable. The polymer of the casing in preferred embodiments is devoid of any hydrogel polymer component or is devoid of hydrophilic hydrogel polymer. In some embodiments, the casing is selected from the group consisting of polycaprolactone, poly(lactic acid), poly(lactic-co-glycolic acid), poly(2-oxazoline), polyglycerol sebacate, polypropylene glycol), a silicone, and a poly(l-amino acid). In one embodiment, the polymer is polycaprolactone (PCL). In some examples, the casing may be composed of extruded PCL. Particularly suitable polymers for the casing are not swellable. In some embodiments, the casing may be formed via a 3D printing technique.

[0062]

[0060] In other embodiments, the casing may comprise a non-polymeric non-swellable material. In one embodiment, the casing may comprise one or more metal or ceramic materials. Ceramic materials are advantageously corrosion resistant and may provide a bioinert alternative to polymers or metals in case of allergic reaction or inflammation caused by other materials. Metal materials provide high strength and rigidity, and may advantageously offer higher imaging contrast using common imaging techniques such as x-ray, computed tomography (CT), or magnetic resonance imaging (MRI). The ceramic may be any suitable ceramic, but in one embodiment, may comprise alumina, zirconia, hydroxyapatite, calcium phosphate, tantalum oxide, bioactive glass, or the like. Such materials may be made and fabricated into casings for use with the present invention by means of sol-gel processing, precipitation, and solid-state reactions that will be known to those of skill in the art. The metal may be any suitable metal, but in one embodiment, may comprise titanium or an alloy thereof, stainless steel, or cobalt-chromium alloys. Methods for forming casings comprising metals will also be known to those of skill in the art, and may utilise casting, forging, and / or 3D printing by way of non-limiting example.

[0063]

[0061] In one embodiment, the casing may comprise a coloured dye or pigment or echogenic material for locating the implant in vivo. In one embodiment, the coloured dye or pigment may be a Federal Food, Drug, and Cosmetic Act approved FD&C) dye or pigment, a D&C dye or pigment, or a natural colour additive. In one embodiment, the echogenic material may comprise microbubbles, microparticles, a silicone-based material, barium sulfate, or nanoparticles. Such additives may be added during extrusion of polymer melts in order to have the dye, pigment or echogenic material in the casing, which may advantageously streamline manufacture and / or increase the durability of the additive in the body. However, in other embodiments, a dye, pigment or echogenic material may be used to coat the casing after fabrication. The dye, pigment, or echogenic material, if added to the polymer melt, may be added in any suitable concentration, such as less than 3 wt%, less than 1 wt%, less than 0.5 wt%, less than 0.05 wt%, etc.

[0064]

[0062] In some embodiments, the casing may be provided with a medical agent, which can be the same or different to the medical agents described in respect of the core. In some embodiments, hydrophilic agents are included in the core, where the hydrogel polymer is located, while hydrophobic agents are included in the casing, especially if the casing comprises or consists essentially of a hydrophobic polymer.

[0065]

[0063] Desirably, walls of the non-swellable polymer casing comprise pores that extend through the casing. In this context, “through” the casing refers to the pores extending from an outer wall of the casing, such as that would be exposed to an in vivo environment, through the casing to the inner wall of the casing, such that would be adjacent to a surface of the solid core positioned within the internal bore of the casing. These pores, referred to herein as “pores” or “through pores”, aid in release of the medical agents from the core when the device is used and aid body fluid to enter the implant to swell the core. The number and dimensions of the pores can be any suitable number or dimensions and can be adjusted as required. For example, additional or larger dimensioned pores may be used where it is desired to release high amounts of the medical agents. However, preferably, the pores, nature, number and arrangement thereof, are selected so as not to interfere in the overall type of release profile. The size and number of pores may also be selected so as not to lessen or reduce the mechanical strength / injectability of the implant. In some embodiments, the pores in the casing can be provided in array form, in one or more areas of the casing, for example, to aid in directional release of the medical agent, and / or to control release of agents loaded in different sections of the core.

[0066]

[0064] In some embodiments, where the casing comprises through pores or apertures, the through pores or apertures are provided as a plurality of apertures, in some embodiments where each aperture has a diameter of about 100 pm, disposed along the length of the casing in spaced apart arrangement. Desirably, the through pores are located in spaced apart configuration, preferably in a 90 ° or a 180 ° offset configuration. In one embodiment, 4 sets of holes are spaced along the length of the casing, such as four rows of holes where each row is about 90 ° from adjacent rows, where the number of holes is 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more, or of from 1 to 20 holes, or of from 1 to 10 holes. In another embodiment, 2 sets of holes are spaced along the length of the casing, such as two rows of holes where each row is about 180 ° from the adjacent row, where the number of holes is 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more, or of from 1 to 20 holes, or of from 1 to 10 holes. In other embodiments, staggered holes may be provided, or holes may be provided not in the form of rows but instead spirally along the casing. Other pore arrangements will be apparent to one of skill in the art. In some embodiments, it is more important to performance of the implant to have the holes arranged to provide drug release in a particular direction, rather than to provide any specific number of pores. In some examples, the pores are formed via a laser cutting, as this technique enables very precise pore placement, formation and consistency. In some examples, pores can be provided in array, having 12, 16, 18, 20, 24, 26, 28, 30, 36, etc. pores throughout any given implant casing. However, other methods of forming holes will be known to those of skill in the art. In one example, an arrangement of 7 x 4 pores has been used. As explained elsewhere, control of the directionality of drug release support by the pore characteristics can be appropriately achieved.

[0067] Solid core

[0068]

[0065] The swellable solid core of the implants herein comprises a hydrogel polymer matrix. In some embodiments the core may comprise a hydrogel polymer matrix as well as other components, such as other polymers and / or additives. The other polymers and / or additives may control or adjust the hydrophilic / hydrophobic balance of the solid core. In other embodiments, the solid core may consist of or consist essentially of the hydrogel polymer matrix. The hydrogel polymer matrix herein comprises one or more crosslinked hydrogel polymers loaded with at least one medical agent. The hydrogel polymers are generally considered to provide the solid core with its swellable property, although other components that enhance swelling may also be included in the core in some embodiments.

[0069]

[0066] The one or more hydrogel polymers of the solid core may be selected from a hydrophilic polymer or a copolymer thereof, such as a block copolymer or random copolymer thereof. Hydrophilic polymers, or copolymers with a hydrophilic component, are preferred for use in the solid core of the implants described herein, as they are swellable in aqueous systems, such as in body fluids containing water. However, hydrophobic components may be present in the core in order to facilitate absorption of hydrophobic medical agents, as needed.

[0070]

[0067] In one embodiment, the hydrogel polymer is a hydrophilic hydrogel polymer. In one embodiment, the one or more hydrogel polymers of the solid core is / are selected from the group consisting of: alginate, gelatin, collagen, chitosan, carboxymethyl cellulose, poly(vinyl alcohol), hyaluronic acid and polyethylene glycol).

[0071]

[0068] In one embodiment, the solid core is produced by spinning a polymer dope solution comprising the hydrogel polymer in aqueous solution. In one embodiment, the solution may comprise from about 1 % to about 10% of the hydrogel polymer, or of from 1 % to 2%, or of from 2% to about 5%, or about 3% to about 7%, or of from about 5% to 10% w / w or w / v of the hydrogel polymer in solution. In one embodiment, the medical agent is loaded into the solid core via loading into the crosslinked hydrogel polymer. In one embodiment, the medical agent is loaded into the solid core via loading into a hydrogel polymer solution. Although any suitable concentration of the medical agent may be introduced into the core hydrogel polymer, in some embodiments, the concentration of medical agent in the crosslinked hydrogel polymer or polymer solution may be of from about 1% to about 10%, or of from 1 % to 2%, or of from 2% to about 5%, or about 3% to about 7%, or of from about 5% to 10% w / w or w / v. In some embodiments, the solid core may comprise different medical agents located in different sections along the core, such as by changing the agent / hydrogel polymer solution, or by loading into different sections of the crosslinked hydrogel polymer.

[0072]

[0069] In some embodiments, the swellable solid core has a generally elongate shape or has a rodlike shape. In some embodiments, the solid core is cylindrical or substantially cylindrical, or prismatic with a long axis and an oval, square or rectangular cross-section, or may be in the form of a fibre. In one embodiment, the solid core has one or more pointed or sharpened end(s). In one embodiment, the solid core may have a constant cross-sectional shape. In other embodiments, the solid core may have a non-constant cross-sectional shape. In such embodiments, the core diameter, De, may vary along the length of the core, either such that the core will have a substantially or completely corresponding profile matching that of the internal bore of the casing or having a different profile to that of the internal bore, provided that at all relevant points along the length of the casing (that is, all points excepting end regions where crimping or other closure of the implant casing may be required), the swellable solid core has a maximum swollen state diameter, Ds, that is greater than the internal diameter of the casing, Db.

[0073]

[0070] The solid core may have any suitable dimensions. In one embodiment, an elongate solid core may have any useful length. In one embodiment, the elongate solid core has a length of from 1 mm to 15 mm, or of from 3 mm to 10 mm, or of from 4 mm to 7 mm. The length used will depend on the application in question, and the location for implantation, as well as tumour size and its location. By way of suggestion only, larger and more accessible tumours may permit or require a longer solid core length than smaller and less accessible tumours.

[0074]

[0071] Each swellable solid core will have a known maximum swollen state diameter, Ds, that can be used to select an appropriately sized internal bore of the non-swellable casing, of internal diameter Db, such that Db < Ds in the final implant. Indeed, the core diameter (cross sectional; external) is not particularly limited as long as the core comprising hydrogel polymer in a fully dry / dehydrated or at least partially dehydrated state can be placed within, and fits within, the casing comfortably and without experiencing damage from positioning within the casing. It is important, however, that on reswelling of the core, the edge-to-edge core diameter (cross sectional) is greater than the internal bore diameter of the casing to ensure the desirable control release properties of the invention.

[0075]

[0072] Accordingly, the swellable solid core, when first synthesised, may have an edge-to-edge diameter (external, cross sectional) along its length of greater than 0.25 mm, greater than 0.3 mm, greater than 0.4 mm, greater than 0.5 mm, greater than 0.6 mm, greater than 0.7 mm, greater than 0.8 mm, greater than 0.9 mm, greater than 1 mm, greater than 1.1 mm, greater than 1.2 mm, greater than 1.3 mm, greater than 1.4 mm, greater than 1.5 mm, greater than 1.6 mm, greater than 1.7 mm, greater than 1.8 mm, greater than 1.9 mm, greater than 2 mm, greater than 2.5 mm, greater than 2.75 mm, or greater than 3 mm, or of from 0.25 mm and 5 mm, or of from 0.1 mm to 1 mm, or of from 0.1 mm to 5 mm, or of from 0.1 mm to 0.25 mm, or of from 0.25 mm to 3 mm. In such embodiments, the solid core may be synthesised in a partially hydrated state or in a completely hydrated state, and thus the diameters in this paragraph may represent external cross-sectional diameters of partially hydrated or completely hydrated solid cores.

[0076]

[0073] In one embodiment, the solid core, when completely dehydrated, or when completely dehydrated for the first time after synthesis, has an edge-to-edge diameter (external, cross sectional) of greater than 0.2 mm, greater than 0.3 mm, greater than 0.4 mm, greater than 0.5 mm, greater than 0.6 mm, greater than 0.7 mm, greater than 0.8 mm, greater than 0.9 mm, greater than 1 mm, greater than 1.1 mm, greater than 1.2 mm, greater than 1.3 mm, or of from 0.25 mm and 3 mm, or of from 0.1 mm to 1 mm, or of from 0.1 mm to 3 mm, or of from 0.1 mm to 0.25 mm, or of from 0.25 mm to 2 mm.

[0074] In one embodiment, the solid core, when reswelled from a partially or completely dehydrated state to its maximum diameter without restriction, that is, Ds, has an edge-to-edge diameter (external, cross sectional) of greater than 0.25 mm, greater than 0.3 mm, greater than 0.4 mm, greater than 0.5 mm, greater than 0.6 mm, greater than 0.7 mm, greater than 0.8 mm, greater than 0.9 mm, greater than 1 mm, greater than 1.1 mm, greater than 1.2 mm, greater than 1.3 mm, greater than 1.4 mm, greater than 1.5 mm, greater than 1.6 mm, greater than 1.7 mm, greater than 1.8 mm, greater than 1 .9 mm, greaterthan 2 mm, greaterthan 2.25 mm, greaterthan 2.5 mm, greaterthan 2.75 mm, greater than 3 mm, or of from 0.25 mm and 5 mm, or of from 0.25 mm to 2 mm, or of from 0.5 mm to 5 mm, or of from 0.1 mm to 0.25 mm, or of from 0.25 mm to 3 mm.

[0077]

[0075] In one embodiment, the solid core has a maximum swollen state diameter, Ds, that is at least 1 ,1xDb, that is, Ds = 1 ,1xDb, or is at least 1 ,2xDb, or at least 1 ,3xDb, or at least 1 ,4xDb, or at least 1 ,5xDb, or at least 2xDb, or at least 3xDb, or at least 4xDb, or at least 5xDb, or at least 8xDb, or at least 10xDb, or is of from 1.1x to 5x Db, or is of from 1.1x to 3x Db, or is of from 1.1x to 10x Db, or is of from 2x to 8x Db, or is of from 3x to 10x Db. It will be understood that measurement of maximum swollen state diameter may be conducted for any given solid core (having known shape, diameter, and length) in an environment where the solid core is not restricted from swelling in any way. In such embodiments, the maximum swollen state diameter of a solid core may be measured in body fluid, or in simulated body fluid, and may be taken as the diameter reached by the solid core beyond which the diameter ceases to increase, or in one embodiment, beyond which the diameter increases by less than 5%, less than 4%, less than 3%, less than 2% or less than 1 % in 24 h, 48 h, 72 h, or 96 h.

[0078]

[0076] In some embodiments, the swellable solid core may be formed from a wet spun single fibre, whereas in other embodiments, the solid core may be 3D printed as a single fibre. Although it is preferred that the swellable solid core is a single fibre, in some embodiments, the solid core may comprise intertwined strands of identical or different hydrogel polymers that are plaited or twisted together to form a pseudo single fibre, rope or the like. In one embodiment, a hydrophobic polymer fibre and a hydrophilic hydrogel fibre may be intertwined or twisted together to form the swellable solid core. In such embodiments, the maximum swollen state diameter, Ds, may be of the entire fibre bundle.

[0079]

[0077] In one embodiment, the core is produced by spinning a polymer dope solution comprising from about 3% to 5%, such as 2%, alginate by weight / volume in solution. In one embodiment, gemcitabine is the medical agent loaded into the solid core, and the gemcitabine is incorporated in the hydrogel polymer via inclusion in a solution of alginate in a concentration range of from about 1% to 2%, such as from 1.2% to 1.5% w / w or w / v. In one embodiment, the rate of release of gemcitabine from the hydrophilic alginate solid core is in the range from about 0.85 mg to about 1.3 mg in a first hour of measurement. Other methods for producing the implants herein are described below.

[0080] Medical agent

[0078] The implants described herein are versatile in that any of a number of medical agents may be included. Generally, the implants herein comprise the medical agent or combination of medical agents in the core only. However, in certain embodiments, one or more medical agents may be additionally loaded in the casing.

[0081]

[0079] The medical agent may be any suitable medical agent, being an agent having recognised medical activity. In one embodiment, the loaded medical agent is one or more agents selected from the group consisting of: a chemotherapeutic agent, a biologic including an immune modulating agent, particularly an immune-oncology agent, a radioactive or radioisotope material, a contrast agent, a fluorescent dye, a steroid, a fatty acid, a nucleic acid, and a vitamin, an anti-inflammatory agent, an antifibrotic agent, a pathway targeted small molecule, an anti-angiogenic agent, a gene editing / RNA based agent, an oncolytic virus, and an anti-microbial agent, or any combination thereof. In one embodiment, the loaded medical agent is a chemotherapeutic agent, a biologic, or a combination of the two. In one embodiment, the biologic is an immune modulating agent. In one embodiment, the immune modulating agent is an immune-oncology agent.

[0082]

[0080] For cancer applications in particular, the medical agent may be one or more chemotherapeutics selected from irinotecan, 5-flurouracil, oxaliplatin, doxorubicin, paclitaxel (pax), gemcitabine (gem), nanoparticle albumin-bound-paclitaxel (nab-pax); and a stromal modulating agent such as a steroid alkalaoid e.g., cyclopamine, fasudil and pirfenidone; camptothecan, everolimus, epothilone, curcumin, docetaxel; or any combination thereof.

[0083]

[0081] For cancer applications in particular, the medical agent may be a biologic-based cancer therapeutic including an immune modulating antibody / immunotherapeutic, particularly those that block checkpoint proteins, such as a CTLA-4 inhibitor (e.g., against melanoma and renal cell cancer), a PD- 1 inhibitor (against PD-1 on T-cell) or a PD-L1 inhibitor (against PD-L1 on tumour cells), e.g., a human or murine monoclonal antibody (mAb), or the like.

[0084]

[0082] In one embodiment, the medical agent may be a checkpoint inhibitor, where the checkpoint inhibitor is pembrolizumab (Keytruda®, against melanoma, Hodgkin lymphoma, non-small cell lung cancer), nivolumab (Opdivo®, against some kidney, head and neck cancers), atezolizumab (Tecentriq®, against lung cancer, some liver cancers, some breast cancers, urothelial cancer, Merkel cell carcinoma, urothelial cancer) (all against PD-1); ipilimumab (Yervoy®), or durvalumab (Imfinzi®, against non-small cell lung cancer).

[0085]

[0083] In one embodiment, the medical agent may be an antibody or targeted therapy (including an immune checkpoint inhibitor) such as an anti-CD40 antibody.

[0086]

[0084] In some particularly preferred embodiments, the medical agent is a combination of medical agents selected from one or more chemotherapeutic agents and one or more immune modulating agents, e.g., an antibody, an immune checkpoint inhibitor, or the like. In some embodiments, the combination may comprise gemcitabine and / or nab-paclitaxel as chemotherapeutics, anti-PD1 (as an immune check point inhibitor-based immunotherapeutic agent) and / or anti-CD40 (as an antibody (e.g. monoclonal antibody)-based immunotherapeutic agent). In one embodiment, the medical agent is a combination involving at least one agent which is a chemotherapeutic agent and at least one agent which is an immune modulating agent. In some embodiments, two or more chemotherapeutic agents in combination with one or more immune modulating agents may be used as the medical agent.

[0087]

[0085] In some embodiments, the medical agent is a combination comprising one or more T-cell immune checkpoint inhibitors (ICIs) such as an anti-PD1 and anti-PDL1 or is a combination of anti- PD1 and anti-CD40 antibodies. In some examples, at least one ICI is used with at least one chemotherapeutic.

[0088]

[0086] In some preferred embodiments, the medical agent is a combination of two or more of: anti- PD1 , antiCD40, gemcitabine (gem), and nab-paclitaxel (nab-pax), for example, for treating a tumour in pancreatic ductal adenocarcinoma (PDAC) cancer. In one embodiment, the combination involves all of anti-PD1 , antiCD40, gemcitabine (gem), and nab-paclitaxel (nab-pax). In some preferred embodiments, the medical agent is a combination of two or more of: an anti-PD1 antibody, an antiCD40 antibody, nab-paclitaxel (nab-pax), and doxorubicin (dox), for example, for treating a tumour in triple negative breast cancer (TNBC). Preferably, the combination involves all of an anti-PD1 antibody, an antiCD40 antibody, nab-paclitaxel (nab-pax), and doxorubicin (dox).

[0089]

[0087] In one embodiment, the medical agent is hydrophobic, in one embodiment selected from the group consisting of paclitaxel, camptothecan, everolimus, epothilone, curcumin, docetaxel, and any combination thereof.

[0090]

[0088] In one embodiment, the medical agent is hydrophilic, in one embodiment selected from the group consisting of: gemcitabine, nab-paclitaxel, nivolumab, a platinum agent, 5-fluorouracil, irinotecan, a taxane, cyclophosphamide, rituximab, cetuximab, trastuzumab, pertuzumab, sunitinib, bevacizumab, an anti-EGFR molecule, an anti-CTLA4 antibody, an anti-PD1 or anti-PDL1 antibody or inhibitor, an anti-CD40 antibody, tisagenlecleucel, an immune modulating agent, and any combination thereof. Persons of skill in the art will be able to determine whether a medical agent is hydrophobic or hydrophilic and therefore suitable for addition to the core or the casing, such as by analysis of the molecular structure of the agent and / or through solubility tests or the like.

[0091]

[0089] Any suitable loading of the medical agent in the solid core may be used. In one embodiment, loadings of from about 10 mg medical agent per metre of solid core to about 200 mg / m of solid core may be used, or of from 10 mg / m to about 100 mg / m, of from 50 mg / m to about 175 mg / m, or of from 100 mg / m to about 200 mg / m. In some embodiments, these dosages are calculated based on a solid core having a cylindrical shape and a fully dehydrated cross-sectional diameter of about 0.5 mm (corresponding to a fully hydrated diameter of from 0.5 cm to 1 .0 cm when swelling is not confined by casing). In one embodiment, these dosages are as used for gemcitabine, and thus equivalent loadings may be calculated for other medical agents accordingly, accounting for the desired dosage of the agent in vivo based on the release profile. Any suitable loading of medical agent in the casing may be used. In some embodiments, medical agent loading in the casing may be from 0.5 wt% to 5 wt%, or of from 0.5 wt% to about 2 wt%, or of from about 2 mg medical agent per metre of casing to about 50 mg per metre of casing, or of from 5 mg / m to about 15 mg / m, of from 7 mg / m to about 25 mg / m, or of from 10 mg / m to about 50 mg / m.

[0090] As noted above, the medical agent may be combined with a polymer dope solution and thereby be incorporated into the solid core through wet extrusion of the core from a coagulation bath. In other embodiments, such as where the solid core is 3D printed, the medical agent may be combined with the polymer printing solution, or may instead be absorbed into the core, such as into the hydrogel polymer matrix component of the core, via immersion of the 3D printed core in a solution comprising the medical agent. In some embodiments where immersion is used, the 3D printed core may need to be dehydrated prior to immersion in the solution comprising the medical agent. Persons of skill in the art will be able to calculate medical agent loading in the core or casing, such as by using the known concentration of the agent in the polymer spin or printing solution and the rate of core / casing formation, or by experimentally measuring medical agent release into solution over time.

[0092]

[0091] It will be understood that the term “medical agent” and “drug” may be used interchangeably herein.

[0093] Implant

[0094]

[0092] The implants herein may be tailored to offer a desired medical agent release rate through use of different solid core compositions, different medical agent loadings in the core, different cross- sectional sizes of the core and casing, different lengths of the core and casing, and / or hole number or position in the casing. However, a key advantage of the implants herein is that in certain embodiments, they are able to achieve previously unachievable steady and sustained release rates of medical agents into surrounding tissue on implantation. In preferred implants, at 96 hours post wetting (or post insertion in an aqueous medium such as subject’s body, such as post implantation), the implants herein release 50% or less of the medical agent from the core into fluid surrounding the device. In preferred embodiments, at 96 hours post wetting, the implants herein release 40% or less, 35% or less, 30% or less, 25% or less or 20% or less of the medical agent from the core. These slower release implants are particularly preferred. In particularly preferred implants, at 24 hours post wetting (or post insertion in an aqueous medium such as subject’s body, such as post implantation), the implants herein release 20% or less of the medical agent from the core. In some embodiments, the implants herein, at 6 hours post wetting (or post insertion in an aqueous medium such as subject’s body, such as post implantation), release 50% or less of the medical agent from their core. These rates of release are in contrast to the release rates associated with previously known coextruded coaxial devices that gave release rates of 75% after 100 hours, and which were significantly closer to the release rate of a bare core without any shell (100% release after 100 hours).

[0095]

[0093] Comparison studies conducted on implants where Db > Ds, such as in W02020 / 056467, and implants as described herein where Db < Ds, used fluorescein and toluide blue as model agents. In these studies, the comparative implant released around 50% of the agent from the device after 25 hours, compared to less than 25% after 25 hours for the implant according to an embodiment of the present invention. The differences in agent release were more dramatic after 100 hours, where the comparative implant released around 100% of loaded fluorescein compared to less than 30% for an implant as described herein in the same time frame. The improved performance is due to improvement made in the implant such that Db < Ds, which was made on realisation that on rehydration of the comparative implant, swelling of the hydrogel polymer core did not result in a swollen core with the same dimensions as the core when it was originally coextruded from the coaxial spinneret with its PCL shell. Instead, despite maximum core swelling occurring, the rehydrated device exhibited a substantial space gap between the reswelled hydrogel core and the coaxial shell component, such that the shell did not assist in control of drug release from the swelling / swollen core.

[0096]

[0094] In some embodiments, the casing is polycaprolactone and the hydrogel polymer of the swellable solid core is a hydrophilic hydrogel polymer, in one embodiment, is alginate. In some embodiments, the casing is extruded polycaprolactone and the hydrogel polymer in the swellable solid core is alginate.

[0097]

[0095] In some embodiments, the implant structure assists in restricting release of the medical agent, that is, assists in restricting a sudden, high concentration release of the medical agent during the first 3 hours, or the first 10 hours, or the first 24 hours, and thereby ensures a sustained release of the medical agent over the next 48 hours, 72 hours, 96 hours, 150 hours, 200 hours, 250 hours, or 300 hours compared to an implant that exhibits burst release behaviour. In one embodiment, a sudden, high concentration release corresponds to release of more than 50%, or more than 60%, or more than 70%, or more than 75%, or more than 80%, of the medical agent in the first 1 hour, or first 2 hours, or first 3 hours, or first 5 hours, or first 8 hours, or first 10 hours, or first 24 hours, or first 48 hours, or first 72 hours, after implantation. In one embodiment, a sudden, high concentration release corresponds to release of 20% or more of the medical agent in the first 8 to 24 hours after implantation. In one embodiment, a sudden, high concentration release corresponds to release of 20% or more of the medical agent in the first 10 hours after implantation. In one embodiment, a sudden, high concentration release corresponds to release of 30% or more of the medical agent in the first 48 hours after implantation.

[0098]

[0096] The implant may be implanted surgically, that is, may be a surgical implant. More desirably, however, the implant is suitable for implantation in a tissue site of a subject by injection through one or more tissue types, that is, it may be an injectable implant. In some embodiments, the implant is implantable by injection via endoscopic ultrasound-guided fine needle injection. Fine needle injection may use needles with particularly small internal cross-sectional diameters, such as of less than 0.4 mm. In some embodiments, the implant is implantable by injection via transdermal intralesional injection for palpable primary or secondary tumours. Transdermal injections may use needles with internal cross-sectional diameters of about 0.5 mm to 0.6 mm. In some embodiments, the implant is implantable by injection via CT-scan or ultrasound guided intra-visceral injection. Intra-visceral injections may use needles with internal cross-sectional diameters of about 1 .6 mm to 2.7 mm. It will be appreciated that the casing size and swellable core size may be adjusted in order to fit within the internal diameter of a suitably sized needle. In one embodiment, the implant is endoscopically injectably implantable. In one embodiment, the implant is intra-viscerally injectable.

[0099]

[0097] In particularly preferred embodiments, the implant is an injectable implantable implant and is implantable by injection via endoscopic ultrasound-guided fine needle injection or via transdermal intralesional injection for palpable primary or secondary tumours or via CT-scan or ultrasound guided intra-visceral injection. Desirably, the implant is a biodegradable implant.

[0100]

[0098] In some embodiments, the implant may comprise a locating means for use in locating the implant when implanted into a subject. The locating means may be a detectable colour additive or an echogenic material, coating and / or nanoparticles associated the core, the casing, and / or an external surface of the casing. In one embodiment, the locating means comprises a colour additive that is a detectable dye or pigment, such a coloured dye or pigment or fluorescent dye or pigment. In one embodiment, a green dye may be used for an implant in the pancreas. In one embodiment, the dye is loaded in the casing as described elsewhere herein. Any suitable dye may be used, but preferably the dye is known to be safe for in vivo use or is approved by a national regulatory body for use in medical devices at the concentrations present, and / or is not leachable from the implant. Suitable dyes may include logwood extract, pyrogallol, ferric ammonium citrate, chromium-cobalt-aluminum oxide, D&C Blue No. 2, D&C Blue No. 9, D&C Green No. 5, D&C Green No. 6, [phthalocyaninato(2-)] copper, D&C Violet No. 2, etc.

[0101]

[0099] In another embodiment, the locating means comprises an echogenic material. The echogenic material enables the implant to be seen with an ultrasound, and may be provided in any suitable form. In one embodiment, the echogenic material is a coating, such as a coating on an external surface of the casing. In one embodiment, the echogenic material comprises nanoparticles, such as in the form of a coating on an external surface of the casing, or is loaded in the casing as described elsewhere herein, or is loaded in the core.

[0102]

[0100] While not particularly limited, a typical tissue site for implantation of the implants described herein is near, around and / or within, a tumour in the subject’s body. In one embodiment, the implant is implanted near, around and / or within a solid tumour, in one embodiment, a solid tumour selected from a pancreatic tumour or a breast tumour. More than one implant can be used in a subject, if needed, in more than one location, if required.

[0103]

[0101] In other embodiments, the implant may be used in applications involving stromal modulating implants and systemic chemotherapy for increased chemotherapy tumour uptake. In other embodiments, the device may be used in applications involving chemotherapy implants combined with systemic chemotherapy to target any metastasis while simultaneously locally treating the primary tumour. In yet further embodiments, immunotherapy-loaded implants may be positioned adjacent to tumour-draining lymph nodes to trigger more effective immune cell activation and anti-tumour immune responses.

[0104] Methods of making the implant

[0105]

[0102] In one aspect, the invention relates to a method of preparing a medical agent delivery implant, the method comprising: providing an implant core comprising a hydrogel polymer matrix composed of one or more at least partially hydrated crosslinked hydrogel polymers loaded with at least one medical agent; at least partially dehydrating the hydrogel polymer(s) of the implant core; positioning the at least partially dehydrated core within an internal bore of a non-swellable casing, wherein the implant core has a maximum swollen state diameter, Ds, and the internal bore of the casing has an internal diameter, Db, and wherein Db < Ds, such that when the at least partially dehydrated implant core swells, the internal bore of the non-swellable casing exerts inward pressure on the implant core.

[0106]

[0103] In one embodiment, providing an implant core comprising a hydrogel polymer matrix composed of one or more at least partially hydrated cross-linked hydrogel polymers loaded with at least one medical agent comprises the steps of: providing a hydrogel polymer precursor solution, optionally comprising at least one medical agent; and crosslinking the hydrogel polymer in the precursor solution to form an at least partially hydrated crosslinked hydrogel polymer.

[0107]

[0104] In one embodiment, the precursor solution is an aqueous hydrogel polymer dope solution, and the crosslinking comprises extruding the precursor solution into a coagulation bath comprising a coagulation agent, wherein the coagulation agent induces crosslinks in the hydrogel polymer in the dope solution that causes an at least partially hydrated crosslinked hydrogel polymer to precipitate. In one embodiment, the precipitate forms the solid core material, and in this embodiment, may form in a fully hydrated state. In one embodiment, the fully hydrated state solid core comprises the swellable solid core on partial or complete dehydration. In one embodiment, extrusion comprises extruding the precursor solution through a uniaxial extrusion nozzle at a controlled speed into the coagulation bath comprising the coagulation agent, such that a user can control the diameter and length of the extruded precursor solution.

[0108]

[0105] In one embodiment, the coagulation bath comprises a solution of ethanol and water. In one embodiment, the coagulation agent is aqueous CaCh.

[0109]

[0106] In another embodiment, the precursor solution is 3D printed. In one embodiment, the crosslinking comprises 3D printing the precursor solution into a coagulation bath comprising a coagulation agent, wherein the coagulation agent induces crosslinks in the hydrogel polymer in the dope solution that causes an at least partially hydrated crosslinked hydrogel polymer to precipitate. In another embodiment, the crosslinking comprises exposing the precursor solution to light and / or heat as a means to crosslink the hydrogel polymer. In another embodiment, the crosslinking comprises 3D printing the precursor solution with a coagulation agent coating to facilitate precipitation of the hydrogel polymer as it is printed, such as coaxially printing the precursor solution in a crosslinking agent sheath.

[0110]

[0107] In one embodiment, the precursor solution comprises the one or more medical agents. In other embodiments, the medical agent is added in a separate step, such as by immersing the hydrogel polymer precipitate in a solution containing the medical agent(s).

[0111]

[0108] It will be understood that the diameter of any nozzle or extrusion die will determine the diameter of the hydrogel polymer precipitate. In some instances, the hydrogel polymer precipitate will form the hydrogel polymer matrix and will form the swellable solid core. In other instances, the hydrogel polymer precipitate is further manipulated, such as have the medical agent separately impregnated into it, to form the hydrogel polymer matrix, and / or is woven or twisted or braided with other fibres to form the swellable solid core.

[0112]

[0109] The method comprises the step of at least partially dehydrating the hydrogel polymer to form the swellable solid core of the implant. In one embodiment, the hydrogel polymer is partially dehydrated, that is, some water remains in the hydrogel polymer, but some is removed, such that the polymer is partially swellable. In one embodiment, the hydrogel polymer is substantially completely dehydrated, that is, where substantially no water remains in the hydrogel polymer, such that the polymer is fully swellable. In one embodiment, the hydrogel polymer of the swellable solid core is positioned within the internal bore of the non-swellable casing (i.e., in a in a fully dry / dehydrated state or an at least partially dehydrated state) when it comprises less than 40 wt% water, or less than 35 wt% water, or less than 30 wt% water, or less than 25 wt%, or less than 20 wt% water, or less than 15 wt% water, or less than 10 wt% water, or less than 5 wt% water, or less than 4 wt% water, or less than 3 wt% water, or less than 2 wt% water, or less than 1 wt% water, or of from 0.1 wt% to 20 wt% water, or of from 0.5 wt% to 15 wt% water, or of from 1 wt% to 10 wt% water, or of from 0.1 wt% to 25 wt% water, or of from 0.1 wt% to 5 wt% water, or of from 0.1 wt% to 1 wt% water. In one embodiment, the hydrogel polymer comprises less than 40 wt% water, or less than 35 wt% water, or less than 30 wt% water, or less than 25 wt%, or less than 20 wt% water, or less than 15 wt% water, or less than 10 wt% water, or less than 5 wt% water, or less than 4 wt% water, or less than 3 wt% water, or less than 2 wt% water, or less than 1 wt% water, or of from 0.1 wt% to 20 wt% water, or of from 0.5 wt% to 15 wt% water, or of from 1 wt% to 10 wt% water, or of from 0.1 wt% to 25 wt% water, or of from 0.1 wt% to 5 wt% water, or of from 0.1 wt% to 1 wt% water when in a fully dry / dehydrated or at least partially dehydrated state. In one embodiment, the hydrogel polymer(s) comprise less than 5 wt% water, or less than 4 wt% water, or less than 3 wt% water, or less than 2 wt% water, or less than 1 wt% water, or of from 0 wt% to 5 wt% water, or of from 0 wt% to 4 wt% water, or of from 0 wt% to 3 wt% water, or of from 0 wt% to 2 wt% water, or of from 0 wt% to 1 wt% water when fully dehydrated.

[0113]

[0110] Water content of the swellable solid core when in a fully dry / dehydrated or at least partially dehydrated state may be measured by any suitable technique in the art, including but not limited to, thermogravimetric analysis. In one embodiment, the wt% water is measured as (mwater / mhydrogei) x 100%, where mwater is the mass of water in the hydrogel, and mhydrogei is the mass of the hydrogel, including water, prior to dehydration. In one embodiment, the hydrogel polymer of the swellable solid core is positioned within the internal bore of the non-swellable casing after a defined period of drying, wherein the defined period of drying is drying at standard laboratory conditions (25 °C, 1 atm, 30-60% relative humidity) for at least 6 h, at least 8 h, at least 10 h, at least 12 h, at least 14 h, at least 16 h, at least 18 h, at least 20 h, at least 22 h or at least 24 h, or of from 8 h to 20 h, or of from 10 h to 24 h, or of from 14 h to 24 h. In one embodiment, the hydrogel polymer of the swellable solid core is dried at standard laboratory conditions (25 °C, 1 atm, 30-60% relative humidity) for at least 6 h, at least 8 h, at least 10 h, at least 12 h, at least 14 h, at least 16 h, at least 18 h, at least 20 h, at least 22 h or at least 24 h, or of from 8 h to 20 h, or of from 10 h to 24 h, or of from 14 h to 24 h. In one embodiment, the hydrogel polymer of the swellable solid core is dried at standard laboratory conditions (25 °C, 1 atm, 30-60% relative humidity) for at least 12 h. In one embodiment, the hydrogel polymer of the swellable solid core is dried at standard laboratory conditions (25 °C, 1 atm, 30-60% relative humidity) for at least 12 h so as to have a water content of less than 20 wt% water, or less than 15 wt% water, or less than 10 wt% water, or less than 5 wt% water, or less than 4 wt% water, or less than 3 wt% water, or less than 2 wt% water, or less than 1 wt% water.

[0111] In one embodiment, the non-swellable casing is provided fully formed for the purposes of, or prior to, positioning the swellable solid core within. The term “fully formed” in this context refers to the non-swellable casing being provided in ready to implant form, such as: in embodiments where the non-swellable casing is mechanically rigid, the casing is provided in mechanically rigid form and / or at a modular strength of at least 70 mPa, and / or in embodiments where the casing comprises a coloured dye and / or pigment and / or echogenic material, the coloured dye and / or pigment and / or echogenic material is in the casing, and / or in embodiments where the casing is provided with a medical agent, the medical agent is in the casing, and / or in embodiments where the casing comprises through pores or apertures, the through pores or apertures are in the casing, prior to positioning the solid core within the internal bore. As discussed above, the casing may be hollow and may comprise an opening at one or each end to aid insertion of the solid core within the internal bore.

[0114]

[0112] In one embodiment, the solid core is positioned within the internal bore in a fully dehydrated or substantially dehydrated state, such that the solid core experiences mild friction on insertion into the internal bore. In this context, the “mild friction” may be such that the solid core can be pushed into the internal bore using hand pressure and without deforming the solid core. In one embodiment, the mild friction arrangement also allows for microscopic and / or macroscopic air spaces between parts of the surface of the solid core and parts of the internal wall of the non-swellable casing and which may be accessed by bodily fluid via one or more pores in the casing when implanted in vivo, and may therefore assist with initial (re)hydration of the solid core and assist to initiate release of the one or more medical agents loaded therein.

[0115]

[0113] The non-swellable casing may be formed using any suitable forming means, including in one embodiment by extrusion, 3D printing, sol-gel processing, precipitation, solid-state reaction, casting, and / or forging. This advantageously allows the conditions of manufacture of the non-swellable casing to be isolated from the manufacture of the hydrogel polymer(s) and any medical agent(s) therein, which may be sensitive to chemicals, heat and / or machining pressure used to form the casing. In one embodiment, the non-swellable casing is formed from a non-swellable casing precursor mixture that also comprises one or more of a medical agent, a dye, a pigment, and / or an echogenic locating means. As noted above, in one embodiment, the pores or apertures are formed in the casing prior to insertion of the solid core. In such embodiments, precise control of the pore size and position is enabled without compromising the structure of the solid core, for example, because laser technology can be used to form the pores. However, there may be embodiments where pores can be drilled while the solid core is in situ in the internal bore.

[0116]

[0114] In one embodiment, the implant described herein is obtained by the method of preparing the implant described herein.

[0117] Medical uses

[0118]

[0115] Described herein is use of the implant to treat a condition. In one embodiment, the treatment of the condition is localised. Localised treatment may avoid toxicity and immune related adverse effects compared to delivering combined treatment modalities systemically. In one embodiment, the condition is cancer. In one embodiment, the condition is a solid cancer.

[0116] The implants described herein advantageously allow in certain embodiments for controlled release of medical agent(s) in the solid core to the site of local treatment in vivo by altering pore number, size and / or position in the casing. The geometry of pores herein may be selected and adjusted based on the loaded medical agent(s) and its / their individual properties, without relying on variable / matrix release properties to control diffusion. Additionally, the separate fabrication of the casing and the solid core allows for a much wider range of synthetic routes to both the core and casing material, and therefore a much greater range in physical and chemical properties of the casing material. In certain embodiments, highly mechanically rigid casings may be synthesised that allow for injection through even narrow gauge needles under pressure without causing deformation of the implant and / or damaging the solid core. Separate fabrication and control of pore geometries also allows a greater range of more thermally and / or chemically sensitive medical agents to be used, as well as greater variation in and tailoring of possible in vivo implant positions.

[0119]

[0117] Also described herein is a method of treating cancer in a subject in need thereof, such as reducing the severity and / or duration of cancer, comprising implanting an implant as described herein on, in or near a tumour in the subject. In one embodiment, the cancer or solid cancer is breast cancer or pancreatic cancer.

[0120] Embodiments

[0121]

[0118] Embodiment 1: A medical agent delivery implant, the implant comprising: a non-swellable casing having an internal bore in which a swellable solid core is positioned, wherein the swellable solid core comprises a hydrogel polymer matrix composed of one or more crosslinked hydrogel polymers loaded with at least one medical agent, and wherein the swellable solid core has a maximum swollen state diameter, Ds, and the internal bore of the non-swellable casing has an internal diameter, Db, and wherein Db < Ds, such that when the swellable solid core swells in use, the internal bore of the non-swellable casing exerts inward pressure on the swellable solid core that assists to restrict release of the medical agent loaded in the swellable solid core into surrounding tissue.

[0122]

[0119] Embodiment 2: The implant of Embodiment 1 , wherein the non-swellable casing comprises pores in one or more wall(s) thereof for directing medical agent release in vivo.

[0123] Embodiment 3: The implant of Embodiment 1 or Embodiment 2, wherein the non-swellable casing is a mechanically rigid non-swellable casing.

[0124]

[0120] Embodiment 4: The implant of any one of the preceding Embodiments, wherein the casing structurally protects the swellable solid core during implantation by injection through tissue.

[0125]

[0121] Embodiment 5: The implant of any one of the preceding Embodiments, wherein the swellable solid core is positioned in close-fitting arrangement in the non-swellable casing when the hydrogel polymer matrix is partially or fully dehydrated.

[0126]

[0122] Embodiment 6: The implant of any one of the preceding Embodiments, wherein the casing is a cylinder-shaped casing, preferably with sealed ends.

[0127]

[0123] Embodiment 7: The implant of any one of the preceding Embodiments, adapted for implantation in one or more tissue sites of a subject by surgical insertion or by injection through one or more tissue types.

[0124] Embodiment 8: The implant of any one of the preceding Embodiments, wherein non-swellable casing has modular strength of at least 70 mPa, as tested by compression testing using a mechanical tester to determine the amount of force required to compress the casing vertically until it bends.

[0128]

[0125] Embodiment 9: The implant of any one of the preceding Embodiments, wherein the polymer casing has a wall thickness not deviating from an average wall thickness by more than ±5%.

[0129]

[0126] Embodiment 10: The implant of any one of the preceding Embodiments, wherein the casing comprises one or more polymers, preferably one or more thermoplastic, extrudable polymers, selected from polycaprolactone, poly(lactic acid), poly(lactic-co-glycolic acid), polypropylene glycol), a silicone, and a poly(l-amino acid), preferably wherein the casing comprises polycaprolactone (PCL).

[0130]

[0127] Embodiment 11: The implant of any one of the preceding Embodiments, wherein the casing is composed of extruded polymer, preferably extruded polycaprolactone (PCL).

[0131]

[0128] Embodiment 12: The implant of any one of the preceding Embodiments, where the implant is implantable by injection via endoscopic ultrasound-guided fine needle injection or via transdermal intralesional injection for palpable primary or secondary tumours or via CT-scan or ultrasound guided intra-visceral injection.

[0132]

[0129] Embodiment 13: The implant of any one of the preceding Embodiments, wherein the non- swellable polymer casing is formed from extrusion of a polymer melt.

[0133]

[0130] Embodiment 14: The implant of any one of the preceding Embodiments, wherein the internal bore diameter, Db, is 1.45 mm or less, preferably about 0.15 mm to 1.45 mm, preferably about 0.90 mm.

[0134]

[0131] Embodiment 15: The implant of any one of the preceding Embodiments, wherein the swellable solid core has an average wall-to-wall diameter at the time of insertion into the casing of 1.45 mm or less, about 0.15 mm to 1.45 mm, or about 0.90 mm.

[0135]

[0132] Embodiment 16: The implant of any one of the preceding Embodiments, wherein the solid core has a maximum swollen state diameter, Ds, that is at least 1 .1 xDb, or at least 2xDb, or of from 1 .1 x to 10x Db.

[0136]

[0133] Embodiment 17: The implant of any one of the preceding Embodiments, wherein at 96 hours post implantation, the implant releases 60% or less, or 30% or less of the medical agent from the core.

[0137]

[0134] Embodiment 18: The implant of any one of the preceding Embodiments, wherein at 24 hours post implantation, the implant releases 20% or less of the medical agent from the core.

[0138]

[0135] Embodiment 19: The implant of any one of the preceding Embodiments, wherein at 6 hours post implantation, the implant releases 15% or less of the medical agent from the core.

[0139]

[0136] Embodiment 20: The implant of any one of the preceding Embodiments, wherein at 4 hours post implantation, the implant releases 10% or less of the medical agent from the core.

[0140]

[0137] Embodiment 21: The implant of any one of the preceding Embodiments, wherein the swellable solid core comprises a single fibre, such as single extruded or 3D printed fibre, preferably having a generally elongate shape.

[0141]

[0138] Embodiment 22: The implant of any one of the preceding Embodiments, wherein the tissue site is a tumour in the subject’s body, such as a pancreatic or breast tumour.

[0139] Embodiment 23: The implant of any one of the preceding Embodiments, wherein the one or more hydrogel polymers of the swellable solid core comprise a hydrophilic polymer or copolymer thereof, such as a hydrophilic polymer selected from the group consisting of: alginate, chitosan, gelatin, collagen, carboxymethyl cellulose, poly(vinyl alcohol), hyaluronic acid and polyethylene glycol), preferably, alginate, or a copolymer thereof.

[0142]

[0140] Embodiment 24: The implant of any one of the preceding Embodiments, wherein the casing comprises through pores and the through pores are provided as a plurality of apertures along at least part of the length of the casing in spaced apart arrangement, preferably in a 90° or a 180° offset configuration.

[0143]

[0141] Embodiment 25: The implant of any one of the preceding Embodiments, wherein the casing is polycaprolactone and the hydrogel polymer is alginate.

[0144]

[0142] Embodiment 26: The implant of any one of the preceding Embodiments, wherein the polymer casing comprises one or more medical agents.

[0145]

[0143] Embodiment 27: The implant of any one of the preceding Embodiments, wherein the at least one medical agent is selected from the group consisting of: a chemotherapeutic agent, a biologic, an immune modulating agent, a radioactive or radioisotope material, a contrast agent, a fluorescent dye, a steroid, a fatty acid, a nucleic acid, a vitamin, and any combination thereof.

[0146]

[0144] Embodiment 28: The implant of any one of the preceding Embodiments, wherein the at least one medical agent is a chemotherapeutic such as irinotecan, 5-flurouracil, oxaliplatin, doxorubicin, gemcitabine, nab-paclitaxel, cyclopamine, paclitaxel, camptothecan, everolimus, epothilone, curcumin, docetaxel; an immunotherapeutic agent such as an immune checkpoint inhibitor, e.g., an anti-PD1 or anti-PDL1 antibody; an immune priming agent including a cancer vaccine (GV AX), an agonistic CD40 antibody (anti-CD40 mAb), a B7.1 or B7.2 costimulatory agent, a chemokine receptor such as CCR2 and CCR5, or any combination thereof.

[0147]

[0145] Embodiment 29: The implant of any one of the preceding Embodiments, wherein the at least one medical agent is a combination of one or more Tceii immune checkpoint inhibitors (ICIs) such as an anti-PD1 or anti-PDL1 antibody, or a combination of both an anti-PD1 and anti-CD40 antibody.

[0148]

[0146] Embodiment 30: The implant of any one of the preceding Embodiments, wherein the at least one medical agent is a combination of an anti-PD1 and an anti-CD40 antibody and gemcitabine and nab-pax, e.g., when used for treating a tumour in pancreatic ductal adenocarcinoma (PDAC) cancer.

[0149]

[0147] Embodiment 31: The implant of any one of Embodiments 1 to 29, wherein the at least one medical agent is a combination of an anti-PD1 and an antiCD40 antibody and nab-pax and dox, e.g., when used for treating a tumour in triple negative breast cancer (TNBC).

[0150]

[0148] Embodiment 32: The implant of any one of the preceding Embodiments, which is biodegradable.

[0151]

[0149] Embodiment 33: The implant of any one of the preceding Embodiments, further comprising locating means for use in locating the implant during and after implantation into a subject.

[0150] Embodiment 34: The implant of Embodiment 33, wherein the locating means is a dye or pigment, such a coloured dye or fluorescent dye; and / or an echogenic material, coating and / or nanoparticles in or on the core and / or casing.

[0152]

[0151] Embodiment 35: A method of preparing a medical agent delivery implant, the method comprising: providing a swellable solid implant core comprising a hydrogel polymer matrix composed of one or more at least partially hydrated cross-linked hydrogel polymers loaded with at least one medical agent; at least partially dehydrating the hydrogel polymer(s) of the implant core; positioning the at least partially dehydrated core within an internal bore of a non-swellable casing, wherein the implant core has a maximum swollen state diameter, Ds, and the internal bore of the casing has an internal diameter, Db, and wherein Db < Ds, such that when the at least partially dehydrated implant core swells, the internal bore of the non-swellable casing exerts inward pressure on the implant core.

[0153]

[0152] Embodiment 36: The method of Embodiment 35, wherein providing a swellable solid implant core comprises the steps of: providing a hydrogel polymer precursor solution, optionally comprising the at least one medical agent; and crosslinking the hydrogel polymer in the precursor solution to form the at least partially hydrated crosslinked hydrogel polymer.

[0154]

[0153] Embodiment 37: The method of Embodiment 35 or Embodiment 36, comprising fully dehydrating the hydrogel polymer(s) of the implant core.

[0155]

[0154] Embodiment 38: The method of any one of Embodiments 35 to 37, wherein the non-swellable polymer casing is mechanically rigid and comprises through pores in a wall thereof.

[0156]

[0155] Embodiment 39: An implant according to any one of Embodiments 1 to 34 obtained by the method of any one of Embodiments 35 to 38.

[0157]

[0156] Embodiment 40: Use of the implant according to any one Embodiments 1 to 34 or 39 in localised treatment and / or localised prevention of a disease in a subject.

[0158]

[0157] Embodiment 41: The use of Embodiment 40, wherein the disease involves solid tumours, such as malignant solid tumours.

[0159]

[0158] Embodiment 42: The use of Embodiment 40 or Embodiment 41 , wherein the implant delivers one or more chemotherapeutics, preferably in combination with immunotherapeutic agents and / or immune priming agents.

[0160]

[0159] Embodiment 43: The use of any one of Embodiments 40 to 42, wherein the implant delivers an immunotherapeutic agent, optionally including an immune checkpoint inhibitors, such as anti-PD1 and anti-PDL1 antibodies.

[0161]

[0160] Embodiment 44: The use of any one of Embodiments 40 to 43, wherein the implant delivers a priming agent, optionally including cancer vaccines (GVAX), agonistic CD40 antibodies (anti-CD40), B7.1 , B7.2 costimulatory agents, and chemokine receptors such as CCR2 and CCR5.

[0162]

[0161] Embodiment 45: A method of treatment and / or prevention of a disease or condition in a subject in need thereof, comprising the step of implanting an implant according to any one of Embodiments 1 to 34 or 39 in one or more tissue areas to be subjected to localised delivery of one or more medical agents.

[0162] Embodiment 46: The method of Embodiment 45, wherein the disease or condition is cancer, such as a solid cancer, such as breast cancer or pancreatic cancer.

[0163] EXAMPLES

[0164] Example 1 - Device Fabrication & Characterisation

[0165]

[0163] Comparative example: “Formulation 1” or “F1”: The device structure consists of a coaxially extruded wet-spun fibre comprising an alginate in the core and polycaprolactone (PCL) in the shell of the coaxial fibre which surrounds the alginate component of the core but wherein Db > Ds (see Figure 1A, Cii, Di). To provide structural rigidity, the coaxial core-shell structure was placed inside an additional PCL sheath. The sheath was hand-rolled and had an outer diameter of 1.5 mm ± 0.09. Drugs loaded into this formulation include gemcitabine in the alginate core and paclitaxel in the shell. No drug was included in the outer PCL sheath. In the Formulation 1 device,

[0166]

[0164] Example according to one embodiment of the present invention: “Formulation 2” or “F2”: The implant consisted of a single fibre alginate core, which was made by extruding or printing an alginate polymer solution through a coagulation bath using calcium chloride as the coagulation agent. The fibre was then dried fully and placed directly into a rigid dry PCL casing (see Figure 1B, Ci, Dii, Diii). The casing was made by extrusion moulding, which allowed for the creation of an even outer diameter of 1 .20 mm ± 0.05 and allowed customisation of the casing length and colour (see arrow, Figure 1E). The non-leaching green dye aided visualisation once implanted into the pancreas, where the green dyed implant can be easily observed through recovered pancreas tissue samples. The nondyed implant is less easily seen in Figure 1F. Holes for drug release were laser cut into the casing. Drugs loaded into this formulation include combinations of chemotherapeutics (irinotecan, 5- flurouracil, oxaliplatin, doxorubicin, gemcitabine, nab-paclitaxel), monoclonal antibodies (human and murine anti-PD1 and anti-CD40), cyclopamine, fasudil, and pirfenidone.

[0167]

[0165] Referring to Figure 2A, encapsulation of a swellable alginate core in a PCL casing where Db < Ds (F2) resulted in a much slower and more consistent drug release, highlighting its improved benefit in controlling drug release compared to F1 (where Db > Ds) and an alginate core alone (with no casing). Furthermore, the inventors investigated whether the inclusion of 4 sets of laser cut holes (90 degrees offset) in the PCL casing affected drug release in F2 implants compared to 2 sets of holes (180 degrees offset), but found that increasing the number of holes minimally impacted the drug release profile (via a 2-way ANOVA) (Figure 2B). This is beneficial in some embodiments, as release can then be arranged in a multidirectional manner, rather than bi-directional, resulting in a more even distribution of the drug throughout the tissue, without substantially affecting the overall rate of drug release.

[0168] Table 1 : Drug loading of the alginate core and PCL casing in F1 and F2 implants of identical length

[0166] The F2 implant enables an 18.6-fold increase in the total amount of drug that can be loaded into the alginate single component core relative to an identical length and internal casing diameter implant made according to F1. This is because the F1 core could only be synthesised using coaxial extrusion such that Db > Ds, and thus on dehydration, the F1 core significantly shrunk to be much smaller in diameter than Db (see Figure 4D). In contrast, the two-step method used in F2 allows for the individual manufacture, drying and assembly of the core and casing components. Alginate is a hydrogel that significantly shrinks when dried. Therefore, by pre-drying the alginate before assembly, the inventors created a final product with an increased amount of alginate and a correspondingly increased amount of agent (see Figure 4C (core only) for F2 compared to Figure 4A (coaxial core and shell) and B (core only) for F1). F1 core and shell were coextruded through a coaxial spinneret nozzle, with a wet core extrusion diameter of 1 mm. F2 core was extruded through a single die and had a wet diameter of 2.5 mm. An unpaired Me st showed a significant increase in dried alginate diameter in F2 compared to F1 (P<0.0001) (Figure 3).

[0169]

[0167] The diameter of the hand-rolled PCL sheath of F1 compared to the extruded casing of F2 were compared, and it was observed via an unpaired Mest that F2 has a significantly smaller diameter (P <0.0001 ; Figure 5). The smaller diameter of F2 allows for implantation using a smaller gauge needle, therefore reducing tissue trauma upon insertion. A smaller overall diameter also increases ease of implanting using approved endoscopy techniques, as the narrower width allows for a greater implantation angle.

[0170]

[0168] To evaluate the suitability of F2 for implantation into pancreatic tumour tissue, compression tests were performed using a Shimadzu EZ-L mechanical tester. The viscoelastic metrics of healthy pancreas tissues and pancreatic tumour tissue have been previously reported to be 1 .06 ± 0.25 kPa and 5.46 ± 3.18 kPa, respectively. Samples were compressed at a speed of 2 mm / min until failure occurred at around the midpoint and the force vs. strain curves for four repeat samples were plotted (Figure 6A). The force vs. strain values (N) for the four samples were converted to modulus (MPa), resulting in an average value of 157.7 ± 85 mPa which represents a 2.9*104-fold increase in modular strength compared to an alginate core without a casing.

[0171]

[0169] A 10% gelatin gel which is comparative to human tissue was prepared, and F1 implants (Figure 6B) and F2 implants (Figure 6C) were inserted. F1 showed compression of the implants occurring on insertion, while F2 maintained their structure due to their superior mechanical strength. The results show that the F2 implant possesses the required mechanical properties for successful implantation into human pancreatic tumour tissue.

[0172]

[0170] Figure 7 shows a schematic of the process used to produce F2 implants according to one embodiment.

[0173] Example 2 - Implant Device Medical Agent Delivery to TNBC tumours

[0174]

[0171] The implants herein can locally deliver anti-PD1 and anti-CD40 together with doxorubicin and nab-ptx in the aggressive 4T1 TNBC model. Tolerability and efficacy of sustained release via the polymeric implantable device were compared to systemic routes of administration in the aggressive 4T1 TNBC mouse model (see Figures 8-15).

[0172] The present invention is described with reference to the above examples. It is to be understood that the examples are illustrative of and not limiting to the invention described herein.

[0175]

[0173] It will be apparent to the person skilled in the art that while the invention has been described in some detail for the purposes of clarity and understanding, various modifications and alterations to the embodiments and methods described herein may be made without departing from the scope of the inventive concept disclosed in this specification.

Claims

Claims1 . A medical agent delivery implant, the implant comprising: a non-swellable casing having an internal bore in which a swellable solid core is positioned, wherein the non-swellable casing comprises pores in one or more wall(s) thereof that extend through the casing; wherein the swellable solid core comprises a hydrogel polymer matrix composed of one or more crosslinked hydrogel polymers loaded with at least one medical agent, and wherein the swellable solid core has a maximum swollen state diameter, Ds, and the internal bore of the non-swellable casing has an internal diameter, Db, and wherein Db < Ds, such that when the swellable solid core swells in use, the internal bore of the non-swellable casing exerts inward pressure on the swellable solid core that assists to restrict release of the medical agent loaded in the swellable solid core into surrounding tissue.

2. The implant of claim 1 , wherein the non-swellable casing is a mechanically rigid non-swellable casing for structurally protecting the swellable solid core during implantation by injection through tissue.

3. The implant of claim 1 or claim 2, wherein the swellable solid core is positioned in close-fitting arrangement in the non-swellable casing when the hydrogel polymer matrix is partially or fully dehydrated.

4. The implant of any one of the preceding claims, wherein the non-swellable casing has modular strength of at least 70 mPa, as tested by compression testing using a mechanical tester to determine the amount of force required to compress the casing vertically until it bends.

5. The implant of any one of the preceding claims, wherein the non-swellable casing has a wall thickness not deviating from an average wall thickness by more than ±5%.

6. The implant of any one of the preceding claims, wherein the non-swellable casing comprises one or more polymers, preferably one or more thermoplastic, extrudable polymers, selected from polycaprolactone, poly(lactic acid), poly(lactic-co-glycolic acid), polypropylene glycol), a silicone, and a poly(l-amino acid), preferably wherein the casing comprises polycaprolactone (PCL).

7. The implant of any one of the preceding claims, wherein the internal bore diameter, Db, is 1.45 mm or less, preferably about 0.15 mm to 1 .45 mm, preferably about 0.90 mm.

8. The implant of any one of the preceding claims, wherein the solid core has a maximum swollen state diameter, Ds, that is at least 1.1xDb, or at least 2xDb, or of from 1.1x to 10x Db.

9. The implant of any one of the preceding claims, wherein the swellable solid core comprises a single fibre, such as single extruded or 3D printed fibre, preferably having a generally elongate shape.

10. The implant of any one of the preceding claims, wherein the one or more hydrogel polymers of the swellable solid core comprise a hydrophilic polymer or copolymer thereof, such as a hydrophilic polymer selected from the group consisting of: alginate, chitosan, gelatin, collagen, carboxymethyl cellulose, poly(vinyl alcohol), hyaluronic acid and polyethylene glycol), preferably, alginate, or a copolymer thereof.11 . The implant of any one of the preceding claims, wherein the non-swellable casing comprises one or more medical agents.

12. The implant of any one of the preceding claims, wherein the pores are provided as a plurality of apertures along at least part of the length of the casing in spaced apart arrangement.

13. The implant of any one of the preceding claims, wherein the medical agent is a chemotherapeutic such as irinotecan, 5-flurouracil, oxaliplatin, doxorubicin, gemcitabine, nab-paclitaxel, cyclopamine, paclitaxel, camptothecan, everolimus, epothilone, curcumin, docetaxel; an immunotherapeutic agent such as an immune checkpoint inhibitor, e.g., an anti-PD1 oranti-PDL1 antibody; an immune priming agent including a cancer vaccine (GVAX), an agonistic CD40 antibody (anti-CD40 mAb), a B7.1 or B7.2 costimulatory agent, a chemokine receptor such as CCR2 and CCR5, or any combination thereof.

14. The implant of any one of the preceding claims, wherein the at least one medical agent is a combination of one or more Tceii immune checkpoint inhibitors (ICIs) such as an anti-PD1 or anti- PDL1 antibody, or a combination of both an anti-PD1 and anti-CD40 antibody or a combination of an anti-PD1 and an anti-CD40 antibody and gemcitabine and nab-pax, or a combination of an anti-PD1 and an antiCD40 antibody and nab-pax and dox.

15. The implant of any one of the preceding claims, which is biodegradable.

16. The implant of any one of the preceding claims, further comprising locating means for use in locating the implant during and after implantation into a subject, optionally wherein the locating means is a dye or pigment, such a coloured dye or fluorescent dye; and / or an echogenic material, coating and / or nanoparticles in or on the core and / or casing.

17. A method of preparing a medical agent delivery implant, the method comprising: providing a swellable solid implant core comprising a hydrogel polymer matrix composed of one or more at least partially hydrated cross-linked hydrogel polymers loaded with at least one medical agent; at least partially dehydrating the hydrogel polymer(s) of the implant core; positioning the at least partially dehydrated core within an internal bore of a non-swellable casing, wherein the non-swellable casing comprises pores in one or more wall(s) thereof that extend through the casing, wherein the implant core has a maximum swollen state diameter, Ds, and the internal bore of the casing has an internal diameter, Db, and wherein Db < Ds,such that when the at least partially dehydrated implant core swells, the internal bore of the non- swellable casing exerts inward pressure on the implant core.

18. The method of claim 17, comprising fully dehydrating the hydrogel polymer(s) of the implant core.

19. Use of the implant according to any one claims 1 to 16 in localised treatment and / or localised prevention of a disease in a subject, optionally wherein the disease involves solid tumours, such as malignant solid tumours.

20. A method of treatment and / or prevention of a disease or condition in a subject in need thereof, comprising the step of implanting an implant according to any one of claims 1 to 16 in one or more tissue areas to be subjected to localised delivery of one or more medical agents, optionally wherein the disease or condition is cancer, such as a solid cancer, such as breast cancer or pancreatic cancer.

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