Implant for delivery of a drug

Abstract

The invention concerns an implant for sustained delivery of a drug. The implant comprises a core comprising at least one drug distributed uniformly in a polymer matrix of a first non-erodible polymer. The implant comprises a means for adjusting the length of the implant to provide a pre-determined dosage of the at least one drug.

Description

[0001] IMPLANT FOR DELIVERY OF A DRUG

[0002] The present invention relates to an implant for sustained delivery of a drug.

[0003] A number of medical conditions require long-term, regular dosing with drugs or pharmaceutical substances. This often involves ingestion of multiple tablets per day over extended periods of time, which can lead to poor patient compliance. In addition, periodic oral administration can result in blood concentrations of the drug peaking quickly after initial administration, then dropping before the next dose. In addition, many drugs are not suitable for delivery via the oral route, for example due to first pass metabolism or drug degradation in the acidic conditions of the stomach or alkaline conditions in the intestine.

[0004] The use of polymeric implantable devices to deliver drug compounds has become a promising alternative delivery method and overcomes a number of the disadvantages associated with oral administration. Specifically, these devices can provide long-term, targeted and sustained delivery of a drug whilst maintaining stable blood concentrations of the drug. In addition, these devices can lead to increased patient compliance and have the potential to deliver drugs which would normally be unsuitable for oral administration.

[0005] Various implantable drug delivery devices are known. US4957119A discloses an implant of polymeric material which can release a contraceptive agent when fitted subcutaneously or locally. The implant comprises a core material of ethylene / vinyl acetate copolymer which functions as a matrix for a contraceptive substance, and ethylene / vinyl acetate membrane encasing the core.

[0006] US2013 / 0189342 discloses a subcutaneous implantable device for delivery of a pharmaceutical substance comprising a core comprising a core polymeric material, optionally containing a core pharmaceutical substance, surrounded by a first-layer polymeric material, optionally surrounded by one or more additional layers comprising an additional pharmaceutical substance and an additional polymeric material.

[0007] WO2018 / 067882 describes an implantable drug delivery device which reduces burst release of a drug. The device comprises a core comprising a polymer and one or more drugs, and an outer shell comprising a polymer and one or more porogen materials. Existing implantable drug delivery devices can only deliver a drug at a single fixed dosage which is pre-determined by the individual implant that is prescribed. This means that different implants need to be manufactured containing various dosages of the drug. In addition, a pharmacist needs to stock multiple implants each containing various dosages of the drug.

[0008] It would therefore be desirable to provide an improved implant for sustained delivery of a drug that can deliver a titratable or adjustable, i.e., customisable, dosage of a drug from a single implant.

[0009] In accordance with a first aspect of the present invention, there is provided an implant for sustained delivery of a drug, the implant comprising: a core comprising at least one drug distributed uniformly in a polymer matrix of a first non-erodible polymer; wherein the implant comprises a means for adjusting the length of the implant to provide a pre-determined dosage of the at least one drug.

[0010] The implants of the present invention are typically subcutaneous, subdermal or intramuscular implants. The implants are preferably subcutaneous implants.

[0011] The term “adjusting” means changing the length of the implant to customise or tailor the dosage of the drug(s) such that the overall or total dosage provided by the implant conforms to the predetermined dosage. The term “means for adjusting" will be interpreted accordingly and will include means for facilitating adjustment of the dosage. These means will include incremental markings on the outside of implant, gaps located between adjacent regions of the implant and the use of one or more discrete units.

[0012] The term “pre-determined” means the dosage of the drug(s) determined by a medical practitioner to be suitable for treating a patient with a particular condition.

[0013] Preferably, the implant further comprises a sheath surrounding the core, the sheath comprising a second non-erodible polymer.

[0014] Preferably, the implant further comprises a rod extending coaxially through the core. The rod comprises a third polymer. The rod may comprise a plurality of anchors spaced along the length of the rod. The plurality of anchors may comprise any means suitable for anchoring or securing the core in place on the rod. For example, the anchors may comprise nodules, flanges or barbs.

[0015] Preferably, the implant comprises one or more discrete units, each unit comprising a unit core defining a unit dosage of the at least one drug and the one or more unit cores forming the implant core.

[0016] The length of the implant may be decreased to decrease the dosage of the drug(s) or increased to increase the dosage of the drug(s). This enables the medical practitioner to select a predetermined dosage of the drug(s), and adjust the length of the implant accordingly.

[0017] In preferred embodiments where the length of the implant is decreased to decrease the dosage of the drug(s), the implant comprises two or more regions of at least substantially, or ideally, equal length, each region comprising an at least substantially, or ideally, equal amount of the drug(s). In these embodiments, the implant comprises two or more regions, e.g., two to ten regions, or three to six regions. In one embodiment, the implant comprises five regions.

[0018] The implant is divisible between adjacent regions and the pre-determined dosage provided by the implant is proportional to the number of regions in the implant as determined by a medical practitioner. The exterior of the implant typically comprises markings to define the regions and to indicate where the implant is to be divided. Such markings are an example of a means for adjusting the length of the implant. The markings are typically graduated, i.e., the markings are used to indicate points on a scale. The markings can be applied onto the exterior of the implant, e.g., printed, or can be indented on the surface e.g., in the form of notches.

[0019] In alternative embodiments where the length of the implant is decreased to decrease the dosage of the drug(s), the number of regions in the implant is one. In these embodiments, the implant is divisible at any point within the single region and the pre-determined dosage provided by the implant is proportional to the length of the implant. The exterior of the implant also typically comprises markings to indicate where the implant is to be divided within the single region, as described above.

[0020] In these embodiments, when the implant is divided, the exposed surface of the core is typically capped with an end cap of suitable capping material. Alternatively, the implant can be sealed without the addition of an end cap by crimping the implant at the appropriate point along its length. For example, the implant can be sealed by heat crimping, which allows the sheath surrounding the core to form a seal.

[0021] In some embodiments where the length of the implant is decreased to decrease the dosage of the drug(s), gaps are located between adjacent regions and the implant is divided at a gap. The gaps are another example of a means for adjusting the length of the implant.

[0022] It is preferred that anchors are located between adjacent regions of the implant.

[0023] In embodiments where the anchors are flanges, the flanges extend radially from the rod. It is preferred that the flanges are discs that are the same size as at least the cross section of the core such that they form caps between adjacent regions.

[0024] In alternative embodiments where the implant does not have a rod, flanges are located between adjacent regions of the implant. A flange is typically defined as a projection from an object e.g., a radial extension from a rod. However, in these embodiments the flange does not include a rod. It is preferred that the flanges are discs that are the same size as at least the cross section of the core such that they form caps between adjacent regions.

[0025] In some embodiments where the length of the implant is increased to increase the dosage of the drug(s), the implant comprises one or more discrete units mounted on the rod, each unit comprising a unit core and a sheath and defining a unit dosage of the drug(s). Each unit comprises a pre-formed conduit, the conduit extending coaxially through the core and dimensioned for mounting the one or more units on the rod. The number of units mounted on the rod determines the pre-determined dosage of the drug(s). Typically, the implant comprises two to ten units e.g., three to six units. In one embodiment, the implant comprises five units. Preferably, the units are mounted such that there are no gaps between the units. Alternatively, gaps may be present between the units, increasing flexibility of the implant.

[0026] In one embodiment, the implant comprises one or more discrete units, each unit comprising a unit core, sheath and rod and defining a unit dosage of the drug(s). The rod comprises any appropriate linkage e.g., a ball and socket joint. In embodiments where the rod comprises a ball and socket joint, each end of the unit is typically closed by a flange extending radially from the rod. A socket is typically formed integrally with the flange at one end, and a ball is typically mounted on a flange at the opposing end. The ball of one unit can be inserted into the socket of another unit, with the number of units determining the dosage of the drug(s).

[0027] In accordance with a second aspect of the present invention, there is provided an implant for delivery of a drug, the implant comprising one or more discrete units and a rod, each discrete unit comprising: a unit core comprising at least one drug distributed uniformly in a matrix of a first non- erodible polymer: a sheath surrounding the unit core, the sheath comprising a second non- erodible polymer; and a conduit extending coaxially through the unit core; wherein the conduit is dimensioned for mounting the one or more discrete units on the rod; wherein each discrete unit defines a unit dosage of the at least one drug; and wherein the number of discrete units mounted on the rod determines the pre-determined dosage of the at least one drug.

[0028] In one embodiment, the rod of the unit comprises a ball and socket joint. In these embodiments, each end of the unit is closed by a flange extending radially from the rod. A socket is typically formed integrally with the flange at one end, and a ball is typically mounted on a flange at the opposing end. The ball of one unit can be inserted into the socket of another unit, with the number of units determining the dosage of the drug(s).

[0029] In accordance with a third aspect of the present invention, there is provided a unit for an implant for delivery of a drug, the unit comprising: a unit core comprising at least one drug distributed uniformly through a polymer matrix of a first polymer; a sheath surrounding the unit core, the sheath comprising a second polymer which is a non-erodible polymer; and a conduit extending coaxially through the unit core.

[0030] The term “surrounding” used in this context means that the sheath surrounds at least the outer cylindrical surface of the core, preferably together with the end surfaces of the core and optionally also the surface of the conduit extending coaxially through the core.

[0031] The term “unit dose” or “unit dosage” as used herein refers to the dose provided by a physically discrete unit that contains a predetermined quantity of active ingredient calculated to produce a desired therapeutic effect. In embodiments where one or more units are mounted on the rod, it is preferred that the rod comprises one or more barbs spaced along the length of the rod to anchor the units in place i.e., the spacing between the barbs is typically equivalent to at least the length of one unit.

[0032] The units according to the present invention typically have a length of from about 5 mm to about 25 mm e.g., from about 5 mm to about 20 mm, or from about 5 to about 15 mm e.g., about 10 mm.

[0033] The units according to the present invention typically have a diameter of from about 1 mm to about 8 mm e.g., from about 1 mm to about 7 mm, or from about 1 mm to about 6 mm, or from 1 mm to about 5 mm, or from about 1 mm to about 4 mm, or from about 1 mm to about 3 mm, or from about 1 mm to about 2 mm, or from about 1 mm to about 1 .5 mm, or from about 2 mm to about 7.5 mm, or from about 3 mm to about 6.5 mm, or from about 4 mm to about 5.5 mm.

[0034] The conduit extends coaxially through the core of the unit. The conduit typically has a diameter of from about 0.2 mm to about 2 mm e.g., from about 0.2 mm to about 1 .8 mm, or from about 0.2 mm to about 1 .6 mm, or from about 0.2 mm to about 1 .4 mm, or from about 0.2 mm to about 1 .2 mm, or from about 0.2 mm to about 1 .0 mm, or from about 0.2 mm to about 0.8 mm, or from about 0.2 mm to about 0.6 mm, or from about 0.2 mm to about 0.4 mm, or from about 0.4 mm to about 1 .9 mm, or from about 0.6 mm to about 1 .7 mm, or from about 0.8 mm to about 1 .5 mm, or from about 0.8 mm to about 1.3 mm e.g., about 1 mm. The diameter of the conduit is selected according to the diameter of the rod on which the units are to be mounted.

[0035] The first and second non-erodible polymers may be the same or different. Examples of non- erodible polymers include poly(ethylmethacrylate) / n-butylmethacrylate, ethylene-vinyl acetate (EVA) copolymers, ultra high molecular weight polyethylene (UHMWPE), polycarbonates, polyesters, polyether ether ketones, polyethylene-co-tetrafluoroethylene, polymethylmethacrylate, polyolefins, polypropylenes, polysulfones, polytetrafluoroethylene, polyurethanes, polyvinylchlorides, polyvinylidene fluoride, silicones, acrylonitrile butadiene styrene (ABS) resins, acrylic polymers and copolymers, acrylonitrile-styrene copolymers, alkyd resins, copolymers of vinyl monomers with each other and olefins, ethylene-methyl methacrylate copolymer, epoxy resins, ethyl vinyl alcohol copolymers, polyacrylonitrile, polyamides, polycarbonates, polycyanoacrylates, polystyrene, polyvinyl esters, polyvinyl acetates, polyvinyl ethers, polyvinyl methyl ethers, silicones, vinyl halide polymers and copolymers, polyvinylchloride, thermoplastic polyurethane polymers, and copolymers of these polymers with polyethylene glycol) (PEG). Preferred non-erodible polymers include ethylene-vinyl acetate (EVA) or poly(ethylmethacrylate) / n-butylmethacrylate. Preferred EVA blends can have about 50 % to about 95 % ethylene content and about 5 % to about 50 % vinyl acetate content.

[0036] The first and second non-erodible polymers may be starch based polymers e.g., poly(lactic acid) (PLA) and poly(lactide-co-glycolide) (PLGA).

[0037] Preferably, the first and second non-erodible polymers are biocompatible, chemically inert to the drug(s) and can be divided, e.g., cut, without undue difficulty by the medial practitioner. A preferred polymer therefore includes ethylene-vinyl acetate (EVA).

[0038] In some embodiments, the rod comprises a third polymer material. The third polymer can be any suitable biocompatible polymer with good mechanical strength and resilience which is also chemically inert to the other components of the implant. Examples of suitable polymers include starch, ultra high molecular weight polyethylene (UHMWPE), low density polyethylene (LDPE) ethylene-vinyl acetate (EVA), and pharmaceutically acceptable epoxy resins or epoxy resin blends. The epoxy resin may be a 3D printable epoxy resin. A particularly preferred epoxy resin is sold under the tradename Accura® Xtreme and comprises a mixture of components selected from 4,4’-isopropylidenedicyclohexanol, 1-chloro-2,3-epoxypropane, phenol, 4,4’-(1- methylethylidene) bis-, 2-(chloromethyl)oxirane, 1 ,6-bis(2,3-epoxypropoxy)hexane, poly[2- (chloromethyl)oxirane-alt-4,4’-(propane-2,2-diyl)diphenol], dipentaerythritol pentaacrylate esters, (sulfanediyldibenzene-4,1-diyl)bis(diphenylsulfonium)bis(hexafluoroantimonate), triarylsulfonium salts and propylene carbonate. In embodiments where the polymer is (EVA), the preferred EVA blend has about 5 % to about 40 % vinyl acetate content, preferably around about 10 % vinyl acetate content. Preferably, the rod is made from ultra high molecular weight polyethylene (UHMWPE).

[0039] In alternative embodiments, the rod is a metal wire made from a biocompatible metal, such as titanium, titanium alloy, stainless steel, cobalt chromium alloy, copper, aluminium, or gold. Preferably, the metal wires can be repeatedly bent without work hardening and can resist fatigue fracture. The implants are typically cylindrical or rod-shaped. In order to prevent elution of the drug(s) from the exposed core region at either end of the implant, one or both ends of the device can be capped with a capping material. The capping material can be made from any suitable material known in the art, such as a polymer e.g., ethylene-vinyl acetate (EVA), ultra high molecular weight polyethylene (UHMWPE), or pharmaceutically acceptable epoxy resins or epoxy resin blends. The epoxy resin may be a 3D printable epoxy resin. A particularly preferred epoxy resin is sold under the tradename Accura®Xtreme and comprises a mixture of components selected from 4,4’- isopropylidenedicyclohexanol, 1-chloro-2,3-epoxypropane, phenol, 4,4’-(1-methylethylidene)bis-, 2-(chloromethyl)oxirane, 1 ,6-bis(2,3-epoxypropoxy)hexane, poly[2-(chloromethyl)oxirane-alt- 4,4’-(propane-2,2-diyl)diphenol], dipentaerythritol pentaacrylate esters, (sulfanediyldibenzene- 4,1-diyl)bis(diphenylsulfonium)bis(hexafluoroantimonate), triarylsulfonium salts and propylene carbonate.

[0040] The capping material can be about 1 mm to about 3 mm thick. The capping material can be impermeable to the drug(s), which serves to prevent elution of the drug(s) from the ends of the implant. The capping material can be permeable to the drug(s), which serves to regulate elution of the drug(s) from the ends of the implant. One or more caps and the rod may be formed as a single backbone of the implant, or the one or more caps can be added separately to the rod. In embodiments where the length of the implant is decreased to decrease the dosage of the drug(s), the implant is preferably capped by at least one end by a flange or disc extending radially from the rod and disc substantially the same size as the cross section of the implant.

[0041] In some embodiments, one end of the implant is shaped, e.g., tapered or rounded, to facilitate insertion of the implant into a subject.

[0042] The implants typically have a diameter of from about 1 mm to about 8 mm e.g., from about 1 mm to about 7 mm, or from about 1 mm to about 6 mm, or from about 1 mm to about 5 mm, or from about 1 mm to about 4 mm, or from about 1 mm to about 3 mm, or from about 1 mm to about 2 mm, or from about 2 mm to about 8 mm, or from about 3 mm to about 8 mm, or from about 4 mm to about 8 mm, or from about 5 mm to about 8 mm, or from about 6 mm to about 8 mm, or from about 7 mm to about 8 mm. In one embodiment, the implant has a diameter of about 2.5 mm.

[0043] The implants typically have a length of from about 10 mm to about 80 mm e.g., from about 10 mm to about 70 mm, or from about 10 mm to about 60 mm, or from about 10 mm to about 50 mm, or from about 10 mm to about 40 mm, or from about 10 mm to about 30 mm, or from about 10 mm to about 20 mm, or from about 20 mm to about 75 mm, or from about 30 mm to about 65 mm, or from about 40 mm to about 55 mm, or from about 50 mm to about 80 mm, or from about 60 mm to about 80 mm, or from about 70 mm to about 80 mm. In one embodiment, the implant has a length of about 50 mm.

[0044] The core and sheath can vary in thickness. The core typically has a diameter of from about 1 mm to about 3 mm and the sheath typically has a thickness of from about 0.1 mm to about 1 mm.

[0045] The core comprises drug(s) distributed uniformly in a polymer matrix of a first non-erodible polymer. The amount of drug(s) in the core depends on at least the release rate ( / .e., a daily dose) and the duration that the implant is inserted into a subject. The actual amount would be determined by the skilled person using his common general knowledge.

[0046] The core will typically comprise a therapeutically effective amount of the or each drug which may be from about 1 wt % to about 80 wt % of the drug(s) based on the total weight of the core e.g., from about 5 wt % to about 80 wt %, or from about 10 wt % to about 80 wt %, or from about 20 wt % to about 80 wt %, or from about 30 wt % to about 40 wt %. The balance of the core is made up of the first non-erodible polymer.

[0047] The implants typically comprise from about 0.0001 mg to about 250000 mg of the drug(s), e.g., from about 0.001 mg to about 100000 mg, or about 0.01 mg to about 10000 mg, or about 0.1 mg to about 1000 mg, or about 1 mg to about 100 mg. In embodiments where the implant comprises two or more regions, each region comprises an equal amount of drug(s). The actual amount of the drug(s) would be determined by the skilled person using his common general knowledge and will depend on the drug(s) used.

[0048] Implants according to the present invention typically provide a release rate ( / .e., a daily dose) of from about 0.1 ng / day to about 700 mg / day e.g., from about 0.1 pg / day to about 700 pg / day, or from about 1 pg / day to about 100 pg / day. Preferably, the release rate is about 25 pg / day, or about 50 pg / day, or about 75 pg / day, or about 100 pg / day, or about 125 pg / day. The actual dosage would be determined by the skilled person using his common general knowledge and will depend on the drug(s) used. In embodiments where the implant comprises two or more units mounted on the rod, each unit typically comprises from 0.00002 mg to 50000 mg of the drug(s), e.g., from about 0.0001 mg to about 5000 mg, or about 0.001 mg to about 500 mg, or about 0.01 mg to about 50 mg. Each unit typically provides a release rate of from about 0.02 ng / day to about 150 mg / day e.g., from about 0.02 pg / day to about 150 pg / day, or from about 0.2 pg / day to about 20 pg / day. The total release rate ( / .e., daily dose) provided by the implant is proportional to the number of units in the implant i.e., it is equal to the sum of the release rates provided the individual units in the implant.

[0049] The implant is usually used to administer a single drug as the sole therapeutically active component. However, more than one drug may be administered in a single implant.

[0050] The implant of the present invention is designed to administer a wide range of drugs. The implant can deliver drugs to humans and / or other animals. The identity of the drug(s) in the implant obviously depends on the condition to be treated. The implant may comprise drug(s) selected from therapeutic agents, hormones, diagnostic agents, nutrients, vitamins, and minerals. Examples of suitable drugs include drugs of the classifications benzodiazepine, cardiac glycoside, fibrate, steroid, thiazide diuretic, triptan, [3-lactam antibiotic, analgesics, antibiotic, anticancer, anticoagulant, antidepressant, antidiabetic, antiepileptic, antipsychotic, antispasmodic, antiviral, cardiovascular, depressant, sedative, and stimulant. Examples of specific drugs include hormone replacement drugs e.g., secretin; enzyme based drugs or large molecule based drugs e.g., alglucerase; and small molecule based drugs e.g., lonafarnib.

[0051] The implant preferably comprises hormones, either natural or synthetic, or hormone derivatives. Use of the implant for hormone treatment can be utilised for humans, as well as for animals in veterinary scenarios. Preferred hormones or hormone derivatives include tyrosine-based hormones that are primarily responsible for regulation of metabolism and progestins such as etonogestrel.

[0052] Methods

[0053] The invention further provides methods of forming the implant according to the first aspect. These methods include: A method comprising: providing a rod; co-injection moulding or co-extruding a first composition comprising a first non-erodible polymer and at least one drug and a second composition comprising a second non-erodible polymer; wherein the first composition is co-injection moulded or co-extruded to form a core around the rod; and wherein the second composition is co-injection moulded or co-extruded to form a sheath around the core.

[0054] A method comprising: providing a rod; forming a core by extruding or injection moulding a first composition comprising the first non-erodible polymer; and coating the core with a second composition comprising the second non-erodible polymer to form a sheath around the core.

[0055] The invention further provides methods of forming the implant according to the second aspect. These methods include:

[0056] A method comprising: providing a rod; forming one or more discrete units by co-extruding or co- injection moulding a first composition comprising the first non-erodible polymer and a second composition comprising the second non-erodible polymer; wherein the first composition is coextruded or co-injection moulded to form a unit core; and wherein the second composition is coextruded or co-injection moulded to form a sheath around the unit core; mounting one or more discrete units on the rod; and optionally cutting the rod once the desired number of discrete units are mounted on the rod.

[0057] A method comprising: providing a rod; forming one or more discrete units by extruding or injection moulding a first composition comprising a first non-erodible polymer and at least one drug to form a unit core, and coating the unit core with a second composition comprising a second non-erodible polymer to form a sheath around the unit core; and mounting one or more discrete units on the rod; and optionally cutting the rod once the desired number of discrete units are mounted on the rod.

[0058] In the methods disclosed herein, the first composition can be formed by combining the first non- erodible polymer with the drug(s). The drug is typically reduced to fine particles by milling (e.g., ball-milling, impact-milling, micronisation by air jet milling), spray-drying, solvent precipitation, screening, or other method or combination of methods known in the art to produce fine particles. The drug can be combined with the first non-erodible polymer which is also typically prepared as fine particles to form the mixture used to form the drug-containing core. The second composition comprises the second non-erodible polymer. The non-erodible polymer is also typically prepared as fine particles to form the composition used to form the sheath around the core. The second composition may further comprise at least one drug.

[0059] The first and / or second composition may further comprise additional excipients e.g., fillers, diluents and / or binders. The specific excipients and amounts thereof, if included at all, would be determined by the skilled person using his common general knowledge.

[0060] In some embodiments, the implant of the present invention can be produced by co-extruding the drug-containing core of the implant and the sheath.

[0061] The first and second compositions are heated to a temperature suitable for extrusion, such as the softening point of the polymer. At this point, optionally and if necessary, either or both of the softened compositions can be homogenized. The first and second compositions are then coextruded. The diameter of extrusion, as well as temperature, pressure and other parameters can be controlled as appropriate for each drug and polymer.

[0062] The extrudate can be extruded horizontally and collected for further processing. The extrudate can be cut into desirable lengths, e.g., from about 10 mm to about 80 mm. The extrudate can then be washed in a solvent, such as a solvent which dissolves and removes excess drug from the surface of the implant, or a solvent which assists in sterilization. Examples of solvents which can be used forwashing the implant include water, saline, aqueous buffers, and alcohols such as ethanol or isopropanol. Mixtures of water and alcohols can also be used, such as ethanol-water mixtures. Preferable solvents are 100 % ethanol orwater-ethanol mixtures.

[0063] Washing may be followed by drying to remove the solvent. Drying is typically done between about 30 °C and about 60 °C for about 6 to about 24 hours, such as at about 40 °C for about 12 hours.

[0064] Drying may be followed by packaging and sterilization. Implants may be vacuum-packed in moisture barrier foil pouches, heat-sealed and / or vacuum — sealed, and then sterilized using gamma irradiation. The implant according to either the first or second aspect can also be prepared by 3D printing methods, for example using fused deposition modelling (FDM), stereolithography (SLA), selective laser sintering (SLS), or binder jetting.

[0065] Other aspect include:

[0066] An implant for sustained delivery of a drug, the implant comprising: a core comprising at least one drug distributed uniformly in a polymer matrix of a first non-erodible polymer; and a sheath surrounding the core, the sheath comprising a second non-erodible polymer; wherein the implant comprises a means for adjusting the length of the implant to provide a pre-determined dosage of the at least one drug.

[0067] An implant for sustained delivery of a drug, the implant comprising: a core comprising at least one drug distributed uniformly in a polymer matrix of a first non-erodible polymer; a sheath surrounding the core, the sheath comprising a second non-erodible polymer; and a rod extending coaxially through the core; wherein the implant comprises a means for adjusting the length of the implant to provide a pre-determined dosage of the at least one drug.

[0068] A kit of parts comprising: one or more discrete units, each discrete unit comprising a unit core comprising at least one drug uniformly distributed through a polymer matrix of a first non-erodible polymer; a sheath surrounding the unit core, the sheath comprising a second non-erodible polymer; and a conduit extending coaxially through the unit core; a rod; and optionally an applicator; wherein the conduit is dimensioned for mounting the one or more discrete units on the rod; and wherein the each discrete unit defines a unit dosage of the at least one drug.

[0069] A method comprising: mounting the one or more discrete units on the rod; wherein the number of discrete units mounted on the rod determines the dosage of the drug to be administered.

[0070] A kit of parts comprising; a cutting device; and optionally an applicator.

[0071] An implant for use in a method of preventing and / or treating a disease in a subject comprising implanting into the subject said implant. Such diseases include all the overarching classes of diseases and subsets within them, such as hormonal diseases, e.g., Cushing's syndrome; infectious diseases e.g., Whipple disease; hereditary diseases e.g., Pompe disease or Gaucher disease (type 1 , 2, 3); physiological diseases e.g., Adrenal cortex carcinoma; psychiatric diseases e.g., Histrionic Personality Disorder.

[0072] The implants can be administered subcutaneously, subdermally or intramuscularly. It is preferred that the implants are administered subcutaneously at a site selected from a group consisting of the upper arm, scapular region, the back, the leg and the abdomen. Before implantation, the patient may be lightly anesthetized, e.g., with isoflurane or other anaesthetic known in the art, and / or may have topical, transdermal, orsubdermal anaesthetic applied at the site of implantation. A small incision can be made through the skin and an applicator inserted subcutaneously then loaded with one implant. A stylet can be inserted to hold the implant in place and the applicator carefully removed, leaving the implant in the subdermal space. Each site can be sutured closed and examined later.

[0073] The term “applicator” used herein means a device used for inserting the implant e.g., a trocar.

[0074] The implants of the invention can be left in the body for up to one year or more. The period of sustained release of drug into the body is thus from about 1 month to about 1 year, or longer, or from about 3 months to about 1 year or longer, e.g., at least about 3 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 15 months, at least about 18 months, at least about 21 months, or at least about 24 months or more. In some embodiments the devices can be left in the body for more than 1 year. Implants may be removed from the body anytime within the treatment period or at the end of the treatment period, through an incision, e.g., a 3 mm incision, using forceps. In some embodiments, the implants comprise a tab or loop at one end to facilitate removal of the device from the body.

[0075] GENERAL DEFINITIONS

[0076] Throughout this application terms should be interpreted according to their standard meaning in the art unless specified otherwise. The following terms should be construed according to their standard meanings, as set out below. As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus for example, a reference to "a method" includes one or more methods, and / or steps of the type described herein and / orwhich will become apparent to those persons skilled in the art upon reading this disclosure and so forth.

[0077] The term “comprising” should be construed as meaning “including but not limited to”.

[0078] Features which are described herein with reference only to a single aspect or embodiment of the invention apply equally to all other aspects and embodiments of the invention. Hence features from one aspect or embodiment may be combined with features from another aspect or embodiment.

[0079] In this specification, unless expressly otherwise indicated, the word ‘or’ is used in the sense of an operator that returns a true value when either or both of the stated conditions is met, as opposed to the operator ‘exclusive or’ which requires that only one of the conditions is met.

[0080] Aspects of the invention include:

[0081] #1 . An implant for sustained delivery of a drug, the implant comprising: a core comprising at least one drug distributed uniformly in a polymer matrix of a first non-erodible polymer; wherein the implant comprises a means for adjusting the length of the implant to provide a pre-determined dosage of the at least one drug.

[0082] #2. An implant as in #1 , further comprising a sheath surrounding the core, the sheath comprising a second non-erodible polymer.

[0083] #3. An implant as in #1 or #2, further comprising a rod extending coaxially through the core.

[0084] #4. An implant as in any of #1 to #3, further comprising one or more discrete units, each unit comprising a unit core defining a unit dosage of the at least one drug and the one or more unit cores forming the implant core. #5. An implant as in #1 or #2, wherein the means for adjusting the length of the implant enables the length of the implant to be decreased to decrease the dosage of the at least one drug.

[0085] #6. An implant as in #5, wherein the means for adjusting the length of the implant comprises two or more regions of at least substantially equal length, each region comprising an at least substantially equal amount of the at least one drug; and wherein the implant is divisible between adjacent regions.

[0086] #7. An implant as in #6, wherein the exterior of the implant comprises graduated markings to define the regions.

[0087] #8. An implant as in #6 or #7, further comprising flanges located between adjacent regions.

[0088] #9. An implant as in #8, wherein the flanges are discs that are the same size as the cross section of the implant.

[0089] #10. An implant as in any of #5 to #9, wherein the implant further comprises a rod extending coaxially through the core.

[0090] #11. An implant as in #10, wherein the rod comprises a plurality of anchors spaced apart along the length of the rod to anchor the core in place.

[0091] #12. An implant as in #11 , wherein the anchors are selected from nodules, flanges or barbs.

[0092] #13. An implant as in #1 or #2, wherein the means for adjusting the length of the implant enables the length of the implant to be increased to increase the dosage of the at least one drug.

[0093] #14. An implant as in #13, wherein the implant further comprises a rod extending coaxially through the core.

[0094] #15. An implant as in #14, wherein the rod comprises a plurality of anchors spaced apart along the length of the rod to anchor the core in place.

[0095] #16. An implant as in #15, wherein the anchors are selected from nodules, flanges or barbs. #17. An implant as in any of #14 to #16, wherein the implant comprises one or more discrete units mounted on the rod, each discrete unit comprising a unit core and a sheath and defining a unit dosage of the at least one drug; wherein each discrete unit comprises a pre-formed conduit, the conduit extending coaxially through the core and dimensioned for mounting the one or more discrete units on the rod; and wherein the number of units mounted on the rod determines the pre-determined dosage of the at least one drug.

[0096] #18. An implant for delivery of a drug, the implant comprising: one or more discrete units and a rod, each discrete unit comprising: a unit core comprising at least one drug distributed uniformly in a matrix of a first non-erodible polymer: a sheath surrounding the unit core, the sheath comprising a second non-erodible polymer; and a conduit extending coaxially through the unit core; wherein the conduit is dimensioned for mounting the one or more discrete units on the rod; wherein each discrete unit defines a unit dosage of the at least one drug; and wherein the number of discrete units mounted on the rod determines the pre-determined dosage of the at least one drug.

[0097] #19. An implant as in #17 or #18 wherein the rod comprises one or more barbs spaced along the length of the rod to anchor the discrete units in place.

[0098] #20. An implant as in any of #10 to #12 or #14 to #19, wherein the rod comprises a third polymer or a metal wire.

[0099] #21 . An implant as in any of the preceding aspects, wherein the first polymer comprises one or more materials selected from the group consisting of ethylene-vinyl acetate and poly(ethylmethacrylate) / n-butylmethacrylate. #22. An implant as in any of #2 to #21 , wherein the second polymer comprises one or more materials selected from the group consisting of ethylene-vinyl acetate and poly(ethylmethacrylate) / n-butylmethacrylate.

[0100] #23. A unit for an implant for delivery of a drug, the unit comprising: a unit core comprising at least one drug distributed uniformly through a polymer matrix of a first polymer; a sheath surrounding the unit core, the sheath comprising a second polymerwhich is a non-erodible polymer; and a conduit extending coaxially through the unit core.

[0101] #24. A method of producing an implant as in any of #10 to #12, the method comprising: providing a rod; co-injection moulding or co-extruding a first composition comprising the first non- erodible polymer and the at least one drug and a second composition comprising the second non-erodible polymer; wherein the first composition is co-injection moulded or co-extruded to form a core around the rod; wherein the second composition is co-moulded or co-extruded to form a sheath around the core; and wherein graduated markings are applied onto the exterior of the implant.

[0102] #25. A method of producing an implant as in any of #10 to #12, the method comprising: providing a rod; forming a core by extruding or injection moulding a first composition comprising the first non-erodible polymer; and coating the core with a second composition comprising the second non-erodible polymer to form a sheath around the core.

[0103] #26. A method of producing an implant as in #18, the method comprising: providing a rod; forming one or more discrete units by co-extruding or co-injection moulding a first composition comprising the first non-erodible polymer and a second composition comprising the second non-erodible polymer; wherein the first composition is co-extruded or co-injection moulded to form a unit core; and wherein the second composition is co-extruded or co-injection moulded to form a sheath around the unit core; mounting one or more discrete units on the rod; and optionally cutting the excess rod once the desired number of discrete units are mounted on the rod.

[0104] #27. A method of producing an implant as in #18, the method comprising: providing a rod; forming one or more discrete units by extruding or injection moulding a first composition comprising a first non-erodible polymer and at least one drug to form a unit core, and coating the unit core with a second composition comprising a second non- erodible polymer to form a sheath around the unit core; and mounting one or more discrete units on the rod; and optionally cutting the excess rod once the desired number of discrete units are mounted on the rod.

[0105] #28. A kit of parts comprising: one or more discrete units, each discrete unit comprising: a unit core comprising at least one drug uniformly distributed through a polymer matrix of a first non-erodible polymer; a sheath surrounding the unit core, the sheath comprising a second non- erodible polymer; a conduit extending coaxially through the unit core; and a rod; and optionally an applicator; wherein the conduit is dimensioned for mounting the one or more discrete units on the rod; and wherein each discrete unit defines a unit dosage of the at least one drug.

[0106] #29. A method of producing an implant for delivery of a drug from a kit as in #28, the method comprising: mounting the one or more discrete units on the rod; wherein the number of discrete units mounted on the rod determines the dosage of the drug to be administered.

[0107] #30. A kit of parts comprising: an implant as in any of #1 to #9 or #26 or #27; a cutting device; and optionally an applicator.

[0108] #31. An implant as in any of #1 to #23 for use in a method of preventing and / or treating a disease in a subject comprising implanting into the subject said implant.

[0109] DETAILED DESCRIPTION

[0110] Embodiments of the present invention will now be described by way of example only with reference to the accompanying drawings, in which:

[0111] FIG. 1A shows a diagrammatic side view of the rod of a first embodiment of the implant.

[0112] FIG. 1 B shows a diagrammatic cross-sectional view of the first embodiment of the implant.

[0113] FIG. 2A shows a diagrammatic side view of the rod of a second embodiment of the implant.

[0114] FIG. 2B shows a diagrammatic isometric view of a first embodiment of the unit.

[0115] FIG. 2C shows a diagrammatic cross-sectional view of a second embodiment of the implant.

[0116] FIG. 2D shows a diagrammatic cross-sectional view of a third embodiment of the implant.

[0117] FIG. 3A shows a diagrammatic isometric view of a second embodiment of the unit.

[0118] FIG. 3B shows a diagrammatic cross-sectional side view of a fourth embodiment of the implant.

[0119] FIG. 3C shows a diagrammatic exploded view of the fourth embodiment of the implant. Features in the drawings without reference numerals but which are substantially similar to features with a reference numeral are to be interpreted as equivalent features.

[0120] In FIG. 1A, a rod 100 is shown. The rod 100 has two flanges in the form of discs 102 extending radially from the rod and located between caps 104, 106. Caps 104, 106 are located each end of the rod 100 respectively. Cap 104 is rounded to facilitate insertion of the implant into a subject. Cap 106 is a disc extending radially from the rod.

[0121] The rod of FIG. 1A is manufactured by injection moulding.

[0122] In FIG. 1 B, an implant is shown. The implant has a rod as provided in FIG. 1A. Cores 108 are located on the rod 100 in between flanges 102 and in between a flange 102 and the caps 104, 106. A sheath 110 surrounds the cores 108, flanges 102 and cap 106. The ends of the caps 104 and 106 are not surrounded by the sheath 110. Cap 104 is rounded.

[0123] The implant of FIG. 1 B is manufactured by over-moulding the core 108 on the rod 100. The sheath 110 is subsequently over-moulded over the cores 108 and rod 100.

[0124] The implant of FIG. 1 B is adjusted by cutting the implant through the sheath 110, core 108 and rod 100 adjacent to a flange 102.

[0125] In FIG. 2A, a rod 200 is shown with a first end cap 202 and a second end cap 204. The first and second end caps 202, 204 are located each end of the rod respectively. The rod does not have any flanges present.

[0126] In FIG. 2B, a unit 206 with a conduit 208 extending coaxially through the unit 206 is shown. The unit is made by injection moulding a core with a drug and co-injection moulding the sheath.

[0127] In FIG. 2C, an implant with a rod 200 with two end caps 202, 204 and three units 206 (as depicted in FIG. 2B) is shown. The units have a core 210 surrounded by a sheath 212.

[0128] To make the implants of FIG. 2C, the rod 200 with a rounded end cap 202 fitted is inserted through the conduit 208 of three units 206. The second end cap 204 is fitted to secure the units 206 on the rod 200. Excess rod 200 is then cut off. In FIG. 2D, an implant is shown as depicted in FIG. 2C, but with gaps 214, 216 present. The gaps 214 between units 206 are larger than the gaps 216 between the units 206 and the end caps 202, 204.

[0129] The implant of FIG. 2D is adjusted by cutting the implant at a gap 214, through the rod 200. Excess rod 200 is then cut off.

[0130] In FIG. 3A, a unit 300 with a ball and socket configuration is shown. On one end, the unit 300 has a ball 302 attached to a radial flange in the form of a disc 308. On the opposite end, the unit has a radial flange in the form of a disc 306 with a socket 304. A rod (not shown) extends coaxially through the unit 300.

[0131] To make the unit of FIG. 3A, the rod 310 with flanges 306, 308 and ball 302 and socket 304 is injection moulded. The core 312 is co-injection moulded. The sheath 314 is co-injection moulded onto the core 312.

[0132] In FIG. 3B, an implant with three units 300 with a ball and socket configuration (as depicted in FIG. 3A) is shown. In each unit 300, a rod 310 extends coaxially through the core 312 of the unit 300. The rod 310 has on a first end a radial flange 308 in the form of a disc with a ball 302. The rod 310 on the second end has a radial flange 306 in the form of a disc with a socket 304. A sheath 314 covers the core 312 and radial flanges 306, 308. A first end cap 316 is engaged with a socket 304 of the implant, and a second end cap 316 is engaged with a ball 302 of the implant.

[0133] To make the implant of FIG. 3B, each unit 300 is attached by inserting the ball 302 of the unit 300 into the socket 304 of a second unit 300. End caps 316, 318 are placed over the remaining ball 302 and socket 304 of the implant.

[0134] FIG 3C shows an exploded view of the rod 310 with radial flanges 306, 308 and ball 302 and socket 304, the core 312, the sheath 314 and end caps 316 and 318.

[0135] EXAMPLES

[0136] The present invention will now be illustrated by the following non-limiting examples. EXAMPLE 1

[0137] An implant is prepared by injection moulding a rod made from ultra high molecular weight polyethylene (UHMWPE). A mixture of EVA and etonogestrel is over-moulded onto the rod to form a core over the rod. EVA is subsequently over-moulded over the rod and core sub-unit to form a sheath. The implant is 100 mm in length and 2.5 mm in diameter. The core has a thickness of 1 mm. The sheath has a thickness of 0.5 mm.

[0138] The implant contains four regions each with 25 mg etonogestrel i.e., 100 mg of etonogestrel in total. To reduce the dosage, the implant is cut at a radial flange to remove a region. Removing one region produces an implant with three regions containing 75 mg of etonogestrel in total.

[0139] EXAMPLE 2

[0140] A unit is made by injection moulding EVA with etonogestrel and co-injection moulding a sheath of EVA. Each unit is 15 mm in length and 2.5 mm in diameter. A conduit with a diameter of 0.5 mm extends coaxially through the unit. Each unit contains 25 mg etonogestrel.

[0141] To make the implant, a rod with a rounded end cap is threaded through the conduit of three units. A second end cap is added at the opposing end and excess rod is cut off. The resulting implant contains 75 mg etonogestrel.

[0142] While the invention has been described with reference to the preferred embodiments depicted in the figures, it will be appreciated that various modifications are possible within the spirit or scope of the invention as defined in the following claims.

Claims

CLAIMS1 . An implant for sustained delivery of a drug, the implant comprising: a core comprising at least one drug distributed uniformly in a polymer matrix of a first non-erodible polymer; wherein the implant comprises a means for adjusting the length of the implant to provide a pre-determined dosage of the at least one drug.

2. An implant as claimed in Claim 1 , further comprising a sheath surrounding the core, the sheath comprising a second non-erodible polymer.

3. An implant as claimed in Claim 1 or Claim 2, further comprising a rod extending coaxially through the core.

4. An implant as claimed in any of Claims 1 to 3, further comprising one or more discrete units, each unit comprising a unit core defining a unit dosage of the at least one drug and the one or more unit cores forming the implant core.

5. An implant as claimed in Claim 1 or Claim 2, wherein the means for adjusting the length of the implant enables the length of the implant to be decreased to decrease the dosage of the at least one drug.

6. An implant as claimed in Claim 5, wherein the means for adjusting the length of the implant comprises two or more regions of at least substantially equal length, each region comprising an at least substantially equal amount of the at least one drug; and wherein the implant is divisible between adjacent regions.

7. An implant as claimed in Claim 6, wherein the exterior of the implant comprises graduated markings to define the regions.

8. An implant as claimed in Claim 6 or Claim 7, further comprising flanges located between adjacent regions.

9. An implant as claimed in Claim 8, wherein the flanges are discs that are the same size as the cross section of the implant.

10. An implant as claimed in any Claims 5 to 9, wherein the implant further comprises a rod extending coaxially through the core.

11. An implant as claimed in Claim 10, wherein the rod comprises a plurality of anchors spaced apart along the length of the rod to anchor the core in place.

12. An implant as claimed in Claim 11 , wherein the anchors are selected from nodules, flanges or barbs.

13. An implant as claimed in Claim 1 or Claim 2, wherein the means for adjusting the length of the implant enables the length of the implant to be increased to increase the dosage of the at least one drug.

14. An implant as claimed in Claim 13, wherein the implant further comprises a rod extending coaxially through the core.

15. An implant as claimed in Claim 14, wherein the rod comprises a plurality of anchors spaced apart along the length of the rod to anchor the core in place.

16. An implant as claimed in Claim 15, wherein the anchors are selected from nodules, flanges or barbs.

17. An implant as claimed in any of Claims 14 to 16, wherein the implant comprises one or more discrete units mounted on the rod, each discrete unit comprising a unit core and a sheath and defining a unit dosage of the at least one drug; wherein each discrete unit comprises a pre-formed conduit, the conduit extending coaxially through the core and dimensioned for mounting the one or more discrete units on the rod; and wherein the number of units mounted on the rod determines the pre-determined dosage of the at least one drug.

18. An implant for delivery of a drug, the implant comprising: one or more discrete units and a rod, each discrete unit comprising: a unit core comprising at least one drug distributed uniformly in a matrix of a first non-erodible polymer: a sheath surrounding the unit core, the sheath comprising a second non-erodible polymer; and a conduit extending coaxially through the unit core; wherein the conduit is dimensioned for mounting the one or more discrete units on the rod; wherein each discrete unit defines a unit dosage of the at least one drug; and wherein the number of discrete units mounted on the rod determines the pre-determined dosage of the at least one drug.

19. An implant as claimed in Claim 17 or Claim 18 wherein the rod comprises one or more barbs spaced along the length of the rod to anchor the discrete units in place.

20. An implant as claimed in any of Claims 10 to 12 or 14 to 19, wherein the rod comprises a third polymer or a metal wire.21 . An implant as claimed in any of the preceding claims, wherein the first polymer comprises one or more materials selected from the group consisting of ethylene-vinyl acetate and poly(ethylmethacrylate) / n-butylmethacrylate.

22. An implant as claimed in any of Claims 2 to 21 , wherein the second polymer comprises one or more materials selected from the group consisting of ethylene-vinyl acetate and poly(ethylmethacrylate) / n-butylmethacrylate.

23. A unit for an implant for delivery of a drug, the unit comprising: a unit core comprising at least one drug distributed uniformly through a polymer matrix of a first polymer; a sheath surrounding the unit core, the sheath comprising a second polymerwhich is a non-erodible polymer; and a conduit extending coaxially through the unit core.

24. A method of producing an implant as claimed in any of Claims 10 to 12, the method comprising: providing a rod; co-injection moulding or co-extruding a first composition comprising the first non- erodible polymer and the at least one drug and a second composition comprising the second non-erodible polymer; wherein the first composition is co-injection moulded or co-extruded to form a core around the rod; wherein the second composition is co-moulded or co-extruded to form a sheath around the core; and wherein graduated markings are applied onto the exterior of the implant.

25. A method of producing an implant as claimed in any of Claims 10 to 12, the method comprising: providing a rod; forming a core by extruding or injection moulding a first composition comprising the first non-erodible polymer; and coating the core with a second composition comprising the second non-erodible polymer to form a sheath around the core.

26. A method of producing an implant as claimed in Claim 18, the method comprising: providing a rod; forming one or more discrete units by co-extruding or co-injection moulding a first composition comprising the first non-erodible polymer and a second composition comprising the second non-erodible polymer; wherein the first composition is co-extruded or co-injection moulded to form a unit core; and wherein the second composition is co-extruded or co-injection moulded to form a sheath around the unit core; mounting one or more discrete units on the rod; and optionally cutting the excess rod once the desired number of discrete units are mounted on the rod.

27. A method of producing an implant as claimed in Claim 18, the method comprising: providing a rod; forming one or more discrete units by extruding or injection moulding a first composition comprising a first non-erodible polymer and at least one drug to form a unit core, and coating the unit core with a second composition comprising a second non- erodible polymer to form a sheath around the unit core; and mounting one or more discrete units on the rod; and optionally cutting the excess rod once the desired number of discrete units are mounted on the rod.

28. A kit of parts comprising: one or more discrete units, each discrete unit comprising: a unit core comprising at least one drug uniformly distributed through a polymer matrix of a first non-erodible polymer; a sheath surrounding the unit core, the sheath comprising a second non- erodible polymer; a conduit extending coaxially through the unit core; and a rod; and optionally an applicator; wherein the conduit is dimensioned for mounting the one or more discrete units on the rod; and wherein each discrete unit defines a unit dosage of the at least one drug.

29. A method of producing an implant for delivery of a drug from a kit as claimed in Claim 28, the method comprising: mounting the one or more discrete units on the rod; wherein the number of discrete units mounted on the rod determines the dosage of the drug to be administered.

30. A kit of parts comprising: an implant as claimed in any of Claims 1 to 9 or 26 or 27; a cutting device; and optionally an applicator.31 . An implant as claimed in any of Claims 1 to 23 for use in a method of preventing and / or treating a disease in a subject comprising implanting into the subject said implant.