Drug-eluting device

Abstract

Drug-eluting device The present invention relates to: (i) a drug delivery device comprising a fibrous material, said fibrous material comprising: (a) a first fibre which comprises: - a first polymeric material comprising a carbon nanoparticle covalently bonded to a polymer; and / or - a first acidic polysaccharide; and / or - a first protein; and (b) a drug, and a method of manufacture thereof, as well as said drug delivery device for use in administering a drug.

Description

[0001] Drug-eluting device

[0002] Field

[0003] The present invention relates to the field of medical devices, more particularly, to the field of drug delivery devices or drug-eluting devices and methods for their production.

[0004] Background

[0005] The delivery of drugs by non-oral route avoids gastro-intestinal drug absorption and hepatic first pass metabolism. Body cavities, such as the vagina, may be used to deliver drugs via direct absorption into the blood stream. The vagina is a viscoelastic muscular tube with epithelium cells lining with a surface area of about 85 cm2and highly vascularised, meaning that the anatomy and physiology of the vagina allows smaller doses of drug to be administered as a result of the effective and direct delivery of drugs by this means.

[0006] To take an example, dysmenorrhoea, a specialist term used to describe menstrual pain, is estimated to affect up to 90% of women of reproductive age, often without an identifiable cause. There are some known causes of pelvic pain, including endometriosis, which can be disabling, resulting in time off work and great impact on mental and social wellbeing. The medical management options for dysmenorrhoea come with a host of systemic side-effects. For example, anti-inflammatory based analgesia greatly increases risks of stomach ulcers and further gastro-intestinal upset. Paracetamol is also an option; however it is often not found to be effective for long durations and it presents high risk of overdose. Cannabis-based products for medicinal use (CBPM) have recently been exploited and investigated for the application as an alternative treatment strategy to manage dysmenorrhoea. CBPMs provide a more natural and less harmful treatment option than the aforementioned forms of analgesia. There is no documented amount at which CBPM results in drug overdose, it is understood to be extremely safe, even at higher doses. If prescribed and delivered in a safe and controlled manner, CBPM can manage dysmenorrhoea.

[0007] Thus, there is need for a safe and effective non-oral drug delivery device or drug-eluting device which allows smaller doses of drug to be administered, allows drugs to be delivered over a longer period of time and which reduces systemic side-effects that each drug may cause. Thus, it is a problem of the present invention to provide a drug delivery device or drug-eluting device for improved delivery of a drug, particularly improved localised drug delivery.

[0008] It is further a problem of the present invention to provide a drug delivery device or drug-eluting device, preferably a drug delivery device or drug-eluting device for insertion into a body cavity, which is nontoxic, is adaptable / conformable to the shape of the body cavity in which it is inserted.

[0009] Moreover, many drug delivery and drug-eluting devices tend to be used only once before being discarded, whereby they end up in landfill or in aqueous environments such as the sea. Therefore, it is also a problem of the present invention to provide a drug delivery device or drug-eluting device which is biodegradeable in landfill or aqueous environments such as freshwater, brackish water or seawater, yet is also recyclable. Furthermore, it is a problem of the present invention to provide a drug delivery device or drug-eluting device which, after degradation in landfill or aqueous environments leaves no toxic substances behind,

[0010] Brief description

[0011] The present invention relates to a drug delivery device ( / .e. a device suitable for delivery or elution of a drug) comprising a fibrous material, said fibrous material comprising:

[0012] (a) a first fibre which comprises: a first polymeric material comprising a carbon nanoparticle covalently bonded to a polymer; and / or a first acidic polysaccharide; and / or a first protein; and

[0013] (b) a drug, preferably wherein said polymer which is covalently bonded to a carbon nanoparticle in said first polymeric material is a polyurethane, more preferably wherein said polyurethane comprised in said first polymeric material comprises at least one polyester moiety which has the same structure as the polyester moiety comprised in polycaprolactone diol, even more preferably wherein said first polymeric material is BioHastalex®.

[0014] The present invention also relates to a method of manufacture of a drug delivery device ( / .e. a device suitable for delivery or elution of a drug) comprising a fibrous material, said fibrous material comprising:

[0015] (a) a first fibre which comprises: a first polymeric material comprising a carbon nanoparticle covalently bonded to a polymer; and / or a first acidic polysaccharide; and / or a first protein; and

[0016] (b) a drug, wherein said method comprises the following steps:

[0017] (i) spinning: said first polymeric material; and / or said first acidic polysaccharide; and / or said first protein, respectively, to form said first fibre; and

[0018] (ii) either:

[0019] (1) charging said first fibre formed in step (i) with said drug; or

[0020] (2) forming said fibrous material using said first fibre formed in step (i); and

[0021] (3) charging said fibrous material formed in step (H)(2) with said drug, preferably wherein said polymer which is covalently bonded to a carbon nanoparticle in said first polymeric material is a polyurethane, more preferably wherein said polyurethane comprised in said first polymeric material comprises at least one polyester moiety which has the same structure as the polyester moiety comprised in polycaprolactone diol, even more preferably wherein said first polymeric material is BioHastalex®.

[0022] The present invention additionally relates to a drug delivery device, as defined herein, or manufactured according to the method defined herein, for use in administering a drug.

[0023] Figures

[0024] Figure 1 shows an illustration of a drug delivery device according to certain embodiments of the invention: A) exploded view of the final drug delivery device in pessary or TLD (tampon-like device) form including fibrous material (202) and string (212); B) exploded view of the final drug delivery device incorporated into the tip of a tampon (302) including fibrous material (202) and string (212); C) close-up view of the fibrous material of the drug delivery device comprising fibre (210) and drug (208).

[0025] Figure 2 shows a rendered graphic illustration (not a photograph) of a drug delivery tampon-like device according to certain embodiments of the invention featuring a porous honeycomb-structured outer tube with bundled fibres inside. The fibres range in diameter from nanometer-scale to micrometer-scale. The device measures 10 mm in diameter and 40 mm in length. The fibres are coated with drugs. Different bundles of fibres are coated with different drugs, namely painkillers, antibiotics, and saffron to relieve dysmenorrhea. In other embodiments, not shown, the centre of said device is also filled with said fibres.

[0026] Figure 3 shows photographs of typical examples of fibre manufactured using wet-spinning technology with BioHastalex® resin precursor, used in certain embodiments of the drug delivery device of the invention:. A) photograph of fibres of various diameters ranging from monofilament fibre (upper fibre) at nanometre scale to multifilament fibre (lower fibre) at micrometre scale; B) photograph of upper fibre depicted in A) on a bobbin and spool.

[0027] Figure 4 shows scanning electron microscopy (SEM) images of the surface of fibre used in certain embodiments of the drug delivery device of the invention and manufactured from BioHastalex® resin precursor and wet-spinning technology at: A) showing the porogen (NaCI) in place, B) lower magnification; C) after porogen in A) was leached from said fibre through phase separation (coagulation) with dimethylacetamide (DMAC) from polymer solution by ion exchange with deionized water (in a coagulation bath) during the manufacturing of fibres using wet-spinning technology to form the porous fibre of B) and C). Fibres have a diameter of 95 + / - 30nm.

[0028] Figure 5 shows a graph illustrating the drug-release profile from fibres used in certain embodiments of the drug delivery device of the invention and from a drug delivery tampon-like device (DDTLD) according to certain embodiments of the invention, wherein said fibres are coated with Diclofenac. Detailed description

[0029] The present invention relates to a drug delivery device ( / .e. a device suitable for delivery or elution of a drug), as well as to a method for its manufacture.

[0030] Said device is suitable for delivery or elution of a drug to a tissue of the human or animal body. Preferably, said device comprises a fibrous material (e.g. a textile, a mesh or weave) comprising a fibre which has a drug adsorbed onto its surface ( / .e. adsorbed or coated into the outer surface of the fibre or adsorbed into pores thereof) which can be released therefrom once said device is inserted into the human or animal body. Upon placement inside the body, drug release occurs due to the thermal conductivity of the polymeric material (in particular the carbon nanoparticles comprised therein) and due to pressure from the cavity in the body into which it is inserted, causing the pores in said fibre to open and release said drug. In a preferred embodiment of the present invention, said drug delivery device is a suppository ( / .e. configured for insertion inside a cavity of the human or animal body and delivery of a drug thereto, preferably for insertion inside a vaginal, anal, urethral, buccal, nasal or surgical cavity). In another preferred embodiment of the present invention, said drug delivery device is selected from the group consisting of a pessary (Figure 1A), tampon (Figure 1 B), menstrual cup and any other gynaecological device. More preferably, said device is selected from a pessary or a tampon.

[0031] Said device comprises a fibrous material. Said fibrous material comprises at least one fibre. The fibrous material comprises spaces between portions of each fibre or between separate fibres. Each fibre may comprise: a biological polymer or a population of biological polymers ( / .e. a polymeric material) that is charged / ionised or is capable of being charged / ionised (e.g. alginate, collagen, hyaluronic acid or a polymer found in seaweed such as agaropectin; or a synthetic polymer or population of synthetic polymers (i.e. a polymeric material), wherein each polymeric material comprises a carbon nanoparticle.

[0032] In an embodiment of the invention, said polymeric material comprises a carbon nanoparticle covalently bonded to a polymer. Said polymeric material is therefore a polymeric material which comprises said carbon nanoparticle (carbon nanoparticle segment) bonded to said polymer (polymeric segment) [ / .e. a carbon nanoparticle moiety (carbon nanoparticle segment) covalently bonded to a polymer moiety (polymeric segment), by e.g. reacting a functionalised carbon nanoparticle, as defined herein, with monomer(s) of said polymer]. In a preferred embodiment of the invention, the carbon nanoparticle is covalently bonded to a polyurethane [ / .e. a carbon nanoparticle moiety bonded to a polyurethane moiety, by e.g. reacting a functionalised carbon nanoparticle, as defined herein, with monomer(s) of said polyurethane]. Preferably, said polymeric material comprises a carbon nanoparticle moiety covalently bonded to a polyurethane moiety via a urea moiety (formed by e.g. reaction of an isocyanate moiety of a diisocyanate or isocyanate-terminated polyurethane prepolymer with a primary amino moiety on the surface of the carbon nanoparticle). However, said polymeric material may also comprise a carbon nanoparticle moiety which is covalently bonded to a polyurethane moiety via a urethane (carbamate) or oxazolidinone moiety (formed by e.g. respective reaction of a hydroxyl or epoxide moiety on the surface of the carbon nanoparticle with an isocyanate moiety of a diisocyanate or isocyanate-terminated polyurethane prepolymer).

[0033] The carbon nanoparticle is selected from the group consisting of graphene oxide, reduced graphene oxide, a carbon nanotube, fullerene, graphite, graphene, diamond, a carbon dot, functionalised graphene oxide, a functionalised carbon nanotube, functionalised fullerene, functionalised graphite, functionalised graphene, functionalised diamond, a functionalised carbon dot and a functionalised graphene oxide to which silica nanoparticles are attached. Preferably the carbon nanoparticle is selected from the group consisting of graphene, functionalised graphene, or functionalised graphene oxide.

[0034] The term "functionalised" means functionalised with at least one moiety independently selected from the group consisting of a carboxylic acid, tertiary alcoholic, epoxide, primary alcoholic or primary amino moiety (ignoring the functionalisation provided by the carbon nanoparticle being covalently bonded to said polyurethane moiety). Preferably "functionalised" means functionalised with at least one moiety independently selected from the group consisting of a primary alcoholic or primary amino moiety. Graphene oxide comprises carboxylic acid, tertiary alcoholic, epoxide and / or primary alcoholic groups, wherein the carboxylic acid groups can be found on the edge of the graphene sheets and in the plane of the sheets, such that graphene oxide is a functionalised graphene in the sense described herein. Thus, when the carbon nanoparticle is functionalised graphene oxide, it may be functionalised with at least one moiety, each moiety being independently selected from the group consisting of a carboxylic acid, tertiary alcoholic, epoxide, primary alcoholic or primary amino group, preferably a primary amino group, more preferably wherein the primary amino groups are in the plane and on the edge of the graphene sheets. Similarly, when the carbon nanoparticle is functionalised graphene, it may be functionalised with at least one moiety, each moiety being independently selected from the group consisting of a carboxylic acid, tertiary alcoholic, epoxide, primary alcoholic or primary amino group, preferably a primary amino group, more preferably wherein the primary amino groups are in the plane and on the edge of the graphene sheets.

[0035] The polyurethane moiety preferably comprises at least one polycarbonate moiety, at least one polyester moiety, at least one polyether moiety or at least one polyalkadiene moiety. More preferably the polyurethane moiety comprises at least one polycarbonate moiety which has the same structure as the polycarbonate moiety comprised in Eternacoll® PH-200 (UBE) or Perstorp Oxymer™ M-112 (Perstorp catalogue HS number: 390740), at least one polyester moiety which has the same structure as the polyester moiety comprised in polycaprolactone diol (polycaprolactone oxydiethylene ester, average Mn ~2,000; Sigma-Aldrich catalogue number 189421), at least one polyether moiety which has the same structure as the polyether moiety comprised in Invista Terethane® PTMEG 2000 (polytetramethylene ether glycol, average Mn ~2,000), or at least one polyalkadiene moiety which has the same structure as the polyalkadiene moiety comprised in Cray Valley Krasol® LBH 2000 (hydroxyl-terminated polybutadiene). Even more preferably, said polyurethane moiety comprises a poly(hexamethylene carbonate) or a poly(caprolactone) moiety, the latter of which is readily biodegradable. In one embodiment, said polymer ( / .e. polymeric material comprising said polymer) is made by a method comprising combining or mixing a functionalised carbon nanoparticle with a polyol and adding a diisocyanate thereto to form a pre-polymer solution. The pre-polymer solution is subjected to chain extension in the presence of a diamine to yield a polymer solution (resin precursor). The polymer solution (resin precursor) is subsequently cured to form a polymeric material comprising said polymer. The polymeric material may exhibit hydrophobicity or hydrophilicity at the surface of the fibre. In some embodiments, the polymeric material may also possess drug management capabilities, such as moisture control.

[0036] In a particularly preferred embodiment, the polymer solution (resin precursor) is made according to any of the methods disclosed in WO2019 / 008381 A1 , in particular any one of Examples 2, 16 and 17 of W02019 / 008381 A1. Said methods may be adapted to use different starting materials, including, for example, replacing the polycarbonate polyol referred to therein with a polycaprolactone diol (e.g. polycaprolactone oxydiethylene ester, average Mn ~2,000; Sigma-Aldrich catalogue number 189421). Likewise, in a particularly preferred embodiment, the porous polymeric material is made from said polymer solution according to the methods disclosed in Example 18 of WO2019 / 008381 A1 used for formation of a porous scaffold. Said methods may be adapted to use different starting materials, including, for example, replacing the porogen referred to therein with an alternative porogen such as sodium chloride.

[0037] In one embodiment, said first polymeric material is the polymeric material known as Hastalex®. The Hastalex® polymeric material is made by curing Hastalex® polymer solution (resin precursor), as described herein. Briefly, Hastalex® polymer solution is made by mixing functionalised graphene oxide nanoparticles, namely a graphene oxide functionalised with at least one primary amine group, with a poly(hexamethylene carbonate) diol [e.g. Eternacoll® PH-200 (UBE catalogue number ) or Perstorp Oxymer™ M-112 (Perstorp catalogue HS number: 390740)], and adding 4,4'-methylenebis(phenyl isocyanate) thereto to form a pre-polymer solution which is subsequently subjected to chain extension in the presence of ethylenediamine and diethylamine or dibutylamine in dimethylacetamide. Preferably, said Hastalex® polymer solution may be obtained according to Example 17 of WO2019 / 008381 A1 , while the corresponding polymeric material may be obtained according to Example 18 of WO2019 / 008381 A1.

[0038] In another embodiment, said polymeric material is the polymeric material known as BioHastalex®. The BioHastalex® polymeric material is made by curing BioHastalex® polymer solution (resin precursor), asdescribed herein. Briefly, BioHastalex® polymer solution is made by mixing functionalised graphene oxide nanoparticles, namely a graphene oxide functionalised with at least one primary amine group, with a polycaprolactone diol (e.g. polycaprolactone oxydiethylene ester, average Mn ~2,000; Sigma- Aldrich catalogue number 189421), and adding 4,4'-methylenebis(phenyl isocyanate) thereto to form a pre-polymer solution which was subsequently subjected to chain extension in the presence of ethylenediamine and diethylamine or dibutylamine in dimethylacetamide. BioHastalex® is biodegradable, recyclable and non-toxic ( / .e. biocompatible). Preferably, said BioHastalex® polymer solution may be obtained according to Example 17 of WO2019 / 008381 A1 by replacing the polycarbonate polyol referred to therein with a polycaprolactone diol (e.g. polycaprolactone oxydiethylene ester, average Mn ~2,000; Sigma-Aldrich catalogue number 189421), while the corresponding polymeric material may be obtained according to Example 18 of WO2019 / 008381 A1 using said BioHastalex® polymer solution as the composite material of Example 17 of WO2019 / 008381 A1 . The BioHastalex® polymer solution and the corresponding polymeric material produced therefrom are biodegraded when in landfilled or seawater over two years. When used as the polymeric material in the drug delivery device according to the present invention, this reduces significantly microplastic pollution in comparison to currently used pessary devices which are made of silicone or vinyl, both materials being non-biodegradable and not environmentally friendly. Conventional pessary rings are changed every 3 to 6 months and are thrown away after use.

[0039] In forming Hastalex® and BioHastalex®, said graphene oxide is functionalised by converting at least one carboxylic acid moiety present thereon into the corresponding primary amine or methyleneamine moieties. Therefore, when said polymeric material is the polymeric material known as Hastalex®, said polymeric material comprises at least one polymer comprising a carbon nanoparticle covalently bonded to a polyurethane moiety which comprises at least one polycarbonate moiety which has the same structure as the polycarbonate moiety comprised in Eternacoll® PH-200 (UBE) or Perstorp Oxymer™ M-112 (Perstorp catalogue HS number: 390740). Similarly, when said polymeric material is the polymeric material known as BioHastalex®, said polymeric material comprises at least one polymer comprising a carbon nanoparticle covalently bonded to a polyurethane moiety which comprises at least one polyester moiety which has the same structure as the polyester moiety comprised in polycaprolactone diol (e.g. polycaprolactone oxydiethylene ester, average Mn ~2,000; Sigma-Aldrich catalogue number 189421).

[0040] By virtue of polymeric materials such as Hastalex® and BioHastalex® comprising a polyurethane moiety (i.e. a polyurethane as said polymeric segment) comprising a polyol moiety (derived from the polyol found in the aforementioned polycarbonate and polyester, respectively), the carbon nanoparticle moiety (i.e. carbon nanoparticle segment) comprised therein may therefore be described as covalently bonded to said polyol moiety via a urethane linkage (formed from reaction of hydroxyl with an isocyanate). In addition, since the carbon nanoparticle used to obtain these polymeric materials is functionalised with amine moieties, the carbon nanoparticle moiety (i.e. carbon nanoparticle segment) comprised therein may also be described as covalently bonded to said polyol moiety via a urea linkage (formed from reaction of said amine with an isocyanate). Should any carboxylic acid moieties remain on the graphene oxide, the carbon nanoparticle moiety (i.e. carbon nanoparticle segment) comprised therein may also be covalently bonded to a polyol moiety via an amide linkage (formed from reaction of said carboxylic acid with an isocyanate).

[0041] Said polymeric material may also comprise polymers other than those disclosed herein, including polymers which do not comprise a carbon nanoparticle. Thus, in one embodiment, said polymeric material comprises at least one polymer, as described herein, and at least a second polymer comprising a polyurethane moiety, as described herein. In this embodiment, the polymeric material is a polymeric material which comprises a polymer and a separate carbon nanoparticle (e.g. said carbon nanoparticle may be admixed with said polymer) if no polymer comprising a carbon nanoparticle is comprised in said polymeric material.

[0042] Said polymeric material may be porous, in which case it therefore comprises pores. Preferably, the porosity of the polymeric material resulting from coagulation and / or curing ( / .e. the fibres comprising said polymeric material) is controlled by the use of porogen in the polymeric material or in the polymer solution (resin precursor) which, after coagulation and / or curing, forms said polymeric material. To achieve the desired porosity, a phase-separation (coagulation) / porogen-leaching method may be employed, in which the polymer solution (resin precursor) is mixed with porogen prior to formation of fibre(s). Additionally, porous fibres can be produced without porogen by exchanging the solvent within the CBN polymer with deionized water.

[0043] Said pores in said polymeric material are preferably filled with gas such as air and / or a liquid such as water and / or a drug or a drug dispersed in a hydrogel matrix. Said pores preferably have a size (equivalent spherical diameter) falling between 50 nm and 1000 pm, more preferably between 65 nm and 1000 pm, even more preferably between 1 and 500 pm. The pore sizes correspond linearly with the size of the porogen particles used to make said pores and are determined according to ISO 15901- 2:2022. Thus, said porogen preferably has a particle size (equivalent spherical diameter) falling in the range of between 50 nm and 1000 pm. More preferably, said porogen has a particle size of between 65 nm and 1000 pm, even more preferably between 1 and 500 pm.

[0044] Thus, the porogen used for making the pores of said polymeric material, when it is a porous polymeric material, comprise a material which is gas, liquid (e.g. a solvent, such as water) or a solid at room temperature (25 °C) and atmospheric pressure (101 ,325 Pa).

[0045] Said gaseous porogen may be removed from the polymeric material during or after coagulation and / or curing by diffusion. Diffusion involves replacing said gaseous porogen with another gas or mixture of gases, preferably with air or nitrogen. In one embodiment, said another gas or mixture of gases comprises a drug.

[0046] Said liquid porogen may be removed from the polymeric material during or after coagulation and / or curing by evaporation and or solvent exchange. Evaporation involves replacing said liquid porogen with a gas (e.g. nitrogen or carbon dioxide gas) or mixture of gases (e.g. air), when conducted in an environment comprising said gas or mixture of gases. In one embodiment, said another gas or mixture of gases comprises a drug. Preferably, evaporation involves removing a liquid porogen selected from water, methanol, ethanol, isopropanol, n-propanol, acetone, dichloromethane, chloroform, diethyl ether, ethyl acetate, formic acid or a mixture thereof. More preferably, evaporation involves replacing water as the liquid porogen, with air. Solvent exchange involves replacing / exchanging said liquid porogen with another liquid. Preferably, solvent exchange involves replacing / exchanging a liquid porogen selected from water or an aqueous solution, methanol, ethanol, isopropanol, n-propanol, acetone, dichloromethane, chloroform, diethyl ether, ethyl acetate, formic acid or a mixture thereof, with another liquid in which said liquid porogen is soluble. More preferably, solvent exchange involves replacing / exchanging a liquid porogen selected from an aqueous solution, methanol, ethanol, isopropanol, n-propanol, acetone, formic acid, or a mixture thereof with water (e.g. deionised water) or a solution of said drug, as defined herein, in water. Said aqueous solution preferably comprises an aqueous solution of the diisocyanate, polyol, water-soluble solid porogen, solvating agent or surfactant referred to herein, or a mixture thereof, and said another liquid is water, more preferably deionised water. In one embodiment, said another liquid comprises a drug.

[0047] Said solid porogen preferably comprises a material which is solid at between 2 and 90 °C. Said solid porogen has a particle size (equivalent spherical diameter) falling in the range of between 50 nm and 1000 pm. In a preferred embodiment of the present invention, the porogen used for making the pores of said porous polymeric material comprises a solid which has a particle size of between 65 nm and 1000 pm, even more preferably between 1 and 500 pm. Said solid porogen is made by grinding the solid material used for making the porogen using a mill, after which at least two sieves are used to separate the ground solid material into solid material falling in size between the above ranges by agitation according to ISO 2591-1 :1988, e.g. separation of porogen into a size falling between 50 nm and 1000 pm was achieved using a sieve of 50 nm and a sieve of 1000 pm. Preferably, said sieves are stainless steel sieves, more preferably sieves comprised in an electric sieve shaker.

[0048] The solid porogen is soluble in a solvent which the polymeric material is not soluble in, and preferably is polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), polyhydroxyalkanoates (PHA) or a water- soluble solid porogen, more preferably a water-soluble salt or sugar, even more preferably a solid porogen selected from the group consisting of sucrose, sodium chloride, sodium hydrogen carbonate, sodium carbonate, sodium sulfate, sodium phosphate, potassium chloride, potassium hydrogen carbonate, potassium carbonate, potassium sulfate, potassium phosphate, calcium chloride and magnesium chloride. Still more preferably, the porogen is a solid porogen selected from the group consisting of sucrose, sodium chloride and sodium hydrogen carbonate.

[0049] Said solid porogen may be removed from the polymeric material during or after coagulation and / or curing by dissolution. Dissolution involves replacing said solid porogen with a liquid in which said solid porogen is soluble. In one embodiment, said liquid comprises a drug. Preferably, dissolution involves replacing said solid porogen with a liquid selected from water (e.g. deionised water) or a solution of said drug in water.

[0050] In one embodiment, the porogen is a biodegradable material such as polylactic acid (PLA), poly(lactic- co-glycolic acid) (PLGA), polyhydroxyalkanoates (PHA), sodium chloride, sucrose (e.g. icing sugar), gas nano-bubbles, biodegradable chemicals, or others. These porogens biodegrade in the coagulated solution or in water, such that after the porogen is biodegraded or otherwise removed, it leaves behind a porous honeycomb structure in the coagulated polymer fibre, as shown in Figure 1.

[0051] The polymer solution (resin precursor) is so-described because it comprises at least one polymer, as described herein, dissolved in it. In addition, said polymer solution may also comprise a solvating agent such as / V, / V-dimethylacetamide (DMAC) or dimethylsulfoxide (DMSO). Said solvating agent may be that which was employed in the formation of said polymer solution. Exposure of the polymer solution or suspension comprising said polymer solution to air at between 50 and 90 °C, or to said solvent at between 2 and 90 °C may result in release of said solvating agent from said polymer solution, leaving behind nanopores ( / .e. pores with internal widths of >2 nm to 100 nm) and micropores ( / .e. pores with internal widths of 2 nm and less) (said pore sizes being determined as per ISO 15901-2:2022). Thus, the pores in the porous polymeric material may form from use of said porogen and / or said solvating agent.

[0052] The polymer solution may also comprise a surfactant e.g. when said polymeric material is a porous polymeric material, to increase wettability of the porogen and decrease aggregation of solid porogen particles in the mixture (suspension) comprising said polymer solution and said porogen (and hence increase uniformity of pore size in the porous polymeric material). Said surfactant is preferably selected from the group consisting of: Tween-20 (Polysorbate 20), Tween-40 (Polysorbate 40), Tween-60 (Polysorbate 60), Tween-80 (Polysorbate 80), Sorbitan monolaurate, Sorbitan monostearate and Sorbitan tristearate, more preferably from Tween-20 or Sorbitan monostearate.

[0053] Removal of any porogen or liquid material during and / or after curing the polymer solution results in pores in the polymeric material. Preferably any such porous polymeric material is polydisperse, having pores of different sizes.

[0054] When said polymeric material is a porous polymeric material, the porogen used for making the pores of said porous polymeric material may be present at between 0.1 and 80 wt.% in the resin precursor (polymer solution) used for making it. Preferably, the porogen used for making the pores of any such porous polymeric material may be present at between 1 and 40 wt.% in the resin precursor (polymer solution) used for making it. More preferably, the porogen used for making the pores of any such porous polymeric material may be present at between 5 and 20 wt.% or at between 21 and 38 wt.% in the resin precursor (polymer solution) used for making it. Thus, in one extreme, any such porous polymeric material is a solid with pores inside it, and in another extreme it is a sponge comprised of open cells. In practice, any such porous polymeric material lies somewhere between these extremes, with a portion of the pores being open to the outside of said polymeric material and allowing drug delivery.

[0055] When said polymeric material is a porous polymeric material, the porous polymeric material is made by a process comprising a step of mixing said polymeric material resin precursor (polymer solution) with a porogen to form a suspension. Said mixing may comprise any process to increase homogeneity of the mixture (suspension) comprising said polymer solution and said porogen as well as to decrease aggregation of solid porogen particles. Preferably said mixing involves agitation (e.g. stirring, swirling and / or shaking), heating and / or sonication. The resulting suspension is then coagulated and cured.

[0056] Coagulation and curing of the polymeric material is preferably achieved by exposing said polymeric material resin precursor (polymer solution) or said suspension to either: air or a gas at between 50 and 90 °C and optionally subsequently treated with a solvent, or said solvent at between 2 and 90 °C, wherein said solvent is a solvent which the polymeric material is not soluble in, but which any porogen, when present, is soluble in. In this manner, the exposure to air or a gas at between 50 and 90 °C or to said solvent at between 2 and 90 °C, coagulates and cures the polymer solution to form the polymeric material, and if any porogen is present, said solvent leaches the porogen from the suspension, creating pores. When said solvent is used for coagulation, coagulation takes place by phase inversion. Preferably said solvent is water, and any porogen, when present, is water-soluble.

[0057] Preferably the time of exposure to said solvent is a minimum of 10 seconds, more preferably between 30 seconds and 10 minutes, even more preferably between 1 and 3 minutes. Exposure to said solvent in this manner allows coagulating and curing, as well as dissolution and leaching of any porogen, when present, and leaching of liquid material, when present.

[0058] Each fibre may be a wet-spun fibre (obtained by wet spinning), dry-spun fibre (obtained by dry spinning), melt-spun fibre (obtained by melt spinning) or an electro-spun fibre (obtained by electro-spinning). Preferably, each fibre ( / .e. each first or second fibre) or fibrous material is formed by polymer spinning, wherein: the polymeric material or polymeric material resin precursor (polymer solution) - or the suspension of said polymeric material or polymeric material resin precursor (polymer solution) and said porogen (when said polymeric material is a porous polymeric material); or said acidic polysaccharide or a precursor thereof (e.g. acidic polysaccharide solution); or said protein or a precursor thereof (e.g. protein solution) is

[0059] (I) extruded or sprayed into air or a gas (i.e. melt-spinning or dry spinning, e.g. in an evaporation chamber, or wet spinning before being immersed into a liquid, e.g. into a coagulation bath); or

[0060] (II) extruded or sprayed or immersed into a liquid (i.e. wet spinning, e.g. in a coagulation bath); or

[0061] (III) drawn into a charged fibre (e.g. a nanofiber) using an electric force (i.e. electrospinning). In one embodiment of the drug delivery device of the present invention, each fibre is a wet-spun fibre or an electro-spun fibre. Similarly, in one embodiment of the method of manufacture of the present invention, spinning comprises wet-spinning or electro-spinning.

[0062] When melt-spun or dry-spun (i.e. extruded or sprayed into air or a gas), said polymeric material or suspension (or precursor thereof), acidic polysaccharide (or precursor thereof), or protein (or precursor thereof), may also be extruded or sprayed onto a surface of a material (e.g. a rod, preferably as defined herein, or a plate or liquid enclosed in an air or gas environment of an evaporation chamber). When wet-spun ( / .e. immersed into a liquid), said polymeric material or suspension (or precursor thereof), acidic polysaccharide (or precursor thereof), or protein (or precursor thereof), may be first extruded or sprayed onto a surface of a material (e.g. a rod, preferably as defined herein, plate or liquid before being immersed in said liquid). In some embodiments, wet spinning involves utilising spinnerets or needles of specific bore sizes, resulting in single or multifilament fibres. These fibres may then be stretched to achieve desired diameters (see below), thereby also enhancing their strength and elasticity while maintaining retention through preconditioning during drying.

[0063] When drawn into a charged fibre, said polymeric material or suspension (or precursor thereof), acidic polysaccharide (or precursor thereof), or protein (or precursor thereof), may also be drawn onto a surface of a material (e.g. a rod, preferably as defined herein, or plate of an electrospinner).

[0064] Subsequent coagulation and curing - as well as evaporation or leaching of the porogen from said extruded material, when said polymeric material is a porous polymeric material - results in a fibre or fibrous material comprising the polymeric material (or porous polymeric material), the acidic polysaccharide or the protein.

[0065] In the case of an acidic polysaccharide or a protein, coagulation or curing may involve ionisation of said acidic polysaccharide or a protein using e.g. alkaline metal or alkali earth metal or transition metal salts, or it may involve cross-linking. Ionisation or cross-linking may require treatment of the extruded fibre or treatment of the solution prior to extrusion.

[0066] Also described herein is a method of manufacture of a fibrous material, as described herein, said fibrous material comprising at least one polymer comprising a carbon nanoparticle, optionally covalently bonded to a polyurethane moiety, wherein said method comprises the following steps:

[0067] (A) optionally mixing said polymeric material resin precursor with a porogen to form a suspension; and

[0068] (B) extruding said polymeric material resin precursor or said suspension into air or a gas (i.e. dry spinning) at between 50 and 90 °C, or into water (i.e. wet spinning) at between 2 and 90 °C.

[0069] Further repeating this spinning technique n times, each time over the previously formed fibrous material, results in a laminate having n+1 layers of fibrous material, wherein n is preferably a whole number selected from the group consisting of from 1 to 20. Thus, in one embodiment of the method of manufacture of a fibrous material described above, said method comprises additional steps of:

[0070] (C) extruding said polymeric material resin precursor or said suspension into air or a gas (i.e. dry spinning) at between 50 and 90 °C, or into water (i.e. wet spinning) at between 2 and 90 °C and onto the fibrous material formed in step (B); and

[0071] (D) optionally repeating step (C). More preferably, n is a whole number from 1 to 25 ( / .e. where steps (A) and (B) are carried out once and step (C) is carried out from 1 to 25 times), even more preferably a whole number from 2 to 15, even more preferably a whole number from 5 to 11 .

[0072] The diameter of each fibre preferably is on the nanometre and / or micrometre scale ( / .e. between 1 nm and 999 pm, preferably between 2 nm and 250 pm. In some embodiments, the diameter of each fibre preferably is on the nanometre scale ( / .e. between 1 and 999 nm, preferably between 2 and 250 nm, even more preferably wherein the fibres have an average value of more preferably between 5 and 100 nm), and / or the diameter of each fibre preferably is on the micrometre scale ( / .e. between 1 and 999 pm, preferably between 2 and 250 pm, even more preferably wherein the fibres have an average value of more preferably between 1 and 100 nm).

[0073] The porogen, when used in the method of manufacture, has a particle size as defined herein. Preferably, said porogen has a particle size of between 65 nm and 1000 pm.

[0074] The porogen, when used in the method of manufacture, is present in the proportions defined herein. Preferably, said porogen is present at between 1 and 40 wt.% in the resin precursor.

[0075] The drug delivery device may comprise more than one fibre. Thus, the drug delivery device may comprise one or more first fibres and one or more second fibres. The first and second fibres may be the same or different in composition, and dimensions. Thus, in a preferred embodiment of the drug delivery device of the present invention, the drug delivery device comprises a second fibre which:

[0076] (c) comprises: a second polymeric material comprising a carbon nanoparticle; and / or a second acidic polysaccharide; and / or a second protein; and

[0077] (d) optionally has a substance adsorbed onto its surface, wherein said substance may be said drug or another drug.

[0078] Similarly, in a preferred embodiment of the method of manufacture of the present invention, said drug delivery device comprises a second fibre which:

[0079] (c) comprises: a second polymeric material comprising a carbon nanoparticle; and / or a second acidic polysaccharide; and / or a second protein; and

[0080] (d) optionally has a substance adsorbed onto its surface, wherein said substance may be said drug or another drug, wherein said method additionally comprises the following steps:

[0081] (iii) spinning: said second polymeric material; and / or said second acidic polysaccharide; and / or said second protein, respectively, to form said second fibre; and

[0082] (iv) when each second fibre has said substance adsorbed on its surface, adsorbing said substance onto the surface of the second fibre formed in step (iii).

[0083] Each of said first and second fibres may be intertwined with or around each other to form a thread or yarn, or they may be woven, knitted, felted, braided, crocheted, bundled (see Figure 2), knotted, or tatted with each other into the fibrous material. Alternatively, said second fibre(s) may be applied to the fibrous material comprising the first fibre (e.g. they may be wrapped inside the fibrous material comprising the first fibre, or the fibrous material comprising the first fibre may be wrapped inside the second fibre(s), or may be formed into an additional fibrous material which is applied to the fibrous material of the drug delivery device.

[0084] Also described herein is a laminate comprising:

[0085] (I) at least one layer of a fibrous material, said fibrous material, as defined herein, comprising a first fibre comprising a first polymeric material comprising a carbon nanoparticle, optionally covalently bonded to a polyurethane moiety; and

[0086] (II) a layer comprising an additional fibrous material comprising a second fibre, as defined herein.

[0087] Said surface, when used in any of the aforementioned spinning techniques ( / .e. wet-spinning, dryspinning, melt-spinning or electrospinning), may be a planar surface or a rounded surface. In one embodiment, said surface is a planar surface wherein said polymeric material resin precursor or said suspension is extruded ( / .e. spun) thereon, prior to coagulation and curing - as well as evaporation or leaching of the porogen from said extruded material, when said polymeric material is a porous polymeric material. In another embodiment, said surface is a rounded surface comprised on a rod, wherein said polymeric material resin precursor or said suspension is extruded ( / .e. spun) thereon, priorto coagulation and curing - as well as evaporation or leaching of the porogen from said extruded material, when said polymeric material is a porous polymeric material. The spinning technique may be repeated n times for each of these embodiments, each time over the previously formed fibrous material, results in a laminate having n layers, wherein n is as defined herein.

[0088] In some embodiments, said rod comprises one or more of an alloy, metal, ceramic, mineral, glass or polymer. Said alloy may be stainless steel, brass or bronze. Said metal may be aluminium, iron, copper, gold, silver, zinc, titanium or tin. Said ceramic may be a vitrified ceramic (e.g. porcelain), metal oxide ceramic or carbide ceramic. Said mineral may be silica or quartz, said glass may be Pyrex® or other borosilicate glass or soda glass. Said polymer may be any polymer inert to reaction with said polymeric material such as polyvinylchloride, polytetrafluoroethylene, high-density polyethylene, polypropylene, polystyrene, polyamide (e.g. Nylon 6 or Nylon 66), or a blend thereof. In some embodiments, said rod is a stainless steel rod or a stainless steel rod coated with a polymer which is inert to reaction with said polymeric material, or a polymer rod whose surface is inert to reaction with said polymeric material. Optionally, the resulting fibre, fibrous material or laminate having from one to 1 +n layers may be triturated ( / .e.. washed / extracted) to remove any remaining porogen, solvating agent starting materials and / or any by-products from the formation of said polymeric material or porous polymeric material (e.g. solvated porogen) before the drug is applied thereto. Preferably, washing is performed in water, ethanol or methanol, or a combination thereof. More preferably, washing is performed in water. Washing is preferably carried out over a period of at least 1 hour, more preferably over a period of 1 day to 1 month, even more preferably over a period of 3 days to 2 weeks, optionally using several cycles of fresh water, ethanol or methanol, or a combination thereof or by Soxhlet extraction.

[0089] The resulting fibre, fibrous material or laminate having from one to 1 +n layers may be directly used in the drug delivery device or a part thereof, or may be cut, bent or folded into a shape suitable for use therein ( / .e. a shape which has a space or reservoir in which a drug may be comprised). Preferably, said device comprises more than one layer of fibrous material ( / .e. a laminate).

[0090] In one embodiment of the drug delivery device of the present invention, said drug is adsorbed onto the surface of said first fibre (Figure 1C). Similarly, in one embodiment of the method of manufacture of the present invention, charging said first fibre formed in step (i) with said drug comprises adsorbing said drug onto the surface of said first fibre. In a preferred embodiment of the method of manufacture of the present invention, adsorbing said drug onto the surface of said first fibre formed in step (i) is performed by: spraying said drug or a solution thereof onto said first fibre; or immersing said first fibre into said drug or a solution thereof.

[0091] In one embodiment of the drug delivery device of the present invention, said drug is adsorbed onto the surface of said first fibre and said first fibre is then inserted inside a device comprising walls made of a fibrous material comprising fibre(s) comprising the same or a different polymeric material as said first fibre.

[0092] Adsorption may include any type of interaction between said drug and said surface of said first fibre, including chemisorption ( / .e. chemical reaction between the surface of said first fibre and the drug) or physisorption ( / .e. where the surface of said first fibre and said drug remain chemically unchanged and only the electronic structure of each is perturbed upon adsorption). In one approach, the drug is adsorbed onto the surface by attraction of opposite charges, such as between a negatively charged drug and a positively charged fibre or vice versa. When said drug is adsorbed onto the surface of said first fibre, said first carbon nanoparticle, first acidic polysaccharide or first protein is preferably exposed on the surface of the first fibre in which it is comprised, and said drug is adsorbed onto said exposed first carbon nanoparticle, first acidic polysaccharide or first protein, respectively. More preferably, said drug is adsorbed onto said exposed first carbon nanoparticle, first acidic polysaccharide or first protein comprised in said first fibre, by at least one of a Van der Waals force, a covalent bond and an ionic bond. In another embodiment of the drug delivery device of the present invention, said drug is encapsulated by said fibrous material. When said drug is encapsulated by said fibrous material, said device preferably comprises a wall separating an internal space of said drug delivery device from the outside of said drug delivery device, wherein said internal space is suitable for containing a drug therein and said wall comprises said fibrous material. Thus, said fibrous material, and hence said wall, is suitable for allowing said drug to be released ( / .e. delivered) from said internal space. Preferably, said wall comprises from one fibrous material to 1 +n layers of fibrous material as a laminate, wherein said layers are formed, for example, according to the aforementioned spinning techniques. Spaces formed between portions of the same fibre or between separate fibres of said fibrous material allow the passage of drugs from the internal space to the exterior of the device for delivery.

[0093] In one embodiment, the polymeric material changes the dimensions of any pores (e.g. pores in the fibre in which a drug is adsorbed) therein upon exposure to temperatures above ambient (25 °C) temperature due to thermal conductivity of said material. Thus, after placing the drug delivery device into a body cavity, the size of any pores may change from that which does not allow drug release to that which does allow drug release.

[0094] Said device may additionally comprise further materials such as a shape-memory material or superelastic material. A shape-memory material is a material that responds to a change in its environment (e.g. a temperature change) by undergoing a material property change. A superelastic material is a material that exhibits elasticity in response to an applied stress (i.e. it is pseudoelastic). Said shape-memory material may also be a superelastic material and vice versa. Said shape-memory material is preferably a shape-memory polymer or a shape-memory alloy while said superelastic material is preferably a superelastic polymer or a superelastic alloy. A polymer having shape-memory and / or superelastic properties is preferably selected from the group consisting of a polyurethane, a polyurethane comprising ionic or mesogenic components made from a prepolymer, a block copolymer of polyethylene terephthalate (PET) and polyethyleneoxide (PEO), a block copolymer containing polystyrene and poly(1 ,4-butadiene), and an ABA triblock copolymer made from poly(2-methyl-2- oxazoline) and polytetrahydrofuran. An alloy having shape-memory and / or superelastic properties is preferably selected from the group consisting of a copper-aluminium-nickel and a nickel-titanium (nitinol) alloy. More preferably, said shape-memory material is also a superelastic materal which is a nickeltitanium alloy. Said material having shape-memory and / or superelastic properties may be embedded within the fibrous material of said device, or encapsulated within an internal space of said device.

[0095] Said drug is preferably selected from the group consisting of: a cannabis-based product for medicinal use (CBPM), a saffron-based product for medicinal use (e.g. aqueous saffron extract to relieve dysmenorrhea), Indometacin, Ketoprofen, Meloxicam, Naproxen, Ibuprofen, Diclofenac (e.g. diclofenac sodium, diclofenac potassium), Mefenamic acid, Aspirin, Codeine phosphate, Tramadol, Dihydrocodeine, Buprenorphine, Co-codamol, Fentanyl, Capsaicin, Gabapentin, Pregabalin, Clonidine, melatonin, Oxytocinon, Estrone, Estriol, Estradiol, Estetrol, Progesterone (including norethisterone, medroxyprogesterone, utrogestan (micronized progesterone), gemstone crinone, dydrogesterone, levnorgestrel, drospirenone, norgestrel), Cycloprogynova (estrodiol with norgestrel), Cyproterone acetate, Tranexamic acid, Letrozole, Tamoxifen, Clomifene citrate, Raloxifene, Misoprostol, Prostaglandin E2, Hydrocortisone, Dexamethasone, Prednisolone, Methylprednisolone, Ondansetron, Clonidine, Gonadorelin, Choriogonadotropin alfa, Chorionic gonadotrophin, Corifollitrophin alfa, Danazol, Triptroelin, Nafarelin, Promethazine, Acyclovir, Famciclovir, Valaciclovir, Clotrimazole, Fluconazole, Isavuconazole, Itraconazole, Ketoconazole, Fenticonazole, Etoconazole, Lactic acid, Miconazole, Dequalinium, Metronidazole, Nitrofurantoin, Co-amoxiclav, Cefalexin, Ceftriaxone, Clindamycin, Ciprofloxacin, Trimethoprim, Gentamicin, Oxybutynin, Darifenacin, Fesoterodine fumarate, Solifenacin, Trospium, Mirabegron, Tolterodine, Propiverine, Lidocaine, Sodium citrate, Cisplatin, Carboplatin, Paclitaxel, Topotecan, Doxorubicin, Gemcitabine, 5-fluorouracil, Azathioprine, Mercaptopurine, 6-thioguanine, Methotraxate, Probiotics, (including e.g. bacterial cultures comprising Lactobacillus acidophilus, Lactobacillus bifidobacterium and / or Lactobacillus rhamnosus), Enfurvitide, Dolutegravir, Elvitegravir, Raltegravir, Etravirine, Nevirapine, Efavirenz, Rilpivirine, Abacavir, Lamivudine, Dolutegravir, Didanosine, Emtricitabine, Mifepristone, Dinoprostone, Carbetocin, Carbeprost, Misoprostol, Gemeprost, Bupivicaine, Levobupivicaine, Mepivacaine, Oxybuprocaine, Prilocaine, Proxymetacaine, and Topivicaine, or a salt of any of said drugs.

[0096] More preferably said drug is a CBPM comprising an anti-inflammatory cannabinoid, even more preferably a CBPM comprising a cannabinoid selected from the group consisting of cannabidiol (CBD), cannabigerol (CBG), A9-tetrahydrocannabinol (THC), 1 ',1 '-dimethylheptyl-delta-8-tetrahydrocannabinol- 11-oic acid (ajulemic acid), 1 , 1 -dimethylheptyl-11 -hydroxy-tetrahydrocannabinol (HU-210), [(1 S,2S,5S)- 2-[2,6-dimethoxy-4-(2-methyloctan-2-yl)phenyl]-7,7-dimethyl-4-bicyclo[3.1 ,1]hept-3-enyl]methanol (HU- 308), (11 R)-2-methyl-11 -[(morpholin-4-yl)methyl]-3-(naphthalene-1-carbonyl)-9-oxa-1- azatricyclo[6.3.1 ,04,12]dodeca-2,4(12),5,7-tetraene (WIN55.212-2), dimethylbutyl-deoxy-A8-THC

[0097] (JWH-133), and a combination thereof. Yet more preferably, said drug is a CBPM comprising an antiinflammatory cannabinoid selected from the group consisting of cannabidiol (CBD), cannabigerol (CBG), tetrahydrocannabinol (THC), and a combination thereof.

[0098] Alternatively, said drug is more preferably a non-steroidal anti-inflammatory drug (NSAID), even more preferably a NSAID selected from the group consisting of diclofenac, ibuprofen, aspirin, naproxen, flurbiprofen, mefanamic acid, meclofenamic acid, flufenamic acid, and combinations thereof.

[0099] Alternatively, said drug is more preferably an antibiotic, even more preferably an antibiotic selected from the group consisting of dequalinium, metronidazole, nitrofurantoin, co-amoxiclav, cefalexin, ceftriaxone, clindamycin, ciprofloxacin, trimethoprim, gentamicin, and combinations thereof.

[0100] Said drug delivery device may comprise one or more drugs, wherein each drug is independently selected from the aforementioned lists. More preferably, said charged drug delivery device comprises one or more drugs, wherein each drug is independently selected from the group consisting of a CBPM or a NSAID, even more preferably wherein said CBMP is CBD, CBG or THC and said NSAID is diclofenac, ibuprofen, aspirin, naproxen, flurbiprofen, mefanamic acid, meclofenamic acid or flufenamic acid.

[0101] In certain embodiments, said drug is not doxorubicin when said carbon nanoparticle is a multi-walled carbon nanotube, preferably when said carbon nanoparticle is a carbon nanotube.

[0102] It will be appreciated that substances ( / .e. additives), which are suitable for formulating or delivering a drug may be included in the drug delivery device as defined herein, particularly additives which modulate rate of delivery ( / .e. release) of said drug from said drug delivery device. For example, the drug may be comprised in a formulation which is a composition (e.g. a hydrogel formulation of said drug), or said drug may be comprised in nanocapsules, micelles or liposomes, or said drug may be bonded to nanoparticles. Said substances may be either co-adsorbed to the first fibre, adsorbed to the second fibre or encapsulated by the fibrous material.

[0103] In one embodiment of the drug delivery device of the present invention, wherein said drug is encapsulated by said fibrous material, said drug is dispersed in a hydrogel matrix encapsulated by said drug delivery device. Similarly, in one embodiment of the method of manufacture of the present invention, wherein charging said fibrous material formed in step (H)(2) with said drug comprises encapsulating said drug in said fibrous material, said drug is dispersed in a hydrogel matrix prior to encapsulating it in said fibrous material. Hydrogels can be selected to respond to stimuli: pH, temperature, ultrasound, electric field, enzymes, and light. Various systems use intelligent hydrogel, supramolecular hydrogel or polymer hydrogel scaffolds and targeted drug delivery. They provide spatial and temporal control over the release of various therapeutic agents, including small molecule drugs, macromolecular drugs and cells, minimising the inconvenience of conventional drug delivery. Compared to nanocapsules, micelles and liposomes, hydrogels exhibit higher drug loading capacity (up to 50% loading efficiency). The hydrogel can exhibit biodegradability, biocompatibility, response to stimuli and high mucoadhesion. The hydrogel may be selected for its specific mucoadhesive properties that allow the absorption and retention time of the drug to be modified according to the type of treatment. In this way, the availability of the drug at the target mucosa can be, for example, increased by selecting a hydrogel having mucoadhesive properties which improve and facilitate the absorption of drugs. For example, when the drug delivery device is a tampon inserted into the vagina, the hydrogel diffuses through the fibrous material comprised therein and changes the structure of vaginal fluid, such that the viscosity of the vaginal mucus will change, and the hydrogel will gradually adhere to the vaginal mucosa, increasing drug delivery.

[0104] Said hydrogel is a water-insoluble 3D crosslinked hydrophilic polymer. Said hydrogel can be either hydrophilic ( / .e. charged), hydrophobic or a hybrid thereof. The cross-linking density of the network of interpenetrating macromolecular chains of the hydrogel offers adjustable swelling capacity, particle size and porosity, allowing controlled drug loading and diffusion. Preferably said hydrogel is charged and retains the drug by charge-charge interaction, so as to delay release of the drug, and / or swells and generates movement or deformation of its network matrix upon contact with physiological fluids or solvents. More preferably said hydrogel is selected from either the group consisting of natural polymers including: gelatin, chitosan, dextran, hyaluronic acid, alginate, collagen, fibrin, pectin, carrageenan, carboxymethyl chitin, xanthan gum, guar gum and cellulose, or from the group of synthetic polymers including: polyglycolic acid, polylactic acid, hydroxyethyl methacrylate, polyiminocarbonates, polyethylene glycol diacrylate / methacrylate, polywinyl alcohol (PVA), polyvinyl pyrrolidone, polyethylene glycol, polyethene imine, polymethacrylate, polyvinyl acetate, polyacrylic acid or polyacrylate, polymethyl methacrylate and carboxymethyl cellulose, or from a charged form of the aforementioned hydrogels.

[0105] More preferably, said hydrogel is a cross-linked PVA ora cross-linked polyacrylate such as a Carbopol® (e.g. Carbopol® 674, 676, 690, 691 , 940 Aqua 25, Aqua30, Aqua CC, EDT2623, EDT2691 , EZ-2, EZ- 3, EZ-4, EZ-5 or EC-1 polymer). In the embodiment of Example 7, said hydrogel is a Carbopol® 940.

[0106] Preferably, the hydrogel matrix is delivered, optionally together with said drug, from an internal space of said drug delivery device ( / .e. said hydrogel is encapsulated by said fibrous material and said drug may be either dispersed in the hydrogel network or said drug may be adsorbed into the surface of the first fibre comprised in the fibrous material) to the outside of said drug delivery device, via the spaces between the fibres or parts of each fibre comprised in the fibrous material comprised in the device of the present invention. Thus, said hydrogel is more preferably poroelastic with respect to the spaces in the fibrous material comprised in the device of the present invention, as defined herein.

[0107] The hydrogel can be synthesised chemically, physically, ionically or radically. This is a simple one-pot, sol-gel gelation process but may comprise several reaction steps depending on the chemical composition of the hydrogel. Hydrogels are easy to synthesise and facilitate the incorporation of active substances.

[0108] In order for the drug to be dispersed through the hydrogel matrix it may be dissolved in an aqueous or organic solution under controlled physical parameters (e.g. temperature, pH), wherein the physicochemical parameters used depend on the drug and the desired release rate. Once the drug solution is homogeneous, the hydrogel reagents are gradually added and mixed into the solution at a fixed pH and temperature. The hydrogel network will form with the drug dispersed therethrough, by absorption of the drug solution in the matrix thus formed and / or encapsulation of the drug in the matrix as it forms. The final product of drug dispersed in hydrogel can be used with the drug delivery device of the present invention in wet form ( / .e. drug encapsulated in wet hydrogel) or in dried form ( / .e. drug encapsulated in a dry macromolecular matrix) by encapsulation therein.

[0109] The present invention also relates to a kit-of-parts comprising:

[0110] (a) a drug delivery device as defined herein or manufactured according to the method as defined herein; and

[0111] (b) a drug and / or substance (e.g. hydrogel) for encapsulation in the fibrous material comprised in said drug delivery device. Preferably, said drug or substance is as defined herein. Thus, the kit-of-parts provides the necessary parts for the drug delivery device to be charged by the user with said drug or substance, prior to administration of the resulting charged drug delivery device to a human or animal subject.

[0112] In one embodiment, the drug included in said kit-of-parts may be dispersed in a hydrogel matrix, wherein said hydrogel matrix is as defined herein. Alternatively, the kit-of-parts may comprise:

[0113] (a) a drug delivery device as defined herein or manufactured according to the method as defined herein;

[0114] (b) a drug for encapsulation in the porous polymeric material comprised in said drug delivery device; and

[0115] (c) a hydrogel, as defined herein.

[0116] In such an embodiment, the kit-of-parts provides the necessary parts for the drug to be dispersed in the hydrogel by the user, and the delivery device to be charged with said dispersion, prior to administration of the resulting charged drug delivery device to a human or other animal.

[0117] The present invention also relates to a drug delivery device for use in administering a drug, wherein said drug delivery device is as defined herein or manufactured according to the method as defined herein.

[0118] Administering a drug means administering a drug to a human or other animal, more preferably a human or other mammal, even more preferably a human female of reproductive age. Similarly, the present invention also relates to use of said drug delivery device or said kit-of-parts for the manufacture of a medicament for administration to a human or other animal. Analogously, the present invention also relates to a method of administering said drug delivery device to a human or other animal, as well as to said drug delivery device for the treatment of disease in a human or other animal.

[0119] Examples

[0120] All materials, methods and examples described herein detail specific examples that fall within the scope of the present invention and support the understanding thereof. In addition, this disclosure is illustrative only, so is not limited to any particular methods and experimental conditions described. As such methods and conditions may vary and it is not intended to be limiting in any way. Although alternative methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below.

[0121] Example 1 Synthesis of polymeric material resin precursor (polymer solution) for use in the manufacture of a drug delivery device

[0122] A. _ Synthesis of graphene oxide functionalised with amine groups

[0123] 3 g of graphene oxide (Sigma) (graphene oxide comprises epoxide, hydroxyl and carboxylic acid groups and it was the carboxylic acid groups which are most relevant in this example) was dispersed in toluene using ultrasonication for 30 minutes, cooled to 4 °C, and 3 mL concentrated sulfuric acid added dropwise and the mixture continuously stirred for 40 minutes. Then 3 g of sodium azide was added to the mixture gradually for 30 minutes while continuously stirring. The mixture was then stirred for a period of 12 hours at 60 °C, cooled down, diluted with distilled water, filtered and dried under vacuum at 65 °C for 12 hours thereby to produce an intermediate product. 2 g amine of the intermediate product was then dispersed in / V, / V’-dimethylformamide (DMF) and reduced with 50 mL hydrazine at 70 °C for 12 hours, filtered, washed with deionized water, and dried under vacuum at 65 °C for 10 hours thereby to produce amine functionalised graphene oxide.

[0124] B. Synthesis of a functionalised graphene oxide - polycarbonate copolymer (polymeric material resin precursor)

[0125] 5 g amine functionalised graphene oxide of Example 1A and 55 g 2000 MW polycarbonate polyol (Sigma) were added to a 500 ml flask containing a mechanical stirrer and nitrogen inlet. The mixture was heated to 80 °C at which point the functionalised graphene oxide dissolved in the polycarbonate polyol. The mixture was then cooled to 40 °C, at which point 16 g 4,4'-methylenebisphenyl isocyanate (MDI) was added to the mixture and the temperature maintained at 75 to 85 °C for 90 minutes thereby to form a pre-polymer. 300 g of dimethylacetamide (DMAC) was then added to the pre-polymer over one hour allowing the temperature to cool to 40 °C thereby to form a pre-polymer solution. A mixture of ethylenediamine and diethylamine in the weight ratio of 7.6 : 1 as a 3.3 % w / v DMAC solution was then added dropwise to the pre-polymer solution at 40 °C over one hour thereby to create a solution of functionalised graphene oxide - polycarbonate copolymer comprising urea and urethane linkages in dimethylacetamide. 3 g of 10 % w / v butanol in DMAC was then added to the solution of functionalised graphene oxide - polycarbonate copolymer to neutralise any excess isocyanate thereby to produce a neutralised functionalised graphene oxide - polycarbonate copolymer solution.

[0126] The final solids content was 23 % w / w. The viscosity of the neutralised functionalised graphene oxide - polycarbonate copolymer solution was 3850 + / - 96 mPas. The density of the neutralised functionalised graphene oxide - polycarbonate copolymer solution was 1.186 + / - 0.010 g / mL.

[0127] C. Formation of a suspension of functionalised graphene oxide - polycaprolactone copolymer (polymeric material resin precursor)

[0128] A functionalised graphene oxide - polycaprolactone copolymer (BioHastalex® resin precursor was made according to Example 1A and 1 B, by replacing 2000 MW polycarbonate polyol (Sigma) with polycaprolactone oxydiethylene ester, average Mn ~2,000; Sigma-Aldrich catalogue number 189421). This functionalised graphene oxide - polycaprolactone copolymer was centrifuged and degassed at 209.4395 rad / s (2000 rpm) for 3 minutes and 146.6077 rad / s (1400 rpm) for 2 minutes respectively, to remove any bubbles and ensure the solution was homogenous in consistency. The resulting a polymeric material resin precursor was then used in the following Examples. Example 2 Method of manufacture of a drug delivery device from a polymeric material resin precursor or from alginate

[0129] A. _ Spinning step

[0130] The polymeric material resin precursor suspension of Example 1 C was mixed with sodium chloride as a porogen in a ratio of 1 :4. The resulting composition was subjected to wet-spinning to form either mono-filaments or multi-filaments ( / .e. fibres or threads, respectively) or a fibrous material, or to electrospinning to form a fibrous material. The fibrous materials formed by wet-spinning and electrospinning comprise carrying out spinning onto a stainless steel rod. Likewise, alginate (as the sodium salt, Sigma Aldrich) was subjected to wet-spinning to form a fibre. Prior to subjecting to subsequent coagulation and curing, the fibres of the wet-spun and electro-spun materials comprised NaCI, as shown in Figure 4A.

[0131] B. _ Coagulation and curing step

[0132] The wet-spun fibres coagulated and cured on contact with water. The wet-spun and electrospun fibrous material was triturated with water while on the tip of the rod. Subsequently, said fibres and fibrous material were cured by subjecting to a heat curing source at about 60 °C for 1-6 hours. As a result, the wet-spun and the electro-spun fibrous material formed on the tip of the rod as a hollow tubular shell approximating a tampon shape, while the wet-spun, coagulated and cured fibres formed individual fibres. Once the fibrous material has been cured and coagulated on the rod, the template is removed from inside the cured resin product (e.g. cured polymeric material) leaving a hollow tubular shell.

[0133] The end(s) of the tube were later sealed or otherwise capped using resin material, which may be the same or different to the fibrous material used for the body of the device. Either the ends of the tube or the caps are secured in place by e.g. stitching them closed using the individual fibres formed above.

[0134] Alternatively, the tube may be curled upon itself so that each of the open ends of the tube meet ( / .e. to form a ring shape). Each of these open ends are sealed to one another by e.g. stitching them together using the individual fibres formed above.

[0135] After fabrication, the tubes of fibrous material, and the individual fibres, are washed in water until organic solvents and by-products are no longer detectable and dried at room temperature (25 °C).

[0136] Thus, both spinning techniques, and the subsequent coagulation, curing and washing steps, yielded porous tubes described herein as tampon-like devices (TLDs), as well as individual fibres. The porosity of said fibres (and hence said devices) is controlled through, amongst other parameters, the nature of the porogen, the fibre diameter and the proximity of fibres to one another in the fibrous material. The diameter of the fibres present in the resulting monofilaments, multi-filaments and fibrous materials range from nanometres e.g. approximately of the nanometre scale ( / .e. between 1 and 999 nm, preferably between 2 and 100 nm - typical or average value 55 nm) to micrometres ( / .e. between 1 and 999 pm, preferably between 2 and 100 pm - typical or average value of 10 pm), as shown in Figures 4B and 4C. The cured and coagulated material did not result in body weight or organ weight gain or loss after subcutaneous insertion into female Sprague Dawley rats for 14 days.

[0137] C. Forming the drug delivery device

[0138] Diclofenac (10 mg) was dissolved in 200 pL of a 1 wt.% aqueous solution of carbopol at 25 °C with stirring. A neutralizing agent was added to activate hydrogel formation, resulting in a carbopol hydrogel matrix comprising diclofenac dispersed within (diclofenac-hydrogel composition).

[0139] The individual fibres formed in step B. were coated with said diclofenac-hydrogel composition. Coating was achieved by immersing said fibres into said diclofenac-hydrogel composition and rotating them to facilitate drug absorption onto the fibre surface, including into the fibre pores, due to said drug and fibres exhibiting hydrophobicity. Subsequently, the coated fibres were removed from said composition and divided into two groups of fibres. One group of coated fibres was retained (Fibres) and another group was inserted inside the TLD formed using wet-spinning technology in step B, thereby resulting in a drug delivery tampon-like device (DDTLD). DDD and DDTLD each represent different embodiments of the drug delivery device of the invention.

[0140] Example 3 Drug delivery devices in use

[0141] The rate of drug release from the drug delivery devices (Fibres and DDTLD) formed in Example 2C was assessed by placing each in distilled water (200 mL) at room temperature and subjecting them to intensive stirring for 6 h. Aliquots (5 mL) of the resulting solution were taken every 30 minutes over the duration of stirring and replaced with an equal volume of distilled water. Each aliquot was analyzed by UV-vis spectroscopy at a wavelength of 282 nm, and the diclofenac concentration was measured according to a calibration curve built within the concentration range of 0.001 to 0.01 mg / mL (R2=0.9971). The rate of diclofenac release, as measured under the described conditions, is presented in Figure 5.

[0142] This data indicates that 94% of loaded diclofenac was released from the Fibres device after four hours, while the release from coated fibres within the cylindrical DDTLD device was slower, with 68% released over four hours. Complete release from the Fibres device occurred within five hours (97%), whereas after six hours, 79% was released with the DDTLD device.

Claims

Claims1 . A drug delivery device comprising a fibrous material, said fibrous material comprising:(a) a first fibre which comprises: a first polymeric material comprising a carbon nanoparticle covalently bonded to a polymer; and / or a first acidic polysaccharide; and / or a first protein; and(b) a drug.

2. The drug delivery device according to claim 1 , wherein said drug is adsorbed onto the surface of said first fibre.

3. The drug delivery device according to claim 1 , wherein said drug is encapsulated by said fibrous material.

4. The drug delivery device according to claim 3, wherein said drug is dispersed in a hydrogel matrix encapsulated by said drug delivery device.

5. The drug delivery device according to any one of claims 1 to 4, comprising a second fibre which:(c) comprises: a second polymeric material comprising a carbon nanoparticle; and / or a second acidic polysaccharide; and / or a second protein; and(d) optionally has a substance adsorbed onto its surface, wherein said substance may be said drug or another drug.

6. The drug delivery device according to claim 5, wherein said second fibre is comprised in the same fibrous material as the first fibre or in a different fibrous material of said drug delivery device.

7. The drug delivery device according to any one of claims 1 to 6, wherein each fibre is a wet-spun fibre or an electro-spun fibre.

8. The drug delivery device according to any one of claims 1 to 7, wherein said polymer to which said carbon nanoparticle is covalently bonded is a polyurethane.

9. The drug delivery device according to any one of claims 1 to 8, wherein said drug delivery device is a suppository.

10. The drug delivery device according to any one of claims 1 to 9, wherein said drug delivery device is selected from the group consisting of a pessary, tampon, menstrual cup and any other gynaecological device.

11. A method of manufacture of a drug delivery device comprising a fibrous material, said fibrous material comprising:(a) a first fibre which comprises: a first polymeric material comprising a carbon nanoparticle covalently bonded to a polymer; and / or a first acidic polysaccharide; and / or a first protein; and(b) a drug, wherein said method comprises the following steps:(i) spinning: said first polymeric material; and / or said first acidic polysaccharide; and / or said first protein, respectively, to form said first fibre; and(ii) either:(1) charging said first fibre formed in step (i) with said drug; or(2) forming said fibrous material using said first fibre formed in step (i); and(3) charging said fibrous material formed in step (H)(2) with said drug.

12. The method of manufacture according to claim 11 , wherein charging said first fibre formed in step (i) with said drug comprises adsorbing said drug onto the surface of said first fibre.

13. The method of manufacture according to claim 12, wherein adsorbing said drug onto the surface of said first fibre formed in step (i) is performed by: spraying said drug or a solution thereof onto said first fibre; or immersing said first fibre into said drug or a solution thereof.

14. The method of manufacture according to claim 10, wherein charging said fibrous material formed in step (H)(2) with said drug comprises encapsulating said drug in said fibrous material.

15. The method of manufacture according to claim 14, wherein said drug is dispersed in a hydrogel matrix prior to encapsulating it in said fibrous material.

16. The method of manufacture according to any one of claims 11 to 15, wherein said drug delivery device comprises a second fibre which:(c) comprises: a second polymeric material comprising a carbon nanoparticle; and / or a second acidic polysaccharide; and / or a second protein; and(d) optionally has a substance adsorbed onto its surface, wherein said substance may be said drug or another drug, wherein said method additionally comprises the following steps:(iii) spinning: said second polymeric material; and / or said second acidic polysaccharide; and / or said second protein, respectively, to form said second fibre; and(iv) when each second fibre has said substance adsorbed on its surface, adsorbing said substance onto the surface of the second fibre formed in step (iii).

17. The method of manufacture according to any one of claims 11 to 16, wherein said spinning comprises wet-spinning or electro-spinning.

18. The method of manufacture according to any one of claims 16 and 17, which additionally comprises a step of combining said second fibre with said first fibre in the same fibrous material or forming a different fibrous material using said second fibre.

19. The method of manufacture according to any one of claims 11 to 18, wherein said polymer to which said carbon nanoparticle is covalently bonded is a polyurethane.

20. The method of manufacture according to any one of claims 11 to 19, wherein said drug delivery device is a suppository.21 . The method of manufacture according to any one of claims 11 to 20, wherein said drug delivery device is selected from the group consisting of a pessary, tampon, menstrual cup and any other gynaecological device.

22. A drug delivery device according to any one of claims 1 to 9 or manufactured according to the method of any one of claims 11 to 21 for use in administering said drug.

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