Bioadhesive microparticle formulations

Abstract

Bioadhesive microparticle formulations and methods for preparation thereof are described. The microparticle formulation comprises cross linked poly-amino acid microparticles and may be delivered alone or may be used for delivery of an agent to a biological surface.

Description

[0001]BIOADHESIVE MICROPARTICLE FORMULATIONS FIELD OF THE INVENTION The present invention relates to bioadhesive microparticle formulations and methods for preparation thereof. Ideally, the microparticle formulation may be delivered alone or may be used for delivery of an agent to a biological surface such as epithelial tissue or the mucosa. The present invention also relates to mucoadhesive microparticle formulations and methods for preparation thereof. Ideally, the mucoadhesive microparticle formulation may be delivered alone or may be used for delivery of an agent to a target tissue via mucosal membranes. BACKGROUND OF THE INVENTION Bioadhesion describes the interaction of a biological surface and that of another surface for an extended period of time, held together by surface and interfacial forces. Examples of bioadhesion include a biological material adhered to a biological surface for use in wound healing, a biological material on a synthetic substrate such as mammalian cells on a plastic tissue culture plate or a synthetic material adhered to a biological surface such as a hydrogel on soft tissue. For drug delivery purposes, a bioadhesive system would imply a drug carrier attached to a specific region of the body such as epithelial tissue or the mucosa. In terms of attachment to the mucosal tissue, the drug carrier would be termed a mucoadhesive drug delivery system. Drug delivery takes a variety of forms, depending on the agent to be delivered and the administration route. Controlled or sustained release systems for drug delivery are typically designed to administer drugs in specific areas of the body. Furthermore, it is also desirable that drug delivery system can be made to target specific sites in the body, such as mucosal surfaces. This invention ideally relates to delivery systems for mucosal tissue, including ocular, gastrointestinal, nasal, buccal, vaginal and respiratory drug delivery. For example, microparticle formulations are known as a means for drug delivery. These formulations generally serve to protect an encapsulated drug and to deliver the drug locally or systemically. Enteric coated formulations have been widely used for many years to protect drugs administered, as well as to delay release. Drug delivery to target a particular tissue of the eye is a significant challenge for scientists. The eye can be broadly classified into two segments: anterior and posterior. Structural variations of each layer of ocular tissue can pose a significant barrier following drug administration via any route, including topical, systemic and periocular. In terms of topical drug administration, drug delivery is highly inefficient. This inefficiency can result in < 7% of the delivered drug being absorbed at the site of action when delivered topically via the eye. A prominent reason for reduced bioavailability is short drug residence time mostly due to natural clearance mechanisms such as non-specific absorption, clearance via the nasolacrimal gland and clearance via the cheek. In most cases, to overcome these limitations and achieve therapeutic drug concentrations, regular drug administration is required. Unsurprisingly, patient compliance is problematic. This inefficiency allows much scope to improve drug delivery with single dose systems that reduce the frequency of administration, lowers costs, improves patient compliance and reduces the risk of resistance to antimicrobials. An example of topical drug therapy to the ocular surface is in the treatment of microbial keratitis, an ocular surface disease. Microbial keratitis (MK) is a leading cause of unilateral blindness across all age ranges worldwide. Incidence rates vary based on geographical location ranging from 11 cases per 100,000 people in the US and 799 cases per 100,000 people in Nepal. In the US alone it is estimated that MK costs approx. $175 M in direct healthcare expenses and a further $75 M in Medicare and Medicaid per annum. The true cost of MK is hard to decipher due to a combination of the unilateral visual impairment and the lack of sufficient reporting systems making it harder to decipher. Topical drug delivery is a convenient route of administration to treat various eye diseases. However, it has serious limitations due to rapid clearance of the formulation from the surface of the eye. This limitation could be addressed by a drug delivery system that can provide sustained drug release as well as reside on the surface of the eye for a prolonged period. In ocular drug delivery bandage contact lenses provide prolonged drug delivery and provide a postoperative protective barrier. For example, Gallagher AG et al. ‘A Novel Peptide Hydrogel for an Antimicrobial Bandage Contact Lens’ Adv Healthc Mater 2016 Aug;5(16):2013-8 discloses a peptide hydrogel with an antimicrobial activity is developed as a bandage contact lens. The antimicrobial activity is enhanced with the addition of the biomolecules penicillin G or ε-polylysine and is positive against Staphylococcus aureus and Escherichia coli. The lens is also non-cytotoxic toward a human corneal epithelial cell line and as a consequence is of great potential as a drug-eluting bandage lens replacing conventional corneal ulcer treatment. However, there are drawbacks to their use including reduced oxygen permeability, foreign object sensation, disruption of the tear film, protein fouling and infection due to improper use. This could be accomplished using well-known technology by encapsulating drugs for slow release with biocompatible microparticles, which provides an attractive form of drug delivery system due to their ease of fabrication, simplicity of administration, and possible use in localized and targeted delivery. However, the short residence time of conventional microparticles on the ocular surface caused by tear drainage could limit the utility of slow release microparticles for therapy of ocular disease. Mucoadhesive microparticles may offer a means for slow drug release from microparticles that remain adherent to the ocular surface for an extended time. Microparticle systems have been developed previously such as poly(lactic-co-glycolic acid) (PLGA) microparticles but these can provide localised toxicity caused by acidic pockets following degradation of the polymer. Chitosan microparticles have also been developed but are usually degraded too quickly due to the abundance of lysozyme in the tear film resulting in a short drug release profile and any antimicrobial activity. Other hydrogel formulations have been generated, such as, Hua et al. ‘Preparation and properties of EDC / NHS mediated cross-linking poly (gamma-glutamic acid) / epsilon- polylysine hydrogels’ Mater Sci Eng C Mater Biol Appl. 2016 Apr 1;61:879-92 discloses a pH-sensitive poly (amino acid) a hydrogel formulation based on poly γ-glutamic acid (γ-PGA) and ε-polylysine (ε-PL) which was prepared by carbodiimide (EDC) and N- hydroxysuccinimide (NHS) mediated polymerization and has a regularly porous structure with 20 μm pore size in average. WO 2015 / 5085633 is also directed to a hydrogel formulation based on a cross-linked polymer of γ-polyglutamic acid and ε-polylysine, characterized in that the hydrogel is prepared by cross-linking γ-polyglutamic acid with ε -polylysine. A general objective of the present invention, is to achieve sustained delivery of a bioadhesive or mucoadhesive microparticle system to to a biological surface or target tissue such as epithelial tissue or the mucosa to treat various disorders. A further general objective of the present invention, is to achieve sustained drug / active agent delivery via a bioadhesive or mucoadhesive microparticle system to treat various disorders with improved drug bioavailability. A still further general objective of the present invention, is to achieve targeted sustained delivery of a bioadhesive or mucoadhesive microparticle system on the surface of the eye to treat ocular disorders. A yet further general objective of the present invention, is to achieve targeted sustained drug / active delivery on the surface of the eye to treat ocular disorders with improved drug bioavailability. SUMMARY OF THE INVENTION In a general context, the present invention is a peptide (poly-amino acid) based microparticle formulation or system, which may advantageously have therapeutic activity on it’s own. Alternatively, or additionally, the peptide (poly-amino acid) based microparticle formulation may be optionally loaded with an active agent, such as an agent with drug delivery capacity, e.g. a pharmaceutical drug such as an antimicrobial / antifungal agent, anti-inflammatory agent, or antibiotic, which may also have bioadhesive or mucoadhesive properties. When the microparticle system is loaded with an active agent drug delivery capacity, it provides for an increased bioavailability of the drug whilst minimising the amount required. This will reduce instances of toxicity and in the case of drugs such as antibiotics, minimises potential for multidrug resistance developing in microorganisms. In a general context, this formulation / system is designed to remain minimally invasive, achieve sustained release, and can be delivered to a specific biological surface. Accordingly, a first general embodiment of the application provides a bioadhesive microparticle formulation comprising discrete microparticles, wherein the microparticle formulation comprises cross-linked poly-amino acid microparticles wherein the poly-amino acids are selected from one or more of poly-lysine including poly-epsilon-lysine (ε-PL) or poly alpha- lysine (α-PL), poly-glutamic acid including poly-gamma-glutamic acid, poly-arginine, poly- aspartic acid, poly-histidine, poly-asparagine, poly-cysteine and natural, synthetic or semi- synthetic derivatives thereof, such as poly-hydroxyethyl-l-glutamine; in which the microparticles are surface modified with a bioadhesive agent; preferably selected from one or more of - a protein or peptide, such as a proteoglycan (e.g. lectin) or an antibody (e.g. anti- MUC1), - a carbohydrate such as a - simple carbohydrate (e.g. mannose) or a - complex carbohydrate (e.g. hyaluronic acid, chitosan, carboxymethylcellulose or hydroxypropyl methylcellulose), - a C6to C18lipid, preferably a C6to C13lipid, such as phospholipids; or lipid components such as fatty acids (e.g. octanoic acid); - an amino acids; and - a poly-amino acid; wherein the average diameter of the microparticles is less than approximately 10 µm measured with dynamic light scattering (DLS) using a zetasizer and light microscopy. The application also provides a general method for preparing a bioadhesive microparticle formulation comprising discrete microparticles, comprising the steps i) dissolving and combining poly-amino acids selected from one or more of poly-lysine including poly-epsilon-lysine (ε-PL) or poly alpha-lysine (α-PL), poly-glutamic acid including poly-gamma-glutamic acid, poly-arginine, poly-aspartic acid, poly-histidine, poly-asparagine, poly-cysteine and natural, synthetic or semi-synthetic derivatives thereof, such as poly-hydroxyethyl-l-glutamine, to form a suspension of self- assembled non-cross-linked microparticles; ii) cross-linking the suspension of step (i) via condensation polymerisation to obtain a monodispersed cross-linked microparticle solution; iii) subjecting the monodispersed cross-linked microparticle solution to a size-grading step to remove particles greater than 40 µm in average diameter, preferably greater than 10 µm in average diameter and to remove nanoparticles below 100 nm in average diameter, as measured with dynamic light scattering (DLS) using a zetasizer and light microscopy; and iv) surface modifying the microparticles from step (iii) with a bioadhesive or mucoadhesive agent, preferably selected from one or more of - a protein or peptide, such as a proteoglycan (e.g. lectin) or an antibody (e.g. anti-MUC1), - a carbohydrate such as a - simple carbohydrate (e.g. mannose) or a - complex carbohydrate (e.g. hyaluronic acid, chitosan, carboxymethylcellulose or hydroxypropyl methylcellulose), - a C6to C18lipid, preferably a C6to C13lipid, such as phospholipids; or lipid components such as fatty acids (e.g. octanoic acid); - an amino acids; and - a poly-amino acid; via condensation polymerisation to form a bioadhesive surface modified microparticle formulation. Advantageous embodiments are provided in the dependent claims. BRIEF DESCRIPTION OF THE FIGURES The present application will now be described with reference to the accompanying Figures and Examples in which: Figures 1A-C: Provides a schematic of the synthesis of the microparticle formulation of the invention described in Examples 1, 4, 5, 6 and 7. Figure 1(A) is a schematic of the synthesis of the microparticle formulation of the invention described in Examples 1, 4 and 7. Figure 1(B) is a schematic of the synthesis of the microparticle formulation of the invention described in Examples 1 and 5. Figure 1(C) is a schematic of the synthesis of the microparticle formulation of the invention described in Examples 1 and 6. Figures 2A-D: Light microscope image of microparticles in aqueous solution, scale bar - 25 µm. Figure 2(A) is SEM image of the microparticle formulation of the invention. Figure 2(B) shows the physical characteristics of a microparticle. Figure 2(C) Size range of a representative microparticle formulation before and after TFF. Figure 2(D) shows the particle size distribution via dynamic light scattering (DLS) of a representative microparticle formulation (Example 4) before and after TFF. N = 4, α value 0.05. Figures 3A-E (from top to bottom): shows infrared spectrums (FTIR) of γ-polyglutamic acid-co-ε-polylysine cross-linked microparticles. Figure 3(A) is an FTIR spectrum of microparticles with octanoic acid addition. Figure 3(B) is an FTIR spectrum of microparticles with cysteine addition. Figure 3(C) is an FTIR spectrum of microparticles with ε-polylysine addition. Figure 3(D) is an XPS spectrum of microparticles with cysteine addition. Figure 3(E) is an XPS spectrum of microparticles with ε-polylysine addition. Figures 4A-C: The addition of functional biomolecules to the microparticle surface promotes an increase in mucoadhesion, specifically, the addition of cysteine or ε-polylysine. Figure 4(A) is a graph showing the increased viscosity at lower shear rates is associated with increased intermolecular bonding between the microparticles and mucin. Figure 4(B) is a graph showing increased viscosity at a shear rate of 10 S-1was observed between microparticles and mucin. Figure 4(C) confirms an increased interaction between microparticles with cysteine compared with any of the other microparticle formulations (ε-polylysine coated, octanoic acid coated or no coating) observed by the viscous microparticle and mucin composition. N = 4, α value 0.05. Figures 5A-B (from top to bottom): Elution of ciprofloxacin was observed over a period of 168 h. Figure 5(A) is a graph showing that therapeutic dose was delivered for up to 96 h Figure 5(B) is a bar chart showing that no significant difference in drug release profile or total amount of therapeutic cargo was observed between the microparticle compositions. N = 4, α value 0.05. Figures 6A-C (top to bottom): A cytotoxicity study of the microparticles against human primary corneal epithelial cells was conducted over a period of 96 h at microparticle concentrations of 0.01 (A), 0.1 (B) and 1 mg cm-3(C). N = 4, α value 0.05. Figures 7A-D: Microparticles (0.1 mg cm-3) loaded with moxifloxacin were incubated separately with S. epidermidis (A) and E. coli (B) and S. epidermidis (C). Log reduction in CFUs were observed when each bacterial strain was incubated with microparticle formulations loaded with moxifloxacin (D). N = 4, α value 0.05. Figures 8A-C (top to bottom): Microparticles (0.01, 0.1, 1 and 10 mg cm-3) coated with ε- polylysine were incubated separately with and E. coli (A), S. epidermidis (B) and B. subtilis (C). N = 4. Figures 9A-C: A murine model of MDR Pseudomonas keratitis was treated with microparticles loaded with meropenem, meropenem alone and a sham (PBS) treatment control. Keratitis clinical scores were observed (A) and recorded over 3 days (B). Pseudomonas CFU data was obtained from infected eyes following completion of the study (C). * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.005 and **** p ≤ 0.001. Figure 10: is an SEM image of the macroporous sheet from Comparative Example 2. Figures 11A-B (from top to bottom): are light microscope images of the microparticles polymerised with differing molecular weights of γ-PGA, 10 kDa (A) and 200 - 500 kDa (B). Figure 12: is a comparison of the hydrogel formulation of Hua et al. ‘Preparation and properties of EDC / NHS mediated cross-linking poly (gamma-glutamic acid) / epsilon- polylysine hydrogels’ Mater Sci Eng C Mater Biol Appl.2016 Apr 1;61:879-92 compared to the microparticle formulation of the present invention. Hua et al. is regularly porous structure with 20 μm pore size in average. The hydrogel of Hua et al. has voids (approx.20 µm) formed by a gas by-product of the reaction that get trapped in the hydrogel as it solidifies. The microparticle formulation of the invention comprise self-assembling polymer constructs (approx.3 µm). Figure 13: provides a table of the particle size distribution via dynamic light scattering (DLS) of the microparticle formulations of Figures 14 to 19. N = 4, α value 0.05. Figure 14: is a light microscope image of γ-PGA-co-polyaspartic acid microparticles (Example 17) Figure 15: is a light microscope image of γ-PGA-co-α-polylysine microparticles (Example 18) Figure 16: is a light microscope image of γ-PGA-co-polyarginine microparticles (Example 15) Figure 17: is a light microscope image of γ-PGA-co-polyhistidine microparticles (Example 16) Figure 18: is a light microscope image of γ-PGA-co-ε-PL microparticles with Hyaluronic acid (500 kDa) (Example 20) Figure 19: is a light microscope image of γ-PGA-co-ε-PL microparticles with cysteine and Hyaluronic acid (500 kDa) (Example 29b) DETAILED DESCRIPTION In this specification, it will be understood that the terms ‘comprise’ ‘comprises’ or ‘comprising’ may be replaced by the terms ‘consists of’, ‘consisting of’, ‘consists essentially of’ or consisting essentially of’. Furthermore, the words comprises / comprising when used in this specification are to specify the presence of stated features, integers, steps or components but does not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof. Any reference herein to ‘selected from one or more’ will be understood to implicitly embrace ‘at least two’ or ‘at least two or more.’ Duchene, et al., Drug Dev. Ind. Pharm.14(2&3), 283-318 (1988), reviews the pharmaceutical and medical aspects of bioadhesive systems for drug delivery. “Bioadhesion” is defined as the ability of a material to adhere to a biological tissue for an extended period of time. Bioadhesion is clearly one solution to the problem of inadequate residence time resulting from the stomach emptying and intestinal peristalsis, and from displacement by ciliary movement. For sufficient bioadhesion to occur, an intimate contact must exist between the bioadhesive and the receptor tissue, the bioadhesive must penetrate into the crevice of the tissue surface and / or mucus, and mechanical, electrostatic, or chemical bonds must form. In this specification, the term ‘bioadhesive’ means the ability of a natural or synthetic material to adhere to a biological surface for an extended period of time. In this specification, the term ‘mucoadhesive’ means a specific type of bioadhesion where a natural or synthetic material adheres to a mucosal surface for an extended period of time. It will be understood that any poly-lysine may be used. Poly-epsilon-lysine may be referred to as ε-polylysine or ε-PL throughout the specification and is interchangeable with poly-lysine. Poly alpha-lysine may be referred to as α--polylysine or α-PL throughout the specification and is interchangeable with poly-lysine. It will be understood that any poly-glutamic acid may be used. Poly-gamma-glutamic acid may be referred to as γ-polyglutamic acid or γ-PGA throughout the specification and is interchangeable with poly-glutamic acid. The term ‘self-assembled mono-dispersed microparticles’ will be understood to mean particles that assemble from individual components into highly ordered single entities with unique properties. The term ‘microparticle formulation’ will be understood to mean a cross-linked microparticle formulation. The ‘microparticle’ may be in the form of a microsphere having a generally uniform spherical shape and / or include particles of irregular shape. Reference to diameter of the microparticle is the average (or mean) diameter. Various methods of detection for microparticles include microscopy, dynamic light scattering (DLS) and flow cytometry. In the examples, the microparticle diameter was measured with DLS using a zetasizer and light microscopy with post-imaging size analysis using ImageJ software following the conventional methodology outlined in the manufacturer’s instructions for use (Schneider, Rasband and Eliceiri, 2012). DLS standard is intensity-based distribution that is most aligned with volume-based distributions. This data provides information on the most detected size of particles of a particular size with the size weighted to give a volume (larger particles = greater weight). The values referred to herein are volume-based distributions (number-based distributions provide the number of particles detected for each size without any weighting for size differences). According to a general aspect of the invention, there is provided a microparticle formulation, comprising discrete microparticles, wherein the microparticle formulation comprises cross-linked poly-amino acid microparticles; wherein the average diameter of the microparticles is less than approximately 10 µm in measured with dynamic light scattering (DLS) using a zetasizer and light microscopy. Ideally, the poly-amino acids comprise one or more of poly-lysine, including poly-epsilon- lysine (ε-polylysine (ε-PL)) or or poly alpha-lysine (α-PL), poly-glutamic acid including poly- gamma-glutamic acid (γ-polyglutamic acid (γ-PGA)), poly-arginine, poly-aspartic acid, poly- histidine, poly-asparagine, poly-cysteine or natural, synthetic or semi-synthetic derivatives thereof, such as poly-hydroxyethyl-l-glutamine. Ideally the microparticles comprise at least two poly-amino acids, or two or more poly-amino acids. It will be understood that any suitable poly-amino acid may be used, excluding poly-alanine. According to another general aspect of the invention, there is provided a microparticle formulation, comprising discrete microparticles, wherein the microparticle formulation comprises cross-linked poly-amino acid microparticles; in which the microparticles are surface modified with a bioadhesive agent; wherein the average diameter of the microparticles is less than approximately 10 µm measured with dynamic light scattering (DLS) using a zetasizer and light microscopy. Ideally, the average diameter of the microparticles is greater than approximately 0.1 µm and less than approximately 10 µm measured with dynamic light scattering (DLS) using a zetasizer and light microscopy. Optionally, each discrete microparticle is approximately 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10 µm in average diameter. Preferably, the average diameter is less than 5 µm. Still optionally, each discrete microparticle is greater than approximately 1 µm and less than approximately 5 µm in average diameter. The smaller the diameter results in enhanced uptake, for example a diameter between about 2 to 5 µm can advantageously be used. Additionally, microspheres less than about 2 µm, or optionally, less than about 1 µm in diameter may be used. Ideally, the poly-amino acids comprise one or more of poly-lysine, including poly-epsilon- lysine (ε-polylysine (ε-PL)) or or poly alpha-lysine (α-PL), poly-glutamic acid including poly- gamma-glutamic acid (γ-polyglutamic acid (γ-PGA)), poly-arginine, poly-aspartic acid, poly- histidine, poly-asparagine, poly-cysteine or natural, synthetic or semi-synthetic derivatives thereof, such as poly-hydroxyethyl-l-glutamine. Ideally the microparticles comprise at least two poly-amino acids, or two or more poly-amino acids. It will be understood that any suitable poly-amino acid may be used, excluding poly-alanine. Ideally, the microparticle formulation is a bioadhesive microparticle formulation itself or may be surface modified with a bioadhesive agent. The bioadhesive agent may be a natural or synthetic material which can adhere to a biological surface for an extended period of time. Ideally, the bioadhesive agent is selected from one of more of - a protein or peptide, such as a proteoglycan (e.g. lectin) or an antibody (e.g. anti- MUC1), - a carbohydrate such as - a simple carbohydrate (e.g mannose) or - a complex carbohydrate (e.g. hyaluronic acid (disaccharide), chitosan, carboxymethylcellulose or hydroxypropyl methylcellulose), - a C6to C18lipid, preferably a C6to C13lipid, s such as phospholipids or lipid components such as fatty acids (e.g. octanoic acid), and - an amino acid; - an additional poly-amino acid including - poly-epsilon-lysine (ε-polylysine (ε-PL)) or poly alpha-lysine (α- PL), or other polylysine, poly-gamma-glutamic acid (γ- polyglutamic acid (γ-PGA)) or other polyglutamic acid, poly- arginine, poly-aspartic acid, poly-histidine, poly-asparagine, poly- cysteine or natural, synthetic or semi-synthetic derivatives thereof, such as poly-hydroxyethyl-l-glutamine and optionally excluding poly-alanine. It will be understood that the lipid may be any C6to C18lipid but must be non-toxic and soluble in aqueous media. C6to C13lipids may be preferable as they are more easy soluble in aqueous media. Ideally, the poly-amino acid may have a molecular weight from approximately 1 to 330kDa. The complex carbohydrates have the following molecular weights: - hyaluronic acid (100 - 1000 kDa); - chitosan (50 - 300 kDa); - carboxymethylcellulose or hydroxypropyl methylcellulose (100 - 1000 kDa). It will be understood that the microparticle formulation may also comprise cross-linked poly amino-acid nanoparticles (in addition to the microparticles). According to a preferred embodiment the microparticle formulation further comprises an agent, preferably an active agent. The active agent may be a pharmaceutical drug such as an anti-infective or antimicrobial / anti-fungal agent, anti-inflammatory agent, antibiotic or nucleic acid based therapeutic. According to a first aspect of the invention, there is provided a bioadhesive microparticle formulation comprising discrete microparticles, wherein the microparticle formulation comprises cross-linked poly-amino acid microparticles wherein the poly-amino acids are selected from one or more of poly-lysine including poly-epsilon-lysine (ε-PL) or poly alpha- lysine (α-PL), poly-glutamic acid including poly-gamma-glutamic acid, poly-arginine, poly- aspartic acid, poly-histidine, poly-asparagine, poly-cysteine and natural, synthetic or semi- synthetic derivatives thereof, such as poly-hydroxyethyl-l-glutamine; in which the microparticles are surface modified with a bioadhesive agent; preferably selected from one or more of a protein or peptide, such as a proteoglycan (e.g. lectin) or an antibody (e.g. anti-MUC1), a carbohydrate such as a simple carbohydrate (e.g mannose) or a complex carbohydrate (e.g. hyaluronic acid, chitosan, carboxymethylcellulose or hydroxypropyl methylcellulose), a C6to C18lipid, preferably a C6to C13lipid such as phospholipids or lipid components such as fatty acids (e.g. octanoic acid); an amino acid; and a poly-amino acid; and wherein the average diameter of the microparticles is less than approximately 10 µm measured with dynamic light scattering (DLS) using a zetasizer and light microscopy as detailed in claim 1. The cross-linked poly-amino acid microparticles are formed via condensation polymerisation of poly-amino acids followed by surface modification. It will be understood that the cross-linked poly-amino acid microparticles comprise a blend of at least two of the above-recited poly-amino acids. It will be understood that the microparticle formulation of the invention comprises discrete microparticles and is typically provided in the form of an aqueous solution. This is in contrast to the hydrogel formulation of Hua et al. which is a hydrogel formulation without discrete microparticles dispersed therein. It will be understood that the formulation may also comprise cross-linked poly amino-acid nanoparticles. Optionally and preferably, a high degree of cross-linking between the poly-amino acid monomer units is needed to result in discrete microparticles, e.g. above 60 mol % of functional groups of the poly(amino acids) discussed below; optionally 60, 65, 70, 75, 80, 85, 90, 95 mol % of these functional groups; preferably from 60 to 90 mol % of these functional groups; more preferably from 65 to 85 mol% of these functional groups, even more preferably greater than 60, 65, 70, 75, 80, 85, 90, 95 mol %. Poly (amino acids) are polyamides only composed of amino acids. It will be understood that the poly-amino acids comprise one or more of poly-lysine including poly-epsilon-lysine (ε-PL) or poly alpha-lysine (α-PL), poly-glutamic acid including poly-gamma-glutamic acid (γ-PGA), poly-arginine, poly-aspartic acid, poly-histidine, poly-asparagine, poly-cysteine or natural, synthetic or semi-synthetic derivatives thereof, such as poly-hydroxyethyl-l-glutamine. It will be understood that any suitable poly-amino acid may be used, excluding poly-alanine. Poly (γ-glutamic acid), γ-PGA, is an unusual anionic homo-polyamide linked by the peptide bond between the α-amino group and the γ-carboxyl group. It is water-soluble, biodegradable, edible and nontoxic towards human. Therefore, γ-PGA and its derivatives have been broadly used in many industrial fields such as medicine, cosmetic and agriculture. It offers a wide range of applications including being used as highly water absorbable hydrogels, drug delivery carrier and biodegradable fibers. Similarly, naturally occurring ε-polylysine (ε-PL) is biodegradable, edible and nontoxic towards humans and the environment as γ-PGA. ε-PL is a cationic homo-polyamide that consists of l-lysine with a ε-NH2-α-COOH linkage. Moreover, ε-PL has a broad-spectrum antibacterial property, and it also shows high water-solubility and heat-stability. Therefore, ε- PL and its derivatives have been of interest in recent years in food, medicine and bioelectronics. They offer a wide range of unique applications such as food preservative, drug carrier and coating material. Other poly-amino acids with polar and / or charged side chains used include poly-arginine, poly-aspartic acid, poly-histidine, poly-asparagine and poly-cysteine. Poly(aspartic acid) is widely used in biomedical applications, especially gene delivery and drug delivery, due to its low toxicity profile, non-antigenic, excellent biocompatibility and biodegradability Additionally, synthetic or semi-synthetic poly-amino acids derivatives may be used, such as poly hydroxyethyl-l-glutamine. Ideally, the microparticle formulation of the invention comprises cross linked γ-polyglutamic acid-co-ε-polylysine microparticles; cross linked γ-polyglutamic acid-co-α-polylysine microparticles; cross linked γ-polyglutamic acid-co-polyarginine microparticles; cross linked γ-polyglutamic acid-co-polyaspartic acid microparticles; or cross linked γ-polyglutamic acid- co-polyhistidine microparticles. The microparticles are optionally and ideally surface modified with a bioadhesive agent. It will be understood that the bioadhesive agent may comprise any biomolecule that provides a desired change in surface modification. For example, the microparticles may have incorporated on the surface molecules which alter the bioadhesive or mucoadhesive properties of the microparticle polymer, such as by adding carboxylic acid-containing moieties to the surface by covalent coupling. The microparticle polymers can be modified using a wide range of different coupling chemistries available in the art to covalently attach ligand molecules with bioadhesive or mucoadhesive properties to the surface-exposed molecules of the polymeric microparticles. Ionic coupling may also be used. Surface modification typically involves the covalent attachment of biomolecules, such as a bioadhesive agent or mucoadhesive agent, primarily to the outer surface of the microparticles. In this manner, the degree of cationic or anionic charge on the outer surface of the microparticles can be modified. The attachment of any positively charged ligand, such as polylysine, to the polymeric microparticles improves bioadhesion due to the electrostatic attraction of the cationic groups coating the polymeric microparticles to the net negative charge of the mucus. The ligand affinity may ideally be based on electrostatic charge, or other physical parameters including solubility in mucin or specific affinity to carbohydrate groups. Preferably, the desired changes in surface modification include changing the degree of cationic (positive) charge on the surface of the microparticle. Any ligand with a high binding affinity for mucin could also be covalently linked to the polymeric microspheres with the appropriate conventional chemistry, and be expected to influence the binding of microspheres to the gut. In this manner the polymeric microparticles may be surface modified to include a fine dispersion of ligand on the surface of the microparticles. Ideally, the bioadhesive agent may be selected from - a protein or peptide, such as a proteoglycan (e.g. lectin) or an antibody (e.g. anti- MUC1); - a carbohydrate such as a simple carbohydrate (e.g mannose) or a complex carbohydrate (e.g. hyaluronic acid, chitosan, carboxymethylcellulose or hydroxypropyl methylcellulose); - a C6to C18lipid, preferably a C6to C13lipid, such as phospholipids or lipid components such as fatty acids (e.g. octanoic acid); and / or - an amino acid; - a poly-amino acid as defined above. The attachment of poly-amino acids containing extra pendant carboxylic acid side groups, such as poly-aspartic acid and polyglutamic acid, may also increase bioadhesiveness. Using poly-amino acids in the 15,000 to 50,000 kDa molecular weight range would yield chains of 120 to 425 amino acid residues attached to the surface of the microspheres. The polyamino chains would increase bioadhesion by means of chain entanglement in mucin strands as well as by increased carboxylic charge. We have found that the surface modified microparticle formulation of the invention advantageously has antimicrobial activity on its own. Additionally, the microparticle may also comprise an agent, specifically an active agent absorbed or adsorbed or covalently bound. The active agent is ideally designed to treat a disease or condition of the subject. This active agent may be any pharmaceutical drug, such as an antimicrobial agent or antibiotic, for example, an ocular drug or antimicrobial agent such as antibiotics ciprofloxacin, Moxifloxacin, Meropenem, Amphotericin B or Natamycin. Other active agents include antifungal agents such as natamycin and amphotericin B, antiseptic agents such as chlorhexidine and anti-inflammatory agents such as ibuprofen. Ocular drugs include cyclosporine for dry eye treatment, ketotifen for allergic conjunctivitis treatment and mannitol for glaucoma treatment. The active agent may be encapsulated or loaded within the discrete microparticles or attached to the surface of the discrete microparticles. For example, the active agent may be added via a process of sorption which covers both encapsulation (absorption) or attachment to surface of the microparticles (adsorption). Alternatively, the active agent may be covalently bound to the microparticles for a more stable (i.e. permanent) bond that would rely on degradation for release of the active compound. Ideally, the average diameter of the microparticles is less than approximately 10 µm in average diameter size as measured using conventional techniques such as dynamic light scattering (DLS) using a zetasizer and light microscopy. Preferably, each discrete microparticle is greater than approximately 0.1 µm and less than approximately 10 µm in average diameter. Optionally, each discrete microparticle is approximately 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10 µm in average diameter. Preferably, the average diameter is less than 5 µm. Still optionally, each discrete microparticle is greater than approximately 1 µm and less than approximately 5 µm in average diameter. The smaller the diameter results in enhanced uptake, for example a diameter between about 2 to 5 µm can advantageously be used. Additionally, microspheres less than about 2 µm, or optionally, less than about 1 µm in diameter may be used. According to a preferred embodiment of the invention, the bioadhesive agent is a mucoadhesive agent selected from one or more of an amino acid selected from cysteine, aspartic acid, lysine and arginine; a poly-amino acid selected from poly-lysine, preferably poly-epsilon-lysine (ε-PL) or α-poly-alpha-lysine (α-PL), poly-glutamic acid, preferably γ-polyglutamic acid (γ- PGA), poly-alanine, poly-arginine, poly-histidine, poly-aspartic acid, andpoly- cysteine, a C6to C18lipid selected from octanoic acid; and a complex carbohydrate selected from hyaluronic acid. Other similar biomolecules that would give the desired change in surface modification may also be contemplated. As discussed in Vigani, B., et al. Mucoadhesive polymers in substance-based medical devices: functional ingredients or what else? Front. Drug Saf. Regul. 3, 1–13 (2023) there are several theories of mucoadhesion that can be utilised in the present invention, including but not limited to: Wetting theory - The wetting theory applies to liquids and substances with low viscosity, with a high affinity for the mucus layer and a good capability to spontaneously spread onto the mucosa surface. Electronic theory - The electronic theory is characterised by different electronic structures between mucin and the mucoadhesive. Electron transfer occurs and leads to the formation of a double electronic layer at the adhesive candidate-mucus interface. This results in an electrostatic attraction between the two surfaces that is responsible for mucoadhesion. Adsorption theory - After contact of adhering surfaces, they mainly interact by hydrogen bonds and Van der Walls forces; hydrophobic interactions may play an important role especially when the adhesive substance has an amphiphilic nature. Chemisorption is the result of covalent bonding between chemical groups of the mucin and mucoadhesive. Diffusion theory - The diffusion theory states that the polymeric chains of the mucoadhesive biomolecules and the mucins interpenetrate to a sufficient depth to create semi-permanent adhesive bonds. Mechanical theory - The mechanical theory describes the effect of the surface roughness of the mucosal tissue on the adhesion of liquids due to their interlocking with the mucosa. Fracture theory - The fracture theory relates the strength of the adhesive bonds to the forces required to detach the two adhering surfaces after contact. All of the formulations of the present invention utilise one or more of the above theories. For example, due to their very aqueous formulation and amphiphilic nature of the microparticle core, the wetting theory is applicable. Furthermore, the positively charged mucoadhesive biomolecules (e.g. poly epsilon lysine) utilises the electronic / electrostatic theory. Negatively charged (e.g. poly gamma glutamic acid, hyaluronic acid) and hydrophobic mucoadhesive biomolecules (e.g. octanoic acid) interact with mucin via hydrogen bonding and Van der Waals forces – utilising the adsorption theory. The thiolated mucoadhesive biomolecules (e.g. cysteine) that from covalent bonds with mucin utilising chemisorption. Finally, the large mucoadhesive biomolecules (e.g. hyaluronic acid) that interpenetrate the large mucin networks and become tangled utilised the diffusion theory. According to a second aspect of the invention, there is provided a mucoadhesive microparticle formulation comprising discrete microparticles, comprising cross-linked poly-amino acid microparticles formed from γ-polyglutamic acid (γ-PGA), optionally with a molecular weight of approximately 800 to 700,000 Daltons, and ε-polylysine (ε-PL), optionally with a molecular weight of approximately 2000 to 5500 Daltons; in which the microparticles are surface modified with a mucoadhesive agent selected from one or more of amino acids selected from cysteine, aspartic acid, lysine and arginine; a poly-amino acid selected from poly-lysine, preferably poly-epsilon-lysine (ε-PL) or α-poly-alpha-lysine (α-PL), poly-glutamic acid, preferably γ-polyglutamic acid (γ- PGA), poly-alanine; poly-arginine, poly-histidine, poly-aspartic acid, and poly- cysteine, a C6to C18lipid selected from octanoic acid; and a complex carbohydrate selected from hyaluronic acid; and an optional agent or active agent, such as an antimicrobial agent, antibiotic or nucleic acid based therapeutic; wherein the average diameter of the microparticles is less than approximately10um in diameter measured with dynamic light scattering (DLS) using a zetasizer and light microscopy. The cross-linked poly-amino acid microparticles are formed via condensation polymerisation of poly-amino acids followed by surface modification. Preferably, the microparticle formulation is based on cross-linking ε-polylysine (ε-PL) and γ- polyglutamic acid (γ-PGA) by carbodiimide (EDC) and N-hydroxysuccinimide (NHS) mediated condensation polymerization followed by surface modification. Alternatively, other cross-linking agents can be used including, but not limited to one or more of sulfo-NHS, DMTMM, HOBt, oxyma. Surface modification typically involves the covalent attachment of biomolecules, such as a bioadhesive agent or mucoadhesive agent, primarily to the outer surface of the microparticles. In this manner, the degree of cationic or anionic charge on the outer surface of the microparticles can be modified. Ideally, the mucoadhesive microparticle formulation has a - zeta potential of - 60 mV to + 60 mV, and / or - a polydispersity index of ≤ 0.5. An optional agent or active agent may be added, such as an anti-infective agent including conventional antimicrobial agents or an antibiotic. The active agent may be encapsulated or loaded within the discrete microparticles or attached to the surface of the discrete microparticles. For example, the active agent may be added via a process of sorption which covers both encapsulation (absorption) or attachment to surface of the microparticles (adsorption). Alternatively, the active agent may be covalently bound to the microparticles for a more stable (i.e. permanent) bond that would rely on degradation for release of the active compound. The active agent may be any pharmaceutical drug, preferably an ocular drug, a nucleic acid based therapeutic, an antimicrobial / antifungal agent or antibiotic such as Ciprofloxacin, Moxifloxacin, Meropenem, or a nucleic acid based therapeutics (e.g. micro RNAs, siRNAs etc). Other active agents include antifungal agents such as natamycin and amphotericin B, antiseptic agents such as chlorhexidine and anti-inflammatory agents such as ibuprofen and dexamethasone. Ocular drugs include cyclosporine for dry eye treatment, ketotifen for allergic conjunctivitis treatment and mannitol for glaucoma treatment. Hyaluronic acid may be used as a dry eye treatment or in wound healing. The mucoadhesive formulation may be used for delivery to the mucosa of a subject in which the mucosa is selected from ocular, gastrointestinal, nasal, buccal, vaginal and respiratory mucosa. According to a preferred embodiment, the mucoadhesive microparticle poly-glutamic acid, preferably γ-polyglutamic acid, has a molecular weight of approximately 800 to 1500 Daltons. According to a preferred embodiment, the mucoadhesive microparticle poly-lysine, preferably ε-polylysine, has a molecular weight of approximately 3000 to 4500 Daltons. Ideally, the bioadhesive or mucoadhesive microparticle formulation comprises microparticles wherein each discrete microparticle is greater than approximately 0.1 µm and less than approximately 10 µm in average diameter. It will be understood that nanoparticles produced as well as microparticles. However, from a regulatory perspective, for example for ocular delivery applications, these nanoparticles are typically filtered out. According to a third aspect of the invention, there is provided a drug delivery system comprising the bioadhesive or mucoadhesive microparticle formulation as described herein. It is envisaged that the drug delivery system would be provided in a container with an applicator device, such as a dropper or spray or other means. Ideally, the bioadhesive or mucoadhesive microparticle formulation or drug delivery system as described herein may be formulated for sustained release of an active agent. According to a fourth aspect of the invention, there is provided a bioadhesive or mucoadhesive microparticle formulation or drug delivery system as described herein for use in therapy; preferably for use in wound healing, for use as an anti-inflammatory, for use as an antimicrobial / antifungal, for use in cancer treatment or for use in gene therapy. In this manner, the bioadhesive or mucoadhesive microparticle formulation or drug delivery system as described herein may be delivered to the mucosa of a subject in need thereof. Additionally, the bioadhesive or mucoadhesive microparticle formulation or drug delivery system as described herein may be used to deliver an active agent as described herein to the mucosa of a subject in need thereof Additionally, there is provided the use of the bioadhesive or mucoadhesive microparticle formulation or drug delivery system as described herein for use in the manufacture of a medicament for wound healing, as an anti-inflammatory, anti-microbial or anti-fungal, treatment of ocular / eye disorders, cancer or gene therapy. According to a fifth aspect of the invention, there is provided a bioadhesive or mucoadhesive microparticle formulation or drug delivery system as described herein for use in treatment of eye disorders, such as microbial keratitis / conjunctivitis, dry eye, glaucoma or allergic conjunctivitis. Ocular drugs include cyclosporine for dry eye treatment, ketotifen for allergic conjunctivitis treatment and mannitol for glaucoma treatment. Hyaluronic acid may be used as a dry eye treatment or in wound healing. The microparticle formulation of the invention will make treatment for microbial keratitis / conjunctivitis, dry eye, glaucoma or allergic conjunctivitis more efficient by increasing drug bioavailability at the site of injury. Thus, increasing patient compliance which will result in the administration of fewer antibiotics in the treatment of this condition. A secondary effect of reducing the potential for antimicrobial resistance developing via decreased antibiotic administration will play a small part in tackling a global problem of the emergence of antimicrobial resistant organisms. It will be understood that the present invention has application in both human and animal health. Alternatively, there is provided a method for the treatment of an ocular disorder, comprising administering to a subject in need thereof the surface modified microparticles of the invention, for example by injection (e.g. intravitreal or suprachoroidal injection) or eye dropper. Additionally, there is provided a method for the treatment of an ocular disorder, ideally with an active agent capable of treating the disorder, comprising administering to a host in need thereof the surface modified microparticles of the invention, for example by injection or eye dropper, ideally to provide sustained release of the active agent. Additionally, there is provided a method for the treatment of inflammation, ideally with an active agent with anti-inflammatory activity, comprising administering to a host in need thereof the surface modified microparticles of the invention, ideally to provide sustained release of the active agent. Additionally, there is provided a method for the treatment of a microbial or fungal infection, ideally with an active agent with anti-microbial or anti-fungal activity, comprising administering to a host in need thereof the surface modified microparticles of the invention, ideally to provide sustained release of the active agent. Additionally, there is provided a method for the treatment of cancer, ideally with an active agent capable of treating cancer, comprising administering to a host in need thereof the surface modified microparticles of the invention, ideally to provide sustained release of the active agent. Additionally, there is provided a method for the treatment of a disease or disorder by gene therapy, comprising administering to a host in need thereof the surface modified microparticles of the invention, ideally to provide sustained release of the active gene therapy agent. According to a sixth aspect of the invention, there is provided a method for preparing a surface modified cross-linked poly-amino acid microparticle formulation comprising discrete microparticles, comprising the following steps: i) dissolving and combining poly-amino acids selected from one or more of poly-lysine including poly-epsilon-lysine (ε-PL) or poly alpha-lysine (α-PL), poly-glutamic acid including poly-gamma-glutamic acid, poly-arginine, poly-aspartic acid, poly-histidine, poly-asparagine, poly-cysteine and natural, synthetic or semi-synthetic derivatives thereof, such as poly-hydroxyethyl-l-glutamine to form a suspension of self- assembled non-cross-linked microparticles; ii) cross-linking the suspension of step (i) via condensation polymerisation to obtain a monodispersed cross-linked microparticle solution; iii) subjecting the monodispersed cross-linked microparticle solution to a size-grading step to remove particles greater than 40 µm in average diameter and to remove nanoparticles below 100 nm in average diameter, as measured with dynamic light scattering (DLS) using a zetasizer and light microscopy;; and iv) surface modifying the microparticles from step (iii) with a bioadhesive or mucoadhesive agent, via condensation polymerisation to form a surface modified microparticle formulation. Preferred microparticle formulations utilised in the above method comprise cross linked γ- polyglutamic acid-co-ε-polylysine microparticles; cross linked γ-polyglutamic acid-co-α- polylysine microparticles; cross linked γ-polyglutamic acid-co-polyarginine microparticles; cross linked γ-polyglutamic acid-co-polyaspartic acid microparticles; or cross linked γ- polyglutamic acid-co-polyhistidine microparticles; More preferred microparticle formulations utilised in the above method comprise cross linked γ-polyglutamic acid-co-ε-polylysine microparticles or cross linked γ-polyglutamic acid-co-α- polylysine microparticles. Preferred bioadhesive or mucoadhesive agents utilised in the above method may be selected from one or more of a simple or complex carbohydrate, preferably hyaluronic acid, chitosan, carboxymethylcellulose or hydroxypropyl methylcellulose; a C6to C18lipid, preferably a C6to C13lipid; a protein such as a peptide; an amino acid; and a poly-amino acid. More preferred bioadhesive or mucoadhesive agents utilised in the above method may be selected from one or more of an amino acid selected from cysteine, aspartic acid, lysine and arginine; a poly-amino acid selected from poly-lysine, preferably poly-epsilon-lysine (ε-PL) or α-poly-alpha-lysine (α-PL), poly-glutamic acid, preferably γ-polyglutamic acid (γ- PGA), poly-alanine; poly-arginine, poly-histidine, poly-aspartic acid or poly-cysteine the C8lipid octanoic acid; and the carbohydrate hyaluronic acid. According to a preferred embodiment, there is provided a method for preparing a surface modified cross-linked poly-epsilon-lysine / ε-polylysine (ε-PL) and poly-gamma-glutamic acid / γ-polyglutamic acid (γ-PGA) microparticle formulation, comprising the following steps: i) dissolving γ-polyglutamic acid with a molecular weight of approximately 800 to 700,000 Daltons and ε-polylysine with a molecular weight of approximately 2000 to 5,500 Daltons separately in deionised water at pH 5 and combining to form a suspension of self-assembled non-cross-linked microparticles; ii) Cross-linking the suspension of step (i) via condensation polymerisation of ε- polylysine and γ-polyglutamic acid to allow for amide bond formation and to obtain a monodispersed cross-linked microparticle solution; iii) subjecting the monodispersed cross-linked microparticle solution to a size-grading step to remove particles greater than 40 µm in average diameter and to remove nanoparticles below 100 nm in average diameter as measured with dynamic light scattering (DLS) using a zetasizer and light microscopy; and iv) surface modifying the microparticles from step (iii) with a mucoadhesive agent, preferably selected from one or more of an amino acid selected from cysteine, aspartic acid, lysine or arginine; a poly-amino acid selected from poly-lysine, preferably poly-epsilon-lysine (ε- PL) or α-poly-alpha-lysine (α-PL), poly-glutamic acid, preferably γ- polyglutamic acid (γ-PGA), poly-alanine; poly-arginine, poly-histidine, poly- aspartic acid, or poly-cysteine the C8lipid octanoic acid; and the carbohydrate hyaluronic acid, via condensation polymerisation to form a surface modified microparticle formulation. In essences, the cross-linked poly-amino acid microparticles are formed via condensation polymerisation of poly-amino acids followed by surface modification. Previously, chemical crosslinking agents were commonly used such as aldehydes, carbodiimides, epoxy, and diisocyanates. But most of these agents are toxic to humans. Therefore, crosslinking agents with low toxicity have gained increased attention in the crosslinking of poly (amino acid) based materials. Such as, the cross-linking agent 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) / N-hydroxysulfosuccinimide (NHS) (EDC / NHS), or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide 1-ethyl-3- dimethylaminopropyl) carbodiimide hydrochloride (EDC) / N-Hydroxysulfosuccinimide sodium salt (EDC / sulfo-NHS) or 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), a water-soluble, non-cytotoxic, and biocompatible carbodiimide offers a safe and effective method to crosslink amino linkage as the coupling agent, and N-hydroxysuccinimide (NHS) is used as a stabilizer to improve the cross-linkage efficiency. Different with common crosslinking agents, EDC and NHS introduce “zero length” amide cross-links between carboxylic groups from γ-PGA and amino groups from ε-PL. Moreover, EDC and NHS are simply used as catalysts and can be removed by dialysis. Preferably, the microparticle formulation is based on cross-linking ε-polylysine (ε-PL) and γ- polyglutamic acid (γ-PGA) by carbodiimide (EDC) and N-hydroxysuccinimide (NHS) mediated condensation polymerization followed by surface modification. Alternatively, other cross-linking agents can be used including, but not limited to one or more of sulfo-NHS, DMTMM, HOBt, oxyma. Cross-linking poly-amino acids involves adjusting parameters including crosslinker type and concentration, reaction time, temperature, and pH to achieve desired properties. A high degree of cross-linking between the poly-amino acid monomer units is needed to result in discrete microparticles, e.g. above 40 mol % of functional groups of the poly(amino acids) is required; optionally 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 mol % of these functional groups; preferably from 60 to 90 mol % of these functional groups; more preferably from 65 to 85 mol% of these functional groups, even more preferably greater than 60, 65, 70, 75, 80, 85, 90, 95 mol %. Ideally, the objective here is to achieve high cross-linking (greater than 40 mol% cross- linking, preferably approximately 60% mol% or greater, more preferably approximately 80% mol% or greater) between the poly-amino acid monomers, for example ideally γ-polyglutamic acid is cross-linked to 80 mol % with ε-polylysine. Typically, a high concentration of EDC is required for EDC / NHS mediated condensation to achieve this high degree of cross-linking. Ideally, the condensation polymerisation of steps (ii) and (iv) comprises EDC / NHS mediated polymerisation, sulfo-EDC / NHS or DMTMM mediated polymerisation. Ideally, these steps take place at ambient or room temperature, preferably approximately 20 to 25°C. The typical reaction pH may be greater than 4, for example from 4-6, 6-7 or 8-9 or any combination thereof. For example, the EDC / NHS mediated polymerisation step (ii) may takes place at room temperature (20 to 25°C), and pH 4-6 for 120 minutes followed by pH 8-9 for 30 minutes or alternatively at pH 6-7 for 240 minutes at room temperature (20 to 25°C). Ideally, the polymer density is from 0.5 - 120 g dm-3, preferably from 1 - 72 g dm3, more preferably from 1 to 55 g dm-3; even more preferably from 1 to 15 g dm-3i.e. comprising microparticles and a polymer ‘lump’ which may be easily separated from the microparticles. Advantageously, the polymer density may be from 1 - 6 g dm-3(where monodispersed microparticles only are present). For example, the polymer density of the γ-polyglutamic acid-co-ε-polylysine polymer concentration is 0.5 g dm-3to 120 g dm-3in aqueous solution, preferably 1 g dm-3to 60 g dm-3, more preferably from 1 to 55 g dm-3; even more preferably from 1 to 15 g dm-3, m; most preferably from from 1 - 6 g dm-3. Ideally, the first poly-amino acid: second poly-amino acid:EDC: ΝHS molar ratio of step (ii) is from 1 : 0.2 : 0.5 : 0.1 to 1 : 1.2 : 3.5 : 1.2; preferably from 1 : 0.5 : 1.2 : 0.2 to 1 : 0.9 : 2.5 : 1.2; most preferably from 1 : 0.5 : 1.2 : 0.2 to 1 : 0.9 : 2.3 : 1.2; most preferably 1: 0.8: 1.8: 0.6. For example, the γ-polyglutamic acid: ε-polylysine: EDC: ΝHS molar ratio range in step (ii) may be1: 0.2 - 1.2: 0.5 - 3.5: 0.1 - 1.2, preferably 1: 0.5 - 0.9: 1.2 - 2.5: 0.2 - 0.7, more preferably 1: 0.5 - 0.9: 1.2 - 2.3: 0.2 - 0.7; even more preferably 1: 0.6 - 0.9: 1.2 - 2: 0.2 - 0.7; most preferably 1: 0.8: 1.8: 0.6. Ideally, step (iii) involves filtering the monodispersed microparticle solution of step through a 10 - 40 µm filter to obtain particles of less than approximately 40 µm in average diameter; followed by purification and concentration by tangential flow filtration (TFF) through a TFF column with a 100 kDa MWCO with deionised water as the wash buffer.In this size grading step 10 - 40 um filters remove anything above this size and nanoparticles below 100 nm are removed via TFF membrane. Ideally, in step (iv), the microparticles are incubated with a mucoadhesive agent in the presence of EDC / NHS to mediate polymerisation and obtain microparticles with a modified chemical functionality. Ideally, the mucoadhesive agent: EDC: ΝHS molar ratio of step (iv) is from 1 : 0.02 : 0.01 to 1: 1 : 0.2; preferably 1 : 0.02 : 0.01. Optionally, the method may comprise a final TFF filtration step to remove reaction by- products and unused raw materials in the surface modified microparticle solution through a TFF column with a 100 kDa MWCO and deionised water as the wash buffer. This step minimises potential for toxicity from reaction by-products. As shown in the examples, microparticles from example 5 and Figure 8 are antimicrobial without the addition of an active pharmaceutical ingredient or active agent. Optionally, the method may also comprise the step of incubating the surface modified microparticle solution with an active agent. In this step, the surface modified microparticle solution may also comprise an added active agent (as defined previously) via electrostatic absorption, sorption and / or covalent bonding. In this manner the active agent may be encapsulated / loaded within or attached to the surface of the microparticles. EXAMPLES Materials & General The reagents used in the following examples are as follows: ^ γ-Polyglutamic acid (γ-PGA, average Mw ~ 0.8 –1.5 kDa), ε-polylysine (ε-PL, average Mw ~ 3.5 – 4.5 kDa), N-hydroxysulfosuccinimide (NHS) and 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide (EDC) were purchased from Biosynth Ltd., Berkshire, UK. ^ Octanoic acid, 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM), N-hydroxysulfosuccinimide sodium salt (Sulfo-NHS), mucin from porcine stomach type II and cysteine were purchased from Merck Life Science Ltd., UK. The equipment used in the following examples was sourced as follows: ^ Tangential Flow Filtration (TFF,100 kDa MWCO column, Repligen Corporation, The Netherlands) ^ Fourier-transform infrared spectroscopy (FTIR, IRSpirit, Shimadzu, Japan) ^ Zetasizer (Litesizer 500, Anton Paar, Austria) ^ Rheometer (MCR 302, Anton Paar, Austria) ^ High performance liquid chromatography (HPLC, LC-2030, Shimadzu, Japan) General Mucoadhesion The γ-PGA-co-ε-PL microparticles were incubated with porcine mucin to determine any molecular interaction between the carriers and mucin. A rheometer (AntonParr) was used to determine the viscosity of each of the compositions. Stock solutions (2 wt% in dH2O) of each of the polymer compositions and mucin (6 wt% in dH2O) were made on the day of testing to ensure fresh stock solutions. An aliquot (0.5 cm3) of microparticle solution and mucin were added together in individual centrifuge tubes (1.5 cm3) at a 1:1 ratio were mixed together and stirred vigorously for 1 h at RT prior to analysis to provide test samples containing 1 wt% polymer and 3 wt% mucin. Control samples were prepared by mixing dH2O and microparticle or mucin stock solution at a ratio of 1:1 to provide reference samples of 1 wt% polymer or 3 wt% mucin. Measurements were performed with an AntonParr Rheometer with a 25 mm flat plate. The rheometer stage temperature was set to 37 °C and an aliquot (0.6 cm3) of each sample was applied for testing. Shear rates went from 0 to 100 s-1with 50 measurements taken over 275 seconds. General In vitro cytotoxicity Testing Methodology Primary Corneal Epithelial Cells; Normal, Human (HCEC, ATCC PCS-700-010) were grown in Corneal Epithelial Cell Basal Media supplemented with Corneal Epithelial Cell Growth Kit components (LGC Standards, Middlesex UK) and Penicillin-Streptomycin Solution, 0.5 cm3(final concentration Penicillin: 10 Units cm-3, Streptomycin: 10 µg cm-3). HCEC were cultured under standard conditions in an incubator at 37 °C with 5% CO2. The cells were used to assess cytotoxicity of the microparticle formulations. Cell medium was replaced every 2 - 3 days until confluence was achieved. Confluent cultures of HCEC cells showing characteristic cobblestone morphology were apparent after 2 weeks and were passaged into T75 flasks for further expansion and use in experimental studies. AlamarBlue® assay for assessing cell metabolic activity: In brief, HCEC cells (10 k cells / well) were seeded in 96-well plates. After 24 h, HCECs were treated with concentrations (10, 100 and 1000 μg cm-3) of each microparticle composition. After 24, 48 and 96 h of treatment, cells were washed with PBS (x3) and 10% alamarBlue® in cell culture media (0.1 cm3) was added to each well and incubated under cell culture conditions for 3 h. The fluorescence was measured at 560 nm excitation, 590 nm emission and the % metabolic activity calculated. Picogreen: Following the alamarBlue® assay, all reagents were removed from the wells and an aliquot (0.05 cm3) of MilliQ H2O was added and the contents of the 96-well plates freeze- thawed (x3) at -80 °C to lyse the cells. The following reagents / samples were added to corresponding wells in a 96-well black plate for fluorescent measurements: TE buffer (1x, 0.1 cm-3), each freeze-thawed sample (0.029 cm3) and Picogreen buffer (0.071 cm3) before incubating at RT for 5 min. The fluorescence was measured at 480 nm excitation, 520 nm emission and the DNA concentration calculated using a standard curve following the manufacturer’s instructions. General Antimicrobial efficacy Testing Methodology Escherichia coli (ATCC 8739), Staphylococcus epidermidis (ATCC 12228) and Bacillus subtilis (ATCC 6051) were grown in Luria Bertani (LB) broth (5 cm3, Fisher Scientific) by adding an inoculation loop from -80 °C glycerol stocks and incubating at 37 °C overnight. An aliquot (1 cm-3) of overnight stock was added to fresh LB media for 3 h until OD600of 0.3 - 0.4 to create a working stock. The bacterial working stock solutions were used to assess antimicrobial efficacy of the microparticle formulations. Each microparticle formulation (2 mg) was suspended in 1 cm3of moxifloxacin (20 mg cm-3) overnight before centrifuging to remove the supernatant and re-suspending in PBS (1 cm3). In each well of a 96-well plate each microparticle formulation (0.05 cm3) at three different concentrations (1, 0.1 and 0.01 mg cm-3) were added along with fresh LB media (0.05 cm3). The 96-well plate was incubated for 24 h at 37 °C with OD600readings taken at 0, 2 and 21 h. At the end of each experiment (21 h) the supernatant was removed from each well and replaced with PBS (0.1 cm3). The PBS was serially diluted 102, 104, 106and 108and an aliquot (0.1 cm3) was pipetted onto an LB agar plate and spread over the plate before incubating at 37 °C overnight before counting the CFUs per plate and calculating the CFUs cm-3for each of the microparticle compositions. Suitable controls included an LB media blank and a bacterial growth control. General In vivo keratitis Testing Methodology In order to establish a microbial infection in the eyes of the mice the corneal epithelium had to be compromised. Under anaesthesia, three scratches of approx. 2 mm in length were applied to the centre of the cornea using a sterile needle. Subsequently, inoculum (5 mm3) was pipetted onto the cornea and was left on the eye for 20 min. Analgesia was applied daily by intraperitoneal injection. The inoculum consisted of multi-drug resistant Pseudomonas aeruginosa, strain 54, which had been cultured on tryptic soy blood agar (TSBA) plates for 24 h at 37 °C, then suspended in Luria Bertani (LB) broth (10 cm3, 2%) for an overnight culture at 37 °C. An aliquot of the overnight culture (0.1 cm3) was diluted in LB broth (10 cm3, 2%) for another 3 h (37 °C) of culturing and finally the suspension was adjusted to an optical density of 10 for inoculation using routine procedures (spectrophotometer, GeneQuant 100). Post-infection treatment was performed at 8 h intervals beginning 6 h post-infection. Treatment was either microparticles + meropenem, meropenem only or PBS only with the non-infected eye serving as a negative control. Treatment: Under anaesthesia (Isoflurane), the corresponding treatment (20 mm3) was applied to the infected eyes with a pipette for 2 min. Grading of corneal infections: The effect on the cornea following PA54 induced keratitis in the infected mouse eyes were examined daily under a stereomicroscope, and recorded as a clinical score using the following scale: Score 0, cornea clear; score 1, <50% cornea is semi-transparent (iris colour behind the lesion can be identified); score 2, >50% cornea is semi-transparent; score 3, <50% cornea is opaque (iris colour behind the lesion cannot be identified); score 4, >50% cornea is opaque; score 5, corneal perforation. Corneal photos were taken under a dissecting microscope when mice were anaesthetised. Bacterial load determinations: Enucleated mouse eyes were homogenised in 1 ml LB broth, and serial dilutions of this homogenate plated on TSBA. After 24 h of incubation at 37 °C, CFUs were counted. EXAMPLE 1 METHOD STEP 1 - CROSS-LINKING γ-POLYGLUTAMIC ACID WITH ε-POLYLYSINE VIA NHS AND EDC MEDIATED CONDENSATION POLYMERISATION As shown in Figure 1A, the peptidic microparticles are synthesised from γ-polyglutamic acid cross-linked to 80 mol % with ε-polylysine using NHS and EDC mediated condensation polymerisation to a polymer density of 6 g dm-3. Specifically, γ-polyglutamic acid (0.450 g, 3.15 mmol of carboxyl groups) and ε-polylysine (0.436 g, 2.52 mmol of amine groups) were weighed into separate centrifuge tubes (50 cm3) and dissolved with dH2O (10 cm3, pH 5) on a roller for 5 minutes. The two solutions were syringe filtered to 0.2 µm and then added together in a centrifuge tube (50 cm3) and the combined solution topped with dH2O to a final volume of 50 cm3before being added to a Duran bottle (250 cm3). NHS (0.218 g, 1.9 mmol) was dissolved in dH2O (10 cm3) in a centrifuge tube (15 cm3) and syringe filtered to 0.2 µm. EDC (1.090 g, 5.68 mmol) was separately dissolved in dH2O (20 cm3) in a centrifuge tube (50 cm3) and syringe filtered to 0.2 µm. The EDC and NHS were mixed together and the combined solution topped with dH2O to a final volume of 50 cm3before immediately adding to the γ-polyglutamic acid / ε-polylysine solution. This was inverted three times before leaving to polymerise for 1 h at RT. The microparticle solution was then filtered through a TFF filter membrane (Repligen, 100 kD MWCO). The molar ratio of γ-polyglutamic acid: ε-polylysine: EDC: NHS was 1: 0.8: 1.8: 0.6. Results are discussed in General Discussion section below. EXAMPLE 2 ALTERNATIVE METHOD STEP 1 - CROSS-LINKING γ-POLYGLUTAMIC ACID WITH ε- POLYLYSINE VIA SULFO-NHS AND EDC MEDIATED CONDENSATION POLYMERISATION The peptidic microparticles are synthesised from γ-polyglutamic acid cross-linked to 80 mol % with ε-polylysine using sulfo-NHS and EDC mediated condensation polymerisation to a polymer density of 6 g dm-3. Specifically, γ-polyglutamic acid (0.450 g, 3.15 mmol of carboxyl groups) and ε-polylysine (0.436 g, 2.52 mmol of amine groups) were weighed into separate centrifuge tubes (50 cm3) and dissolved with dH2O (10 cm3, pH 5) on a roller for 5 minutes. The two solutions were syringe filtered to 0.2 µm and then added together in a centrifuge tube (50 cm3) and the combined solution topped with dH2O to a final volume of 50 cm-3before being added to a Duran bottle (250 cm3). Sulfo-NHS (0.413 g, 1.9 mmol) was dissolved in dH2O (10 cm3) in a centrifuge tube (15 cm3) and syringe filtered to 0.2 µm. EDC (1.090 g, 5.68 mmol) was separately dissolved in dH2O (20 cm3) in a centrifuge tube (50 cm3) and syringe filtered to 0.2 µm. The EDC and Sulfo-NHS were mixed together and the combined solution topped with dH2O to a final volume of 50 cm3before immediately adding to the γ- polyglutamic acid / ε-polylysine solution. This was inverted three times before leaving to polymerise for 1 h at RT. The microparticle solution was then filtered through a TFF filter membrane (Repligen, 100 kD MWCO). The molar ratio of γ-polyglutamic acid: ε-polylysine: EDC: sulfo-NHS was 1: 0.8: 1.8: 0.6. The resulting microparticle solution was opaque with clumps of miccroparticles and some mono-dispersed microparticles observed of approx.10 µm in diameter. EXAMPLE 3 ALTERNATIVE METHOD STEP 1 - CROSS-LINKING γ-POLYGLUTAMIC ACID WITH ε- POLYLYSINE VIA DMTMM MEDIATED POLYMERISATION The peptidic microparticles are synthesised from γ-polyglutamic acid cross-linked to 80 mol % with ε-polylysine using DMTMM mediated polymerisation to a polymer density of 6 g dm-3. Specifically, γ-polyglutamic acid (0.450 g, 3.15 mmol of carboxyl groups) and ε-polylysine (0.436 g, 2.52 mmol of amine groups) were weighed into separate centrifuge tubes (50 cm3) and dissolved with dH2O (10 cm3, pH 5) on a roller for 5 minutes. The two solutions were syringe filtered to 0.2 µm and then added together in a centrifuge tube (50 cm3) and the combined solution topped with dH2O to a final volume of 50 cm3before being added to a Duran bottle (250 cm3). DMTMM (0.697 g, 2.55 mmol) was separately dissolved in dH2O (30 cm3) in a centrifuge tube (50 cm3) and syringe filtered to 0.2 µm. The DMTMM solution was topped with dH2O to a final volume of 50 cm3before immediately adding to the γ-polyglutamic acid / ε-polylysine solution. This was inverted three times before leaving to polymerise for 1 h at RT. The microparticle solution was then filtered through a TFF filter membrane (Repligen, 100 kD MWCO). The molar ratio of γ-polyglutamic acid: ε-polylysine: DMTMM was 1: 0.8: 0.8. The resulting microparticle solution was opaque with clumps of miccroparticles and some mono-dispersed microparticles observed of approx.10 µm in diameter. COMPARATIVE EXAMPLE 1 METHOD STEP 1 - CROSS-LINKING γ-POLYGLUTAMIC ACID WITH ε-POLYLYSINE VIA NHS AND EDC MEDIATED CONDENSATION POLYMERISATION The peptidic microparticles are synthesised from γ-polyglutamic acid cross-linked to 80 mol % with ε-polylysine using NHS and EDC mediated condensation polymerisation to a polymer density of 60 g dm-3. Specifically, γ-polyglutamic acid (0.450 g, 3.15 mmol of carboxyl groups) and ε-polylysine (0.436 g, 2.52 mmol of amine groups) were weighed into separate centrifuge tubes (15 cm3) and dissolved with dH2O (2.5 cm3, pH 6) on a roller for 5 minutes. The two solutions were syringe filtered to 0.2 µm and then added together in a centrifuge tube (50 cm3) and the combined solution topped with dH2O to a final volume of 5 cm3. NHS (0.327 g, 2.85 mmol) was dissolved in dH2O (1 cm3) in a centrifuge tube (15 cm3) and syringe filtered to 0.2 µm. EDC (0.219 g, 1.14 mmol) was separately dissolved in dH2O (4 cm3) in a centrifuge tube (15 cm3) and syringe filtered to 0.2 µm. The EDC and NHS were mixed together and the combined solution topped with dH2O to a final volume of 10 cm3before immediately adding to the γ-polyglutamic acid / ε-polylysine solution. This was inverted three times before leaving to polymerise for 4 h at RT. The molar ratio of γ-polyglutamic acid: ε-polylysine: EDC: NHS was 1: 0.8: 0.36: 0.9. This polymer formulation consisted of an increase in the amount of NHS and a decrease in the amount of EDC in relation to Example 1. It resulted in the formation of amorphous polymer lumps and no evidence of mono-dispersed microparticles. Results are discussed in General Discussion section below. COMPARATIVE EXAMPLE 2 METHOD STEP 1 - CROSS-LINKING γ-POLYGLUTAMIC ACID WITH ε-POLYLYSINE VIA NHS AND EDC MEDIATED CONDENSATION POLYMERISATION The peptidic microparticles are synthesised from γ-polyglutamic acid cross-linked to 105 mol % with ε-polylysine using NHS and EDC mediated condensation polymerisation to a polymer density of 20 g dm-3. Specifically, γ-polyglutamic acid (0.135 g, 0.95 mmol of carboxyl groups) and ε-polylysine (0.173 g, 1.00 mmol of amine groups) were weighed into separate centrifuge tubes (15 cm3) and dissolved with dH2O (2.5 cm3, pH 6) on a roller for 5 minutes. The two solutions were syringe filtered to 0.2 µm and then added together in a centrifuge tube (50 cm3) and the combined solution topped with dH2O to a final volume of 5 cm3. NHS (0.066 g, 0.57 mmol) was dissolved in dH2O (1 cm3) in a centrifuge tube (15 cm3) and syringe filtered to 0.2 µm. EDC (0.430 g, 2.24 mmol) was separately dissolved in dH2O (4 cm3) in a centrifuge tube (15 cm3) and syringe filtered to 0.2 µm. The EDC and NHS were mixed together and the combined solution topped with dH2O to a final volume of 10 cm3before immediately adding to the γ-polyglutamic acid / ε-polylysine solution. This was inverted three times before leaving to polymerise for 4 h at RT. The molar ratio of γ-polyglutamic acid: ε-polylysine: EDC: NHS was 1: 1.05: 2.35: 0.6. This polymer formulation consisted of an increase in the amount of ε-polylysine and EDC in relation to Example 1. It resulted in the formation of macroporous polymer sheet and no evidence of mono-dispersed microparticles. The microparticles appear to have fused together to form the sheet as evidenced in Figure 10. Results are discussed in General Discussion section below. EXAMPLE 4 METHOD STEP 2 – γ-POLYGLUTAMIC ACID-CO-ε-POLYLYSINE MICROPARTICLE SURFACE MODIFICATION WITH CYSTEINE As shown in Figure 1A, the γ-polyglutamic acid-co-ε-polylysine microparticles from Example 1 were thiolated by covalently binding cysteine to them using the NHS and EDC mediated condensation polymerisation chemistry described in Example 1. Three different concentrations of cysteine were separately covalently bound to γ-polyglutamic acid-co-ε- polylysine microparticles via their available amine sites. The microparticles (100 mg) were placed in a Duran bottle (200 cm3) and re-suspended with dH2O (60 cm3) before adding an aqueous solution (20 cm3) of cysteine (28 or 56 or 224 mg) followed by an aqueous solution (20 cm3) of EDC (43.75 or 87.5 or 350 mg) / NHS (5.25 or 10.5 or 42 mg) mixing and leaving for 1 h at RT. The microparticle solution was then filtered through a TFF filter membrane (Repligen, 100 kD MWCO). The molar ratio of cysteine (0.23 or 0.46 or 1.84 mmol): EDC: NHS was 1: 1: 0.2. Table 1 Results are discussed in General Discussion section below. EXAMPLE 5 ALTERNATIVE METHOD STEP 2 – γ-POLYGLUTAMIC ACID-CO-ε-POLYLYSINE MICROPARTICLE SURFACE MODIFICATION WITH OCTANOIC ACID As shown in Figure 1B, the γ-polyglutamic acid-co-ε-polylysine microparticle surface from Example 1 was made more hydrophobic by covalently binding octanoic acid to them using NHS and EDC mediated condensation polymerisation chemistry described in Example 1. Three different concentrations of octanoic acid were separately covalently bound to γ- polyglutamic acid-co-ε-polylysine microparticles via their available amine sites. The microparticles (100 mg) were placed in a Duran bottle (200 cm3) and re-suspended with dH2O (60 cm3) before adding an aqueous solution (20 cm3) of octanoic acid (48 or 96 or 192 mg) followed by an aqueous solution (20 cm3) of EDC (43.75 or 87.5 or 350 mg) / NHS (5.25 or 10.5 or 42 mg) mixing and leaving for 1 h at RT. The microparticle solution was then filtered through a TFF filter membrane (Repligen, 100 kD MWCO). The molar ratio of octanoic acid (0.33 or 1.19 or 4.74 mmol): EDC: NHS was 1: 0.75: 0.14. Table 2 Results are discussed in General Discussion section below. EXAMPLE 6 ALTERNATIVE METHOD STEP 2 – γ-POLYGLUTAMIC ACID-CO-ε-POLYLYSINE MICROPARTICLE SURFACE MODIFICATION WITH ε-POLYLYSINE As shown in Figure 1C, the γ-polyglutamic acid-co-ε-polylysine microparticles from Example 1 were positively charged by covalently binding ε-polylysine to them using the NHS and EDC mediated condensation polymerisation chemistry described in Example 1. Three different concentrations of ε-polylysine were separately covalently bound to γ-polyglutamic acid-co-ε- polylysine microparticles via their available amine sites. The microparticles (100 mg) were placed in a Duran bottle (200 cm3) and re-suspended with dH2O (60 cm3) before adding an aqueous solution (20 cm3) of ε-polylysine (988 or 1980 or 7920 mg) followed by an aqueous solution (20 cm3) of EDC (43.75 or 87.5 or 350 mg) / NHS (5.25 or 10.5 or 42 mg) mixing and leaving for 1 h at RT. The microparticle solution was then filtered through a TFF filter membrane (Repligen, 100 kD MWCO). The molar ratio of ε-polylysine (0.272 or 0.545 or 2.18 mmol): EDC: NHS was 1: 0.84: 0.2. Table 3 Results are discussed in General Discussion section below. EXAMPLE 7 METHOD STEP 3 – γ-POLYGLUTAMIC ACID-CO-ε-POLYLYSINE MICROPARTICLES WITH CYSTEINE AND ELECTROSTATIC ABSORPTION OF CIPROFLOXACIN, MOXIFLOXACIN OR MEROPENEM The methodology of example 4 was followed to result in thiolated γ-polyglutamic acid-co-ε- polylysine microparticles which were then further modified by electrostatic absorption of various antimicrobials including ciprofloxacin, moxifloxacin or meropenem. The γ-polyglutamic acid-co-ε-polylysine microparticles (10 mg cm-3) were incubated in a solution of each antibiotic (10 mg cm-3) individually. The microparticles (10 mg) were placed in a centrifuge tube (1.5 cm3) and re-suspended with dH2O (0.5 cm3) before adding an aqueous solution (0.5 cm3) of ciprofloxacin, moxifloxacin or meropenem (10 mg) before mixing and leaving overnight at 5 °C. The microparticle solution was then centrifuged and the supernatant removed before re-suspending in PBS (1 cm3) to obtain a solution of microparticles and each individually associated antibiotic (10 mg cm-3). Results are discussed in General Discussion section below. EXAMPLE 8 ALTERNATIVE METHOD STEP 3 – γ-POLYGLUTAMIC ACID-CO-ε-POLYLYSINE MICROPARTICLES WITH OCTANOIC ACID AND ELECTOSTATIC ABSORPTION OF CIPROFLOXACIN OR MOXIFLOXACIN The methodology of example 5 was followed to result in hydrophobic γ-polyglutamic acid-co- ε-polylysine microparticles which were then further modified by electrostatic absorption of various antimicrobials including ciprofloxacin or moxifloxacin. The γ-polyglutamic acid-co-ε-polylysine microparticles (10 mg cm-3) were incubated in a solution of each antibiotic (10 mg cm-3) individually. The microparticles (10 mg) were placed in a centrifuge tube (1.5 cm3) and re-suspended with dH2O (0.5 cm3) before adding an aqueous solution (0.5 cm3) of ciprofloxacin or moxifloxacin (10 mg) before mixing and leaving overnight at 5 °C. The microparticle solution was then centrifuged and the supernatant removed before re-suspending in PBS (1 cm3) to obtain a solution of microparticles and each individually associated antibiotic (10 mg cm-3). Results are discussed in General Discussion section below. EXAMPLE 9 ALTERNATIVE METHOD STEP 3 – γ-POLYGLUTAMIC ACID-CO-ε-POLYLYSINE MICROPARTICLES WITH ε-POLYLYSINE AND ELECTOSTATIC ABSORPTION OF CIPROFLOXACIN OR MOXIFLOXACIN The methodology of example 6 was followed to result in positively charged γ-polyglutamic acid-co-ε-polylysine microparticles which were then further modified by electrostatic absorption of various antimicrobials including ciprofloxacin or moxifloxacin. The γ-polyglutamic acid-co-ε-polylysine microparticles (10 mg cm-3) were incubated in a solution of each antibiotic (10 mg cm-3) individually. The microparticles (10 mg) were placed in a centrifuge tube (1.5 cm3) and re-suspended with dH2O (0.5 cm3) before adding an aqueous solution (0.5 cm3) of ciprofloxacin or moxifloxacin (10 mg) before mixing and leaving overnight at 5 °C. The microparticle solution was then centrifuged and the supernatant removed before re-suspending in PBS (1 cm3) to obtain a solution of microparticles and each individually associated antibiotic (10 mg cm-3). Results are discussed in General Discussion section below. EXAMPLE 10 ALTERNATIVE METHOD STEP 1 - CROSS-LINKING γ-POLYGLUTAMIC ACID WITH ε- POLYLYSINE VIA NHS AND EDC MEDIATED CONDENSATION POLYMERISATION The methodology of Example 1 was followed, except the polymer density was 5-fold less (1.2 g dm-3). The peptidic microparticles are synthesised from γ-polyglutamic acid cross- linked to 80 mol % with ε-polylysine using NHS and EDC mediated condensation polymerisation. Specifically, γ-polyglutamic acid (0.450 g, 3.15 mmol of carboxyl groups) and ε-polylysine (0.436 g, 2.52 mmol of amine groups) were weighed into separate centrifuge tubes (50 cm3) and dissolved with dH2O (10 cm3, pH 5) on a roller for 5 minutes. The two solutions were syringe filtered to 0.2 µm and then added together in a Duran bottle (500 cm3) and the combined solution topped with dH2O to a final volume of 450 cm3. NHS (0.218 g, 1.9 mmol) was dissolved in dH2O (10 cm3) in a centrifuge tube (15 cm3) and syringe filtered to 0.2 µm. EDC (1.090 g, 5.68 mmol) was separately dissolved in dH2O (20 cm3) in a centrifuge tube (50 cm3) and syringe filtered to 0.2 µm. The EDC and NHS were mixed together and the combined solution topped with dH2O to a final volume of 50 cm3before immediately adding to the γ-polyglutamic acid / ε-polylysine solution. This was inverted three times before leaving to polymerise for 1 h at RT. The microparticle solution was then filtered through a TFF filter membrane (Repligen, 100 kD MWCO). The molar ratio of γ-polyglutamic acid: ε- polylysine: EDC: NHS was 1: 0.8: 1.8: 0.6. This polymer formulation consisted of decrease in the polymer density. It resulted in the formation of mono-dispersed microparticles at a higher dilution to aid flow through the subsequent filtration system. EXAMPLE 11 ALTERNATIVE METHOD STEP 1 - CROSS-LINKING γ-POLYGLUTAMIC ACID WITH ε- POLYLYSINE VIA NHS AND EDC MEDIATED CONDENSATION POLYMERISATION The methodology of Example 1 was followed, except the molar ratio of γ-polyglutamic acid: ε-polylysine: EDC: NHS was 1: 0.8: 1.65: 0.27 and a polymer density of 1.2 g dm-3. The peptidic microparticles are synthesised from γ-polyglutamic acid cross-linked to 80 mol % with ε-polylysine using NHS and EDC mediated condensation polymerisation. Specifically, γ-polyglutamic acid (0.450 g, 3.15 mmol of carboxyl groups) and ε-polylysine (0.436 g, 2.52 mmol of amine groups) were weighed into separate centrifuge tubes (50 cm3) and dissolved with dH2O (10 cm3, pH 5) on a roller for 5 minutes. The two solutions were syringe filtered to 0.2 µm and then added together in a Duran bottle (500 cm3) and the combined solution topped with dH2O to a final volume of 450 cm3. NHS (0.100 g, 0.87 mmol) was dissolved in dH2O (10 cm3) in a centrifuge tube (15 cm3) and syringe filtered to 0.2 µm. EDC (1.000 g, 5.22 mmol) was separately dissolved in dH2O (20 cm3) in a centrifuge tube (50 cm3) and syringe filtered to 0.2 µm. The EDC and NHS were mixed together and the combined solution topped with dH2O to a final volume of 50 cm3before immediately adding to the γ-polyglutamic acid / ε-polylysine solution. This was inverted three times before leaving to polymerise for 1 h at RT. The microparticle solution was then filtered through a TFF filter membrane (Repligen, 100 kD MWCO). The molar ratio of γ-polyglutamic acid: ε-polylysine: EDC: NHS was 1: 0.8: 1.65: 0.27. The resulting microparticle solution was transparent, however, when the solution was placed under a light microscope, mono-dispersed microparticles were observed of approx.10 µm in diameter. EXAMPLE 12 ALTERNATIVE METHOD STEP 1 - CROSS-LINKING γ-POLYGLUTAMIC ACID WITH ε- POLYLYSINE VIA NHS AND EDC MEDIATED CONDENSATION POLYMERISATION The peptidic microparticles are synthesised from γ-polyglutamic acid cross-linked to 80 mol % with ε-polylysine using NHS and EDC mediated condensation polymerisation to a polymer density of 6 g dm-3using γ-polyglutamic acid with a molecular weight of either 10 kDa, 200 - 500 kDa or 700 kDa. Specifically, γ-polyglutamic acid (0.450 g, 3.15 mmol of carboxyl groups) and ε-polylysine (0.436 g, 2.52 mmol of amine groups) were weighed into separate centrifuge tubes (50 cm3) and dissolved with dH2O (10 cm3, pH 5) on a roller for 5 minutes. The two solutions were syringe filtered to 0.2 µm and then added together in a centrifuge tube (50 cm3) and the combined solution topped with dH2O to a final volume of 50 cm3before being added to a Duran bottle (250 cm3). NHS (0.218 g, 1.9 mmol) was dissolved in dH2O (10 cm3) in a centrifuge tube (15 cm3) and syringe filtered to 0.2 µm. EDC (1.090 g, 5.68 mmol) was separately dissolved in dH2O (20 cm3) in a centrifuge tube (50 cm3) and syringe filtered to 0.2 µm. The EDC and NHS were mixed together and the combined solution topped with dH2O to a final volume of 50 cm3before immediately adding to the γ-polyglutamic acid / ε- polylysine solution. This was inverted three times before leaving to polymerise for 1 h at RT. The molar ratio of γ-polyglutamic acid: ε-polylysine: EDC: NHS was 1: 0.8: 1.8: 0.6. This polymer formulations consisted of differing molecular weights of γ-polyglutamic acid (10 kDa, 200 - 500 kDa or 700 kDa) in relation to Example 1 (0.8 - 1.5 kDa. It resulted in the formation of amorphous polymer lumps and mono-dispersed microparticles in an opaque solution. The ratio of polymer lumps to microparticles increased as the molecular weights increased as observed in Figure 11. EXAMPLE 13 ALTERNATIVE METHOD STEP 1 - CROSS-LINKING γ-POLYGLUTAMIC ACID WITH ε- POLYLYSINE VIA NHS AND EDC MEDIATED CONDENSATION POLYMERISATION The peptidic microparticles are synthesised from γ-polyglutamic acid cross-linked to 60 mol % with ε-polylysine using NHS and EDC mediated condensation polymerisation to a polymer density of 72 g dm-3. Specifically, γ-polyglutamic acid (0.598 g, 4.19 mmol of carboxyl groups) and ε-polylysine (0.436 g, 2.52 mmol of amine groups) were weighed into separate centrifuge tubes (15 cm3) and dissolved with dH2O (2.5 cm3, pH 6) on a roller for 5 minutes. The two solutions were syringe filtered to 0.2 µm and then added together in a centrifuge tube (50 cm3) and the combined solution topped with dH2O to a final volume of 5 cm3. NHS (0.218 g, 1.9 mmol) was dissolved in dH2O (1 cm3) in a centrifuge tube (15 cm3) and syringe filtered to 0.2 µm. EDC (1.090 g, 5.68 mmol) was separately dissolved in dH2O (4 cm3) in a centrifuge tube (15 cm3) and syringe filtered to 0.2 µm. The EDC and NHS were mixed together and the combined solution topped with dH2O to a final volume of 5 cm3before immediately adding to the γ-polyglutamic acid / ε-polylysine solution. This was inverted three times before leaving to polymerise for 1 h at RT. The molar ratio of γ-polyglutamic acid: ε-polylysine: EDC: NHS was 1: 0.73: 1.35: 0.6. This polymer formulation consisted of an increase in the polymer density and a decrease in the mol % cross-linking in relation to Example 1. It resulted in the formation of amorphous polymer lumps and mono-dispersed microparticles in an opaque solution. EXAMPLE 14 ALTERNATIVE METHOD STEP 1 - CROSS-LINKING γ-POLYGLUTAMIC ACID WITH ε- POLYLYSINE VIA NHS AND EDC MEDIATED CONDENSATION POLYMERISATION The peptidic microparticles are synthesised from γ-polyglutamic acid cross-linked to 80 mol % with ε-polylysine using NHS and EDC mediated condensation polymerisation to a polymer density of 60 g dm-3. Specifically, γ-polyglutamic acid (0.450 g, 3.15 mmol of carboxyl groups) and ε-polylysine (0.436 g, 2.52 mmol of amine groups) were weighed into separate centrifuge tubes (15 cm3) and dissolved with dH2O (2.5 cm3, pH 6) on a roller for 5 minutes. The two solutions were syringe filtered to 0.2 µm and then added together in a centrifuge tube (50 cm3) and the combined solution topped with dH2O to a final volume of 5 cm3. NHS NHS (0.218 g, 1.9 mmol) was dissolved in dH2O (1 cm3) in a centrifuge tube (15 cm3) and syringe filtered to 0.2 µm. EDC (0.545 g, 2.84 mmol) was separately dissolved in dH2O (4 cm3) in a centrifuge tube (15 cm3) and syringe filtered to 0.2 µm. The EDC and NHS were mixed together and the combined solution topped with dH2O to a final volume of 10 cm3before immediately adding to the γ-polyglutamic acid / ε-polylysine solution. This was inverted three times before leaving to polymerise for 1 h at RT. The molar ratio of γ-polyglutamic acid: ε- polylysine: EDC: NHS was 1: 0.8: 0.9: 0.6. This polymer formulation consisted of a decrease in the amount of EDC in relation to Example 1. It resulted in the formation of amorphous polymer lumps and mono-dispersed microparticles in an opaque solution. EXAMPLE 15 TO EXAMPLE 35 MATERIALS All materials listed below are commercially available: polyarginine (PLA, average Mw ~ 5 – 15 kDa) hyaluronic acid (HA, average Mw ~ 10 kDa or 500 kDa) γ-polyglutamic acid (γ-PGA, average Mw ~ 10 kDa) polyhistidine (PHIS, average Mw ~ 5 - 25 kDa) polyaspartic acid (PASP, average Mw ~ 2 - 11 kDa) polyalanine (PALA, average Mw ~ 1 - 5 kDa) α-polylysine (α-PL, average Mw ~ 150 - 300 kDa) aspartic acid lysine arginine amphotericin B natamycin cyclosporine chlorhexidine ketotifen ibuprofen mannitol EXAMPLE 15 ALTERNATIVE METHOD STEP 1 - CROSS-LINKING γ-POLYGLUTAMIC ACID WITH POLYARGININE VIA NHS AND EDC MEDIATED CONDENSATION POLYMERISATION The methodology of Example 10 was followed, except polyarginine replaced ε-polylysine and the scale of the reaction was reduced to 1 / 50. The peptidic microparticles are synthesised from γ-polyglutamic acid cross-linked to 80 mol % with polyarginine using NHS and EDC mediated condensation polymerisation to a polymer density of 1.2 g dm-3. Specifically, γ- polyglutamic acid (9.0 mg, 0.063 mmol of carboxyl groups) and polyarginine (10.5 mg, 0.050 mmol of guanidino groups) were weighed into separate centrifuge tubes (15 cm3) and dissolved with dH2O (2.5 cm3, pH 5) on a roller for 5 minutes. The two solutions were syringe filtered to 0.2 µm and then added together in a centrifuge tube (15 cm3) and the combined solution topped with dH2O to a final volume of 5 cm3. NHS (4.4 mg, 0.038 mmol) was dissolved in dH2O (2.5 cm3) in a centrifuge tube (15 cm3) and syringe filtered to 0.2 µm. EDC (21.8 mg, 0.114 mmol) was separately dissolved in dH2O (2.5 cm3) in a centrifuge tube (15 cm3) and syringe filtered to 0.2 µm. The EDC and NHS were mixed together and the combined solution topped with dH2O to a final volume of 5 cm3before immediately adding to the γ-polyglutamic acid / polyarginine solution. This was inverted three times before leaving to polymerise for 1 h at RT. The microparticle solution was then filtered through a dialysis membrane (Repligen, 1000 kD MWCO). The molar ratio of γ-polyglutamic acid: polyarginine: EDC: NHS was 1: 0.8: 1.8: 0.6. Results are shown in Figure 16 and discussed in General Discussion section below. Microparticle formation was observed. This was due to γ-polyglutamic acid having a negatively charged carboxylic acid group and polyarginine containing a positively charged guanidino group. This allowed amide bond formation via condensation polymerisation critical for stable microparticle formation. EXAMPLE 16 ALTERNATIVE METHOD STEP 1 - CROSS-LINKING γ-POLYGLUTAMIC ACID WITH POLYHISTIDINE VIA NHS AND EDC MEDIATED CONDENSATION POLYMERISATION The methodology of Example 10 was followed, except polyhistidine replaced ε-polylysine and the scale of the reaction was reduced to 1 / 50. The peptidic microparticles are synthesised from γ-polyglutamic acid cross-linked to 80 mol % with polyhistidine using NHS and EDC mediated condensation polymerisation to a polymer density of 1.2 g dm-3. Specifically, γ-polyglutamic acid (9.0 mg, 0.063 mmol of carboxyl groups) and polyhistidine (7.8 mg, 0.050 mmol of imidazole groups) were weighed into separate centrifuge tubes (15 cm3) and dissolved with dH2O (2.5 cm3, pH 5) on a roller for 5 minutes. The two solutions were syringe filtered to 0.2 µm and then added together in a centrifuge tube (15 cm3) and the combined solution topped with dH2O to a final volume of 5 cm3. NHS (4.4 mg, 0.038 mmol) was dissolved in dH2O (2.5 cm3) in a centrifuge tube (15 cm3) and syringe filtered to 0.2 µm. EDC (21.8 mg, 0.114 mmol) was separately dissolved in dH2O (2.5 cm3) in a centrifuge tube (15 cm3) and syringe filtered to 0.2 µm. The EDC and NHS were mixed together and the combined solution topped with dH2O to a final volume of 5 cm3before immediately adding to the γ-polyglutamic acid / polyhistidine solution. This was inverted three times before leaving to polymerise for 1 h at RT. The microparticle solution was then filtered through a dialysis membrane (Repligen, 1000 kD MWCO). The molar ratio of γ-polyglutamic acid: polyhistidine: EDC: NHS was 1: 0.8: 1.8: 0.6. Results are shown in Figure 17 and discussed in General Discussion section below. Microparticle formation was observed as well as polymer clumps. This was due to γ- polyglutamic acid having a negatively charged carboxylic acid group and polyhistidine containing a positively charged imidazole group. This allowed amide bond formation via condensation polymerisation critical for stable microparticle formation. EXAMPLE 17 ALTERNATIVE METHOD STEP 1 - CROSS-LINKING γ-POLYGLUTAMIC ACID WITH POLYASPARTIC ACID VIA NHS AND EDC MEDIATED CONDENSATION POLYMERISATION The methodology of Example 10 was followed, except polyaspartic acid replaced ε-polylysine and the scale of the reaction was reduced to 1 / 50. Peptidic microparticles are synthesised from γ-polyglutamic acid cross-linked to 80 mol % with polyaspartic acid using NHS and EDC mediated condensation polymerisation to a polymer density of 1.2 g dm-3. Specifically, γ- polyglutamic acid (9.0 mg, 0.063 mmol of carboxyl groups) and polyaspartic acid (7.8 mg, 0.050 mmol of carboxyl groups) were weighed into separate centrifuge tubes (15 cm3) and dissolved with dH2O (2.5 cm3, pH 5) on a roller for 5 minutes. The two solutions were syringe filtered to 0.2 µm and then added together in a centrifuge tube (15 cm3) and the combined solution topped with dH2O to a final volume of 5 cm3. NHS (4.4 mg, 0.038 mmol) was dissolved in dH2O (2.5 cm3) in a centrifuge tube (15 cm3) and syringe filtered to 0.2 µm. EDC (21.8 mg, 0.114 mmol) was separately dissolved in dH2O (2.5 cm3) in a centrifuge tube (15 cm3) and syringe filtered to 0.2 µm. The EDC and NHS were mixed together and the combined solution topped with dH2O to a final volume of 5 cm3before immediately adding to the γ-polyglutamic acid / polyaspartic acid solution. This was inverted three times before leaving to polymerise for 1 h at RT. The solution was then filtered through a dialysis membrane (Repligen, 1000 kD MWCO). The molar ratio of γ-polyglutamic acid: polyaspartic acid: EDC: NHS was 1: 0.8: 1.8: 0.6. Results are shown in Figure 14 and discussed in General Discussion section below. Microparticle formation was observed. This was due to polyaspartic acid having a negatively charged carboxylic acid group and ε-polylysine containing a positively charged amine group. This allowed amide bond formation via condensation polymerisation critical for stable microparticle formation. COMPARATIVE EXAMPLE 3 ALTERNATIVE METHOD STEP 1 - CROSS-LINKING γ-POLYGLUTAMIC ACID WITH POLYALANINE VIA NHS AND EDC MEDIATED CONDENSATION POLYMERISATION The methodology of Example 10 was followed, except polyalanine replaced ε-polylysine and the scale of the reaction was reduced to 1 / 50. The methodology involved γ-polyglutamic acid cross-linked to 80 mol % with polyalanine using NHS and EDC mediated condensation polymerisation to a polymer density of 1.2 g dm-3. Specifically, γ-polyglutamic acid (9.0 mg, 0.063 mmol of carboxyl groups) and polyalanine (4.5 mg, 0.050 mmol) were weighed into separate centrifuge tubes (15 cm3) and dissolved with dH2O (2.5 cm3, pH 5) on a roller for 5 minutes. The two solutions were syringe filtered to 0.2 µm and then added together in a centrifuge tube (15 cm3) and the combined solution topped with dH2O to a final volume of 5 cm3. NHS (4.4 mg, 0.038 mmol) was dissolved in dH2O (2.5 cm3) in a centrifuge tube (15 cm3) and syringe filtered to 0.2 µm. EDC (21.8 mg, 0.114 mmol) was separately dissolved in dH2O (2.5 cm3) in a centrifuge tube (15 cm3) and syringe filtered to 0.2 µm. The EDC and NHS were mixed together and the combined solution topped with dH2O to a final volume of 5 cm3before immediately adding to the γ-polyglutamic acid / polyalanine solution. This was inverted three times before leaving to polymerise for 1 h at RT. The solution was then filtered through a dialysis membrane (Repligen, 1000 kD MWCO). The molar ratio of γ-polyglutamic acid: polyalanine: EDC: NHS was 1: 0.8: 1.8: 0.6. No evidence of polymer formation was observed due to γ-polyglutamic acid having a negatively charged carboxylic acid group and polyalanine having a neutral, hydrophobic side chain. This inhibited amide bond formation via condensation polymerisation critical for stable microparticle formation. EXAMPLE 18 ALTERNATIVE METHOD STEP 1 - CROSS-LINKING γ-POLYGLUTAMIC ACID WITH α- POLYLYSINE VIA NHS AND EDC MEDIATED CONDENSATION POLYMERISATION The methodology of Example 10 was followed, except α-polylysine replaced ε-polylysine and the scale of the reaction was reduced to 1 / 50. The peptidic microparticles are synthesised from γ-polyglutamic acid cross-linked to 80 mol % with α-polylysine using NHS and EDC mediated condensation polymerisation to a polymer density of 1.2 g dm-3. Specifically, γ- polyglutamic acid (9.0 mg, 0.063 mmol of carboxyl groups) and α-polylysine (8.7 mg, 0.050 mmol of amine groups) were weighed into separate centrifuge tubes (15 cm3) and dissolved with dH2O (2.5 cm3, pH 5) on a roller for 5 minutes. The two solutions were syringe filtered to 0.2 µm and then added together in a centrifuge tube (15 cm3) and the combined solution topped with dH2O to a final volume of 5 cm3. NHS (4.4 mg, 0.038 mmol) was dissolved in dH2O (2.5 cm3) in a centrifuge tube (15 cm3) and syringe filtered to 0.2 µm. EDC (21.8 mg, 0.114 mmol) was separately dissolved in dH2O (2.5 cm3) in a centrifuge tube (15 cm3) and syringe filtered to 0.2 µm. The EDC and NHS were mixed together and the combined solution topped with dH2O to a final volume of 5 cm3before immediately adding to the γ-polyglutamic acid / α-polylysine solution. This was inverted three times before leaving to polymerise for 1 h at RT. The microparticle solution was then filtered through a dialysis membrane (Repligen, 1000 kD MWCO). The molar ratio of γ-polyglutamic acid: α-polylysine: EDC: NHS was 1: 0.8: 1.8: 0.6. Results are shown in Figure 15 and discussed in General Discussion section below. Microparticle formation was observed. This was due to γ-polyglutamic acid having a negatively charged carboxylic acid group and α-polylysine containing a positively charged amine group. This allowed amide bond formation via condensation polymerisation critical for stable microparticle formation. EXAMPLE 19 ALTERNATIVE METHOD STEP 2 – γ-POLYGLUTAMIC ACID-CO-ε-POLYLYSINE MICROPARTICLE SURFACE MODIFICATION WITH γ-POLYGLUTAMIC ACID The γ-polyglutamic acid-co-ε-polylysine microparticles from Example 1 were negatively charged by covalently binding γ-polyglutamic acid to them using the NHS and EDC mediated condensation polymerisation chemistry described in Example 1. γ-Polyglutamic acid (10 kDa) was covalently bound to γ-polyglutamic acid-co-ε-polylysine microparticles via their available amine sites. The microparticles (5 mg) were placed in an Eppendorf tube (1.5 cm3) and re-suspended with dH2O (0.5 cm3) before adding an aqueous solution (0.25 cm3) of γ- polyglutamic acid (300 mg, 2.10 mmol) followed by an aqueous solution (0.25 cm3) of EDC (8.0 mg, 0.042 mmol) / NHS (2.2 mg, 0.019 mmol) mixing and leaving for 1 h at RT. The microparticle solution was then filtered through a dialysis membrane (Repligen, 1000 kD MWCO). The molar ratio of γ-polyglutamic acid: EDC: NHS was 1: 0.02: 0.01. A negative zeta potential (-9.31 mV) was observed from the microparticles. This was due to γ-polyglutamic acid having negatively charged carboxylic acid groups. EXAMPLE 20 ALTERNATIVE METHOD STEP 2 – γ-POLYGLUTAMIC ACID-CO-ε-POLYLYSINE MICROPARTICLE SURFACE MODIFICATION WITH HYALURONIC ACID The γ-polyglutamic acid-co-ε-polylysine microparticles from Example 1 were negatively charged by covalently binding hyaluronic acid to them using the NHS and EDC mediated condensation polymerisation chemistry described in Example 1. Hyaluronic acid (10 or 500 kDa) was covalently bound to γ-polyglutamic acid-co-ε-polylysine microparticles via their available amine sites. The γ-polyglutamic acid-co-ε-polylysine microparticles (10 mg cm-3) were incubated in a solution of each hyaluronic acid mw (5 mg cm-3) individually. The microparticles (0.5 cm3) were placed in a centrifuge tube (1.5 cm3) before adding an aqueous solution (0.5 cm3) of hyaluronic acid followed by an aqueous solution (0.25 cm3) of EDC (18 mg, 0.095 mmol) / NHS (2.0 mg, 0.017 mmol) before mixing and leaving overnight at RT. The microparticle solution was washed through a filter membrane (0.4 µm) to remove unbound hyaluronic acid and obtain a solution of microparticles with bound hyaluronic acid (10 mg cm-3). Results are shown in Figure 18 and discussed in General Discussion section below. A negative zeta potential (-31.25 mV) was observed from the microparticles. This was due to large molecules of hyaluronic acid having negatively charged hydroxyl groups. EXAMPLE 21 ALTERNATIVE METHOD STEP 2 – γ-POLYGLUTAMIC ACID-CO-ε-POLYLYSINE MICROPARTICLE SURFACE MODIFICATION WITH POLYARGININE The γ-polyglutamic acid-co-ε-polylysine microparticles from Example 1 were positively charged by covalently binding polyarginine to them using the NHS and EDC mediated condensation polymerisation chemistry described in Example 1. Polyarginine was covalently bound to γ-polyglutamic acid-co-ε-polylysine microparticles via their available carboxylic acid sites. The γ-polyglutamic acid-co-ε-polylysine microparticles (1 cm3of 5 mg cm-3) were placed in an Eppendorf tube (1.5 cm3) before adding polyarginine (0.8 mg, 0.004 mmol) followed by an aqueous solution (0.25 cm3) of EDC (4.4 mg, 0.023 mmol) / NHS (0.5 mg, 0.005 mmol) mixing and leaving for 1 h at RT. The microparticle solution was then centrifuged (3,000 x g for 5 mins) to remove unbound material. The molar ratio of polyarginine: EDC: NHS was 1: 0.02: 0.01. A positive zeta potential (21.30 mV) was observed from the microparticles. This was due to polyarginine containing positively charged guanidino groups. EXAMPLE 22 ALTERNATIVE METHOD STEP 2 – γ-POLYGLUTAMIC ACID-CO-ε-POLYLYSINE MICROPARTICLE SURFACE MODIFICATION WITH POLYASPARTIC ACID The γ-polyglutamic acid-co-ε-polylysine microparticles from Example 1 were negatively charged by covalently binding polyaspartic acid to them using the NHS and EDC mediated condensation polymerisation chemistry described in Example 1. Polyaspartic acid was covalently bound to γ-polyglutamic acid-co-ε-polylysine microparticles via their available amine sites. The γ-polyglutamic acid-co-ε-polylysine microparticles (1 cm3of 5 mg cm-3) were placed in an Eppendorf tube (1.5 cm3) before adding polyaspartic acid (3.6 mg, 0.023 mmol) followed by an aqueous solution (0.25 cm3) of EDC (4.4 mg, 0.023 mmol) / NHS (0.5 mg, 0.005 mmol) mixing and leaving for 1 h at RT. The microparticle solution was then centrifuged (3,000 x g for 5 mins) to remove unbound material. The molar ratio of polyaspartic acid: EDC: NHS was 1: 0.02: 0.01. A negative zeta potential (-31.80 mV) was observed from the microparticles. This was due to polyaspartic acid having negatively charged carboxylic acid groups. EXAMPLE 23 ALTERNATIVE METHOD STEP 2 – γ-POLYGLUTAMIC ACID-CO-ε-POLYLYSINE MICROPARTICLE SURFACE MODIFICATION WITH POLYHISTIDINE The γ-polyglutamic acid-co-ε-polylysine microparticles from Example 1 were positively charged by covalently binding polyhistidine to them using the NHS and EDC mediated condensation polymerisation chemistry described in Example 1. Polyhistidine was covalently bound to γ-polyglutamic acid-co-ε-polylysine microparticles via their available carboxylic acid sites. The γ-polyglutamic acid-co-ε-polylysine microparticles (1 cm3of 5 mg cm-3) were placed in an Eppendorf tube (1.5 cm3) before adding polyhistidine (1.2 mg, 0.008 mmol) followed by an aqueous solution (0.25 cm3) of EDC (4.4 mg, 0.023 mmol) / NHS (0.5 mg, 0.005 mmol) mixing and leaving for 1 h at RT. The microparticle solution was then centrifuged (3,000 x g for 5 mins) to remove unbound material. The molar ratio of polyhistidine: EDC: NHS was 1: 0.02: 0.01. A positive zeta potential (31.60 mV) was observed from the microparticles. This was due to polyhistidine containing positively charged imidazole groups. EXAMPLE 24 ALTERNATIVE METHOD STEP 2 – γ-POLYGLUTAMIC ACID-CO-ε-POLYLYSINE MICROPARTICLE SURFACE MODIFICATION WITH POLYALANINE The γ-polyglutamic acid-co-ε-polylysine microparticles from Example 1 had a neutral charge added by covalently binding polyalanine to them using the NHS and EDC mediated condensation polymerisation chemistry described in Example 1. Polyalanine was covalently bound to γ-polyglutamic acid-co-ε-polylysine microparticles via their available functional sites. The γ-polyglutamic acid-co-ε-polylysine microparticles (1 cm3of 5 mg cm-3) were placed in an Eppendorf tube (1.5 cm3) before adding polyalanine (2.1 mg, 0.023 mmol) followed by an aqueous solution (0.25 cm3) of EDC (4.4 mg, 0.023 mmol) / NHS (0.5 mg, 0.005 mmol) mixing and leaving for 1 h at RT. The microparticle solution was then centrifuged (3,000 x g for 5 mins) to remove unbound material. The molar ratio of polyalanine: EDC: NHS was 1: 0.02: 0.01. A positive zeta potential (24.20 mV) was observed from the microparticles. EXAMPLE 25 ALTERNATIVE METHOD STEP 2 – γ-POLYGLUTAMIC ACID-CO-ε-POLYLYSINE MICROPARTICLE SURFACE MODIFICATION WITH α-POLYLYSINE The γ-polyglutamic acid-co-ε-polylysine microparticles from Example 1 were positively charged by covalently binding α-polylysine to them using the NHS and EDC mediated condensation polymerisation chemistry described in Example 1. α-Polylysine was covalently bound to γ-polyglutamic acid-co-ε-polylysine microparticles via their available carboxylic acid sites. The γ-polyglutamic acid-co-ε-polylysine microparticles (1 cm3of 5 mg cm-3) were placed in an Eppendorf tube (1.5 cm3) before adding α-polylysine (4.0 mg, 0.023 mmol) followed by an aqueous solution (0.25 cm3) of EDC (4.4 mg, 0.023 mmol) / NHS (0.5 mg, 0.005 mmol) mixing and leaving for 1 h at RT. The microparticle solution was then centrifuged (3,000 x g for 5 mins) to remove unbound material. The molar ratio of α-polylysine: EDC: NHS was 1: 0.02: 0.01. A positive zeta potential was observed from the microparticles. This was due to α-polylysine containing a positively charged amino groups. EXAMPLE 26 ALTERNATIVE METHOD STEP 2 – γ-POLYGLUTAMIC ACID-CO-ε-POLYLYSINE MICROPARTICLE SURFACE MODIFICATION WITH ASPARTIC ACID The γ-polyglutamic acid-co-ε-polylysine microparticles from Example 1 were negatively charged by covalently binding aspartic acid to them using the NHS and EDC mediated condensation polymerisation chemistry described in Example 1. Aspartic acid was covalently bound to γ-polyglutamic acid-co-ε-polylysine microparticles via their available amine sites. The γ-polyglutamic acid-co-ε-polylysine microparticles (1 cm3of 5 mg cm-3) were placed in an Eppendorf tube (1.5 cm3) before adding aspartic acid (3.6 mg, 0.023 mmol) followed by an aqueous solution (0.25 cm3) of EDC (4.4 mg, 0.023 mmol) / NHS (0.5 mg, 0.005 mmol) mixing and leaving for 1 h at RT. The microparticle solution was then centrifuged (3,000 x g for 5 mins) to remove unbound material. The molar ratio of aspartic acid: EDC: NHS was 1: 0.02: 0.01. A positive zeta potential (30.45 mV) was observed from the microparticles. EXAMPLE 27 ALTERNATIVE METHOD STEP 2 – γ-POLYGLUTAMIC ACID-CO-ε-POLYLYSINE MICROPARTICLE SURFACE MODIFICATION WITH LYSINE The γ-polyglutamic acid-co-ε-polylysine microparticles from Example 1 were positively charged by covalently binding lysine to them using the NHS and EDC mediated condensation polymerisation chemistry described in Example 1. Lysine was covalently bound to γ- polyglutamic acid-co-ε-polylysine microparticles via their available carboxylic acid sites. The γ-polyglutamic acid-co-ε-polylysine microparticles (1 cm3of 5 mg cm-3) were placed in an Eppendorf tube (1.5 cm3) before adding lysine (4.0 mg, 0.023 mmol) followed by an aqueous solution (0.25 cm3) of EDC (4.4 mg, 0.023 mmol) / NHS (0.5 mg, 0.005 mmol) mixing and leaving for 1 h at RT. The microparticle solution was then centrifuged (3,000 x g for 5 mins) to remove unbound material. The molar ratio of lysine: EDC: NHS was 1: 0.02: 0.01. A positive zeta potential (21.55 mV) was observed from the microparticles. This was due to lysine containing a positively charged amino group. EXAMPLE 28 ALTERNATIVE METHOD STEP 2 – γ-POLYGLUTAMIC ACID-CO-ε-POLYLYSINE MICROPARTICLE SURFACE MODIFICATION WITH ARGININE The γ-polyglutamic acid-co-ε-polylysine microparticles from Example 1 were positively charged by covalently binding arginine to them using the NHS and EDC mediated condensation polymerisation chemistry described in Example 1. Arginine was covalently bound to γ-polyglutamic acid-co-ε-polylysine microparticles via their available carboxylic acid sites. The γ-polyglutamic acid-co-ε-polylysine microparticles (1 cm3of 5 mg cm-3) were placed in an Eppendorf tube (1.5 cm3) before adding arginine (4.8 mg, 0.023 mmol) followed by an aqueous solution (0.25 cm3) of EDC (4.4 mg, 0.023 mmol) / NHS (0.5 mg, 0.005 mmol) mixing and leaving for 1 h at RT. The microparticle solution was then centrifuged (3,000 x g for 5 mins) to remove unbound material. The molar ratio of arginine: EDC: NHS was 1: 0.02: 0.01. A positive zeta potential (29.50 mV) was observed from the microparticles. This was due to arginine containing positively charged guanidino groups. EXAMPLE 29a / b ALTERNATIVE METHOD STEP 3 – γ-POLYGLUTAMIC ACID-CO-ε-POLYLYSINE MICROPARTICLES WITH CYSTEINE AND COVALENT ATTACHMENT OF HYALURONIC ACID The methodology of Example 4 was followed to result in thiolated γ-polyglutamic acid-co-ε- polylysine microparticles which were then further modified by covalent attachment of hyaluronic acid (10 and 500 kDa). The γ-polyglutamic acid-co-ε-polylysine microparticles with cysteine (10 mg cm-3) were incubated in a solution of each hyaluronic acid mw (5 mg cm-3) individually. The microparticles (0.5 cm3) were placed in a centrifuge tube (1.5 cm3) before adding an aqueous solution (0.5 cm3) of hyaluronic acid followed by an aqueous solution (0.25 cm3) of EDC (18 mg, 0.095 mmol) / NHS (2.0 mg, 0.017 mmol) before mixing and leaving overnight at RT. The microparticle solution was washed through a filter membrane (0.4 µm) to remove unbound hyaluronic acid and obtain a solution of microparticles with bound hyaluronic acid (10 mg cm-3). Results are shown in Figure 19 for Example 29a and discussed in General Discussion section below. A negative zeta potential (hyaluronic acid 10 kDa, -27.90 mV and 500 kDa, -25.55 mV) was observed from the microparticles. This was due to large molecules of hyaluronic acid having negatively charged hydroxyl groups. EXAMPLE 30 ALTERNATIVE METHOD STEP 3 – γ-POLYGLUTAMIC ACID-CO-ε-POLYLYSINE MICROPARTICLES WITH CYSTEINE AND ELECTROSTATIC ABSORPTION OF AMPHOTERICIN B AND NATAMYCIN The methodology of Example 4 was followed to result in thiolated γ-polyglutamic acid-co-ε- polylysine microparticles which were then further modified by electrostatic absorption of the antifungals amphotericin B and natamycin. The γ-polyglutamic acid-co-ε-polylysine microparticles with cysteine (50 mg cm-3) were incubated in a solution of amphotericin B (0.25 mg cm-3in dH2O) or natamycin (1 mg cm-3in 95% EtOH) individually. The microparticles (0.5 cm3) were placed in a centrifuge tube (1.5 cm3) before adding a solution of amphotericin B (0.5 cm3) or natamycin (0.5 cm3) before mixing and leaving overnight at RT. The microparticle solution was then centrifuged (3000 xg) for 5 min and the supernatant removed before re-suspending in dH2O (1 cm3) to obtain a solution of microparticles and each individually associated antibiotic. This resulted in the active agents amphotericin b and natamycin loaded into the cysteine surface modified γ- polyglutamic acid-co-ε-polylysine microparticles. EXAMPLE 31 ALTERNATIVE METHOD STEP 3 – γ-POLYGLUTAMIC ACID-CO-ε-POLYLYSINE MICROPARTICLES WITH CYSTEINE AND ELECTROSTATIC ABSORPTION OF CYCLOSPORIN The methodology of Example 4 was followed to result in thiolated γ-polyglutamic acid-co-ε- polylysine microparticles which were then further modified by electrostatic absorption of cyclosporin. The γ-polyglutamic acid-co-ε-polylysine microparticles with cysteine (50 mg cm-3) were incubated in a solution of cyclosporin (10 mg cm-3in 95% EtOH). The microparticles (0.5 cm3) were placed in a centrifuge tube (1.5 cm3) before adding a solution (0.5 cm3) of cyclosporin before mixing and leaving overnight at RT. The microparticle solution was then centrifuged (3000 xg) for 5 min and the supernatant removed before re-suspending in dH2O (1 cm3) to obtain a solution of microparticles and cyclosporin. This resulted in the active agent cyclosporin loaded into the cysteine surface modified γ-polyglutamic acid-co-ε-polylysine microparticles. EXAMPLE 32 ALTERNATIVE METHOD STEP 3 – γ-POLYGLUTAMIC ACID-CO-ε-POLYLYSINE MICROPARTICLES WITH CYSTEINE AND ELECTROSTATIC ABSORPTION OF CHLORHEXADINE The methodology of Example 4 was followed to result in thiolated γ-polyglutamic acid-co-ε- polylysine microparticles which were then further modified by electrostatic absorption of chlorhexadine. The γ-polyglutamic acid-co-ε-polylysine microparticles with cysteine (50 mg cm-3) were incubated in a solution of chlorhexadine (10 mg cm-3in dH2O). The microparticles (0.5 cm3) were placed in a centrifuge tube (1.5 cm3) before adding a solution (0.5 cm3) of chlorhexadine before mixing and leaving overnight at RT. The microparticle solution was then centrifuged (3000 xg) for 5 min and the supernatant removed before re-suspending in dH2O (1 cm3) to obtain a solution of microparticles and chlorhexadine. This resulted in the active agent chlorhexadine loaded into the cysteine surface modified γ-polyglutamic acid-co-ε-polylysine microparticles. EXAMPLE 33 ALTERNATIVE METHOD STEP 3 – γ-POLYGLUTAMIC ACID-CO-ε-POLYLYSINE MICROPARTICLES WITH CYSTEINE AND ELECTROSTATIC ABSORPTION OF KETOTIFEN The methodology of Example 4 was followed to result in thiolated γ-polyglutamic acid-co-ε- polylysine microparticles which were then further modified by electrostatic absorption of ketotifen. The γ-polyglutamic acid-co-ε-polylysine microparticles with cysteine (50 mg cm-3) were incubated in a solution of ketotifen (10 mg cm-3in dH2O). The microparticles (0.5 cm3) were placed in a centrifuge tube (1.5 cm3) before adding a solution (0.5 cm3) of ketotifen before mixing and leaving overnight at RT. The microparticle solution was then centrifuged (3000 xg) for 5 min and the supernatant removed before re-suspending in dH2O (1 cm3) to obtain a solution of microparticles and ketotifen. This resulted in the active agent ketotifen loaded into the cysteine surface modified γ-polyglutamic acid-co-ε-polylysine microparticles. EXAMPLE 34 ALTERNATIVE METHOD STEP 3 – γ-POLYGLUTAMIC ACID-CO-ε-POLYLYSINE MICROPARTICLES WITH CYSTEINE AND ELECTROSTATIC ABSORPTION OF IBUPROFEN The methodology of Example 4 was followed to result in thiolated γ-polyglutamic acid-co-ε- polylysine microparticles which were then further modified by electrostatic absorption of ibuprofen. The γ-polyglutamic acid-co-ε-polylysine microparticles with cysteine (50 mg cm-3) were incubated in a solution of ibuprofen (10 mg cm-3in 95% EtOH). The microparticles (0.5 cm3) were placed in a centrifuge tube (1.5 cm3) before adding a solution (0.5 cm3) of ibuprofen before mixing and leaving overnight at RT. The microparticle solution was then centrifuged (3000 xg) for 5 min and the supernatant removed before re-suspending in dH2O (1 cm3) to obtain a solution of microparticles and ibuprofen. This resulted in the active agent ibuprofen loaded into the cysteine surface modified γ-polyglutamic acid-co-ε-polylysine microparticles. EXAMPLE 35 ALTERNATIVE METHOD STEP 3 – γ-POLYGLUTAMIC ACID-CO-ε-POLYLYSINE MICROPARTICLES WITH CYSTEINE AND ELECTROSTATIC ABSORPTION OF MANNITOL The methodology of Example 4 was followed to result in thiolated γ-polyglutamic acid-co-ε- polylysine microparticles which were then further modified by electrostatic absorption of mannitol. The γ-polyglutamic acid-co-ε-polylysine microparticles with cysteine (50 mg cm-3) were incubated in a solution of mannitol (10 mg cm-3in 95% EtOH). The microparticles (0.5 cm3) were placed in a centrifuge tube (1.5 cm3) before adding a solution (0.5 cm3) of mannitol before mixing and leaving overnight at RT. The microparticle solution was then centrifuged (3000 xg) for 5 min and the supernatant removed before re-suspending in dH2O (1 cm3) to obtain a solution of microparticles and mannitol. This resulted in the active agent mannitol loaded into the cysteine surface modified γ-polyglutamic acid-co-ε-polylysine microparticles. EXAMPLE 36 This animal study involves a comparison of the safety and ocular tolerance of γ-polyglutamic acid-co-ε-polylysine microparticles surface modified with cysteine and loaded with the antimicrobial agent, moxifloxacin against conventional eye drops (0.5% moxifloxacin ophthalmic eye drops) and γ-polyglutamic acid-co-ε-polylysine microparticles surface modified with cysteine without any active agent, aiming to assess local ocular tolerance and the concentration and distribution of moxifloxacin in ocular tissue and systemically. GENERAL DISCUSSION Figures 1 A, 1 B and 1 C provide a schematic of the synthesis of the microparticle formulation of the invention described in Examples 1, 4 and 7, Examples 1 and 5 and Examples 1 and 6 respectively. We synthesised γ-PGA-co-ε-PL microparticles (Examples 1-3 and 10-14) with a range of different biomolecules conjugated, including ε-PL, cysteine and octanoic acid (see Tables 1 – 3 of Examples 4, 5 and 6), to their surface to test three of the theories of mucoadhesion. As shown in Figure 2 C, the average diameter of the resultant microparticles (MP) ranged in size (from 0.97 - 7.55 µm, mean of approx. 3 µm), zeta potential (0.72 - 20.73 mV) and polydispersity index (from 21.11 - 35.21). Scanning electron and light microscopy confirmed that microparticles were spherical, monodispersed, with a typical diameter of approx.3 µm as measured using ImageJ software (Figure 2 A / B). As expected, the concentration and chemical functionality of the conjugated (added) biomolecules altered the overall and surface composition of the microparticle formulations with varying degrees of cationic charge. This is optimal for an ocular mucoadhesive system due to most mucins having a net negative charge primarily due to sialylation (Vigani et al., 2023). Additionally, the range of the particle size distributions of some of the microparticle formulations before and after Tangential Flow Filtration (TFF) suggest the presence of nanoparticles of approx. ≤ 50 nm in diameter as measured by dynamic light scattering (DLS) and larger microparticles of approx. ≥10 µm in diameter as measured by DLS (Figure 2 D). Fourier Transform Infrared Spectroscopy (FTIR) of γ-polyglutamic acid-co-ε-polylysine cross- linked microparticles (Figure 3 A-C) confirmed differences in chemical bonding within the microparticle polymeric network depending on the biomolecule conjugated. A reduction in primary amine functional groups and amide bonds in proportion to CH stretch was observed with increasing conjugation of the highest molecular weight biomolecule (ε-PL, average Mw ~ 3.5 – 4.5 kDa) that we investigated. Increased amide and carboxyl functional groups were observed from microparticles containing increased amounts of both cysteine and octanoic acid. This was further confirmed by X-ray photoelectron spectroscopy (XPS, Figure 3 D / E) as the CH2, thiolation and increased amine functionality was observed on the surface of the microparticle compositions, thereby confirming the addition of the mucoadhesive biomolecules to the microparticles. Microparticle properties such as size, charge and shape can influence how closely they interact with mucosal surfaces. Mucoadhesive potential of the γ-PGA-co-ε-PL microparticles (Figure 4 A-C) was investigated following their incubation with porcine mucin and any corresponding changes to viscosity measured. No changes to the viscosity of the solutions was observed for the uncoated microparticles or those with the lowest concentrations of ε- PL or cysteine or any concentration with hydrophobic side chain conjugated. However, significant increases in viscosity were observed from microparticle formulations with higher concentrations of ε-PL (49.68 mPa s-1, SD ± 12.48) or cysteine (38.53 mPa s-1, SD ± 17.54) added compared to the uncoated microparticle / mucin (11.55 mPa s-1, SD ± 5.70) and mucin only solutions alone (8.95 mPa s-1, SD ± 0.49). This directly corresponds to inter / intramolecular interaction within these solutions of microparticle and mucin suggesting that the positively charged interaction from the amine or thiol groups (as per Example 4) on the microparticle surface is an important factor in the mucoadhesive potential from these formulations. The positive charge allows for electrostatic interaction with anionic groups contained within mucin. Furthermore, thiol groups on branched mucin chains can facilitate more stable disulphide bridge formation between thiol groups on the microparticles and mucin resulting in gel formation. Microparticles were incubated with moxifloxacin at two different (1 mg cm-3, 10 mg cm-3) concentrations to determine optimal loading conditions. The 10 mg cm-3of higher drug concentration has displayed high loading efficiency (17.6%). It was seen that ciprofloxacin release from the microparticle systems in simulated tear film conditions media, was sustained over 96 h with a mean release of 51.2% (Figure 5 A / B). We found minimal cytotoxicity from the microparticle formulations (from 10 to 1000 μg cm-3concentrations) in human primary corneal epithelial (HCEC) cells after 24 h in vitro (Figure 6 A-C) determined by AlamarBlue™ and PicoGreen™ assays. Some cytotoxicity was observed for microparticle formulations conjugated with greater concentrations of cationic charged biomolecules (ε-PL x2 and ε-PL x4) at 1000 μg cm-3. This indicates that the majority of γ-PGA-co-ε-PL microparticle formulations tested (except ε-PL x2 and ε-PL x4) have potential as suitable drug carriers to deliver therapeutic loads to the eye with reduced potential for inflammation of the ocular surface. Microparticles (0.1 mg cm-3) loaded with moxifloxacin (as in Example 9) were incubated separately with and E. coli (A), B. subtilis (B) and S. epidermidis (C) (Figure 7). A significant reduction in bioburden was observed across all compositions against each strain of bacteria compared to the negative control. Furthermore, CFU data (Figure 7 D) was obtained for two microparticle formulations (Cys x2 and ε-PL x2) against all three strains of bacteria. A 4 - 6 log reduction in bioburden was observed after 24 h in culture confirming both formulations delivering a therapeutic dose of moxifloxacin and indicating their potential as drug carriers. Microparticles (0.01, 0.1, 1 and 10 mg cm-3) coated with ε-polylysine were incubated separately with and E. coli (A), S. epidermidis (B) and B. subtilis (C) as shown in Figure 8. We demonstrate an inherent antimicrobial efficacy of these microparticles against all three bacterial strains was observed from 1 and 10 mg cm-3concentrations compared to the negative control. This indicates that the antimicrobial peptide (ε-PL) retains its antimicrobial efficacy after conjugation to the microparticles. These particles could provide an antimicrobial microparticle formulation without the need for an active ingredient to be loaded in the microparticles. A murine model of MDR Pseudomonas keratitis was treated with microparticles loaded with meropenem, meropenem alone and a sham (PBS) treatment control. Keratitis clinical scores were observed and recorded over 3 days (Figure 9). A 50% reduction in keratitis severity was observed in the mice treated with microparticles loaded with meropenem compared to the sham treated mice. The mice treated with meropenem alone reduced the keratitis severity by 25% under the same conditions compared to the sham treated group. Pseudomonas CFU data was obtained from infected eyes following completion of the study with only the microparticles loaded with meropenem treated animals showing a significant reduction in bioburden to almost baseline levels. These data give strong indications that the presence of the microparticles in the meropenem treatments greatly enhances treatment outcome by 100% with almost complete reduction in bioburden present in the mouse eyes. Figures 14 to 19 show that microparticles formed using γ-polyglutamic acid with polyarginine (Figure 16 – Example 15), polyhistidine (Figure 17 – Example 16), α- polylysine (Figure 15 - Example 18) and polyaspartic acid (Figure 14 – Example 17). However, microparticles did not form using γ-polyglutamic acid with polyalanine. Figure 18 shows γ-PGA-co-ε-PL microparticles which were surface modified with hyaluronic acid (500 kDa) (Example 20). Figure 19 shows γ-PGA-co-ε-PL microparticles surface modified with cysteine and hyaluronic acid (500 kDa) (Example 29b). GENERAL CONCLUSION We have developed a mucoadhesive drug delivery platform for localised therapeutic delivery to the ocular surface in the treatment of ocular surface disease. We have shown the system has minimal toxicity in vitro and in vivo to the corneal epithelium. Furthermore, we have proven efficacy of the drug delivery system in a murine model of Pseudomonas keratitis resulting in a better treatment outcome, halving the disease severity after three days with almost complete eradication of bioburden. This delivery platform has application beyond ocular surfaces to all mucosal membranes, including ocular, gastrointestinal, nasal, buccal, vaginal and respiratory membranes. Furthermore, this delivery platform has general application for bioadhesion, not limited to mucosal membrane delivery. REFERENCES: Schneider, C.A., Rasband, W.S. and Eliceiri, K.W. (2012) ‘NIH Image to ImageJ: 25 years of image analysis’, Nature Methods, 9(7), pp.671–675. Vigani, B. et al. (2023) ‘Mucoadhesive polymers in substance-based medical devices: functional ingredients or what else?’, Frontiers in Drug Safety and Regulation, 3(August), pp.1–13. The invention will now be described by the following sequentially number non-limiting statements: 1. A bioadhesive microparticle formulation comprising discrete microparticles, wherein the microparticle formulation comprises cross linked poly-amino acid microparticles wherein the poly-amino acids are selected from one or more of poly-lysine including poly-epsilon-lysine, poly-glutamic acid including poly-gamma-glutamic acid, poly-arginine, poly-aspartic acid, poly-histidine, poly- asparagine, poly-cysteine and natural, synthetic or semi-synthetic derivatives thereof, such as poly hydroxyethyl-l-glutamine; in which the microparticles are surface modified with a bioadhesive agent; preferably selected from one or more of a protein, carbohydrate, lipid, and poly-amino acids; and wherein each discrete microparticle is less than approximately 10 µm in average diameter. 2. The microparticle formulation of statement 1 further comprising an agent; preferably an active agent, such as an antimicrobial agent, antibiotic or nucleic acid based therapeutic. 3. The microparticle formulation of statement 1 or statement 2 wherein the bioadhesive agent is a mucoadhesive agent selected from one or more of cysteine, poly- lysine including ε-polylysine, poly-glutamic acid including γ-polyglutamic acid and octanoic acid. 4. A mucoadhesive microparticle formulation comprising discrete microparticles, comprising cross-linked poly-amino acid microparticles formed from γ-polyglutamic acid (γ-PGA) and ε-polylysine (ε-PL) ; in which the microparticles are surface modified with a mucoadhesive agent selected from one or more of cysteine, ε-polylysine, γ-polyglutamic acid and octanoic acid; and an optional agent or active agent; preferably a pharmaceutical drug such as an antimicrobial agent, antibiotic or nucleic acid based therapeutic; wherein each discrete microparticle is less than approximately 10 µm in average diameter. 5. The bioadhesive or mucoadhesive agent of any of the preceding statements, comprising cross-linked poly-amino acid microparticles formed from γ-polyglutamic acid (γ-PGA) with a molecular weight of approximately 800 to 700,000 Daltons; and ε-polylysine (ε-PL) with a molecular weight of approximately 2000 to 5500 Daltons. 6. The mucoadhesive formulation of statement 4 or 5 or delivery to mucosa selected from ocular, gastrointestinal, nasal, buccal, vaginal and respiratory mucosa. 7. The mucoadhesive microparticle formulation of statement 4 or 5 or 6 wherein γ-polyglutamic acid has a molecular weight of up to approximately 10,000 Daltons, preferably approximately 800 to 1500 Daltons. 8. The mucoadhesive microparticle formulation of any of statements 4 to 7 wherein ε-polylysine has a molecular weight of approximately 3000 to 4500 Daltons. 9. The bioadhesive or mucoadhesive microparticle formulation of any of the preceding statements wherein each discrete microparticle is greater than approximately 0.1 µm and less than approximately 10 µm in average diameter. 10. A drug delivery system comprising the bioadhesive or mucoadhesive microparticle formulation of any of the preceding statements. 11. The bioadhesive or mucoadhesive microparticle formulation or drug delivery system of any of the preceding statements formulated for sustained release of an active agent. 12. The bioadhesive or mucoadhesive agent or drug delivery system of any of the preceding statements for use in therapy; preferably for use in wound healing or for use as an antimicrobial. 13. The bioadhesive or mucoadhesive agent or drug delivery system of any of the preceding statements for use in treatment of eye disorders, such as microbial keratitis / conjunctivitis, dry eye, glaucoma or allergic conjunctivitis. 14. A method for preparing a bioadhesive microparticle formulation comprising discrete microparticles, comprising the steps i) dissolving and combining poly-amino acids selected from one or more of poly- epsilon-lysine, poly-gamma-glutamic acid, poly-arginine, poly-aspartic acid, poly- histidine, poly-asparagine, poly-cysteine and natural, synthetic or semi-synthetic derivatives thereof, such as poly-hydroxyethyl-l-glutamine, to form a suspension of self-assembled non-cross-linked microparticles; ii) cross-linking the suspension of step (i) via condensation polymerisation to obtain a monodispersed cross-linked microparticle solution; iii) subjecting the monodispersed cross-linked microparticle solution to a size-grading step to remove particles greater than 40 µm, preferably greater than 10 µm, in diameter and to remove nanoparticles below 100 nm in diameter; and iv) surface modifying the microparticles from step (iii) with a bioadhesive or mucoadhesive agent; preferably selected from one or more of a protein, carbohydrate, lipid, and poly-amino acid; and via condensation polymerisation to form a bioadhesive surface modified microparticle formulation. 15. A method for preparing a surface modified cross linked poly-epsilon-lysine / ε- polylysine (ε-PL) and poly-gamma-glutamic acid / γ-polyglutamic acid (γ-PGA) microparticle formulation comprising discrete microparticles, comprising the following steps: i) dissolving γ-polyglutamic acid with a molecular weight of approximately 800 to 700,000 Daltons and ε-polylysine with a molecular weight of approximately 2000 to 5500 Daltons separately in deionised water at pH 5 and combining to form a suspension of self-assembled non-cross-linked microparticles; ii) Cross-linking the suspension of step (i) via condensation polymerisation of ε- polylysine and γ-polyglutamic acid to allow for amide bond formation and to obtain a monodispersed cross-linked microparticle solution; iii) subjecting the monodispersed cross-linked microparticle solution to a size-grading step to remove particles greater than 40 µm in diameter, preferably greater than 10 µm, and to remove nanoparticles below 100 nm in diameter; and iv) surface modifying the microparticles from step (iii) with a mucoadhesive agent, such as cysteine, ε-polylysine, γ-polyglutamic acid and octanoic acid via condensation polymerisation to form a mucoadhesive surface modified microparticle formulation. 16. The method of statement 15, in which steps (ii) and (iv) comprises (ii) Cross-linking the suspension of step (i) via EDC / NHS, sulfo-EDC / NHS or DMTMM mediated polymerisation of ε-polylysine and γ-polyglutamic acid to allow for amide bond formation and to obtain a monodispersed cross-linked microparticle solution; iv) surface modifying the microparticles from step (iii) with a mucoadhesive agent, such as cysteine, ε-polylysine, γ-polyglutamic acid and octanoic acid via via EDC / NHS, sulfo- EDC / NHS or DMTMM mediated polymerisation to form a surface modified microparticle formulation. 17. The method of statement 16 wherein the surface modified microparticle solution is incubated with an agent; preferably an active agent; more preferably a pharmaceutical drug such as an antimicrobial agent, antibiotic or nucleic acid based therapeutic.

Claims

1. CLAIMS:

1. A bioadhesive microparticle formulation comprising discrete microparticles, wherein the microparticle formulation comprises cross linked poly-amino acid microparticles wherein the poly-amino acids are selected from one or more of poly-lysine, preferably poly-epsilon-lysine (ε-PL) or poly alpha- lysine (α-PL), poly-glutamic acid, preferably poly-gamma-glutamic acid (γ-PGA), poly- arginine, poly-aspartic acid, poly-histidine, poly-asparagine, poly-cysteine, and natural, synthetic or semi-synthetic derivatives thereof, preferably poly hydroxyethyl-l-glutamine; in which the microparticles are surface modified with a bioadhesive agent; preferably a bioadhesive agent selected from one or more of a simple or complex carbohydrate; preferably hyaluronic acid, chitosan, carboxymethylcellulose or hydroxypropyl methylcellulose; a C6to C18lipid; preferably a C6to C13lipid; a protein such as a peptide; an amino acid; and a poly-amino acid; wherein the average diameter of the microparticles is less than approximately 10 µm measured with dynamic light scattering (DLS) using a zetasizer and light microscopy.

2. The microparticle formulation of claim 1, wherein the microparticle formulation comprises cross linked poly-amino acid microparticles wherein the poly-amino acids are selected from one or more of poly-lysine, preferably poly-epsilon-lysine (ε-PL) or α-poly- alpha-lysine (α-PL), poly-glutamic acid, preferably poly-gamma-glutamic acid (γ-PGA); poly- arginine, poly-aspartic acid, and poly-histidine.

3. The microparticle formulation of claim 2, wherein the microparticle formulation comprises cross linked γ-polyglutamic acid-co-ε-polylysine microparticles; cross linked γ-polyglutamic acid-co-α-polylysine microparticles; cross linked γ-polyglutamic acid-co-polyarginine microparticles; cross linked γ-polyglutamic acid-co-polyaspartic acid microparticles; or cross linked γ-polyglutamic acid-co-polyhistidine microparticles.

4. The microparticle formulation of any preceding claim, wherein the bioadhesive agent is selected from one or more of an amino acid selected from cysteine, aspartic acid, lysine and arginine; a poly-amino acid selected from poly-lysine, preferably poly-epsilon-lysine (ε-PL) or α-poly-alpha-lysine (α-PL), poly-glutamic acid, preferably γ-polyglutamic acid (γ- PGA), poly-alanine, poly-arginine, poly-histidine, poly-aspartic acid, and poly- cysteine the C8lipid octanoic acid; and the carbohydrate hyaluronic acid.

5. The microparticle formulation of any preceding claim, wherein the microparticle formulation comprises cross linked poly-amino acid microparticles wherein the poly-amino acids are selected from one or more of poly-lysine, preferably poly-epsilon-lysine (ε-PL) or α-poly- alpha-lysine (α-PL), poly-glutamic acid, preferably poly-gamma-glutamic acid (γ-PGA), poly- arginine, poly-aspartic acid, and poly-histidine, in which the microparticles are surface modified with a bioadhesive agent selected from one or more of amino acids selected from cysteine, aspartic acid, lysine and arginine; a poly-amino acid selected from poly-lysine, preferably poly-epsilon-lysine (ε-PL) or α-poly-alpha-lysine (α-PL), poly-glutamic acid, preferably γ-polyglutamic acid (γ- PGA), poly-alanine, poly-arginine, poly-histidine, poly-aspartic acid, and poly- cysteine the C8lipid octanoic acid; and the carbohydrate hyaluronic acid.

6. The microparticle formulation of any preceding claim, further comprising an agent; preferably an active agent, such as an antimicrobial agent, antibiotic or nucleic acid based therapeutic.

7. A mucoadhesive microparticle formulation comprising discrete microparticles, wherein the microparticle formulation comprises cross-linked poly-amino acid microparticles formed from γ-polyglutamic acid (γ-PGA) and ε-polylysine (ε-PL); in which the microparticles are surface modified with a mucoadhesive agent selected from one or more of amino acids selected from cysteine, aspartic acid, lysine and arginine; a poly-amino acid selected from poly-lysine, preferably poly-epsilon-lysine (ε-PL) or α-poly-alpha-lysine (α-PL), poly-glutamic acid, preferably γ-polyglutamic acid (γ- PGA), poly-alanine, poly-arginine, poly-histidine, poly-aspartic acid and poly-cysteine the C8lipid octanoic acid; and the carbohydrate hyaluronic acid; and an optional agent or active agent; preferably a pharmaceutical drug such as an antimicrobial agent, antibiotic or nucleic acid based therapeutic; wherein the average diameter of the microparticles is less than approximately 10 µm measured with dynamic light scattering (DLS) using a zetasizer and light microscopy.

8. The mucoadhesive microparticle formulation of claim 7, comprising discrete, microparticles, wherein the microparticle formulation comprises cross-linked poly-amino acid microparticles formed from γ-polyglutamic acid (γ-PGA) and ε-polylysine (ε-PL); in which the microparticles are surface modified with a mucoadhesive agent selected from one or more of cysteine, ε-polylysine, γ-polyglutamic acid and octanoic acid; and an optional agent or active agent; preferably a pharmaceutical drug such as an antimicrobial agent, antibiotic or nucleic acid based therapeutic; wherein the average diameter of the microparticles is less than approximately 10 µm measured with dynamic light scattering (DLS) using a zetasizer and light microscopy.

9. The microparticle formulation of any preceding claim, comprising cross-linked poly- amino acid microparticles formed fromγ-polyglutamic acid (γ-PGA) with a molecular weight of approximately 800 to 700,000 Daltons; and ε-polylysine (ε-PL) with a molecular weight of approximately 2000 to 5500 Daltons.

10. The mucoadhesive microparticles formulation of claims 7 to 9 for delivery to mucosa selected from ocular, gastrointestinal, nasal, buccal, vaginal and respiratory mucosa.

11. The mucoadhesive microparticle formulation of claims 7 to 9 wherein γ-polyglutamic acid has a molecular weight of up to approximately 10,000 Daltons, preferably approximately 800 to 1500 Daltons.

12. The mucoadhesive microparticle formulation of claims 7 to 9 wherein ε-polylysine has a molecular weight of approximately 3000 to 4500 Daltons.

13. The bioadhesive or mucoadhesive microparticle formulation of any preceding claim wherein the average diameter of the microparticles is greater than approximately 0.1 µm and less than approximately 10 µm in average diameter, preferably less than 5 µm in average diameter.

14. A drug delivery system comprising the bioadhesive or mucoadhesive microparticle formulation of any preceding claim.

15. The bioadhesive or mucoadhesive microparticle formulation or drug delivery system of any preceding claim formulated for sustained release of an active agent.

16. The bioadhesive or mucoadhesive microparticle formulation or drug delivery system of any preceding claim for use in therapy.

17. The bioadhesive or mucoadhesive microparticle formulation or drug delivery system of any preceding claim for use in wound healing.

18. The bioadhesive or mucoadhesive microparticle formulation or drug delivery system of any preceding claim for use as an antimicrobial or an antifungal.

19. The bioadhesive or mucoadhesive microparticle formulation or drug delivery system of any preceding claim for use in treatment of eye disorders, preferably for use in the treatment of microbial keratitis / conjunctivitis, dry eye, glaucoma or allergic conjunctivitis.

20. A method for preparing a bioadhesive microparticle formulation comprising discrete microparticles, comprising the steps i) dissolving and combining poly-amino acids selected from one or more of poly- epsilon-lysine(ε-PL) or poly alpha-lysine (α-PL), poly-gamma-glutamic acid, poly- arginine, poly-aspartic acid, poly-histidine, poly-asparagine, poly-cysteine and natural, synthetic or semi-synthetic derivatives thereof, such as poly-hydroxyethyl-l- glutamine, to form a suspension of self-assembled non-cross-linked microparticles; ii) cross-linking the suspension of step (i) via condensation polymerisation to obtain a monodispersed cross-linked microparticle solution; iii) subjecting the monodispersed cross-linked microparticle solution to a size-grading step to remove particles greater than 40 µm in average diameter, preferably greater than 10 µm in average diameter and to remove nanoparticles below 100 nm in average diameter, as measured with dynamic light scattering (DLS) using a zetasizer and light microscopy; and iv) surface modifying the microparticles from step (iii) with a bioadhesive or mucoadhesive agent; preferably selected from one or more of a simple or complex carbohydrate; a C6to C18lipid, preferably a C6to C13lipid; a protein such as a peptide; an amino acid; and a poly-amino acid; via condensation polymerisation to form a bioadhesive surface modified microparticle formulation.

21. The method of claim 20 wherein the poly-amino acids of step (i) is selected from one or more of poly-lysine, preferably poly-epsilon-lysine (ε-PL) or poly alpha-lysine (α-PL); poly- glutamic acid, preferably poly-gamma-glutamic acid (γ-PGA); poly-arginine; poly-aspartic acid; and poly-histidine; preferably wherein the poly-amino acids of step (i) comprises poly-epsilon-lysine (ε- PL) and poly-gamma-glutamic acid (γ-PGA).

22. The method of claim 20 or claim 21, wherein the surface modifying agent of step (iv) is selected from one or more of an amino acid selected from cysteine, aspartic acid, lysine and arginine; a poly-amino acid selected from poly-lysine, preferably poly-epsilon-lysine (ε-PL) or α-poly-alpha-lysine (α-PL), poly-glutamic acid, preferably γ-polyglutamic acid (γ- PGA), poly-alanine; poly-arginine, poly-histidine, poly-aspartic acid, poly-cysteine the C8octanoic acid; and the carbohydrate hyaluronic acid.

23. A method for preparing a surface modified cross linked poly-epsilon-lysine / ε- polylysine (ε-PL) and poly-gamma-glutamic acid / γ-polyglutamic acid (γ-PGA) microparticle formulation comprising discrete microparticles, comprising the following steps: i) dissolving γ-polyglutamic acid with a molecular weight of approximately 800 to 700,000 Daltons and ε-polylysine with a molecular weight of approximately 2000 to 5500 Daltons separately in deionised water at pH 5 and combining to form a suspension of self-assembled non-cross-linked microparticles; ii) Cross-linking the suspension of step (i) via condensation polymerisation of ε- polylysine and γ-polyglutamic acid to allow for amide bond formation and to obtain a monodispersed cross-linked microparticle solution; iii) subjecting the monodispersed cross-linked microparticle solution to a size-grading step to remove particles greater than 40 µm in average diameter, preferably greater than 10 µm in average diameter, and to remove nanoparticles below 100 nm in average diameter, as measured with dynamic light scattering (DLS) using a zetasizer and light microscopy; andiv) surface modifying the microparticles from step (iii) with a mucoadhesive agent; preferably selected from one or more of an amino acid selected from cysteine, aspartic acid, lysine or arginine; a poly-amino acid selected from poly-lysine, preferably poly-epsilon-lysine (ε- PL) or α-poly-alpha-lysine (α-PL), poly-glutamic acid, preferably γ- polyglutamic acid (γ-PGA), poly-alanine; poly-arginine, poly-histidine, poly- aspartic acid, or poly-cysteine the C8lipid octanoic acid; and the carbohydrate hyaluronic acid; via condensation polymerisation to form a mucoadhesive surface modified microparticle formulation.

24. The method of claim 23, wherein the mucoadhesive agent of step (iv) is selected from an amino acid selected from cysteine, aspartic acid, lysine or arginine; a poly-amino acid selected from poly-lysine, preferably poly-epsilon-lysine (ε- PL) or α-poly-alpha-lysine (α-PL), poly-glutamic acid, preferably γ- polyglutamic acid (γ-PGA), poly-alanine; poly-arginine, poly-histidine, poly- aspartic acid, or poly-cysteine the C8lipid octanoic acid; and the carbohydrate hyaluronic acid; preferably selected from an amino acid selected from cysteine, aspartic acid, lysine or arginine; a poly-amino acid selected from poly-lysine, preferably poly-epsilon-lysine (ε- PL) or α-poly-alpha-lysine (α-PL), poly-glutamic acid, preferably γ- polyglutamic acid (γ-PGA), poly-alanine; poly-arginine, poly-histidine or poly- aspartic acid; the C8lipid octanoic acid; and the carbohydrate hyaluronic acid.

25. The method of claim 23 or 24, in which step (ii) comprises cross-linking the suspension of step (i) via EDC / NHS, sulfo-EDC / NHS or DMTMM mediated polymerisation of ε-polylysine and γ-polyglutamic acid to allow for amide bond formation and to obtain a monodispersed cross-linked microparticle solution.

26. The method of claims 23, 24, or 25, in which step (iv) comprises surface modifying the microparticles from step (iii) with the mucoadhesive agent, via EDC / NHS, sulfo-EDC / NHS or DMTMM mediated polymerisation to form a surface modified microparticle formulation.

27. The method of claims 20 to 26 wherein the surface modified microparticle solution is incubated with an agent; preferably an active agent; more preferably a pharmaceutical drug such as an antimicrobial agent, antibiotic or nucleic acid based therapeutic.

28. The method of claims 23 to 27, wherein the γ-polyglutamic acid-co-ε-polylysine polymer density is from 0.5 to 120 g dm-3in aqueous solution; preferably from 1 to 72 g dm-3; more preferably from 1 to 55 g dm-3; even more preferably from 1 to 15 g dm-3.

29. The method of any of claims 23 to 28, wherein the γ-polyglutamic acid-co-ε-polylysine polymer density is from 1 g dm-3to 6 g dm-3.

30. The method of claims 25 to 29 wherein the γ-polyglutamic acid: ε-polylysine: EDC: ΝHS molar ratio of step (ii) is from 1 : 0.2 : 0.5 : 0.1 to 1 : 1.2 : 3.5 : 1.2; preferably from 1 : 0.5 : 1.2 : 0.2 to 1 : 0.9 : 2.3 : 1.

2.

31. The method of claims 25 to 30 wherein the γ-polyglutamic acid: ε-polylysine: EDC: ΝHS molar ratio of step (ii) is approximately 1: 0.8: 1.8: 0.

6.

32. The method of claims 26 to 31 wherein the mucoadhesive agent: EDC: ΝHS molar ratio of step (iv) is from 1 : 0.01 : 0.001 to 1: 0.1 : 0.02; preferably approximately 1 : 0.02 : 0.01.

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