Compositions for in situ implant formation

Abstract

The present invention provides a composition for in situ implants comprising a biodegradable first polymer, pH responsive second polymer, one or more organic solvents and a viscosity modifying vehicle. The present invention also provides a composition for an in situ implant, the composition comprising a first polymer, said first polymer being biodegradable, a second polymer, said second polymer being able to form an inclusion complex with one or more pharmaceutically active ingredients (APIs), one or more polar organic solvents, and a viscosity modifying vehicle. Injectables comprising said compositions are also described. The compositions and injectables can be used as a sustained-release dosage form of a pharmaceutical substance in therapeutic applications.

Description

Compositions for in situ implant formationCross-reference to related applications

[0001] This application claims the benefit of priority from Australian provisional application no. 2024903936, filed on 28 November 2024, the content of which is incorporated herein by reference in its entirety.Field of the invention

[0002] The present disclosure relates to compositions for in situ implants and injectables comprising said compositions. The present disclosure further relates to methods of making compositions for in situ implants and their use in therapeutic applications.Background of the invention

[0003] Long acting injectables have gained attraction as a system for the treatment of chronic conditions due to improved patient compliance, adherence to medication and reduction in dosing frequency.

[0004] Long acting injectables aim to provide sustained release of a drug with constant plasma levels of the drug being maintained. Long acting injectables are also used to reduce the dosing frequency and side effects of the selected drug. Long acting injectables include various approaches such microparticle, liposomes, microneedle, oily solutions, and suspension, oloegel, and solid implants.

[0005] In situ systems have gathered interest as they offer easy, painless administration using small needles. The classification of in situ implant systems is based on the mechanism of implant formation, namely in situ solidifying organogels, in situ cross linking system and in situ precipitating. In situ precipitation implants are formed from phase separation due to change in temperature, pH, or solvent exchange. Solvent induced phase inversion implants have attracted special attention over other systems as they do not require any temperature change, or the presence of ions for implant formation.

[0006] The composition of solvent induced phase separation systems includes a water insoluble polymer, which is dissolved in an organic biocompatible solvent (water1006280349miscible) and a drug either in dispersed or dissolved form. On administration the solvent dissipates into the aqueous environment, followed by diffusion of water, leading to precipitation of polymer resulting in implant formation.

[0007] However, in addition to these systems, alternative techniques are required for overcoming issues with them. These issues include limited drug loading, inadequate dispersion affecting the dosing, syringeability of the implant, and some implants requiring surgery for their removal.

[0008] Therefore, there is a need for new and / or improved compositions for forming in situ implants and methods of use thereof.

[0009] Reference to any prior art in the specification is not an acknowledgment or suggestion that this prior art forms part of the common general knowledge in any jurisdiction or that this prior art could reasonably be expected to be understood, regarded as relevant, and / or combined with other pieces of prior art by a skilled person in the art.Summary of the invention

[0010] In a first aspect, the present disclosure provides a composition for an in situ implant, the composition comprising: a first polymer, said first polymer being biodegradable; a second polymer, said second polymer being pH responsive and dissolvable above about pH 6; one or more polar organic solvents; and a viscosity modifying vehicle.

[0011] In a second aspect, the present disclosure provides a composition for an in situ implant, the composition comprising: a first polymer, said first polymer being biodegradable; a second polymer, said second polymer being able to form an inclusion complex with one or more pharmaceutically active ingredients (APIs);1006280349one or more polar organic solvents; and a viscosity modifying vehicle.

[0012] In some embodiments of the first or second aspect, the first polymer is present in an amount from about 15 to about 40 wt.%, or from about 20 to about 30 wt.%, based on the total weight of the composition.

[0013] In some embodiments of the first or second aspect, the first polymer is present in an amount from about 15 to about 40 % w / v, or from about 20 to about 30 % w / v.

[0014] In some embodiments of the first or second aspect, the first polymer is present in an amount from about 5 to about 50 wt.%, or from about 10 to about 40 wt.%, based on the total weight of the composition.

[0015] In some embodiments of the first or second aspect, the first polymer is present in an amount from about 5 to about 50 % w / v, or from about 10 to about 40 % w / v.

[0016] In some embodiments of the first or second aspect, the second polymer is present in an amount from about 2 to about 15 wt.%, or from about 5 to about 10 wt.%, based on the total weight of the composition.

[0017] In some embodiments of the first or second aspect, the second polymer is present in an amount from about 2 to about 15 % w / v, or from about 5 to about 10 % w / v.

[0018] In some embodiments of the first or second aspect, the second polymer is present in an amount from about 0.1 to about 15 wt.%, or from about 1 to about 10 wt.%, based on the total weight of the composition.

[0019] In some embodiments of the first or second aspect, the second polymer is present in an amount from about 0.1 to about 15 % w / v, or from about 1 to about 10 % w / v.

[0020] In some embodiments of the first or second aspect, the one or more polar organic solvents are present in an amount from about 25 to about 55 wt.%, or from about 30 to about 40 wt.%, based on the total weight of the composition.1006280349

[0021] In some embodiments of the first or second aspect, the one or more polar organic solvents are present in an amount from about 25 to about 55 % w / v, or from about 30 to about 40 % w / v.

[0022] In some embodiments of the first or second aspect, the one or more polar organic solvents are present in an amount from about 20 to about 50 wt.%, or from about 30 to about 40 wt.%, based on the total weight of the composition.

[0023] In some embodiments of the first or second aspect, the one or more polar organic solvents are present in an amount from about 20 to about 50 % w / v, or from about 30 to about 40 % w / v.

[0024] In some embodiments of the first or second aspect, the viscosity modifying vehicle is present in an amount from about 15 to about 40 wt.%, or from about 30 to about 40 wt.%, based on the total weight of the composition.

[0025] In some embodiments of the first or second aspect, the viscosity modifying vehicle is present in an amount from about 15 to about 40 % w / v, or from about 30 to about 40% w / v.

[0026] In some embodiments of the first or second aspect, the viscosity modifying vehicle is present in an amount from about 15 to about 50 wt.%, or from about 20 to about 40 wt.%, based on the total weight of the composition.

[0027] In some embodiments of the first or second aspect, the viscosity modifying vehicle is present in an amount from about 15 to about 50 % w / v, or from about 20 to about 40% w / v.

[0028] In some embodiments of the first or second aspects, the composition further comprises one or more pharmaceutically active ingredients (APIs).

[0029] In a third aspect, the present disclosure provides a composition for an in situ implant, the composition comprising: a first polymer, said first polymer being biodegradable; a second polymer, said second polymer being pH responsive and dissolvable above about pH 6;1006280349one or more polar organic solvents; a viscosity modifying vehicle; and one or more pharmaceutically active ingredients (APIs).

[0030] In a fourth aspect, the present disclosure provides a composition for an in situ implant, the composition comprising: a first polymer, said first polymer being biodegradable; a second polymer, said second polymer being able to form an inclusion complex with one or more pharmaceutically active ingredients (APIs); one or more polar organic solvents; a viscosity modifying vehicle; and one or more pharmaceutically active ingredients (APIs); wherein the second polymer and at least one of the one or more pharmaceutically active ingredients are present as an inclusion complex.

[0031] In some embodiments of the third or fourth aspects, the first polymer is present in an amount from about 15 to about 30 wt.% based on the total weight of the composition.

[0032] In some embodiments of the third or fourth aspects, the first polymer is present in an amount from about 15 to about 30 % w / v.

[0033] In some embodiments of the third or fourth aspects, the second polymer is present in an amount from about 3 to about 10 wt.% based on the total weight of the composition.

[0034] In some embodiments of the third or fourth aspects, the second polymer is present in an amount from about 3 to about 10 % w / v.

[0035] In some embodiments of the third or fourth aspects, the one or more polar organic solvents are present in an amount from about 25 to about 35 wt.%, based on the total weight of the composition.1006280349

[0036] In some embodiments of the third or fourth aspects, the one or more polar organic solvents are present in an amount from about 25 to about 35 % w / v.

[0037] In some embodiments of the third or fourth aspects, the viscosity modifying vehicle is present in an amount from about 25 to about 35 wt.%, based on the total weight of the composition.

[0038] In some embodiments of the third or fourth aspects, the viscosity modifying vehicle is present in an amount from about 25 to about 35 % w / v.

[0039] In some embodiments of the third or fourth aspects, the one or more pharmaceutically active ingredients are present in an amount from about 5 to about 15 wt.%, based on the total weight of the composition.

[0040] In some embodiments of the third or fourth aspects, the one or more pharmaceutically active ingredients are present in an amount from about 5 to about 15% w / v.

[0041] In some embodiments, the second polymer is dissolvable below pH 7.

[0042] In some embodiments, the first polymer comprises one or more of poly(lactic- co-glycolic acid) (PLGA), polycaprolactone (PCL), polylactic acid (PLA), polyglycolide, poly-3-hydroxybutane, poly(glycolide-co-trimethylene carbonate), polyanhydrides or polyurethanes, preferably the first polymer comprises poly(lactic-co-glycolic acid) (PLGA).

[0043] In some embodiments, the PLGA has a monomeric ratio of lactide:glycolide from about 15:85 to about 85:15.

[0044] In some embodiments, the PLGA has an acid endcap.

[0045] In some embodiments, the PLGA has a molecular weight from about 7 kDa to about 54 kDa, or from about 10 kDa to about 20 kDa, or from about 7 kDa to about 17 kDa, or from about 10 kDa to about 20 kDa, or from about 24 kDa to about 38 kDa, or from about 38 kDa to about 54 kDa.

[0046] In some embodiments, the second polymer comprises a hydrophilic polymer.1006280349

[0047] In some embodiments, the second polymer comprises a methacrylic acid copolymer.

[0048] In some embodiments, the second polymer comprises a pharmaceutically acceptable cyclodextrin. In some embodiments, the pharmaceutically acceptable cyclodextrin comprises an a-cyclodextrin, p-cyclodextrin or y-cyclodextrin. In some embodiments, the pharmaceutically acceptable cyclodextrin comprises hydroxy propylcyclodextrin. In some embodiments, the second polymer comprises one or more of hydroxypropyl-alpha-cyclodextrin, hydroxypropyl-beta-cyclodextrin, hydroxypropyl- gamma-cyclodextrin, sulfobutylether-beta-cyclodextrin, methyl-beta-cyclodextrin or carboxymethyl-beta-cyclodextrin.

[0049] In some embodiments, the second polymer comprises a poly(methacrylic acid- co-methyl methacrylate) polymer.

[0050] In some embodiments, the ratio of methacrylic acid and methyl methacrylate in the poly(methacrylic acid-co-methyl methacrylate) polymer is 1:1.

[0051] In some embodiments, the one or more polar organic solvents comprises N,N- dimethyl acetamide (DMAc or DMAC), dimethyl sulfoxide (DMSO), benzyl alcohol, benzyl benzoate, ethanol, triacetin or N-methyl pyrrolidone (NMP), preferably the one or more polar organic solvents comprises dimethyl acetamide.

[0052] In some embodiments, the viscosity modifying vehicle comprises a non-ionic polyether, functionalised or unfunctionalized polyethylene glycol, isopropyl myristate, glycerol formal, polysorbate, glycerine or propylene glycol.

[0053] In some embodiments, the polyethylene glycol has a molecular weight of less than about 1 kDa, or less than about 500 Da.

[0054] In some embodiments, the viscosity of the composition is from about 0.35 to about 0.70 Pascal-seconds at 25 °C.

[0055] In some embodiments, the one or more active pharmaceutical ingredients comprises one or more of pramipexole, levodopa and carbidopa. Where the active pharmaceutical ingredient comprises levodopa and carbidopa, the composition may comprise a weighed amount of levodopa and carbidopa at a 1:1 ratio, 1:2 ratio, 1:31006280349ratio, 1:4 ratio, 1:5 ratio, 2:1 ratio, 3:1 ratio, 4:1 ratio or 5:1 ratio. Preferably, the composition may comprise a weighted amount of levodopa and carbidopa at a 4:1 ratio.

[0056] In some embodiments, the composition further comprises one or more excipients.

[0057] In some embodiments, the excipients comprise one or more antioxidants.

[0058] In some embodiments, the antioxidants include one or more of sodium bisulfite, sodium metabisulfite, sodium thiosulfate, preferably sodium bisulfite.

[0059] In a further aspect, the present disclosure provides a composition for an in situ implant, the composition comprising:PLGA; poly(methacrylic acid-co-methyl methacrylate); one or more polar organic solvents selected from dimethylacetamide or N- methyl-2-pyrrolidone;PEG; and one or more active pharmaceutical ingredients (APIs).

[0060] In a further aspect, the present disclosure provides a composition for an in situ implant, the composition comprising:PLGA; hydroxypropyl-beta-cyclodextrin; one or more polar organic solvents selected from dimethylacetamide or N- methyl-2-pyrrolidone;PEG; and one or more active pharmaceutical ingredients (APIs).

[0061] In a further aspect, the present disclosure provides a composition for an in situ implant, the composition comprising:100628034915 to 30 wt.% of PLGA;3 to 10 wt.% of poly(methacrylic acid-co-methyl methacrylate);25 to 35 wt.% of one or more polar organic solvents selected from dimethylacetamide or N-methyl-2-pyrrolidone;25 to 35 wt.% of PEG; and one or more pharmaceutically active ingredients (APIs), wherein the values in wt.% are based on the total weight of the composition.

[0062] In a further aspect, the present disclosure provides a composition for an in situ implant, the composition comprising:15 to 30 wt.% of PLGA;3 to 10 wt.% of hydroxypropyl-beta-cyclodextrin;25 to 35 wt.% of one or more polar organic solvents selected from dimethylacetamide or N-methyl-2-pyrrolidone;25 to 35 wt.% of PEG; and one or more pharmaceutically active ingredients (APIs), wherein the values in wt.% are based on the total weight of the composition.

[0063] In a further aspect, the present disclosure provides a composition for an in situ implant, the composition comprising:15 to 30 % w / v of PLGA;3 to 10 % w / v of poly(methacrylic acid-co-methyl methacrylate);25 to 35% w / v of one or more polar organic solvents selected from dimethylacetamide or N-methyl-2-pyrrolidone;25 to 35% w / v of PEG; and one or more pharmaceutically active ingredients (APIs).1006280349

[0064] In a further aspect, the present disclosure provides a composition for an in situ implant, the composition comprising:15 to 30 % w / v of PLGA;3 to 10 % w / v of hydroxypropyl-beta-cyclodextrin;25 to 35% w / v of one or more polar organic solvents selected from dimethylacetamide or N-methyl-2-pyrrolidone;25 to 35% w / v of PEG; and one or more pharmaceutically active ingredients (APIs).

[0065] In a further aspect, the present disclosure provides a composition for an in situ implant, the composition comprising:15 to 30 wt.% of PLGA;3 to 10 wt.% of poly(methacrylic acid-co-methyl methacrylate);25 to 35 wt.% of one or more polar organic solvents selected from dimethylacetamide or N-methyl-2-pyrrolidone;25 to 35 wt.% of PEG; and5 to 15 wt.% of one or more pharmaceutically active ingredients (APIs), wherein the values in wt.% are based on the total weight of the composition.

[0066] In a further aspect, the present disclosure provides a composition for an in situ implant, the composition comprising:15 to 30 wt.% of PLGA;3 to 10 wt.% of hydroxypropyl-beta-cyclodextrin;25 to 35 wt.% of one or more polar organic solvents selected from dimethylacetamide or N-methyl-2-pyrrolidone;25 to 35 wt.% of PEG; and10062803495 to 15 wt.% of one or more pharmaceutically active ingredients (APIs), wherein the values in wt.% are based on the total weight of the composition.

[0067] In a further aspect, the present disclosure provides a composition for an in situ implant, the composition comprising:15 to 30 % w / v of PLGA;3 to 10 % w / v of poly(methacrylic acid-co-methyl methacrylate);25 to 35 % w / v of one or more polar organic solvents selected from dimethylacetamide or N-methyl-2-pyrrolidone;25 to 35 % w / v of PEG; and5 to 15 % w / v of one or more pharmaceutically active ingredients (APIs).

[0068] In a further aspect, the present disclosure provides a composition for an in situ implant, the composition comprising:15 to 30 % w / v of PLGA;3 to 10 % w / v of hydroxypropyl-beta-cyclodextrin;25 to 35 % w / v of one or more polar organic solvents selected from dimethylacetamide or N-methyl-2-pyrrolidone;25 to 35 % w / v of PEG; and5 to 15 % w / v of one or more pharmaceutically active ingredients (APIs).

[0069] In some embodiments, the composition is a single-phase composition.

[0070] In a further aspect, the present disclosure provides an injectable comprising the composition according to any one of the herein disclosed embodiments.

[0071] In a further aspect, the present disclosure provides a method of making a composition according to any one of the herein disclosed embodiments, the method comprising the steps of:1006280349(a) combining a first polymer and a second polymer in the one or more polar organic solvents to form a solution; and(b) adding a viscosity modifying vehicle to the solution.

[0072] In some embodiments, the method further comprises the step of adding one or more pharmaceutically active ingredients after adding the viscosity modifying vehicle to the solution.

[0073] In some embodiments, step (a) and / or step (b) are conducted at a temperature greater than or equal to about 70 °C, or greater than or equal to about 80 °C, or greater than to equal to about 90 °C.

[0074] In a further aspect, the present disclosure provides a method of treating a neurodegenerative disease or disorder comprising administering a composition according to any one of the herein disclosed embodiments to a patient in need thereof, wherein the composition is administered as an injectable.

[0075] In a further aspect, the present disclosure provides the use of composition according to any one of the herein disclosed embodiments, in the manufacture of a medicament for treating a neurodegenerative disease or disorder, wherein the medicament is to be administered as an injectable.

[0076] In a further aspect, the present disclosure provides a composition according to any one of the herein disclosed embodiments for use in the treatment of a neurodegenerative disease or disorder, wherein the composition is to be administered as an injectable.

[0077] In some embodiments, the neurodegenerative disease or disorder is Parkinson’s disease.

[0078] Any embodiment herein shall be taken to apply mutatis mutandis to any other embodiment unless specifically stated otherwise.

[0079] As used herein, except where the context requires otherwise, the term "comprise" and variations of the term, such as "comprising", "comprises" and "comprised", are not intended to exclude further additives, components, integers or steps.1006280349

[0080] Further aspects of the present invention and further embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, given by way of example and with reference to the accompanying drawings.Brief description of the drawings

[0081] Figure 1. Schematic showing the preparation of the in situ forming implant formulation.

[0082] Figure 2. Graphs showing the in vitro drug release data for levodopa and carbidopa containing in situ implant formulations. The formulations tested relate to compositions 1-5 in Table 1.

[0083] Figure 3. FTIR spectra of the formulation and formulation components. From top to bottom, the traces represent a formulation according to one embodiment of the present disclosure (P5), sodium bisulfite, a physical mixture of the components, Eudragit L100, PEG 400, PLGA 50:50, carbidopa and levodopa.

[0084] Figure 4. Effect of shear rate on the viscosity of (a) Composition 5 of Table 1 and (b) blank formulation.

[0085] Figure 5. SEM images of Day 1 (a) surface and (b) cross section, Day 3 (c) surface and (d) cross section and Day 7 (e) and (f) cross section.

[0086] Figure 6. Graph showing the in vitro cytotoxicity results of formulation using MTT assay on 3T3 cell lines. Bars from left to right are control, drug release in DMEM 2x, drug release in DMEM 5x, drug release in DMEM 10x and drug release in DMEM 20x respectively.

[0087] Figure 7. Graph showing the degradation pattern for in situ formed implant (n=3).

[0088] Figure 8. Graph showing cumulative ex-vivo and in-vitro drug release profile (mean ±SEM, n=3). Traces from top to bottom are in-vitro levodopa release, in-vitro carbidopa release, ex-vivo levodopa release and ex-vivo carbidopa release.

[0089] Figure 9. Graphs showing In-vitro ex vivo correlation between the cumulative drug release (A) Levodopa and (B) Carbidopa.1006280349

[0090] Figure 10. Graph showing in-vitro release profile of levodopa from compositions 5, 16 and 37 of the present disclosure. Traces from top to bottom are composition 5, 37 and 16 respectively.

[0091] Figure 11. Graph showing in-vitro release profile of carbidopa from compositions 5, 16 and 37 of the present disclosure. Traces from top to bottom are composition 5, 37 and 16 respectively.Detailed description of the embodiments

[0092] The present disclosure describes a composition for an in situ implant. Pharmaceuticals incorporated into the in situ implant can be delivered in a sustained release, reducing the dosing frequency and improving patient adherence / compliance. The compositions of the present disclosure may be used in a long-lasting injectable implant which can be administered to a patient through a typical syringe. These compositions provide a drug delivery platform that could be used to treat a wide range of indications where a sustained release profile is preferred.

[0093] An advantage of the present invention is that the compositions show Newtonian behaviour, meaning they can be administered by a typical syringe. After administration, the implant forms and begins to release the pharmaceutical to the patient. Over time, the implant completely degrades which means that removal of the implant is not required.General definitions

[0094] It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.

[0095] Reference will now be made in detail to certain embodiments of the invention. While the invention will be described in conjunction with the embodiments, it will be understood that the intention is not to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention as defined by the claims.1006280349

[0096] One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.

[0097] All of the patents and publications referred to herein are incorporated by reference in their entirety.

[0098] For purposes of interpreting this specification, terms used in the singular will also include the plural and vice versa.

[0099] The general chemical terms used in the formulae herein have their usual meaning.

[0100] As used herein, the term "and / or" means "and", or "or", or both.

[0101] The term "(s)" following a noun contemplates the singular and plural form, or both.

[0102] It is intended that reference to a range of numbers disclosed herein (for example, 1 to 10) also incorporates reference to all rational numbers within that range (for example, 1 , 1.1 , 2, 3, 3.9, 4, 5, 6, 6.5, 7, 8, 9, and 10) and also any range of rational numbers within that range (for example, 2 to 8, 1.5 to 5.5, and 3.1 to 4.7) and, therefore, all sub-ranges of all ranges expressly disclosed herein are hereby expressly disclosed. These are only examples of what is specifically intended and all possible combinations of numerical values between the lowest value and the highest value enumerated are to be considered to be expressly stated in this application in a similar manner.

[0103] Various features of the invention are described with reference to a certain value, or range of values. These values are intended to relate to the results of the various appropriate measurement techniques, and therefore should be interpreted as including a margin of error inherent in any particular measurement technique. Some of the values referred to herein are denoted by the term “about” to at least in part account for this1006280349variability. The term “about”, when used to describe a value, may mean an amount within ±10%, ±5%, ±1% or ±0.1% of that value.

[0104] In every instance herein where “about” is used, also contemplated in the disclosure is that same context without the term “about”.Selected definitions

[0105] As used herein, “biodegradable” refers to a material that is capable of, or designed to, degrade or be resorbed inside the body during or after administration.

[0106] As used herein, “pH responsive” is used to describe a material where the properties of said material change based on the pH of the surrounding medium. For example, a pH responsive material may swell, collapse, dissolve or degrade when the pH of the surrounding medium is varied.

[0107] As used herein, “inclusion complex” refers to molecular host-guest compound where the guest molecule is trapped inside the cavity or cage-like structure of the host molecule. In context of the present specification, the guest may be a pharmaceutically active compound, and the host may be a polymer compound, for example a cyclodextrin.In situ implant forming compositions

[0108] An in situ implant forming composition refers to liquid formulation that generates a solid or semisolid depot following administration. Methods of administration in situ implants include parenteral injection. In situ implants may be preferred to other formulations due to bypassing the first-pass metabolism effect which can affect medicines for oral administration and may increase patient compliance and / or adherence.

[0109] In a first aspect, the present disclosure provides a composition for an in situ implant, the composition comprising: a first polymer, said first polymer being biodegradable; a second polymer, said second polymer being pH responsive and dissolvable above about pH 6;1006280349one or more polar organic solvents; and a viscosity modifying vehicle.

[0110] In a second aspect, the present disclosure provides a composition for an in situ implant, the composition comprising: a first polymer, said first polymer being biodegradable; a second polymer, said second polymer being able to form an inclusion complex with one or more pharmaceutically active ingredients (APIs); one or more polar organic solvents; and a viscosity modifying vehicle.

[0111] In some embodiments of the first or second aspect, the first polymer may be present in an amount from about 15 to about 40 wt.%, or from about 20 to about 40 wt.%, or from about 25 to about 40 wt.%, or from about 30 to about 40 wt.%, or from about 35 to about 40 wt.%, or from about 20 to about 35 wt.%, or from about 25 to about 35 wt.%, or from about 30 to about 35 wt.%, or from about 20 to about 30 wt.%, or from about 25 to about 30 wt.%, or from about 20 to about 25 wt.%, based on the total weight of the composition.

[0112] In some embodiments of the first or second aspect, the first polymer may be present in an amount from about 15 to about 40 % w / v, or from about 20 to about 40 % w / v, or from about 25 to about 40 % w / v, or from about 30 to about 40 % w / v, or from about 35 to about 40 % w / v, or from about 20 to about 35 % w / v, or from about 25 to about 35 % w / v, or from about 30 to about 35 % w / v, or from about 20 to about 30 % w / v, or from about 25 to about 30 % w / v, or from about 20 to about 25 % w / v.

[0113] In some embodiments of the first or second aspect, the first polymer may be present in an amount from about 5 to about 50 wt.%, or from about 10 to about 50 wt.%, or from about 15 to about 50 wt.%, or from about 20 to about 50 wt.%, or from about 25 to about 50 wt.%, or from about 30 to about 50 wt.%, or from about 35 to about 50 wt.%, or from about 5 to about 45 wt., or from about 10 to about 45 wt.%, or from about 15 to about 45 wt.%, or from about 20 to about 45 wt.%, or from about 25 to about 45 wt.%, or from about 30 to about 45 wt.%, or from about 35 to about 45 wt.%, or from about 51006280349to about 40 wt., or from about 10 to about 40 wt.%, or from about 15 to about 40 wt.%, or from about 20 to about 40 wt.%, or from about 25 to about 40 wt.%, or from about 30 to about 40 wt.%, or from about 35 to about 40 wt.%, based on the total weight of the composition.

[0114] In some embodiments of the first or second aspect, the first polymer may be present in an amount from about 5 to about 50 % w / v, or from about 10 to about 50 % w / v, or from about 15 to about 50 % w / v, or from about 20 to about 50 % w / v, or from about 25 to about 50 % w / v, or from about 30 to about 50 % w / v, or from about 35 to about 50 % w / v, or from about 5 to about 45 % w / v, or from about 10 to about 45 % w / v, or from about 15 to about 45 % w / v, or from about 20 to about 45 % w / v, or from about 25 to about 45 % w / v, or from about 30 to about 45 % w / v, or from about 35 to about 45 % w / v, or from about 5 to about 40 % w / v, or from about 10 to about 40 % w / v, or from about 15 to about 40 % w / v, or from about 20 to about 40 % w / v, or from about 25 to about 40 % w / v, or from about 30 to about 40 % w / v, or from about 35 to about 40 % w / v.

[0115] In some embodiments of the first or second aspect, the second polymer may present in an amount from about 2 to about 15 wt.%, or from about 5 to about 15 wt.%, or from about 2 to about 10 wt.%, or from about 5 to about 10 wt.%, based on the total weight of the composition.

[0116] In some embodiments of the first or second aspect, the second polymer may present in an amount from about 2 to about 15 % w / v, or from about 5 to about 15 % w / v, or from about 2 to about 10 % w / v, or from about 5 to about 10 % w / v.

[0117] In some embodiments of the first or second aspect, the second polymer may present in an amount from about 0.1 to about 15 wt.%, or from about 0.5 to about 15 wt.%, or from about 1 to about 15 wt.%, or from about 2 to about 15 wt.%, or from about 5 to about 15 wt.%, or from about 0.1 to about 10 wt.%, or from about 0.5 to about 10 wt.%, or from about 1 to about 10 wt.%, or from about 2 to about 10 wt.%, or from about 5 to about 10 wt.%, based on the total weight of the composition.

[0118] In some embodiments of the first or second aspect, the second polymer may present in an amount from about 0.1 to about 15 % w / v, or from about 0.5 to about 15 % w / v, or from about 1 to about 15 % w / v, or from about 2 to about 15 % w / v, or from1006280349about 5 to about 15 % w / v, or from about 0.1 to about 10 % w / v, or from about 0.5 to about 10 % w / v, or from about 1 to about 10 % w / v, or from about 2 to about 10 % w / v, or from about 5 to about 10 % w / v, based on the total weight of the composition.

[0119] In some embodiments of the first or second aspect, the one or more polar organic solvents may be present in an amount from about 25 to about 55 wt.%, or from about 30 to about 55 wt.%, or from about 35 to about 55 wt.%, or from about 40 to about 55 wt.%, or from about 45 to about 55 wt.%, or from about 50 to about 55 wt.%, or from about 25 to about 50 wt.%, or from about 30 to about 50 wt.%, or from about 35 to about 50 wt.%, or from about 40 to about 50 wt.%, or from about 45 to about 50 wt.%, or from about 25 to about 45 wt.%, or from about 30 to about 45 wt.%, or from about 35 to about 45 wt.%, or from about 40 to about 45 wt.%, or from about 25 to about 40 wt.%, or from about 30 to about 40 wt.%, or from about 35 to about 40 wt.%, or from about 25 to about 35 wt.%, or from about 30 to about 35 wt.%, or from about 25 to about 30 wt.%, based on the total weight of the composition.

[0120] In some embodiments of the first or second aspect, the one or more polar organic solvents may be present in an amount from about 25 to about 55 % w / v, or from about 30 to about 55 % w / v, or from about 35 to about 55 % w / v, or from about 40 to about 55 % w / v, or from about 45 to about 55 % w / v, or from about 50 to about 55 % w / v, or from about 25 to about 50 % w / v, or from about 30 to about 50 % w / v, or from about 35 to about 50 % w / v, or from about 40 to about 50 % w / v, or from about 45 to about 50 % w / v, or from about 25 to about 45 % w / v, or from about 30 to about 45 % w / v, or from about 35 to about 45 % w / v, or from about 40 to about 45 % w / v, or from about 25 to about 40 % w / v, or from about 30 to about 40 % w / v, or from about 35 to about 40 % w / v, or from about 25 to about 35 % w / v, or from about 30 to about 35 % w / v, or from about 25 to about 30 % w / v.

[0121] In some embodiments of the first or second aspect, the one or more polar organic solvents may be present in an amount from about 20 to about 50 wt.%, or from about 25 to about 50 wt.%, or from about 30 to about 50 wt.%, or from about 35 to about 50 wt.%, or from about 40 to about 50 wt.%, or from about 45 to about 50 wt.%, or from about 20 to about 45 wt.%, or from about 25 to about 45 wt.%, or from about 30 to about 45 wt.%, or from about 35 to about 45 wt.%, or from about 40 to about 45 wt.%, or from about 20 to about 40 wt.%, or from about 25 to about 40 wt.%, or from about 30 to about 40 wt.%, or from about 35 to about 40 wt.%, or from about 20 to about 35 wt.%,1006280349or from about 25 to about 35 wt.%, or from about 30 to about 35 wt.%, or from about 20 to about 30 wt.%, or from about 25 to about 30 wt.%, or from about 20 to about 25 wt.%, based on the total weight of the composition.

[0122] In some embodiments of the first or second aspect, the one or more polar organic solvents may be present in an amount from about 20 to about 50 % w / v, or from about 25 to about 50 % w / v, or from about 30 to about 50 % w / v, or from about 35 to about 50 % w / v, or from about 40 to about 50 % w / v, or from about 45 to about 50 % w / v, or from about 20 to about 45 % w / v, or from about 25 to about 45 % w / v, or from about 30 to about 45 % w / v, or from about 35 to about 45 % w / v, or from about 40 to about 45 % w / v, or from about 20 to about 40 % w / v, or from about 25 to about 40 % w / v, or from about 30 to about 40 % w / v, or from about 35 to about 40 % w / v, or from about 20 to about 35 % w / v, or from about 25 to about 35 % w / v, or from about 30 to about 35 % w / v, or from about 20 to about 30 % w / v, or from about 25 to about 30 % w / v, or from about 20 to about 25 % w / v.

[0123] In some embodiments of the first or second aspect, the viscosity modifying vehicle may be present in an amount from about 15 to about 40 wt.%, or from about 20 to about 40 wt.%, or from about 25 to about 40 wt.%, or from about 30 to about 40 wt.%, or from about 35 to about 40 wt.%, or from about 15 to about 35 wt.%, or from about 20 to about 35 wt.%, or from about 25 to about 35 wt.%, or from about 30 to about 35 wt.%, or from about 15 to about 30 wt.%, or from about 20 to about 30 wt.%, or from about 25 to about 30 wt.%, or from about 15 to about 25 wt.%, or from about 20 to about 25 wt.%, or from about 15 to about 20 wt.%, based on the total weight of the composition.

[0124] In some embodiments of the first or second aspect, the viscosity modifying vehicle may be present in an amount from about 15 to about 40 % w / v, or from about 20 to about 40 % w / v, or from about 25 to about 40 % w / v, or from about 30 to about 40 % w / v, or from about 35 to about 40 % w / v, or from about 15 to about 35 % w / v, or from about 20 to about 35 % w / v, or from about 25 to about 35 % w / v, or from about 30 to about 35 % w / v, or from about 15 to about 30 % w / v, or from about 20 to about 30 % w / v, or from about 25 to about 30 % w / v, or from about 15 to about 25 % w / v, or from about 20 to about 25 % w / v, or from about 15 to about 20 % w / v.

[0125] In some embodiments of the first or second aspect, the viscosity modifying vehicle may be present in an amount from about 15 to about 50 wt.%, or from about 151006280349to about 40 wt.%, or from about 20 to about 50 wt.%, or from about 20 to about 40 wt.%, or from about 25 to about 40 wt.%, or from about 30 to about 40 wt.%, or from about 35 to about 40 wt.%, or from about 15 to about 35 wt.%, or from about 20 to about 35 wt.%, or from about 25 to about 35 wt.%, or from about 30 to about 35 wt.%, or from about 15 to about 30 wt.%, or from about 20 to about 30 wt.%, or from about 25 to about 30 wt.%, or from about 15 to about 25 wt.%, or from about 20 to about 25 wt.%, or from about 15 to about 20 wt.%, based on the total weight of the composition.

[0126] In some embodiments of the first or second aspect, the viscosity modifying vehicle may be present in an amount from about 15 to about 50 % w / v, or from about 15 to about 40 % w / v, or from about 20 to about 50 % w / v, or from about 20 to about 40 % w / v, or from about 25 to about 40 % w / v, or from about 30 to about 40 % w / v, or from about 35 to about 40 % w / v, or from about 15 to about 35 % w / v, or from about 20 to about 35 % w / v, or from about 25 to about 35 % w / v, or from about 30 to about 35 % w / v, or from about 15 to about 30 % w / v, or from about 20 to about 30 % w / v, or from about 25 to about 30 % w / v, or from about 15 to about 25 % w / v, or from about 20 to about 25 % w / v, or from about 15 to about 20 % w / v.

[0127] In some embodiments of the first or second aspects, the composition may further comprise one or more pharmaceutically active ingredients (APIs).

[0128] In a third aspect, the present disclosure provides a composition for an in situ implant, the composition comprising: a first polymer, said first polymer being biodegradable; a second polymer, said second polymer being pH responsive and dissolvable above about pH 6; one or more polar organic solvents; a viscosity modifying vehicle; and one or more pharmaceutically active ingredients (APIs).

[0129] In a fourth aspect, the present disclosure provides a composition for an in situ implant, the composition comprising: a first polymer, said first polymer being biodegradable;1006280349a second polymer, said second polymer being able to form an inclusion complex with one or more pharmaceutically active ingredients (APIs); one or more polar organic solvents; a viscosity modifying vehicle; and one or more pharmaceutically active ingredients (APIs); wherein the second polymer and at least one of the one or more pharmaceutically active ingredients are present as an inclusion complex.

[0130] In some embodiments of the third or fourth aspects, the first polymer may be present in an amount from about 15 to about 30 wt.%, or from about 20 to about 30 wt.%, or from about 25 to about 30 wt.%, or from about 15 to about 25 wt.%, or from about 20 to about 25 wt.%, or from about 15 to about 20 wt.%, based on the total weight of the composition.

[0131] In some embodiments of the third or fourth aspects, the first polymer may be present in an amount from about 15 to about 30 % w / v, or from about 20 to about 30 % w / v, or from about 25 to about 30 % w / v, or from about 15 to about 25 % w / v, or from about 20 to about 25 % w / v, or from about 15 to about 20 % w / v.

[0132] In some embodiments of the third or fourth aspects, the second polymer may be present in an amount from about 3 to about 10 wt.%, or from about 4 to about 10 wt.%, or from about 5 to about 10 wt.%, or from about 6 to about 10 wt.%, or from about 7 to about 10 wt.%, or from about 8 to about 10 wt.%, or from about 9 to about 10 wt.%, or from about 3 to about 9 wt.%, or from about 4 to about 9 wt.%, or from about 5 to about 9 wt.%, or from about 6 to about 9 wt.%, or from about 7 to about 9 wt.%, or from about 8 to about 9 wt.%, or from about 3 to about 8 wt.%, or from about 4 to about 8 wt.%, or from about 5 to about 8 wt.%, or from about 6 to about 8 wt.%, or from about 7 to about 8 wt.%, or from about 3 to about 7 wt.%, or from about 4 to about 7 wt.%, or from about 5 to about 7 wt.%, or from about 6 to about 7 wt.%, or from about 3 to about 6 wt.%, or from about 4 to about 6 wt.%, or from about 5 to about 6 wt.%, or from about 3 to about 5 wt.%, or from about 4 to about 5 wt.%, or from about 3 to about 4 wt.%, based on the total weight of the composition.1006280349

[0133] In some embodiments of the third or fourth aspects, the second polymer may be present in an amount from about 3 to about 10 % w / v, or from about 4 to about 10 % w / v, or from about 5 to about 10 % w / v, or from about 6 to about 10 % w / v, or from about 7 to about 10 % w / v, or from about 8 to about 10 % w / v, or from about 9 to about 10 % w / v, or from about 3 to about 9 % w / v, or from about 4 to about 9 % w / v, or from about 5 to about 9 % w / v, or from about 6 to about 9 % w / v, or from about 7 to about 9 % w / v, or from about 8 to about 9 % w / v, or from about 3 to about 8 % w / v, or from about 4 to about 8 % w / v, or from about 5 to about 8 % w / v, or from about 6 to about 8 % w / v, or from about 7 to about 8 % w / v, or from about 3 to about 7 % w / v, or from about 4 to about 7 % w / v, or from about 5 to about 7 % w / v, or from about 6 to about 7 % w / v, or from about 3 to about 6 % w / v, or from about 4 to about 6 % w / v, or from about 5 to about 6 % w / v, or from about 3 to about 5 % w / v, or from about 4 to about 5 % w / v, or from about 3 to about 4 % w / v.

[0134] In some embodiments of the third or fourth aspects, the one or more polar organic solvents may be present in an amount from about 25 to about 35 wt.%, or from about 27 to about 35 wt.%, or from about 30 to about 35 wt.%, or from about 32 to about 35 wt.%, or from about 25 to about 32 wt.%, or from about 27 to about 32 wt.%, or from about 30 to about 32 wt.%, or from about 25 to about 30 wt.%, or from about 27 to about 30 wt.%, or from about 25 to about 27 wt.%, based on the total weight of the composition.

[0135] In some embodiments of the third or fourth aspects, the one or more polar organic solvents may be present in an amount from about 25 to about 35 % w / v, or from about 27 to about 35 % w / v, or from about 30 to about 35 % w / v, or from about 32 to about 35 % w / v, or from about 25 to about 32 % w / v, or from about 27 to about 32 % w / v, or from about 30 to about 32 % w / v, or from about 25 to about 30 % w / v, or from about 27 to about 30 % w / v, or from about 25 to about 27 % w / v.

[0136] In some embodiments of the third or fourth aspects, the viscosity modifying vehicle may be present in an amount from about from about 25 to about 35 wt.%, or from about 27 to about 35 wt.%, or from about 30 to about 35 wt.%, or from about 32 to about 35 wt.%, or from about 25 to about 32 wt.%, or from about 27 to about 32 wt.%, or from about 30 to about 32 wt.%, or from about 25 to about 30 wt.%, or from about 27 to about 30 wt.%, or from about 25 to about 27 wt.%, based on the total weight of the composition.1006280349

[0137] In some embodiments of the third or fourth aspects, the viscosity modifying vehicle may be present in an amount from about from about 25 to about 35 % w / v, or from about 27 to about 35 % w / v, or from about 30 to about 35 % w / v, or from about 32 to about 35 % w / v, or from about 25 to about 32 % w / v, or from about 27 to about 32 % w / v, or from about 30 to about 32 % w / v, or from about 25 to about 30 % w / v, or from about 27 to about 30 % w / v, or from about 25 to about 27 % w / v.

[0138] In some embodiments of the third or fourth aspects, the one or more pharmaceutically active ingredients may be present in an amount from about 5 to about 15 wt.%, from about 7 to about 15 wt.%, or from about 10 to about 15 wt.%, or from about 12 to about 15 wt.%, or from about 5 to about 12 wt.%, or from about 7 to about 12 wt.%, or from about 10 to about 12 wt.%, or from about 5 to about 10 wt.%, or from about 7 to about 10 wt.%, or from about 5 to about 7 wt.%, based on the total weight of the composition.

[0139] In some embodiments of the third or fourth aspects, the one or more pharmaceutically active ingredients may be present in an amount from about 5 to about 15 % w / v, from about 7 to about 15 % w / v, or from about 10 to about 15 % w / v, or from about 12 to about 15 % w / v, or from about 5 to about 12 % w / v, or from about 7 to about 12 % w / v, or from about 10 to about 12 % w / v, or from about 5 to about 10 % w / v, or from about 7 to about 10 % w / v, or from about 5 to about 7 % w / v.

[0140] In a further aspect, the present disclosure provides a composition for an in situ implant, the composition comprising:PLGA; poly(methacrylic acid-co-methyl methacrylate); one or more polar organic solvents selected from dimethylacetamide or N- methyl-2-pyrrolidone;PEG; and one or more pharmaceutically active ingredients (APIs).

[0141] In a further aspect, the present disclosure provides a composition for an in situ implant, the composition comprising:100628034915 to 30 wt.% of PLGA;3 to 10 wt.% of poly(methacrylic acid-co-methyl methacrylate);25 to 35 wt.% of one or more polar organic solvents selected from dimethylacetamide or N-methyl-2-pyrrolidone;25 to 35 wt.% of PEG; and one or more pharmaceutically active ingredients (APIs), wherein the values in wt.% are based on the total weight of the composition.

[0142] In a further aspect, the present disclosure provides a composition for an in situ implant, the composition comprising:15 to 30 % w / v of PLGA;3 to 10 % w / v of poly(methacrylic acid-co-methyl methacrylate);25 to 35 % w / v of one or more polar organic solvents selected from dimethylacetamide or N-methyl-2-pyrrolidone;25 to 35 % w / v of PEG; and one or more pharmaceutically active ingredients (APIs).

[0143] In a further aspect, the present disclosure provides a composition for an in situ implant, the composition comprising:15 to 30 wt.% of PLGA;3 to 10 wt.% of poly(methacrylic acid-co-methyl methacrylate);25 to 35 wt.% of one or more polar organic solvents selected from dimethylacetamide or N-methyl-2-pyrrolidone;25 to 35 wt.% of PEG; and5 to 15 wt.% of one or more pharmaceutically active ingredients (APIs), wherein the values in wt.% are based on the total weight of the composition.1006280349

[0144] In a further aspect, the present disclosure provides a composition for an in situ implant, the composition comprising:15 to 30 % w / v of PLGA;3 to 10 % w / v of poly(methacrylic acid-co-methyl methacrylate);25 to 35 % w / v of one or more polar organic solvents selected from dimethylacetamide or N-methyl-2-pyrrolidone;25 to 35 % w / v of PEG; and5 to 15 % w / v of one or more pharmaceutically active ingredients (APIs).

[0145] In a further aspect, the present disclosure provides a composition for an in situ implant, the composition comprising:PLGA; hydroxypropyl-beta-cyclodextrin; one or more polar organic solvents selected from dimethylacetamide or N- methyl-2-pyrrolidone;PEG; and one or more pharmaceutically active ingredients (APIs).

[0146] In a further aspect, the present disclosure provides a composition for an in situ implant, the composition comprising:15 to 30 wt.% of PLGA;3 to 10 wt.% of hydroxypropyl-beta-cyclodextrin;25 to 35 wt.% of one or more polar organic solvents selected from dimethylacetamide or N-methyl-2-pyrrolidone;25 to 35 wt.% of PEG; and1006280349one or more pharmaceutically active ingredients (APIs), wherein the values in wt.% are based on the total weight of the composition.

[0147] In a further aspect, the present disclosure provides a composition for an in situ implant, the composition comprising:15 to 30 % w / v of PLGA;3 to 10 % w / v of hydroxypropyl-beta-cyclodextrin;25 to 35 % w / v of one or more polar organic solvents selected from dimethylacetamide or N-methyl-2-pyrrolidone;25 to 35 % w / v of PEG; and one or more pharmaceutically active ingredients (APIs).

[0148] In a further aspect, the present disclosure provides a composition for an in situ implant, the composition comprising:15 to 30 wt.% of PLGA;3 to 10 wt.% of hydroxypropyl-beta-cyclodextrin;25 to 35 wt.% of one or more polar organic solvents selected from dimethylacetamide or N-methyl-2-pyrrolidone;25 to 35 wt.% of PEG; and5 to 15 wt.% of one or more pharmaceutically active ingredients (APIs), wherein the values in wt.% are based on the total weight of the composition.

[0149] In a further aspect, the present disclosure provides a composition for an in situ implant, the composition comprising:15 to 30 % w / v of PLGA;3 to 10 % w / v of hydroxypropyl-beta-cyclodextrin;25 to 35 % w / v of one or more polar organic solvents selected from dimethylacetamide or N-methyl-2-pyrrolidone;100628034925 to 35 % w / v of PEG; and5 to 15 % w / v of one or more pharmaceutically active ingredients (APIs).

[0150] In some embodiments, the composition may further comprise one or more excipients.

[0151] In some embodiments, the excipients may include, for example, one or more pharmaceutically acceptable pH modifiers, reducing agents, antioxidants, and / or free radical scavengers.

[0152] The phrase “pharmaceutically acceptable” indicates that the substance or composition must be compatible chemically and / or toxicologically, with the other ingredients comprising the composition, and / or the subject being treated therewith.

[0153] Modifiers of pH include, but are not limited to, inorganic and organic salts including zinc carbonate, magnesium carbonate, calcium carbonate, magnesium hydroxide, calcium hydrogen phosphate, calcium acetate, calcium hydroxide, calcium lactate, calcium maleate, calcium oleate, calcium oxalate, calcium phosphate, magnesium acetate, magnesium hydrogen phosphate, magnesium phosphate, magnesium lactate, magnesium maleate, magnesium oleate, magnesium oxalate, zinc acetate, zinc hydrogen phosphate, zinc phosphate, zinc lactate, zinc maleate, zinc oleate, zinc oxalate, and combinations thereof.

[0154] Reducing agents include, but are not limited to, cysteine or methionine.

[0155] Antioxidants include, but are not limited to, sodium bisulfite, sodium metabisulfite, sodium thiosulfate, d-alpha tocopherol acetate, dl-alpha tocopherol, ascorbyl palmitate, butylated hydroxyanidole, ascorbic acid, butylated hydroxyanisole, butylatedhydroxyquinone, butylhydroxyanisol, hydroxycomarin, butylated hydroxytoluene, cephalm, ethyl gallate, propyl gallate, octyl gallate, lauryl gallate, propylhydroxybenzoate, trihydroxybutylrophenone, dimethylphenol, diterlbulylphenol, vitamin E, lecithin, and ethanolamine.

[0156] In some embodiments, the excipients may comprise an antioxidant, preferably the antioxidant is sodium bisulfite.1006280349

[0157] In some embodiments, the excipients may be present in an amount from about 0.1 to about 1.0 wt.%, or from about 0.2 to about 0.5 wt.%.

[0158] In some embodiments, the excipients may be present in an amount from about 0.1 to about 1.0 % w / v, or from about 0.2 to about 0.5 % w / v.

[0159] In any aspect or embodiment, the composition is injectable or has a syringeability that allows an individual to inject or eject the composition from the syringe. The lower the force needed to expel the formulation, the better the syringeability. Typically, the composition has an average force required to expel the formulation from a 22G needle of equal to, or less than, 40N; equal to, or less than 39N; equal to, or less than, 38N; equal to, or less than, 37N; equal to, or less than, 36N; equal to, or less than, 35N; equal to, or less than, 34N; equal to, or less than, 33N; or equal to, or less than, 32N.

[0160] In any aspect or embodiment, the composition comprising one or more active pharmaceutical ingredients (APIs) and the stability of the API under storage conditions at 25 °C ± 2°C and 60 % ± 5% Relative Humidity (RH) for 3 months is equal to or greater than 80% of the initial starting amount; is equal to or greater than 85% of the initial starting amount; is equal to or greater than 90% of the initial starting amount; or is equal to or greater than 95% of the initial starting amount.

[0161] In some embodiments, the composition substantially completely degrades in about 14 days. In some embodiments, the weight of the composition is reduced by about 95% of the initial starting weight in 14 days, or about 90% of the initial starting weight in 14 days, or about 85% of the initial starting weight in 14 days, or about 80% of the initial starting weight in 14 days. In some embodiments, the weight of the composition is reduced by about 80% of the initial starting weight in 7 days, or about 75% of the initial starting weight in 7 days, or about 70% of the initial starting weight in 7 days.

[0162] In some embodiments, the composition may be a single-phase composition. As used herein, “single phase” defines that the composition may be uniform in both physical and chemical characteristics, such that the composition is homogenous without notably distinct phase boundaries.1006280349First polymer

[0163] The first polymer is a biodegradable polymer. This is advantageous for the present invention as the composition should (as much as practicable) be able to degrade or be reabsorbed into the body post administration.

[0164] In some embodiments, the first polymer may comprise one or more of poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polylactic acid (PLA), polyglycolide, poly-3-hydroxybutane, poly(glycolide-co-trimethylene carbonate) polyanhydrides or polyurethanes. Other biodegradable polymers known in the art are contemplated.

[0165] Preferably the first polymer comprises poly(lactic-co-glycolic acid) (PLGA). PLGA comprises a copolymer of lactic acid and glycolic acid. As used herein, the term "lactic acid" includes the isomers L-lactic acid, D-lactic acid, DL-lactic acid and lactide, while the term "glycolic acid" includes glycolide.

[0166] In some embodiments, the PLGA may have a monomeric ratio of lactide:glycolide from about 15:85 to about 85:15, preferably from about 75:25 to about 30:70, more preferably from about 60:40 to about 40:60, and an especially useful copolymer has a monomer ratio of lactic acid / glycolic acid of about 50:50. Other ratios of lactide:glycolide known in the art are contemplated.

[0167] In some embodiments, the PLGA may have an acid endcap.

[0168] In some embodiments, the PLGA may have a molecular weight from about 7 kDa to about 54 kDa, or from about 10 kDa to about 54 kDa, or from about 17 kDa to about 54 kDa, or from about 24 kDa to about 54 kDa, or from about 38 kDa to about 54 kDa, or from about 7 kDa to about 38 kDa, or from about 10 kDa to about 38 kDa, or from about 17 kDa to about 38 kDa, or from about 24 kDa to about 38 kDa, or from about 7 kDa to about 24 kDa, or from about 10 kDa to about 24 kDa, or from about 17 kDa to about 24 kDa, or from about 7 kDa to about 17 kDa, or from about 10 kDa to about 17 kDa.

[0169] In some embodiments, the PLGA may have a molecular weight from about 10 kDa to about 20 kDa, or from about 12 kDa to about 20 KDa, or from about 14 kDa to about 20 kDa, or from about 10 kDa to about 18 kDa, or from about 12 kDa to about 181006280349KDa, or from about 14 kDa to about 18 kDa, or from about 10 kDa to about 16 kDa, or from about 12 kDa to about 16 KDa, or from about 14 kDa to about 16 kDa.Second polymer

[0170] The second polymer is a pH responsive polymer. This is advantageous for the present invention as once injected, changes in the microenvironment surrounding the in situ implant allows dissolution of the second polymer, releasing the pharmaceutical active in a sustained release. Polymers which dissolve above pH 6 are particularly useful for in situ formulations that are administered by intramuscular injection.

[0171] In some embodiments, the second polymer may comprise a hydrophilic polymer.

[0172] In some embodiments, the second polymer may comprise a methacrylic acid copolymer.

[0173] Methacrylic acid copolymers (or methacrylates) refer to polymers comprising monomers selected from methacrylic acid and methacrylate ester derivatives. Several commercially available polymethacrylates are known, including but not limited to, Acryl- EZE MP, Eastacryl 30D, Eudragit and other polymeric methacrylates.

[0174] In some embodiments, the second polymer comprises a pharmaceutically acceptable cyclodextrin. In some embodiments, the pharmaceutically acceptable cyclodextrin comprises an a-cyclodextrin, p-cyclodextrin or y-cyclodextrin. In some embodiments, the pharmaceutically acceptable cyclodextrin comprises hydroxy propylcyclodextrin. In some embodiments, the second polymer comprises one or more of hydroxypropyl-alpha-cyclodextrin, hydroxypropyl-beta-cyclodextrin, hydroxypropyl- gamma-cyclodextrin, sulfobutylether-beta-cyclodextrin, methyl-beta-cyclodextrin or carboxymethyl-beta-cyclodextrin.

[0175] Cyclodextrins, such as hydroxypropyl-p-cyclodextrin, may enhance drug solubility and loading through reversible inclusion complexation and may help maintain a stable drug equilibrium within the implant. This may minimise burst release by retaining the API during early phase transition and reduces crystallisation to support sustained diffusion.1006280349

[0176] The inventors have surprisingly found that the combination of PLGA and cyclodextrins can improve drug incorporation enhancing solubility during encapsulation or in-situ implant formation. Without being bound by theory, the initial burst may be reduced as the cyclodextrin can hold a drug molecule within the PLGA network. The cyclodextrin helps stabilise the API throughout PLGA erosion, resulting in a smoother long-term release. This synergy creates a robust and adaptable platform suitable for diverse long-acting injectable applications.

[0177] In some embodiments, the composition comprises both a methacrylic acid copolymer and a pharmaceutically acceptable cyclodextrin.

[0178] In some embodiments, the second polymer may comprise a poly(methacrylic acid-co-methyl methacrylate) polymer. Examples of poly(methacrylic acid-co-methyl methacrylate) polymers include Eudragit L and Eudragit S.

[0179] In some embodiments, the ratio of methacrylic acid and methyl methacrylate in the poly(methacrylic acid-co-methyl methacrylate) polymer may be 1:1.

[0180] In some embodiments, the second polymer may be dissolvable below pH 7.

[0181] In some embodiments, the second polymer may have a molecular weight from about 100 kDa to about 200 kDa, or from about 120 kDa to about 200 kDa, or from about 100 kDa to about 180 kDa, or from about 120 kDa to about 180 kDa, or from about 100 kDa to about 150 kDa, or from about 120 kDa to about 150 kDa, or from about 100 kDa to about 140 kDa, or from about 120 kDa to about 140 kDa.

[0182] The choice of the first polymer and the second polymer can be varied according to the release profile required. For example, certain first polymers may be preferred due to the degradation products being acid or basic in nature, such that the pH of the microenvironment around the implant is controlled. Controlling the microenvironment allows the release profile of the implant to be varied depending on the release kinetics required.

[0183] In some embodiments, the ratio of the first polymer to the second polymer may be 1:1 , 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9, 1 :10, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1 or 10:1. Preferably, the ratio of the first polymer to the second polymer is 4: 1 , or 5: 1 , or 6:1, or 7:1 , or 8:1, or 9:1.1006280349

[0184] In some embodiments where the first polymer is PLGA and the second polymer is poly(methacrylic acid-co-methyl methacrylate) (eg Eudragit L100), the amount of the first polymer in the composition is 26% and the amount of the second polymer in the composition is 6% based on the total weight of the composition.Polar organic solvents

[0185] The polar organic solvent for inclusion in the composition should be biocompatible.

[0186] Biocompatible means that as the organic solvent disperses or diffuses from the composition, it does not result in substantial tissue irritation or necrosis surrounding the implant site.

[0187] In some embodiments, the one or more polar organic solvents may comprise N,N-dimethyl acetamide, dimethyl sulfoxide, benzyl alcohol, bezyl benzoate, ethanol, triacetin or N-methyl pyrrolidone, preferably the one or more polar organic solvents comprises dimethyl acetamide. Other suitable organic solvents are contemplated.

[0188] The polar organic solvents should have suitably high water solubility, thus allowing formation of the implant once injected through solvent exchange with the microenvironment of the implant site.Viscosity modifying vehicle

[0189] The viscosity modifying vehicle described by the present invention is used to alter the viscosity of the composition to allow injectability. The viscosity modifying vehicle may be a solid or a liquid, preferably a liquid. Preferably, the viscosity modifying vehicle should be miscible with the polar organic solvent.

[0190] In some embodiments, the viscosity modifying vehicle is a second solvent. In some embodiments, the viscosity modifying vehicle reduces the viscosity of the in situ implant to allow injectability.

[0191] In some embodiments, the viscosity modifying vehicle may comprise a nonionic polyether, functionalised or unfunctionalized polyethylene glycol, isopropyl myristate, glycerol formal, polysorbate, glycerine or propylene glycol.1006280349

[0192] Polyethylene glycol (PEG) refers to an oligomer or polymer of ethylene oxide. PEG may sometimes be referred to as polyethylene oxide (PEG) or polyoxyethylene (POE). The structure of unfunctionalized PEG is commonly expressed as H-(O-CH2- CH2)n-OH.

[0193] In some embodiments, the polyethylene glycol may have a molecular weight of less than about 1 kDa, or less than about 900 Da, or less than about 800 Da, or less than about 700 Da, or less than about 600 Da, or less than about 500 Da.

[0194] In some embodiments, the viscosity of the composition may be from about 0.35 to about 0.70 Pascal-seconds at 25 °C, or from about 0.35 to about 0.65 Pascal- seconds at 25 °C, or from about 0.35 to about 0.60 Pascal-seconds at 25 °C, or from about 0.40 to about 0.70 Pascal-seconds at 25 °C, or from about 0.45 to about 0.70 Pascal-seconds at 25 °C, or from about 0.50 to about 0.70 Pascal-seconds at 25 °C, or from about 0.40 to about 0.65 Pascal-seconds at 25 °C, or from about 0.45 to about 0.65 Pascal-seconds at 25 °C, or from about 0.50 to about 0.65 Pascal-seconds at 25 °C.

[0195] The person skilled in the art would be aware of several ways to determine the viscosity of a composition. For example, including but not limited to, a capillary viscometer, Zahn Cup method, a falling sphere viscometer, a vibrational viscometer, a rotational viscometer or a VROC viscometer.Active pharmaceutical ingredients (APIs)

[0196] Although the present disclosure discloses specific active pharmaceutical ingredients, it should not be considered limiting in any way. Composition of the present disclosure are envisaged to work with any active pharmaceutical ingredient suitable for an in situ implant or for sustained-release. For example, leuprolide acetate (for advanced prostate cancer), doxycycline hyclate (for adult paradontitis), bupivacaine (for postoperative pain), risperidone (for Schizophrenia and bipolar disorder) and paclitazel (for cancer therapy) are all considered suitable for in situ implants. Other active pharmaceutical ingredients are contemplated.

[0197] In some embodiments, the active pharmaceutical ingredient may be hydrophilic (Log P < 0), amphiphilic (Log P » 0-3) or lipophilic (Log P >3).1006280349

[0198] In some embodiments, the active pharmaceutical ingredient is an antigen binding protein (for example a peptide, protein or antibody), an antigen binding proteindrug conjugate, a vaccine, a small molecule or a small molecule conjugate. In some embodiments, the active pharmaceutical ingredient is a small molecule. As used herein “small molecule” refers to a molecule with a molecular weight of 1000 Da or less.

[0199] In some embodiments, the one or more active pharmaceutical ingredients may comprise a dopamine replacement agent. The term "dopamine replacement agent", as used herein, refers to an agent whose administration to a human, correlates with increased dopamine levels in the brain as compared with those observed absent such administration. Preferably, the dopamine replacement agent is selected from the group consisting of metabolic precursors of dopamine (eg, levodopa, melevodopa, etilevodopa etc and combinations thereof), dopamine agonists (eg, apomorphine, bromocriptine, cabergoline, dihydroergocristine mesylate, pergolide, piribedil pramipexole, ropinirole, rotigotine, pramipexole etc and combinations thereof), agents that block dopamine degradation (eg, MAO-B inhibitors such as selegiline, rasagiline, etc and combinations thereof) and / or agents (eg, budipine) that otherwise stimulate dopamine production.

[0200] In some embodiments, the one or more active pharmaceutical ingredients may comprise a dopamine decarboxylate inhibitor (DDI). Exemplary dopamine decarboxylase inhibitors include carbidopa, benzerazide, a difluoromethyldopa [(2S)-2- amino-2-[3,4-dihydroxyphenyl)-methyl]-3,3-difluoropropanoic acid] and a-methyldopa [(S)-2-amino-3-[3,4-dihydroxyphenyl)-2-methyl-propanoic acid],

[0201] In some embodiments, the one or more active pharmaceutical ingredients may comprise one or more of pramipexole, levodopa or carbidopa.

[0202] Levodopa (also known as L-DOPA) is shown in formula (I) and is used as the first line of treatment for patients with Parkinson’s disease:Formula (I).1006280349

[0203] Carbidopa (or lodosyn) is shown in Formula (II) and is often used in combination with levodopa to treat patients with Parkinson’s disease as it inhibits peripheral metabolism of levodopa:Formula (II).

[0204] Pramipexole (or mirapex) is shown in Formula (III) and is often used either alone, or in combination with levodopa, to treat patients with Parkinson’s disease and / or restless leg syndrome. Pramipexole is a dopamine agonist of the non-ergoline class:Formula (III).

[0205] As used herein, “pramipexole”, “levodopa” or “carbidopa” may also refer to pharmaceutically acceptable derivatives of pramipexole, levodopa or carbidopa respectively.

[0206] The term “pharmaceutically acceptable derivative” may include any pharmaceutically acceptable salt, hydrate or prodrug, or any other compound which upon administration to a subject, is capable of providing (directly or indirectly) a compound of formula I or an active metabolite or residue thereof.

[0207] Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic,1006280349sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.

[0208] General information on types of pharmaceutically acceptable salts and their formation is known to those skilled in the art and is as described in general texts such as “Handbook of Pharmaceutical salts” P. H. Stahl, C. G. Wermuth, 1st edition, 2002, Wiley- VCH.

[0209] In some embodiments where the one or more active pharmaceutical ingredients comprise levodopa, the percentage of levodopa released from the composition in 7 days is greater than or equal to about 70%, or greater than or equal to about 75%, or greater than or equal to about 80%, or greater than or equal to about 85%, or greater than or equal to about 90%, or greater than or equal to about 95% of the initial amount of levodopa.

[0210] In some embodiments where the one or more active pharmaceutical ingredients comprise carbidopa, the percentage of levodopa released from the composition in 7 days is greater than or equal to about 70%, or greater than or equal to about 75%, or greater than or equal to about 80%, or greater than or equal to about 85%, or greater than or equal to about 90%, or greater than or equal to about 95% of the initial amount of carbidopa.Methods of making compositions

[0211] In a further aspect, the present disclosure provides a method of making a composition according to any one of the herein disclosed embodiments, the method comprising the steps of:(a) combining a first polymer and a second polymer in the one or more polar organic solvents to form a solution; and(b) adding a viscosity modifying vehicle to the solution.

[0212] In some embodiments, the method may further comprise the step of adding one or more pharmaceutically active ingredients after adding the viscosity modifying vehicle to the solution.1006280349

[0213] In some embodiments, step (a) and / or step (b) may be conducted at a temperature greater than or equal to about 70 °C, or greater than or equal to about 80 °C, or greater than or equal to about 90 °C.Injectables

[0214] In a further aspect, the present disclosure provides an injectable comprising the composition according to any one of the herein disclosed embodiments. An injectable as used herein refers to a composition that is capable of being administered to a subject using a needle and a syringe.

[0215] In some embodiments, the injectable is administered through a syringe with a 18-22 gauge or 20-21 gauge needle.

[0216] The injectable composition can be administered to a subject in one or more injection sites on the same day and still be considered as being part of the same dosing period. For example, part of a dose can be administered to a first injection site and another part of the same dose can be administered to another injection site. A singlebody implant will form at each injection site. Such a mode of administration within a same day is considered to be administration of a single dose with a dosing period.

[0217] As used herein, the term “dosing period” refers to the period of days or weeks as measured from the initial day after administration to at least 14 days after administration. During the dosing period, the implant will provide therapeutic plasma levels of drug for at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 21 days, at least 28 days, at least 31 days or at least 36 days. The dosing period can exceed two weeks and can be up to three weeks, four weeks, five weeks, six weeks, two months, three months, four months, five months or six months. A dosing period can end after expiration of a predetermined number of days or after the plasma level of the active pharmaceutical ingredient drops below therapeutic levels.

[0218] Alternatively, administration can be modified such that there is one point of needle entry into the subject but more than one injection site below the skin, which can be achieved by making a first penetration into the skin and muscle and administering a portion of a dose, then partially withdrawing and redirecting the needle into another section of muscle, while maintaining the tip of the needle beneath the skin, and then1006280349injecting another portion of the dose into this other section of muscle. Such a mode of administration is still considered to be administration of a single dose within a dosing period.Methods of use

[0219] In a further aspect, the present disclosure provides a method of treating a neurodegenerative disease or disorder comprising administering a composition according to any one of the herein disclosed embodiments to a patient in need thereof, wherein the composition is administered as an injectable.

[0220] In some embodiments, the patient is human. In alternative embodiments, the patient is an animal. In some embodiments, the animal is a companion animal and / or a farm animal.

[0221] As used herein, “companion animal” refers to any animal that may be kept as a pet or other domestic animal. Non-limiting examples of companion animals may include dogs, cats, birds, rats, mice, lizards, snakes, rabbits, hamsters, guinea pigs, ferrets, turtles and the like.

[0222] As used herein, “farm animal” refers to an animal raised on a farm for various purposes, including producing food (meat, milk, eggs), labour, or other products such as wool or leather. Non-limiting examples of farm animals may include cows, sheep, goats, pigs, chickens, horses, donkeys, alpacas, llamas, geese and the like.

[0223] In a further aspect, the present disclosure provides the use of composition according to any one of the herein disclosed embodiments, in the manufacture of a medicament for treating a neurodegenerative disease or disorder, wherein the medicament is to be administered as an injectable.

[0224] In a further aspect, the present disclosure provides a composition according to any one of the herein disclosed embodiments for use in the treatment of a neurodegenerative disease or disorder, wherein the composition is to be administered as an injectable.

[0225] In some embodiments, the injectable may be administered, or is to be administered as a single-use device. In alternative embodiments, the injectable may be administered, or is to be administered as a multi-use device.1006280349

[0226] In some embodiments, the injectable may be self-administered.

[0227] In some embodiments, the injectable may be suitable for intramuscular, subcutaneous or intradermal administration.

[0228] In a further aspect, the present disclosure provides a kit for treating a neurodegenerative disease or disorder, the kit comprising: one or more doses of a composition according to any one of the herein disclosed embodiments; and one or more injectable devices.

[0229] In some embodiments, the kit may further comprise instructions to prepare the injectable devices for administration.

[0230] In some embodiments, the injectable devices may comprise a syringe, wearable pump or an autoinjector. Other injectable devices known in the art are contemplated.

[0231] In some embodiments, the kit may further comprise a needle. In some embodiments, the needle gauge may be from about 14 to about 31. In some embodiments, the needle may have an outer diameter from about 2.0 mm to about 0.3 mm.

[0232] In some embodiments, each dose of the composition may independently have a volume of about 0.1 to about 5 mL.Neurodegenerative diseases or disorders

[0233] Neurodegenerative diseases or disorders encompass a wide range of conditions that result from progressive damage to cells and nervous system connections that are essential for mobility, coordination, strength, sensation, and cognition. For example, the neurodegenerative disease or disorder may include Alzheimer’s disease, ataxia, Huntington’s disease, Parkinson’s disease, motor neuron disease, multiple system atrophy or progressive supranuclear palsy.

[0234] In some embodiments, the neurodegenerative disease or disorder may be Parkinson’s disease.1006280349

[0235] Parkinson’s disease is a brain disorder that causes unintended or uncontrollable movements, such as shaking or tremors in hands, arms, legs, jaw or head, stiffness, slowness of movement, and difficulty with balance and coordination. Successful treatment of Parkinson’s disease may reduce or slow the progression of one or more of these symptoms.

[0236] It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.ExamplesExample 1 - Materials and methodsMaterials

[0237] PLGA 5o;5o polymer (M.W- 15,000 Da, acid end cap) was purchased from Nomisma healthcare (Gujrat, India). Polyethylene glycol 400 (PEG-400) was purchased from Sigma Aldrich. N,N-dimethyl acetamide was purchased from Sigma Aldrich (MO, USA), Sodium bisulfite was purchased from Sigma Aldrich (India), Eudragit L-100 was purchased from Evonik (Darmstadt, Germany), Tween 80 was purchased from Chemsupply (Gillman, Australia), Acetonitrile was purchased from Sigma Aldrich (Darmstadt, Germany), Trizma base was purchased from Sigma life science (MO, USA) and Trizma HOL was purchased from Sigma Aldrich (MO, USA). N-methyl pyrrolidone was purchased from Chemsupply (Gillman, Australia). 2-Hydroxypropyl-beta- cyclodextrin was purchased from Sigma Aldrich and used as received.Drug content (assay) determination

[0238] Drug content of all the formulations was determined by weighing 20 mg of each formulation into a volumetric flask and adding 500 pL DMSO to dissolve the PLGA completely. The mixture was vortexed, and the volume was adjusted to 20 mL with 0.1 M phosphoric acid. All samples were sonicated for 1 hour to allow extraction of the drugs. All the samples were filtered through 0.45 pm PVDF filter and analysed by HPLC at 280 nm wavelength. The results are reported as mean ± SD (n=3).1006280349In vitro drug release testing

[0239] In vitro drug release was performed by directly adding -100 mg of each formulation into 10 mL of tris buffer pH 7.4 with 0.2% v / v tween 80 in a clear glass vial. The in situ implant was formed instantaneously after addition of the formulation into the buffer. All the vials were kept in an incubator at 37 °C at 250 RPM. At each time point the release media was replaced with fresh buffer for maintaining the stability of the drugs. The collected release samples were stored at -20°C until analysis by HPLC.Mathematical models

[0240] Based on the in vitro drug release information, the mechanism of release of levodopa and carbidopa from the formulation was assessed. The release data fitting was done for various release models via the Microsoft excel add-in software program DDsolver. The best fitting model was selected based on adjusted coefficient of determination (R2adjusted) and Akaike information criterion (AIC). While comparing different models with various parameters R2adjusted is considered more meaningful. The model with highest value for R2adjusted and smaller AIC values are illustrated as the best fitting model.Fourier transform infrared spectroscopy (FTIR)

[0241] For confirming the compatibility of a drug with the polymeric solution, FTIR spectra were recorded using a FTIR spectrometer (Bruker, Massachusetts, USA). For recording the FTIR spectra, a small amount of each sample was placed on the ATR diamond crystal with the application of the clamp for ensuring proper contact between the sample and crystal. All recordings were performed at room temperature in transmittance mode in the range of 4000 to 450 cm1with 16 scans per sample.Viscosity measurement

[0242] For evaluating the rheological behaviour of the formulations, Rheosys merlin VR (23) (Scientex Pty ltd, Melbourne, Victoria, Australia) was used with a parallel plate of diameter 30 mm with 0.5 gap. The observed viscosity was plotted against shear rate (1 / s).1006280349Syringeability

[0243] Syringeability is the maximum force required for expelling the formulation through the syringe and it is a crucial parameter for injectable formulations. A texture analyser (TA. XT plus texture) was used in compression mode where the prepared formulation was drawn into a 1 mL syringe fitted with a 22G needle. Parameters such as distance and test speed of compression were kept at 40 mm and 5.00 mm / sec respectively and evaluation was performed in triplicate at room temperature. The force required to expel the formulation is expressed in newtons (N).Scanning electron microscopy (SEM)

[0244] The structural morphology of implants formed in-vitro was studied using scanning electron microscopy. Implants were prepared in-vitro by injection 100 pL of formulation into 10 mL of pH 7.4 buffer. At different time intervals (Day 1 , 4 and 7) the implants were taken out of the buffer and frozen with liquid nitrogen, followed by freeze drying for 72 hours. The cross section of the freeze-dried implants, as well as the control implant, were observed under the microscope. All the samples were placed on an aluminium stub followed by coating with platinum using Agar high resolution sputter. SEM micrographs were obtained for all the samples using Zeiss Merlin FEG SE.Cell viability study (MTT assay)

[0245] Sterilized in situ gel was evaluated for cytotoxicity using the viability and growth of fibroblasts using 3T3 fibroblast cells and MTT assay. 3T3 cells are the standard fibroblastic cells which are commonly present in the various connective tissues and are generally used for testing biocompatibility of biomaterials. MTT assay is considered a gold standard for testing the cytotoxicity compared to other available assays.

[0246] Cytotoxicity studies were carried out using 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide MTT assay. The cytotoxicity assay was conducted according to ISO 10993-5 standards. Fibroblasts of line NIH 3T3 were grown in DMEM media supplemented with 10% FBS, 1% penicillin streptomycin with 5% CO2 at 37 °C. For the cell viability study, 100 mg of the in situ implant was extracted at 37 °C for 12 h in a 10 mL DMEM media. The extracted samples were further diluted as 2x, 5x,10x and 20x using DMEM media for treating the cells. 100 pL of 3T3 cells were seeded into a 96 well plate at a density of 5,000 cells per well and incubated for 24 hours. Extracts were1006280349placed on the mouse fibroblast cell line NIH 3T3 which were examined for cytolysis.After treating cells with the extract and incubation at 37 °C for 24h, serum-free medium of 90 pL and 10 pL MTT (5 mg / mL) were added to each well followed by incubation for 3h at 37 °C until the formation of formazan crystals occurred. Then, 150 pL of Dimethyl sulfoxide (DMSO) was added to each well for dissolving the formazan crystal and absorbance was measured at 540 nm using a PerkinElmer Wallac plate reader (PerkinElmer, Inc., Waltham, MA, USA) (34). The cell viability was calculated using the following formula: 100OD-optical density.Degradation studies

[0247] The degradation studies were performed for estimating degradation time for in situ formed implants. The degradation of in situ formed implants was performed by adding 100 mg of the formulation in pH 7.4 buffer which was incubated at 37 °C with stirring at 250 rpm. The implants were removed from the buffer at regular intervals and the extra water was eliminated with the help of tissue paper followed by weighing the implant. The percentage weight loss was calculated by using following formula: 100Where Wt is the weight of degrading implant and W is the initial weight of the implant.Stability study

[0248] For ensuring the drug stability during storage, stability of the prepared formulation was evaluated at accelerated stability conditions by storing at 25°C ± 2 °C and 60 % ± 5% relative humidity (RH) according to ICH conditions for samples needing to be stored in a refrigerator. Samples were stored as vial A containing polymer solution and vial B containing drug. Samples were withdrawn at different time intervals (Day 1, 7, 14, 1 month, 2 months and 3 months) and mixed, followed by drug content determination using HPLC. In addition, the mixed formulation was kept at room temperature for 7 days and analyzed for drug content.1006280349Ex-vivo release studies and In-vitro Ex-vivo correlation

[0249] The ex-vivo release studies were performed in triplicates using the pig hind leg muscle of size ~ 7 cm by 5 cm size. The composition was filled into the 1 ml syringe with a 22 G needle injected into each muscle (300 pL) and the muscle was transferred to the beaker containing 60 ml of tris buffer pH 7.4 with 0.1% sodium azide. All the beakers were kept at 37 °C with agitation of 250 RPM. The release samples were collected at each time point and release media was completely changed every 24 h. The release samples were analyzed by HPLC. The in-vitro drug and ex-vivo were fitted using linear regression in Excel.

[0250] The in-vivo performance of the composition was predicted by the convolution approach. Based on the in-vitro drug release data and the pharmacokinetics of the intravenous levodopa injection obtained from the literature (Robertson DR, Wood ND, Everest H, et al. Br J Clin Pharmacol. 1989;28:61-9.) the in-vivo pharmacokinetics were predicted. The convolution was performed using the convolve function in the R programming language. Convolution is an integration process that involves modelling the in-vivo plasma drug concentrations obtained on the administration of a unit dose of a formulation. Convolution-based modelling involves the identification of Unit input Response (UIR) data for the drug which characterizes the pharmacokinetics of the drug. Convolution is an integration process that involves modelling the in-vivo plasma drug concentrations obtained on the administration of each formulation dose unit. This is further combined with the fraction dissolved in-vitro for each dosage unit in a single step that integrates the convolution integral.

[0251] Where C(t) is the plasma concentration of the drug at time t following administration of the composition. If I (t) is the rate at which the drug is released from the formulation at time t and the UIR is denoted by U(t) which is the plasma concentrationtime relationship, then the plasma concentration of the drug C (t) from the entire dose l(t) is given by above equation.1006280349Example 2 - Preparation of in situ implant formulations

[0252] Polymeric solutions were prepared by dissolving the polymers in organic solvent (N,N-Dimethylacetamide or NMP) at 100 °C, with constant stirring at 700 RPM. Once a clear solution was formed, a measured volume of PEG 400 was added until a homogenous solution was obtained. Heating was stopped, followed by addition of a weighed amount of drug (levodopa and carbidopa (4:1 ratio)) to the solutions. The solutions were stirred on magnetic stirrer for 30 minutes (illustrated in Figure 1).

[0253] Exemplary formulations containing levodopa contained 8.75% w / v of levodopa suspended in the polymeric solutions. The prepared formulations were stored at 8 °C until characterization was performed. Different ratios of polymers were tested for the effect on the drug release profile of levodopa and carbidopa. The formulation compositions prepared are listed in Table 1. Selected formulations were further tested for in-vitro drug release. All numerical values are given as % w / v of the total composition in the absence of the drug.Table 1 : formulations of in situ implants100628034920: 15 high weight to low weight PLGA.1006280349Example 3 - Preparation of the in situ forming implants

[0254] PLGA gel was prepared in DMAC and NMP and evaluated for drug release, the gels containing DMAC as solvent showed consistent drug release whereas NMP containing gels showed very high initial burst release followed by lag phase. When the concentration of PLGA was reduced, indistinguishable difference was observed (Figure 2). Due to the hydrophobic nature of PLGA, very slow drug release was observed on reducing the concentration of PLGA, but high initial burst release was observed. Therefore, to modulate the drug release for reduced initial burst release, the combination of PLGA and other hydrophilic polymers were selected and evaluated for the effect on the drug release profile. The gels were prepared using 9:1 ratio of PLGA with Pluronic F-68, Pluronic F-127, Pluronic F-108, HPMC K4, Eudragit L-100, Eudragit E 100, and PEG 4000 as set out in Table 1.

[0255] The drug release studies were carried out for all the developed formulations. Except Eudragit L-100 all formulations showed burst release with more than 60% drug release in 24 hours. However with Eudragit L-100, lower burst release with consistent drug release over time was observed.

[0256] Eudragit L100 was selected for preparing further gels and evaluated for its effect on drug release at different concentrations in combination with PLGA. For dissolving polymers, DMAC and PEG-400 were used as using DMAC alone in higher concentrations could be harmful for intramuscular (IM) delivery. The addition of PEG- 400 helps in maintaining the viscosity. DMAC and PEG-400 are miscible with each other. An exemplary formulation with particularly good performance was obtained at 26% PLGA and 6% Eudragit L-100, which showed good syringeability and a favourable drug release profile. This formulation was evaluated for FTIR, SEM, syringeability, drug release, drug content, viscosity, and stability under storage conditions.Example 4 - Characterisation of the in situ forming implantsDrug content determination

[0257] Levodopa and carbidopa (a treatment for Parkinson’s disease) were used to exemplify the drug content of the in situ forming implants. The drug content for levodopa was found to be 96.54±1.83%, whereas for carbidopa it was found to be 111±3.14%. The extraction method was validated by using the pure drug as well as the blank gel.1006280349In vitro drug release studies

[0258] The in vitro drug release data from gels containing DMAC as the solvent (compositions 1 and 3 in Table 1) at different concentration of PLGA showed lower burst release of 26.04% and 33.78% levodopa in 24 hours, followed by consistent release of drug over a period of time. Whereas compositions 2 and 4 in T able 1 , containing NMP as the solvent, showed very high burst release of 61.88% and 54.15%, followed by steady release up to 59.33 and 69.12% of levodopa in 144 hours. Formulations containing DMAC were further modified with addition of hydrophilic polymer to optimize the drug release.

[0259] Composition 5 in Table 1 showed 2.036% levodopa release in the first 8 hours, followed by 34.17% release of levodopa in 24 hours. Whereas 25.72% carbidopa was released in the first 8 hours, followed by 37.16% drug release in 24 hours. Slow and continuous release was observed up to 7 days. Release studies were continued for 7 days and 92% cumulative levodopa was released in 144 hours, whereas up to 80% carbidopa was released in 144 hours. Without being bound by theory, as the drug was in the suspended form in the polymer solution, the release mechanism is attributed to the diffusion of the drug from within the formulation into the release media.Fourier-transform infrared (FTIR) of formulation

[0260] FTIR analysis was carried out to assess the potential interactions of levodopa and carbidopa with the formulation components (Figure 3). The characteristic peaks were observed for levodopa at 3200, 3062 and 2981 due to O-H stretching and the phenyl group C=C vibrations were observed at 1458, 1402, 1353, 816 and 672 cm-1. The C-H stretching was observed at 2929 and 2981 cm-1. At 1562 cm-1, NH2 stretches were observed and C=O stretching is visible at 1651 cm-1. For carbidopa characteristic peaks were observed at 1527 and 1124 cm-1due to NH and NH2 stretching and O-H stretching arises at 3518, 3322, 3289 cm-1. The phenyl group C=C vibrations were observed at 1458, 1402, 1261 , 878, 829 cm-1for carbidopa. The peaks observed at 3102, 3060, 1373 cm-1are attributed to C-H stretching. The characteristics peaks for PLGA were O-H stretching at 3512 cm-1and C-H peak at 2952 cm-1. A strong peak was observed at 1745 cm-1due to C=O stretching, and due to C-O-C stretching a strong peak was observed at 1085 cm-1.1006280349

[0261] Eudragit L 100 shows a strong peak at 1712 cm-1due to vibration of esterified carboxyl group. Peaks observed at 1155 cm-1and 1254 cm-1are from the ester vibrations. The peak observed at 3200 cm-1was attributed to the O-H vibrations, and the peaks at 1450 cm-1and 2952 cm-1were due to CHx vibrations.

[0262] Comparing the spectra of pure levodopa and carbidopa with the formulation peaks, the O-H peak of PLGA and carbidopa merged with a broad peak at 3403 cm-1. A peak at 3202 cm-1was observed due to the O-H stretching of levodopa and Eudragit L100. Peaks were shifted to 3062 cm-1and 2941 cm-1for the O-H stretching of levodopa and carbidopa. The phenyl group C=C vibration of levodopa and carbidopa overlapped at 1455 cm-1and 1399 cm-1. A strong peak appeared at 1758 cm-1in the formulation due to the merging of the C=O stretching of PLGA and Eudragit L100. The C-O-C stretching peak of PLGA was observed at 1092 cm-1in the formulation. The characteristic N-H peak for levodopa was present at 1562 cm-1whereas for carbidopa the NH2 peak was observed at 1524 cm-1and NH peak at 1122 cm-1.Mathematical modelling

[0263] The prediction of drug release kinetics have been widely done using mathematical models. The coefficient of determination (R2) and AIC (Akaike information criterion) can be used for model fitting and determining a suitable model for the formulation. The amount of drug released from the formulation plays an important role in maintaining the therapeutic concentration of the drug. The best fitting model is the one with highest value of R2and lowest AIC. The release kinetics of levodopa and carbidopa were modelled with zero order, first order, Higuchi model, kormeyer-peppas equation, makoid-banakar model and peppas sahlin model. The models with R2>0.97 and AIC near <50 were considered to be adequate (Table 2).

[0264] The best fitting model for levodopa was Higuchi model, whereas for carbidopa Peppas-Sahlin model showed best fitting.

[0265] The Higuchi model is represented by following equation:F = K2tF'2

[0266] Where F is the fraction of drug released, K2 is the Higuchi dissolution constant, t is time at drug release. A number of models were developed by Higuchi explaining the1006280349release mechanism of water soluble and low water-soluble drugs, which were dispersed in the uniform matrix which behaves as the diffusion media. Higuchi models define the mechanism of drug release is the diffusion based on the Fick’s law which states the rate of drug release is proportional to the square root of time. This model is widely applied for describing the drug release mechanism from the modified release products. Based on the mode fitting, levodopa seems to obey the Higuchi diffusion model responsible for drug release from the implant matrix.

[0267] The Peppas-Sahlin model is represented by the following equation:F = K tm+ K2t2m

[0268] Where Ki is the fickian kinetic constant, K2 is the erosion rate constant, m is the diffusional exponent and t is the time of drug release. If Ki / k2 > 1 than release occurs due to fickian diffusion, if Ki / k2 < 1 then release occurs by erosion and if Ki / k2 = 1 than both mechanisms are responsible for release. For carbidopa Ki / k2 was observed to be < 1 which indicates that release of carbidopa occurs due to the erosion of the polymer.Table 2: Mathematical Modelling for release kinetics of levodopa and carbidopa1006280349Viscosity measurement

[0269] Viscosity measurements of the blank formulation (without drug) and the formulation containing drug were carried out at different shear rates to evaluate the impact of shear rate on the viscosity of the sample. Both samples showed no major difference in the viscosity when exposed to a shear rate from 100 to 1000 as shown in the Figure 4a. The polymer solution, as well as the formulation, were freely flowing with low viscosity and showed Newtonian behaviour.

[0270] The low viscosity of the formulation indicates good injectability of the formulation. Injectability was confirmed by syringeability testing. The viscosity of the formulation was also recorded at different temperatures to evaluate the impact of temperature on the viscosity. At room temperature, viscosity at shear rate (1 / s) 100 was found to be 0.567 (Pa.s), whereas at 37 °C, viscosity dropped to 0.338 (Pa.s) which demonstrated that with an increase in temperature the viscosity of the formulation being reduced indicates easy injectability of the formulation at 37 °C.Syringeability

[0271] Syringeability of an injectable formulation is the force required to inject or eject the formulation from the syringe. The lower the force needed to expel the formulation, the better the syringeability. The average force required to expel the formulation was found to be 32.98 ± 0.72 N with a 22G needle, which is within the acceptable maximum injectable force of 40 N.Scanning electron microscopy (SEM) of the implant collected from release samples

[0272] SEM images of the implants are shown in Figure 5. The SEM images are of samples collected on Day 1, Day 3 and Day 7. Noticeable differences were observed in the surface porosity of the samples collected at different time points. As shown in Figure 5a, the day 1 sample showed a compact structure on the surface, as well as the cross section. Hence the drug release in first 8 hours is likely to be from the surface of the implant. With increasing time, there was the formation of a porous structure. At day 3, pores started forming on the surface of the implant with a less compact structure on cross section observed (Figure 5 d). In addition, swelling of the internal structure was observed on day 3, which could enhance the drug release from the implant via diffusion1006280349towards to the release media. On day 7, up to 90% drug release was observed. As shown in Figure 5e, the surface became very porous with erosion of the polymer structure observed.Cell viability (MTT Assay)

[0273] The amount of levodopa in the extracted sample was quantified with HPLC. The cell viability of the extracted samples was compared to that of the control group. The exposure to levodopa extracted from the formulation in a concentration between 30-300 pg / ml (20x-2x dilutions) caused dose dependent cyctotoxicity in 3T3 cells as shown in Figure 6. The cell viability was found to decrease with an increase in the concentration of levodopa. At a 60 pg / mL (10x dilution) concentration of levodopa, % cell viability was 81% which reduced to 72% for a 120 pg / mL (5x dilution).In vitro degradation studies

[0274] The polymers used for preparing gels should be biodegradable, therefore it is necessary to estimate the degradation time of the polymer used. PLGAso:5o is biodegradable in nature but Eudragit L-100 are non-biodegradable and non-toxic.However, Eudragit L-100 solubilises at pH 7.4. The rate of degradation helps in understanding the time required for degradation of polymer upon injection.

[0275] The degradation studies were carried out by monitoring the weight loss of an in situ formed implant compared to that of the initial weight. As shown in Figure 7, in first 8 hours 41.09% weight loss was observed which, as expected, increased over time. After 24 hours weight loss gradually increased to 46.80%, followed by 60.28% on day 3.PLGA is made up of several hydroxyl acid monomers such as d-lactic acid, l-lactic acid, and glycolic acid. The hydrophobicity, release rate, and degradation rate of PLGA are determined by the lactic acid content and molecular weight. Higher lactic acid content will degrade over a longer period with the slow release.

[0276] On day 6, 78.06% weight loss was observed which indicated the biodegradable nature of the formulation. On day 7, 81.89% weight loss was observed, which compliments the release study with 90% drug release in 7 days and the SEM studies showing the porous implant structure. The implants degraded completely in 13 days with loss of 97.38% weight of the formed implant.1006280349

[0277] The degradation of PLGA occurs due to the hydrolytic cleavage of the ester linkages in the initial stage of PLGA’s degradation, which results in the formation of oligomers and monomers. During this time, huge amounts of lactic and glycolic acids are formed, which causes the pH values to significantly decrease. The microspheres mass reduces in the second step, and the rate of polymer chain scission could accelerate. The two phases are classified as erosion and degradation for drug release. The Krebs cycle eventually converts the generated lactic and glycolic acids to CO2 and water.Stability studies

[0278] It is important to establish formulation stability on storage for ensuring patient safety, efficacy of the formulation, and the overall integrity of the product. According to ICH guidelines, the accelerated stability conditions for a product intended to be stored in a refrigerator is at 25°C ± 2°C and 60 % ± 5% Relative Humidity (RH). In use, in situ formulations are typically stored with the drug mixture and polymer solution being stored separately, and mixed just before injection. The % of levodopa and carbidopa in the formulation upon storage at the accelerated conditions was evaluated and showed that both the drug mixture and polymer solutions are stable upon prolonged storage as there was no significant reduction in drug release. Results showed the content of levodopa and carbidopa was above 80% for up to 6 months (Table 3).Table 3. Drug content of the formulation under storage conditions at 25 °C ± 2°C and 60 % ± 5% RH for 6 months.1006280349

[0279] The stability results indicated that levodopa, carbidopa and the polymer solution were stable on storage for up to 6 months prior to formulation.

[0280] Stability studies for the in situ implant formulation containing levodopa and carbidopa were evaluated at the same conditions as above, and the results are shown in Table 4.Table 4. Drug content of the mixed formulation under storage condition at 25°CExample 5 - Ex-vivo release studies and in-vitro ex-vivo correlation

[0281] The ex-vivo release in the case of levodopa was up to 78% drug release observed in 7 days from the muscle whereas with carbidopa up to 51% drug release was observed as shown in Figure 8. The ex-vivo drug release profile followed a similar release pattern to Composition no 5 of Example 2 with 8.75% levodopa and 2.18% carbidopa suspended in the composition. However, some differences might be due to differences in the environment between the in-vitro systems and the tissue, implant formed in-vitro might show higher release compared to the muscle.

[0282] Figure 9 shows the correlation between the in-vitro drug release profile and ex- vivo drug release for levodopa and carbidopa using the linear model. The straight line and the correlation coefficient of 0.91 and 0.90 for levodopa and carbidopa demonstrate a strong correlation between the in-vitro drug release and ex-vivo drug release.Example 6 - Release for up to 7 days

[0283] 8.75 %w / v levodopa and 2.18 %w / v carbidopa were added to compositions 5 (F2), 16 (F3) and 37 (F1) and the in-vitro drug release tested in accordance with Example 1 over 7 days. The results are shown in Figure 10 and Figure 11.1006280349

[0284] The results show that the formulation without a second polymer gave lower cumulative drug release for both levodopa and carbidopa. This was most notable for Levodopa where the cumulative release for Composition 16 plateaued at around 50%. Both compositions with a second polymer (5 and 37) showed increased cumulative drug release compared to Composition 16 over the 7 days. Composition 37 gave a faster initial release, while Composition 5 gave a more sustained release profile.Example 7 - Rat pharmacokinetic study

[0285] All studies received ethics approval from the University of South Australia (UniSA). All animal experiments were conducted in accordance with institutional guidelines and were approved by the UniSA Animal Ethics Committee. The in-vivo pharmacokinetic studies were performed using female Sprague Dawley rats. Rats weighing 200-250 g were randomly assigned to each composition group (n = 3).

[0286] A further composition (composition 37) was developed and tested. Composition 37 contained 30 % w / v PLGA, 3 % w / v 2-hydroxypropyl-beta-cyclodextrin, 33 % w / v DMAC and 34 % w / v PEG-400 in the absence of drug. 8.75 % w / v levodopa and 2.18 % w / v carbidopa were added to composition 37 for drug release testing.

[0287] Compositions 5, 16 and 37 were chosen for testing. Each test composition contained 20 mg / kg levodopa and 5 mg / kg carbidopa, administered as a 50 pL intramuscular (IM) injection into the leg. Blood samples were collected from the saphenous vein at 0 h, 10 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, 168 h, and 192 h.

[0288] For the control group, levodopa and carbidopa dispersed in saline at the same doses (20 mg / kg levodopa and 5 mg / kg carbidopa) were administered via a 50 pL IM injection into the leg. Blood samples were collected at 0 h, 20 min, 40 min, 1 h, 6 h, 8 h, 10 h, 24 h, and 30 h.

[0289] Blood samples were collected into tubes containing heparin and sodium metabisulfite, then centrifuged at 5,000 rpm for 5 min to obtain plasma. Plasma samples were stored at -80 °C until analysis. A validated LC-MS method was used to quantify levodopa and carbidopa concentrations in plasma. Pharmacokinetic parameters were determined using WinNonlin software. The results are shown in Table 5.1006280349Table 5. pharmacokinetic data for levodopa and carbidopa using saline control and Compositions 5, 16 and 37 of the present disclosure.

[0290] The saline control exhibited a pronounced burst release with the highest Cmax and shortest duration of detectable drug levels, whereas all formulated compositions maintained measurable concentrations through day 7-8 and achieved higher AUCIast, confirming their suitability for prolonged systemic exposure and sustained release. Notably, the formulation lacking a second polymer (composition 16) showed reduced Cmax and AUCIast, which could potentially be due to limited drug solubilisation, weaker depot structure, or less controlled diffusion, while formulations containing a second polymer demonstrated enhanced systemic exposure (compositions 5 and 37). Secondary polymers such as Eudragit® and hydroxypropyl-beta-cyclodextrin, in combination with PLGA, may improve drug solubility, could strengthen depot formation, may reduce early burst, and could support more controlled release, collectively resulting in potentially higher Cmax, greater AUCIast, and improved long-acting performance.1006280349

Claims

CLAIMS1. A composition for an in situ implant, the composition comprising: a first polymer, said first polymer being biodegradable; a second polymer, said second polymer being pH responsive and dissolvable above about pH 6; one or more polar organic solvents; and a viscosity modifying vehicle.

2. A composition for an in situ implant, the composition comprising: a first polymer, said first polymer being biodegradable; a second polymer, said second polymer being able to form an inclusion complex with one or more pharmaceutically active ingredients (APIs); one or more polar organic solvents; and a viscosity modifying vehicle.

3. The composition according to claim 1 or claim 2, wherein the first polymer is present in an amount from about 5 to about 50 % w / v, or from about 15 to about 40 % w / v, or from about 20 to about 30 % w / v.

4. The composition according to any one of claims 1 to 3, wherein the second polymer is present in an amount from about 0.1 to about 15 % w / v, or from about 2 to about 15 % w / v, or from about 5 to about 10 wt%.

5. The composition according to any one of claims 1 to 4, wherein the one or more polar organic solvents are present in an amount from about 20 to about 55 % w / v, or from about 20 to about 50 % w / v, or from about 30 to about 40 % w / v.

6. The composition according to any one of claims 1 to 5, wherein the viscosity modifying vehicle is present in an amount from about 15 to about 50 % w / v, or from about 15 to about 40 % w / v, or from about 30 to about 40 % w / v.10062803497. The composition according to any one of claims 1 to 6, further comprising one or more pharmaceutically active ingredients (APIs).

8. A composition for an in situ implant, the composition comprising: a first polymer, said first polymer being biodegradable; a second polymer, said second polymer being able to form an inclusion complex with one or more pharmaceutically active ingredients (APIs); one or more polar organic solvents; a viscosity modifying vehicle; and one or more pharmaceutically active ingredients (APIs).

9. A composition for an in situ implant, the composition comprising: a first polymer, said first polymer being biodegradable; a second polymer, said second polymer being pH responsive and dissolvable above about pH 6; one or more polar organic solvents; a viscosity modifying vehicle; and one or more pharmaceutically active ingredients (APIs) wherein the second polymer and at least one of the one or more pharmaceutically active ingredients are present as an inclusion complex.

10. The composition according to claim 8 or claim 9, wherein the first polymer is present in an amount from about 15 to about 30 % w / v.

11. The composition according to any one of claims 8 to 10, wherein the second polymer is present in an amount from about 3 to about 10 % w / v.

12. The composition according to any one of claims 8 to 11 , wherein the one or more polar organic solvents are present in an amount from about 25 to about 35 % w / v.100628034913. The composition according to any one of claims 8 to 12, wherein the viscosity modifying vehicle is present in an amount from about 25 to about 35 % w / v.

14. The composition according to any one of claims 8 to 13, wherein the one or more pharmaceutically active ingredients are present in an amount from about 5 to about 15 % w / v.

15. The composition according to any one of claims 1 to 14, wherein the second polymer is dissolvable below pH 7.

16. The composition according to any one of claims 1 to 15, wherein the first polymer comprises one or more of poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polylactic acid (PLA), polyglycolide, poly-3- hydroxybutane, poly(glycolide-co-trimethylene carbonate), polyanhydrides or polyurethanes.

17. The composition according to any one of claims 1 to 16, wherein the first polymer comprises poly(lactic-co-glycolic acid) (PLGA).

18. The composition according to claim 17, wherein the PLGA has a monomeric ratio of lactide:glycolide from about 15:85 to about 85:15.

19. The composition according to claim 17 or claim 18, wherein the PLGA has an acid endcap.

20. The composition according to any one of claims 17 to 19, wherein the PLGA has a molecular weight from about 7 kDa to about 54 kDa.

21. The composition according to any one of claims 1 to 20, wherein the second polymer comprises a hydrophilic polymer.

22. The composition according to any one of claims 1 to 21 , wherein the second polymer comprises a methacrylic acid copolymer and / or a pharmaceutically acceptable cyclodextrin.

23. The composition according to any one of claims 1 to 22, wherein the second polymer comprises one or more of hydroxypropyl-alpha-cyclodextrin, hydroxypropyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin,1006280349sulfobutylether-beta-cyclodextrin, methyl-beta-cyclodextrin or carboxymethyl- beta-cyclodextrin.

24. The composition according to any one of claims 1 to 22, wherein the second polymer comprises a poly(methacrylic acid-co-methyl methacrylate) polymer and / or a hydroxypropyl-beta-cyclodextrin.

25. The composition according to claim 24, wherein the ratio of methacrylic acid and methyl methacrylate in the poly(methacrylic acid-co-methyl methacrylate) polymer is 1:1.

26. The composition according to any one of claims 1 to 25, wherein the one or more polar organic solvents comprises N,N-dimethyl acetamide, dimethyl sulfoxide, benzyl alcohol, benzyl benzoate, ethanol, triacetin or N-methyl pyrrolidone.

27. The composition according to any one of claims 1 to 26, wherein the viscosity modifying vehicle comprises a non-ionic polyether, functionalised or unfunctionalized polyethylene glycol, isopropyl myristate, glycerol formal, polysorbate, glycerine or propylene glycol.

28. The composition according to any one of claims 1 to 27, wherein the viscosity modifying vehicle is polyethylene glycol.

29. The composition according to claim 28, wherein the polyethylene glycol has a molecular weight of less than about 1 kDa, or less than about 500 Da.

30. The composition according to any one of claims 1 to 29, wherein the viscosity of the composition is from about 0.35 to about 0.70 Pascal-seconds at 25 °C.

31. The composition according to any one of claims 8 to 30, wherein the one or more active pharmaceutical ingredients comprises one or more of pramipexole, levodopa or carbidopa.

32. The composition according to any one of claims 1 to 31 , wherein the composition is a single-phase composition.

33. A method of making a composition according to any one of claims 1 to 32, the method comprising the steps of:1006280349(a) combining a first polymer and a second polymer in the one or more polar organic solvents to form a solution; and(b) adding a viscosity modifying vehicle to the solution.

34. The method according to claim 33, wherein the method further comprises the step of adding one or more pharmaceutically active ingredients after adding the viscosity modifying vehicle to the solution.

35. The method of claim 33 or claim 34, wherein step (a) and / or step (b) are conducted at a temperature greater than about 70 °C, or greater than about 80 °C, or greater than about 90 °C.

36. An injectable comprising the composition according to any one of claims 1 to 32.

37. A method of treating a neurodegenerative disease or disorder comprising administering a composition according to any one of claims 1 to 32 to a patient in need thereof, wherein the composition is administered as an injectable.

38. Use of composition according to any one of claims 1 to 32, in the manufacture of a medicament for treating a neurodegenerative disease or disorder, wherein the medicament is to be administered as an injectable.

39. A composition according to any one of claims 1 to 32 for use in the treatment of a neurodegenerative disease or disorder, wherein the composition is to be administered as an injectable.

40. The method according to claim 37, the use according to claim 38, or the composition for use according to claim 39, wherein the neurodegenerative disease or disorder is Parkinson’s disease.1006280349

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