WO2025074120A1

WO2025074120A1 - Nanoparticles for extended release drug delivery

Info

Publication number: WO2025074120A1
Application number: PCT/GB2024/052564
Authority: WO
Inventors: Nazila Kamaly; Luka BLAGOJEVIC
Original assignee: Imperial College Innovations Ltd
Current assignee: Ip2ipo Innovations Ltd
Priority date: 2023-10-06
Filing date: 2024-10-04
Publication date: 2025-04-10
Anticipated expiration: 2026-04-06

Abstract

The present invention is directed to nanoparticle compositions obtainable from the polymerisation of oligolactoglycolic acid dimethacrylates (OLGADMAs), methods for preparing said OLGADMAs, methods for preparing said nanoparticle compositions, and uses thereof. In one aspect the present invention provides a nanoparticle composition obtainable from precipitation polymerisation of one or more oligomers of formula (I), as defined herein.

Description

NANOPARTICLES FOR EXTENDED RELEASE DRUG DELIVERY

FIELD OF THE INVENTION

The present invention relates generally to the field of nanoparticle compositions and delivery of an active agent. In particular, the invention is directed to nanoparticle compositions obtainable from the polymerisation of oligolactoglycolic acid dimethacrylates (OLGADMAs), methods for preparing said OLGADMAs, methods for preparing said nanoparticle compositions, and uses thereof.

BACKGROUND OF THE INVENTION

Nanoparticles (NPs) have been used as drug carriers due to their ability to reduce sideeffects, increase therapeutic efficacy, and enable the use of bioactive molecules bearing suboptimal pharmaceutical properties. A wide range of different types of NPs are available including those based on lipid, polymeric and inorganic materials. For useful application in medicine, nanoparticle compositions comprising an active agent should be biocompatible. In particular, nanoparticle compositions comprising an active agent should be sufficiently stable in an aqueous biological environment so that the drug reaches the intended target but degrade over time and be excreted from the body.

Biocompatible polymers are examples of materials that have found extensive application in the field of medicine. Examples of widely used biocompatible polymers include poly(D,L-lactic acid) (PLA), poly(D,L-lactic-co-glycolic acid) (PLGA), poly(s-caprolactone) (PCL), and polyethylene glycol (PEG). Poly(a-hydroxy acids) such as PLA and PLGA were originally developed for medical applications such as degradable sutures and remain amongst the most investigated degradable polymers (J. M. Chan et. al., Polymeric Nanoparticles for Drug Delivery, Methods Mol. Biol., 2010, 624, 163-175 and Kamaly, N. et. al., Degradable Controlled-Release Polymers and Polymeric Nanoparticles: Mechanisms of Controlling Drug Release, Chem. Rev. 2016, 116(4), 2602-2663). PLA attracts significant industrial interest with an estimated global production of 190,000 tons in 2019. PLGA is an FDA approved, biocompatible polymer which is degradable via ester hydrolysis, releasing metabolizable glycolic and lactic acids.

Despite the relatively common use of PLGA in the broader medical field, there are currently no approved PLGA-based nanoscale-formulations available on the market. Various translation obstacles are responsible including difficulties in manufacturing and scale-up, generation of acidic by-products via degradation, poor drug loading, high initial burst release and nanotoxicology.

There are many well-known drawbacks associated with using state of the art nanoparticles in combination with cosmetics. Nanoparticle formulations are often used because the small particle size allows deep penetration of the nanoparticle/active agent into the skin. However, several types of nanoparticles result in damage to cells. For example, TiO₂ nanoparticles have been shown in in vivo studies to penetrate the dermal layer and cause pathological lesions (J. Wu et. al., Toxicity and Penetration of TIO2 Nanoparticles in Hairless Mice and Porcine Skin after Subchronic Dermal Exposure, Toxicol. Lett., 2009, 191(1), 1-8). In another example, keratinocytes exposed to ZnO nanoparticles have been shown to affect mitochondrial function, cellular morphology, free radical production, and cell cycle profiles (P. Kocbek et. al., Toxicological Aspects of Long-Term Treatment of Keratinocytes with ZnO and TIO2 Nanoparticles, Small, 2010, 6(17), 1908-1917. A lack of toxicity towards cells is also important when nanoparticles are used in combination with a drug, in particular when the drug is intended to penetrate the skin, for example in the treatment of hair loss. Further, when nanoparticles are used in combination with an agrochemical, it is desirable to avoid toxicity towards cells in either the plants that are being treated with the product, or the wildlife with which it comes into contact.

There is therefore a real need in the art to develop nanoparticles for extended-release drug/cosmetic/agrochemical delivery that are biocompatible. Additionally, there is a need for such nanoparticles to be stable in aqueous and protein-rich biological media, stable during storage at room temperature, have high drug-loading efficiencies, demonstrate sustained drug/cosmetic/agrochemical release overtime; and/or possess an excellent cytotoxicity profile in vitro. Further, the processes for producing these nanoparticles for extended-release drug/cosmetic/agrochemical delivery should ideally be amenable to fine tuning, in order to optimise the size of the nanoparticles for a particular active agent and/or application. SUMMARY OF THE INVENTION

In one aspect the present invention provides a nanoparticle composition obtainable from precipitation polymerisation of one or more oligomers of formula (I):

wherein:

L is a direct bond or a linker group selected from (la), and (lb):

R¹ and R² are independently H or -Me;

R³ and R⁴ are independently H or -Me; and wherein R³ R⁴ _;

R⁵ is independently selected from: H, -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Cio)cycloalkyl, - (C₆-Cio)aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, halo, and -CN; wherein said -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Cio)cycloalkyl, -(C₆-Cio)aryl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl group is optionally substituted with one or more group independently selected from: -(Ci-C₆)alkyl, -O(Ci- C₆)alkyl, halo, -CN, -OH, and -NH₂;

R⁶ is independently selected from: H, -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Ci₀)cycloalkyl, - (C₆-Cio)aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, halo, and -CN; wherein said -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Ci₀)cycloalkyl, -(C₆-Cio)aryl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl group is optionally substituted with one or more group independently selected from: -(Ci-C₆)alkyl, -O(Ci- C₆)alkyl, halo, -CN, -OH, and -NH₂;

R⁷ is independently selected from: H, -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Ci₀)cycloalkyl, - (C₆-Cio)aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, halo, and -CN; wherein said -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Ci₀)cycloalkyl, -(C₆-Cio)aryl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl group is optionally substituted with one or more group independently selected from: -(Ci-C₆)alkyl, -O(Ci- C₆)alkyl, halo, -CN, -OH, and -NH₂; p is an integer from 1 to 20; s is an integer from 1 to 20; q is an integer from 0 to 9; r is an integer from 0 to 18; p + 2q + r + s = 2 to 20; and wherein when q + r = 0, L is a direct bond.

In another aspect the present invention provides a method for preparing a nanoparticle composition by precipitation polymerisation, said method comprising the steps of: i) providing a mixture comprising an oligomer of formula (I) as defined herein and a water-miscible organic solvent; ii) contacting an agitated aqueous solution with the mixture of step i) in the presence of a polymerisation initiator; wherein the aqueous solution is at a temperature of 60 to 80 °C, preferably from 65 to 75 °C, when contacted; and iii) obtaining a precipitate comprising a nanoparticle composition.

In another aspect the present invention provides a nanoparticle composition comprising an active pharmaceutical ingredient, as defined herein, for use in therapy. In another aspect the present invention provides a nanoparticle composition comprising an active pharmaceutical agent as defined herein, wherein the active pharmaceutical ingredient is an anti-inflammatory drug, preferably a synthetic glucocorticoid, such as dexamethasone, betamethasone, or prednisolone, for use in treating nausea in a subject, for example where the nausea is a symptom of chemotherapy and/or radiotherapy.

In another aspect the present invention provides the use of a nanoparticle composition comprising an agrochemical ingredient, as defined herein, as a controlled release agrochemical composition.

In another aspect the present invention provides the non-therapeutic use of a nanoparticle composition comprising a cosmetic, as defined herein, as a controlled release cosmetic composition.

In another aspect the present invention provides an oligomer of formula (I):

wherein:

L is a direct bond or a linker group selected from (la), and (lb):

R¹ and R² are independently H or -Me;

R³ and R⁴ are independently H or -Me; and wherein R³ R⁴ _;

R⁵ is independently selected from: H, -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃- Cio)cycloalkyl, -(C₆-Cio)aryl, 4- to 10-membered heterocycloalkyl, 5- to 10- membered heteroaryl, halo, and -CN; wherein said -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Cio)cycloalkyl, -(C₆-Cio)aryl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl group is optionally substituted with one or more group independently selected from: -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, halo, -CN, -OH, and - NH₂;

R⁶ is independently selected from: H, -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃- Cio)cycloalkyl, -(C₆-Cio)aryl, 4- to 10-membered heterocycloalkyl, 5- to 10- membered heteroaryl, halo, and -CN; wherein said -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Cio)cycloalkyl, -(C₆-Cio)aryl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl group is optionally substituted with one or more group independently selected from: -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, halo, -CN, -OH, and - NH₂;

R⁷ is independently selected from: H, -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃- Cio)cycloalkyl, -(C₆-Cio)aryl, 4- to 10-membered heterocycloalkyl, 5- to 10- membered heteroaryl, halo, and -CN; wherein said -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Cio)cycloalkyl, -(C₆-Cio)aryl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl group is optionally substituted with one or more group independently selected from: -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, halo, -CN, -OH, and - NH₂; p is an integer from 1 to 20; s is an integer from 1 to 20; q is an integer from 0 to 9; r is an integer from 0 to 18; p + 2q + r + s = 2 to 20; and wherein when q + r = 0, L is a direct bond.

In another aspect the present invention provides an acid of formula (IV):

wherein:

L is a direct bond or a linker group selected from (la), and (lb):

R¹ and R² are independently H or -Me;

R³ and R⁴ are independently H or -Me; and wherein R³ R⁴ _; p is an integer from 1 to 20; s is an integer from 1 to 20; q is an integer from 0 to 9; r is an integer from 0 to 18; p + 2q + r + s = 2 to 20; wherein when q + r = 0, L is a direct bond; and with the proviso that at least one of R¹ to R⁴ is H.

In another aspect the present invention provides an oligomer of formula (V):

(V) ; wherein:

L is a direct bond or a linker group selected from (la), and (lb):

R¹ and R² are independently H or -Me;

R³ and R⁴ are independently H or -Me; and wherein R³ R⁴ _;

R⁷ is independently selected from: H, -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃- Cio)cycloalkyl, -(C₆-Cio)aryl, 4- to 10-membered heterocycloalkyl, 5- to 10- membered heteroaryl, halo, and -ON; wherein said -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Cio)cycloalkyl, -(C₆-Cio)aryl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl group is optionally substituted with one or more group independently selected from: -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, halo, -ON, -OH, and - NH₂; p is an integer from 1 to 20; s is an integer from 1 to 20; q is an integer from 0 to 9; r is an integer from 0 to 18; p + 2q + r + s = 2 to 20; and wherein when q + r = 0, L is a direct bond.

In another aspect the present invention provides a process for preparing an oligomer described herein, the process comprising: a) performing an esterification of an acid of formula (IV):

wherein L, R¹, R², p and s are as defined herein and PG is a protecting group, preferably a silyl ether protecting group: with a compound of formula (VI):

wherein R⁵, R⁶ and R⁷ are as defined herein; to yield an oligomer of formula (V):

wherein L, R¹, R², R⁵, R⁶, R⁷, p and s are as defined herein and PG is a protecting group, preferably a silyl ether protecting group; and b) deprotecting the oligomer of formula (V), and performing an esterification with a compound of formula (VII):

wherein R⁵, R⁶ and R⁷ are as defined herein, and wherein LG is a leaving group, preferably selected from -F, -Cl, -Br, -OH, -OMe, -OCF₃, -OCeHs, -

to provide an oligomer of formula (I).

In a final aspect the present invention provides a process for preparing an oligomer as described herein, the process comprising: a) performing an esterification of an acid of formula (IV):

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the ATR FTIR spectra of a) 4Aa, b) PEGDA700, c) physical mixture of 4Aa, PEGDA700 and AIBN at reaction ratios and room temperature and d) NP4Aa.

FIG. 2 shows a) comparison of ¹H NMR (400 MHz, (CDs^SO) spectra of a mixture of 4Aa and PEGDA700 at standard reaction concentrations, and the crude reaction mixture of the nanoprecipitation polymerization of 4Aa and PEGDA700 recorded over 6 h (PEG resonance at 3.51 ppm highlighted in grey), and b) evolution of nanoparticle size expressed as z-average mean diameter during nanoprecipitation polymerization of 4Aa and PEGDA 700, measured by DLS analysis of the crude reaction mixture over 6 h.

FIG. 3 shows ATR FTIR spectra of a) dexamethasone, b) physical mixture of dexamethasone and NP4Bb in a 1 :1 weight ratio and c) DNP4Bb. The O-H, C=O and C=C vibrations are highlighted in grey.

FIG. 4 shows nanoparticle (a) size expressed as z-average mean diameter, (b) polydispersity index (PI), (c) ^-potential and (d) estimation of encapsulation efficiency (EE) and loading efficiency (LE).

FIG. 5 shows TEM micrographs of (a) NP4Aa (80 kV, 8000x, scale bar = 1 pm) (b) NP4Aa (80 kV, 50000x, scale bar = 100 nm) and (c) DNP4Aa (80 kV, 2000x, scale bar = 2 pm).

FIG. 6 shows analysis of nanoparticle (a) size expressed as z-average mean diameter, (b) polydispersity index (PI) and (c) ^-potential during 5 weeks of incubation at 37 °C in deionized water.

FIG. 7 shows ATR FTIR spectra of a) NP4Aa, b) NP4Ab, and c) NP4Bb over 5 weeks in deionized water at 37 °C.

FIG. 8 shows the cumulative release of dexamethasone from dexamethasone-loaded NPs under experimental conditions: (a) phase 1 and phase 2 combined, and (b) phase 1. Concentrations of released dexamethasone below the limit of quantitation are labelled with an asterisk.

FIG. 9 shows (a) NP size expressed as z-average mean diameter and (b) PI of DNP4Aa, DNP4Ab and DNP4Bb in water at room temperature and after 2 h of incubation in water, DMEM and DMEM+FBS at 37 °C. FIG. 10 shows (a) size expressed as z-average mean diameter and (b) polydispersity index (PI) of DNP4Aa, DNP4Ab and DNP4Bb over 4 weeks of storage at room temperature, in the absence of mechanical stirring.

FIG. 11 shows viability of HeLa cells upon (a) 24 h of incubation and (b) 48 h of incubation with NP suspensions containing 0.01 to 0.5 mg/mL of NPs prepared from tetramer OLGADMAs, measured by CCK-8 assay.

FIG. 12 shows uptake of fluorescein labelled NP4Aa in HeLa cells, 40 x magnification, scale bar: 50 pm.

FIG. 13 A) - AB) shows intensity-weighted size distributions and corresponding correlation functions of the NPs.

FIG. 14 A) - F) shows FTIR spectra of lyophilized NPs.

FIG. 15 A) - F) shows FTIR spectra of lyophilized drug-loaded NPs.

FIG. 16 shows pH of OLGADMA-based and PLGA-based NP suspensions during 5 weeks of incubation at 37 °C in deionized water.

FIG. 17 shows ^-potential of DNP4Aa, DNP4Ab and DNP4Bb over 4 weeks of storage at room temperature, in the absence of mechanical stirring.

FIG. 18 shows a comparison of the ¹H NMR spectrum (400 MHz, acetone-d₆) of dexamethasone and the solid obtained from the procedure for investigating the stability of dexamethasone under typical reaction conditions described in Example 4.

FIG. 19 shows a comparison of the ¹H NMR spectrum (400 MHz, DMSO-d₆) of dexamethasone and the freeze-dried solid obtained from the dexamethasone release assay of DNP4Aa.

DETAILED DESCRIPTION

Definitions

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Singleton, et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY, 20 ED., John Wiley and Sons, New York (1994), and Hale & Marham, THE HARPER COLLINS DICTIONARY OF BIOLOGY, Harper Perennial, NY (1991) provide the skilled person with a general dictionary of many of the terms used in this disclosure. The meaning and scope of the terms should be clear; however, in the event of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. It should be understood that this invention is not limited to the particular methodology, protocols, and reagents, etc., described herein and as such can vary.

This invention is not limited by the exemplary methods and materials disclosed herein, and any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of this invention. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the appended claims.

The description of embodiments of the invention is not intended to be exhaustive or to limit the invention to the precise form disclosed. While specific embodiments of, and examples for, the invention are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the invention, as those skilled in the relevant art will recognize. The various embodiments described herein can be combined to provide further embodiments. These and other changes can be made to the invention in the light of the detailed description. All such modifications are intended to be included within the scope of the appended claims.

The headings provided herein are not limitations of the various aspects or embodiments of this invention.

The term “administering” as used herein as a means of providing a nanoparticle composition comprising an active agent, or a composition thereof, to a subject in a manner that results in the nanoparticle composition comprising an active agent being on or inside the subject’s body. Such an administration can be by any route including, without limitation, oral, transdermal (e.g. vagina, rectum, oral mucosa), by injection (e.g. subcutaneous, intravenous, parenterally, intraperitoneally, into the CNS), or by inhalation (e.g. oral or nasal). Pharmaceutical preparations are, of course, given by forms suitable for each administration route.

The term “active agent” as used herein refers to a chemical or biological substance capable of utility in a therapeutic, cosmetic or agrochemical application. In some embodiments the active agent is an active pharmaceutical ingredient, a cosmetic, or an agrochemical ingredient. In some embodiments the active agent is a prodrug of an active pharmaceutical ingredient or a prodrug of an agrochemical ingredient. In some embodiments the active agent is an active pharmaceutical ingredient or a prodrug of an active pharmaceutical ingredient.

In the context of therapy, the term “prodrug” as used herein refers to a pharmacological derivative of a parent molecule that requires biotransformation, either spontaneous or enzymatic, within the organism to release the active drug. In the context of agrochemicals, the term “prodrug” as used herein refers to an agrochemical derivative of a parent molecule that requires transformation, for example biotransformation, either spontaneous or enzymatic, either within the organism or on the surface of the organism, to release the active agrochemical ingredient. For example, prodrugs are variations of derivatives of an active pharmaceutical ingredient or an agrochemical ingredient that have groups cleavable under certain conditions, for example metabolic conditions, which when cleaved become the active pharmaceutical ingredient or agrochemical ingredient. In the context of therapy, such prodrugs then are pharmaceutically active in vivo, when they undergo solvolysis under physiological conditions or undergo enzymatic degradation. In the context of agrochemicals, such prodrugs then are agrochemically active in vivo, when they undergo solvolysis under physiological conditions or undergo enzymatic degradation. In the context of agrochemicals, such prodrugs may additionally be active ex vivo, for example on the surface of an organism, for example when applied to a leaf, when they undergo solvolysis or enzymatic degradation.

In the context of therapy, prodrugs often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism. In the context of agrochemicals, prodrugs often offer advantages of administration, permeability, absorption, and distribution of the agrochemical ingredient.

In some embodiments, the active agent is encapsulated by the nanoparticles of the invention. In other embodiments, the active agent is adsorbed onto the surface of the nanoparticles of the invention.

The term "alkyl" as used herein refers to a monovalent straight- or branched-chain alkyl moiety. Unless specifically indicated otherwise, the term “alkyl” does not include optional substituents. The term "haloalkyl" as used herein refers to an alkyl group substituted with one or more halo atoms. The term "halo" as used herein refers to any of fluorine, chlorine, bromine, or iodine.

The term "cycloalkyl" as used herein refers to a monovalent saturated aliphatic hydrocarbyl moiety containing at least one ring, wherein said ring has at least 3 ring carbon atoms. The cycloalkyl groups mentioned herein may optionally have alkyl groups attached thereto. Examples of cycloalkyl groups include groups that are monocyclic, polycyclic (e.g., bicyclic) or bridged ring system. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The term "heterocycloalkyl" as used herein refers to a cycloalkyl group wherein the ring contains at least one heteroatom selected from oxygen, nitrogen, and sulphur. Examples of heterocycloalkyl groups include morpholine, piperidine, piperazine and the like.

As used herein, the term “comprising” or “comprises” is intended to mean that the compositions and methods include the recited elements, but not excluding others. “Consisting essentially of’ when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives and the like. “Consisting of’ shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions of this invention or process steps to produce a composition or achieve an intended result. Embodiments defined by each of these transition terms are within the scope of this invention. Use of the term “comprising” herein is intended to encompass “consisting essentially of’ and “consisting of’.

The term “encapsulation efficiency” as used herein is defined as the percentage of the total drug added that was encapsulated in nanoparticles.

The term "halo" as used herein refers to any of fluorine, chlorine, bromine, or iodine.

The term "heteroaryl" as used herein refers to an aromatic ring containing the indicated number of atoms (e.g., 5 to 20, 5 to 12, or 5 to 10 membered heteroaryl) made up of one or more heteroatoms (e.g., 1 , 2, 3 or 4 heteroatoms) selected from N, O, and S and with the remaining ring atoms being carbon. Heteroaryl groups do not contain adjacent Sand O atoms. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 1. Unless otherwise indicated, heteroaryl groups may be bound to the parent structure by a carbon or nitrogen atom, as valency permits. For example, "pyridyl" includes 2- pyridyl, 3-pyridyl and 4-pyridyl groups, and "pyrrolyl" includes 1 -pyrrolyl, 2-pyrrolyl and 3- pyrrolyl groups.

In some embodiments, a heteroaryl group is monocyclic. Examples include pyrrole, pyrazole, imidazole, triazole ( e.g., 1 ,2,3-triazole, 1 ,2,4-triazole, 1 ,2,4-triazole ), tetrazole, furan, isoxazole, oxazole, oxadiazole (e.g., 1 ,2,3-oxadiazole, 1 ,2,4-oxadiazole, 1 ,3,4- oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (e.g., 1 ,2,3-thiadiazole, 1 ,2,4- thiadiazole, 1 ,3,4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (e.g., 1 ,2,4- triazine, 1 ,3,5-triazine), and tetrazine.

In some embodiments, both rings of a polycyclic heteroaryl group are aromatic. Examples include indole, isoindole, indazole, benzoimidazole, benzotriazole, benzofuran, benzoxazole, benzoisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzoisothiazole, benzothiadiazole, 1 H-pyrrolo[2,3-b]pyridine, 1 H-pyrazolo[3,4-b]pyridine, 3H-imidazo[4,5-b]pyridine, 3H-[1 ,2,3]triazolo[4,5-b]pyridine, 1 H-pyrrolo[3,2-b]pyridine, 1 H- pyrazolo[4,3-b]pyridine, 1 H-imidazo[4,5-b]pyridine, 1 H-[1 ,2,3]triazolo[4,5-b]pyridine, 1 H- pyrrolo[2,3-c]pyridine, 1 H-pyrazolo[3,4-c]pyridine, 3H-imidazo[4,5-c]pyridine, 3H-

[1.2.3]triazolo[4,5-c]pyridine, 1 H-pyrrolo[3,2-c]pyridine, 1 H-pyrazolo[4,3-c]pyridine, 1 H- imidazo[4,5-c]pyridine, 1 H-[1 ,2,3]triazolo[4,5-c]pyridine, furo[2,3-b]pyridine, oxazolo[5,4- b]pyridine, isoxazolo[5,4-b]pyridine, [1 ,2,3]oxadiazolo[5,4-b]pyridine, furo[3,2-b]pyridine, oxazolo[4,5-b]pyridine, isoxazolo[4,5-b]pyridine, [1 ,2,3]oxadiazolo[4,5-b]pyridine, furo[2,3- c]pyridine, oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine, [1 ,2,3]oxadiazolo[5,4-c]pyridine, furo[3,2-c]pyridine, oxazolo[4,5-c]pyridine, isoxazolo[4,5-c]pyridine, [1 ,2,3]oxadiazolo[4,5- c]pyridine, thieno[2,3-b]pyridine, thiazolo[5,4-b]pyridine, isothiazolo[5,4-b]pyridine,

[1.2.3]th iad iazolo[5,4- b] py rid i ne, thieno[3,2-b]pyridine, thiazolo[4,5-b]pyridine, isothiazolo[4,5- b]pyridine, [1 ,2,3]thiadiazolo[4,5-b]pyridine, thieno[2,3-c]pyridine, thiazolo[5,4-c]pyridine, isothiazolo[5,4-c]pyridine, [1 ,2,3]thiadiazolo[5,4-c]pyridine, thieno[3,2-c]pyridine, thiazolo[4,5- c]pyridine, isothiazolo[4,5-c]pyridine, [1 ,2,3]thiadiazolo[4,5-c]pyridine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine (e.g., 1 ,8-naphthyridine, 1 ,7- naphthyridine, 1 ,6-naphthyridine, 1 ,5-naphthyridine, 2, 7-naphthyridine, 2,6-naphthyridine), imidazo[1 ,2-a]pyridine, 1 H-pyrazolo[3,4-d]thiazole, 1 H-pyrazolo[4,3-d]thiazole, and imidazo[2, 1 -b]thiazole.

The term “molecular weight” (MW) as used herein has its normal meaning in the art. In the context of polymers described herein, the term “molecular weight” refers to the number average molecular weight (Mn), i.e. the total weight of polymer divided by the number of polymer molecules. The molecular weight of a molecule or nanoparticle composition may be presented in units of Da (Daltons). Molecular weight may be measured by size exclusion chromatography methods as will be known by those skilled in the relevant art. For example, size exclusion chromatography may be coupled with differential viscometry detection to determine molecular weight.

The term “nanoparticle” as used herein refers to a particle having a z-average mean diameter from 1 to 1000 nm, as measured by dynamic light scattering. The term "NP" as used herein refers to a nanoparticle. The term "z-average" as used herein refers to the z-average mean diameter, i.e. the intensity weighted mean hydrodynamic size of the ensemble collection of particles of a sample, as determined by dynamic light scattering. References to "z-average" and "z-average mean diameter" as used herein refer to z-average mean diameter as determined by dynamic light scattering.

Z-average mean diameter was determined by DLS analysis of aqueous suspensions performed at 25°C using a Malvern Zetasizer Ultra instrument. Samples were prepared by mixing 40-50 pL of nanoparticle dispersions with the appropriate dispersant (1 ml_). Measurements were performed using polystyrene cuvettes at 25 °C, measuring the scattered light at an angle of 173°.

The term “OLGADMA” as used herein refers to oligolactog lycol ic acid dimethacrylates. OLGADMAs are monomers used to prepare the nanoparticle compositions of the invention.

The term "optional" or "optionally" as used herein means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl," as defined herein. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible, and/or inherently unstable. It will also be understood that where a group or moiety is optionally substituted, the invention includes both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is unsubstituted.

The terms “PLA”, “PLGA”, “PCL”, and “PEG” as used herein refer to poly(D,L-lactic acid), poly(lactic-co-glycolic acid), poly(s-caprolactone), and polyethylene glycol, respectively.

The terms "patient," "individual," and "subject" as used herein refer to an animal, such as a mammal, bird, or fish. In some embodiments, the patient or subject is a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows and humans. In some embodiments, the patient or subject is a human, for example a human that has been or will be the object of treatment, observation or experiment. In some preferred embodiments, the patient or subject is a paediatric human, preferably a paediatric human that has been or will be the object of treatment, observation or experiment. The compounds, compositions and methods described herein can be useful in both human therapy and veterinary applications.

The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" as used herein includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in pharmaceutical compositions is contemplated. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.

The term “prodrug” as used herein means a pharmacological derivative of a parent drug molecule that requires biotransformation, either spontaneous or enzymatic, within the organism to release the active drug. For example, prodrugs are variations or derivatives of compounds that have groups cleavable under certain metabolic conditions, which when cleaved, become the pharmacologically active form. Such prodrugs then are pharmaceutically active in vivo when they undergo solvolysis under physiological conditions or undergo enzymatic degradation. Prodrug compounds herein may be called single, double, triple, etc., depending on the number of biotransformation steps required to release the active drug within the organism, and the number of functionalities present in a precursor-type form. Prodrug forms often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism.

Prodrugs commonly known in the art include well-known acid derivatives, such as, for example, esters prepared by reaction of acid compounds with a suitable alcohol, amides prepared by reaction of acid compounds with an amine, and basic groups reacted to form an acylated base derivative. Other prodrug derivatives may be combined with other features disclosed herein to enhance bioavailability. As such, those of skill in the art will appreciate that certain of the presently disclosed compounds having, for example, free amino or hydroxy groups can be converted into prodrugs. Prodrugs include compounds having an amino acid residue, or a polypeptide chain of two or more (e.g. two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy or carboxylic acid groups of the presently disclosed compounds. The amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, betaalanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Prodrugs also include compounds having a carbonate, carbamate, amide or alkyl ester moiety covalently bonded to any of the above substituents disclosed herein.

The term “treatment” (and related terms, such as "treat", "treated", "treating") as used herein includes one or more of: inhibiting a disease or disorder; slowing or arresting the development of clinical symptoms of a disease or disorder; and/or relieving a disease or disorder (i.e., causing relief from or regression of clinical symptoms). The term covers both complete and partial reduction of the condition or disorder, and complete or partial reduction of clinical symptoms of a disease or disorder. Thus, nanoparticle compositions comprising an active agent described and/or disclosed herein may prevent an existing disease or disorder from worsening, assist in the management of the disease or disorder, or reduce or eliminate the disease or disorder.

As used in the specification and claims, the singular form “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a nanoparticle” includes a plurality of nanoparticles, including mixtures thereof. Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive. The term “including” is used herein to mean, and is used interchangeably with, the phrase “including but not limited to”.

The nanoparticle compositions of the present invention are prepared from oligomers as described herein. These oligomers can themselves be prepared following procedures described herein through a flexible and modular approach allowing precise control over the composition and properties of the nanoparticles prepared. This is particularly important because the nanoparticles have many varied applications, for example they may comprise an active agent such as an active pharmaceutical, cosmetic, or agrochemical, and these applications often require nanoparticles to have specific properties.

In one aspect, the present invention provides a nanoparticle composition obtainable from precipitation polymerisation of one or more oligomers of formula (I):

wherein:

L is a direct bond or a linker group selected from (la), and (lb):

R¹ and R² are independently H or -Me;

R³ and R⁴ are independently H or -Me; and wherein R³ R⁴ _;

R⁵ is independently selected from: H, -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Cio)cycloalkyl, - (C₆-Cio)aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, halo, and - CN; wherein said -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Cio)cycloalkyl, -(C₆-Cio)aryl, 4- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl group is optionally substituted with one or more group independently selected from: -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, halo, -CN, -OH, and -NH₂;

R⁶ is independently selected from: H, -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Ci₀)cycloalkyl, - (C₆-Cio)aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, halo, and - CN; wherein said -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Ci₀)cycloalkyl, -(C₆-Cio)aryl, 4- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl group is optionally substituted with one or more group independently selected from: -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, halo, -CN, -OH, and -NH₂;

R⁷ is independently selected from: H, -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Ci₀)cycloalkyl, - (C₆-Cio)aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, halo, and - CN; wherein said -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Ci₀)cycloalkyl, -(C₆-Cio)aryl, 4- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl group is optionally substituted with one or more group independently selected from: -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, halo, -CN, -OH, and -NH₂; p is an integer from 1 to 20; s is an integer from 1 to 20; q is an integer from 0 to 9; r is an integer from 0 to 18; p + 2q + r + s = 2 to 20; and wherein when q + r = 0, L is a direct bond.

Formula (I) comprises two polyesters of up to 20 a-hydroxy carboxylic acid moieties that are bonded to each other through a linker, L. The a-hydroxy carboxylic acid moieties may either be derived from glycolic acid or lactic acid. L may either be a bond (in this case the two a-hydroxy carboxylic acid moieties are directly bonded together to form an ester group), or L may be a linker selected from (la) and (lb), as described herein. When L is a linker (la) or (lb), the two polyesters of up to 20 a-hydroxy carboxylic acid moieties are bonded to each other via further ester groups.

In some embodiments R¹

R². In these embodiments the nanoparticle composition comprises both glycolic acid and lactic acid derived residues. The use of glycolic acid and lactic acid in the preparation of oligomers of formula (I) has been found to result in nanoparticle compositions obtainable therefrom having particularly favourable properties.

In some embodiments q is 1 to 9; r is 0; and preferably wherein R¹ = R⁴; and R² = R³. In these embodiments, wherein R¹ = R⁴; and R² = R³, the nanoparticle composition comprises alternating glycolic acid and lactic acid derived moieties.

In some embodiments q is 0 and/or r is 0 to 18; preferably where r is 1 to 10; more preferably wherein r is 1 to 4. In these embodiments the nanoparticle composition comprises block oligomers.

In some embodiments i) at least one of R¹ and R² is -Me; ii) q 0 and one of R³ and R⁴ is -Me; and/or iii) r 0 and R³ is -Me.

In some embodiments wherein when any of R¹ to R⁴ are -Me: a) the resulting chiral centre has an (S) absolute configuration; b) the resulting chiral centre has an (R) absolute configuration; or c) the resulting chiral centre is racemic.

In some embodiments: a) p is an integer from 1 to 10; preferably 1 to 5; more preferably 1 to 3; b) s is an integer from 1 to 10; preferably 1 to 5; more preferably 1 to 3; c) q is an integer from 0 to 9; preferably 1 to 3; more preferably 1 to 2; and/or d) r is an integer from 0 to 18; preferably 1 to 4; more preferably 1 to 2.

In some embodiments p + 2q + r + s = 2 to 10, preferably p + 2q + r + s = 2 to 8, more preferably p + 2q + r + s = 4 to 6.

In a preferred embodiment the nanoparticle is formed from a precipitation copolymerisation of one or more oligomers of formula (IA) and one or more oligomers of formula (IB):

y is an integer from 2 to 20; z is an integer from 2 to 20; and

R⁵ R⁶, and R⁷ are as defined herein.

In these embodiments, the oligomers of formula (I) have the general formula (IA) and (IB). As can be seen from formula (IA) and formula (IB), one or more oligomers comprising glycolic acid derived moieties (and not lactic acid derived) may be used in a copolymerisation reaction with one or more oligomers comprising lactic acid derived moieties (and not glycolic acid derived) to provide the nanoparticles.

In some embodiments: a) R⁵ is independently selected from: H, -(Ci-C₆)alkyl, -(C₆)aryl, halo, and -CN; wherein said -(Ci-C₆)alkyl or -(C₆)aryl group is optionally substituted with one or more group independently selected from: -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, halo, and -OH; b) R⁶ is independently selected from: H, -(Ci-C₆)alkyl, -(C₆)aryl, halo, and -CN; wherein said -(Ci-C₆)alkyl or -(C₆)aryl group is optionally substituted with one or more group independently selected from: -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, halo, and -OH; and/or c) R⁷ is independently selected from: H, -(Ci-C₆)alkyl, -(C₆)aryl, halo, and -CN; wherein said -(Ci-C₆)alkyl or -(C₆)aryl group is optionally substituted with one or more group independently selected from: -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, halo, and -OH; preferably wherein R⁵, R⁶, and/or R⁷ are independently selected from H or -Me; more preferably wherein R⁵, R⁶, and R⁷ are independently selected from H or -Me. In some embodiments at least two of R⁵, R⁶, and R⁷ are H. Preferably, R⁶ and R⁷ are H, and R⁵ is -Me. Steric hindrance is known to reduce the rate of reactions, and may also affect the nanoprecipitation polymerisation reactions used in the present invention. There is a balance to be achieved between too much steric hindrance (resulting in a low rate of reaction), and too little steric hindrance (resulting in intramolecular or uncontrolled reaction of the oligomers). The ability to prepare a broad range of oligomers with different properties is a significant advantage of the present invention because it allows the skilled person to fine tune the properties of the nanoparticles for a desired application.

In some embodiments the oligomers of formula (I) have the structures shown in Table 1 , below.

In some embodiments the oligomers of formula (I) have the structures shown in Table 2, below.

oligomer starting material. For example, in some embodiments the nanoparticle is obtainable from precipitation copolymerisation of: i) one or more oligomers of formula (I), (IA) and (IB);

5 and ii) one or more oligomers of formula (II), (I I A) and (I I B) :

wherein:

R⁸ is independently H or -Me;

R⁹ is independently H or -Me;

R¹⁰ is independently H or -Me;

R¹¹ is independently H or -Me

R¹² is H or -Me;

X is independently -Ci-C₃-alkyl-; and m is an integer from 5 to 50.

In a preferred embodiment, the nanoparticles of the present invention may be prepared from more than one oligomer starting material, although this is not essential to the working of the present invention. This approach has several advantages. First, more than one type of oligomer may be used in combination to prepare the nanoparticle compositions, so it allows greater opportunities for fine tuning the properties of the nanoparticle compositions. Second, some of the oligomers of formula (II) are commercially available, so this results in lower cost and a time saving. For example, in a preferred embodiment the oligomer of formula (II) is PEGDA700. Additionally, it was found in some cases that the use of a second oligomer of formula (II), (IIA) and (IIB) in combination with the one or more oligomers of formula (I), (IA) and (IB), resulted in better drug encapsulation when an active pharmaceutical agent was used. Whilst not essential, the use of a second oligomer of formula (II), for example PEGDA700, in combination with the one or more oligomers of formula (I), (IA) and (IB), resulted in better drug encapsulation when an active pharmaceutical agent was used, as shown in the examples herein. Whilst not essential, the use of a second oligomer of formula (II), for example PEGDA700, in combination with the one or more oligomers of formula (I), (IA) and (IB), was also found to facilitate the preparation of drug-loaded nanoparticle compositions when higher loadings of an active pharmaceutical agent was used, as shown in the examples herein

The present invention allows the skilled person to fine tune and control the physical properties of the nanoparticles. For example, both the molecular weight and z-average mean diameter of the nanoparticles may be controlled. The molecular weight and z-average mean diameter of the nanoparticles are influenced by both the structure of the specific oligomers used to prepare the nanoparticles, and the conditions used in the process. In many cases, the properties of the nanoparticles are dependent on their molecular weight and z-average mean diameter. For example, nanoparticles of a particular range of molecular weights and z-average mean diameters will be sufficiently small to be able to be taken up by cells. In embodiments where the nanoparticle additionally comprises an active agent, for example an active pharmaceutical, the ability to be taken up by cells will increase the efficacy of the therapeutic treatment. In addition, it is well known in the art that nanoparticles below a certain z-average mean diameter, for example 10 nm, are readily filtered from the blood by the kidneys and excreted. In embodiments where the nanoparticles comprise an active agent, the extended release of the agent will not be experienced by a patient if the nanoparticles are readily excreted. Therefore, another advantage of the present invention is that nanoparticles may be designed to be larger than 10 nm to avoid this issue.

In some embodiments the nanoparticle molecular weight (MW) of the nanoparticle composition is <1000 kDa. In some embodiments the nanoparticle molecular weight (MW) of the nanoparticle composition is <800 kDa. In some embodiments the nanoparticle molecular weight (MW) of the nanoparticle composition is <600 kDa. In some embodiments the nanoparticle molecular weight (MW) of the nanoparticle composition is <400 kDa. In some embodiments the nanoparticle molecular weight (MW) of the nanoparticle composition is 200 kDa. In some embodiments the nanoparticle molecular weight (MW) of the nanoparticle composition is <150 kDa. In preferred embodiments the nanoparticle molecular weight (MW) of the nanoparticle composition is <100 kDa.

In some embodiments the z-average mean diameter of the nanoparticles of the nanoparticle composition is from 1 to 1000 nm, as measured by dynamic light scattering. In some embodiments the z-average mean diameter of the nanoparticles of the nanoparticle composition is from 1 to 800 nm, as measured by dynamic light scattering. In some embodiments the z-average mean diameter of the nanoparticles of the nanoparticle composition is from 1 to 700 nm, as measured by dynamic light scattering. In some embodiments the z-average mean diameter of the nanoparticles of the nanoparticle composition is from 5 to 700 nm, as measured by dynamic light scattering. In some embodiments the z-average mean diameter of the nanoparticles of the nanoparticle composition is from 5 to 600 nm, as measured by dynamic light scattering. In some embodiments the z-average mean diameter of the nanoparticles of the nanoparticle composition is from 5 to 500 nm, as measured by dynamic light scattering. In some embodiments the z-average mean diameter of the nanoparticles of the nanoparticle composition is from 10 to 500 nm, as measured by dynamic light scattering. In some embodiments the z-average mean diameter of the nanoparticles of the nanoparticle composition is from 80 to 350 nm, as measured by dynamic light scattering. In preferred embodiments the z-average mean diameter of the nanoparticles of the nanoparticle composition is from 100 to 320 nm, as measured by dynamic light scattering.

The nanoparticle compositions of the present invention are particularly useful because they have a spherical shape. Spherical nanoparticles have many different applications due to their high surface area to volume ratio. The spherical shape of the nanoparticles of the present invention is a significant advantage because in embodiments where the nanoparticle compositions comprise an active agent, the spherical shape means that a greater proportion of the active agent is encapsulated by the nanoparticles. Therefore, the encapsulation efficiency of the compositions is high. A high encapsulation efficiency is beneficial when the active agent is an active pharmaceutical ingredient because this results in a stronger therapeutic effect with reduced side effects. Likewise, a high encapsulation efficiency is also beneficial when the active agent is a cosmetic or an agrochemical ingredient because it allows greater control over the release of the active agent over time. In some embodiments, the encapsulation efficiency of a nanoparticle composition comprising an active agent is at least 20%, at least 30%, at least 40%, preferably at least 50%, more preferably at least 60%, most preferably at least 70%. The spherical shape of the nanoparticles of the present invention is also advantageous because this results in homogenous intramolecular interactions, for example hydrogen bonding and Van der Waals’ forces, between an active agent that is encapsulated by or adsorbed onto the surface of the nanoparticle compositions, and the nanoparticle compositions themselves.

In preferred embodiments the nanoparticle composition comprises nanospheres. In preferred embodiments the nanoparticle composition comprises nanospheres. Following the methods of the present invention that are described herein, nanospheres are formed spontaneously. The spontaneous formation of nanospheres is particularly important when the nanoparticle compositions of the present invention comprise an active agent, wherein the active agent is a pharmaceutical ingredient, cosmetic, or agrochemical ingredient, because the spontaneous formation of nanospheres results in a high encapsulation efficiency - the nanospheres spontaneously encapsulate the active agent in the methods of the present invention. These reliable methods to produce nanospheres and nanospheres comprising an active agent are a significant advantage of the present invention.

The nanoparticle compositions of the present invention show superior size stability in aqueous solution at elevated temperature over known nanoparticle compositions, such as PLGA-PEG nanoparticles (NP-PLGA-PEG). The nanoparticle compositions of the present invention show remarkable size stability and are able to be stored for weeks at a time in an aqueous environment at elevated temperature with limited size-oscillations, as evidenced in the examples. In addition, nanoparticle compositions of the present invention comprising an active agent also show excellent size stability when stored in aqueous solution for extended periods of time. The size stability of the nanoparticle compositions of the present invention is a significant advantage because it increases the utility of these compositions in applications such as therapy, cosmetics, and agriculture. As a person skilled in the art will appreciate, it is desirable for nanoparticle compositions, and in particular nanoparticle compositions comprising an active agent, to have stable physical properties.

The nanoparticle compositions of the present invention show excellent colloidal stability in aqueous solution and biological media at elevated temperature. As the skilled person will appreciate, the environment of a cell, for example a cell of a plant, or a cell of a mammal, such as a human, is rich in electrolytes and proteins. These components have the potential to significantly affect the colloidal stability of nanoparticle compositions. However, the nanoparticle compositions of the present invention show excellent colloidal stability in aqueous solution and biological media at elevated temperature. This is a particularly important advantage of the present invention because it is desirable for the colloidal compositions of the present invention not to aggregate and show colloidal instability in aqueous solution and biological media, and therefore maintain their desired physical properties.

The nanoparticles of the present invention comprise biocompatible glycolate and/or lactate moieties that can be metabolised in the body. The nanoparticles (either alone or in combination with an active agent) therefore do not result in harmful undesired effects, such as cytotoxicity. This is a significant advantage of the present invention and makes the nanoparticle compositions and nanoparticle compositions comprising an active agent particularly suited to uses in therapy, cosmetics, and agriculture.

A significant advantage of the present invention is that the nanoparticle compositions may be readily prepared from a broad range of different oligomers. Further, a broad range of oligomers may themselves be prepared following the processes disclosed herein through a flexible and modular approach. The ability to prepare a broad range of oligomers and have precise control over their structure and properties allows precise control over the composition and properties of the nanoparticles which are prepared from the oligomers. The ability to fine tune the structure of the nanoparticle compositions is particularly important when the compositions comprise an active agent, for example an active pharmaceutical, cosmetic, or agrochemical. For example, in the case of an active pharmaceutical, the rate at which the agent is released in the aqueous environment inside the patient is dependent on the structure of the nanoparticle, which is in turn dependent on the structure of the oligomers that were used to prepare it. Degradation controlled release of an active agent from a nanoparticle is known to depend on the structure of the nanoparticles, and, in this case, the structure of the oligomers that were used to prepare the nanoparticle. The nanoparticle compositions of the present invention show superior size stability in aqueous solution at elevated temperature over known nanoparticle compositions, such as PLGA-PEG nanoparticles (NP-PLGA-PEG). This stability is highly influenced by the oligomers that are used to prepare the nanoparticle compositions. The nanoparticle compositions of the present invention show remarkable size stability and are able to be stored for weeks at a time in an aqueous environment at elevated temperature with limited size-oscillations detected, as evidenced in the examples. In addition, nanoparticle compositions of the present invention comprising an active agent also show excellent size stability when stored in aqueous solution for extended periods of time. The size stability of the nanoparticle compositions of the present invention is a significant advantage because it increases the utility of these compositions in applications such as therapy, cosmetics, and agriculture. As a person skilled in the art will appreciate, it is desirable for nanoparticle compositions, and in particular nanoparticle compositions comprising an active agent, to have stable physical properties. The ability to optimise the size stability of the nanoparticle compositions by fine tuning the oligomers used to prepare the nanoparticle compositions is a significant advantage of the present invention.

The nanoparticle compositions of the present invention show excellent colloidal stability in aqueous solution and biological media at elevated temperature. As the skilled person will appreciate, the environment of a cell, for example a cell of a plant, or a cell of a mammal, such as a human, is rich in electrolytes and proteins. These components have the potential to significantly affect the colloidal stability of nanoparticle compositions. However, the nanoparticle compositions of the present invention show excellent colloidal stability in aqueous solution and biological media at elevated temperature. This is a particularly important advantage of the present invention because it is desirable for the colloidal compositions of the present invention not to aggregate and show colloidal instability in aqueous solution and biological media, and therefore maintain their desired physical properties. The ability to optimise the colloidal stability of the nanoparticle compositions by fine tuning the oligomers used to prepare the nanoparticle compositions is a significant advantage of the present invention.

The nanoparticles of the present invention comprise biocompatible glycolate and/or lactate moieties that can be metabolised in the body. These biocompatible moieties are integrated into the structure of the nanoparticle compositions via the oligomers that are used in their preparation. The nanoparticles (either alone or in combination with an active agent) therefore do not result in harmful undesired effects, such as cytotoxicity. This is a significant advantage of the present invention and makes the nanoparticle compositions and nanoparticle compositions comprising an active agent particularly suited to uses in therapy, cosmetics, and agriculture. The nanoparticle compositions comprising an active agent, for example an active pharmaceutical ingredient, a cosmetic, or an agrochemical ingredient, provided by the present invention have highly tuneable active agent release profiles in aqueous or biological solution. The nanoparticle compositions comprising an active agent provide an extended release of the active agent over time. Due to the highly flexible and modular design of the nanoparticle compositions (deriving from oligomers), the nanoparticle compositions may be fine-tuned so that they release a certain proportion of the active agent within a certain period of time. This may either be a high, medium, or low proportion of the active agent depending on the desired application. In contrast, the applications of known PLGA nanoparticle compositions comprising an active agent are severely limited because these compositions are restricted to releasing only a very small amount of active agent in a certain period of time. The oligomers of the present invention (and methods of preparing them) used to prepare the nanoparticle compositions of the present invention are therefore particularly advantageous.

In some embodiments the oligomers of formula (I) have the structures shown in Table A, below.

Table A

Stereoisomers (e.g. cis and trans isomers) and all optical isomers of a presently disclosed compound (e.g. R and S enantiomers), as well as racemic, diastereomeric and other mixtures of such isomers are within the scope of the present invention. The same rationale applies to nanoparticle compositions of the present invention which may also comprise cis, trans, R, and/or S isomers.

In some embodiments the oligomers of formula (I) have the structures shown in Table B, below.

wherein:

L is a direct bond or a linker group selected from (la), and (lb):

R¹ and R² are independently H or -Me;

R³ and R⁴ are independently H or -Me; and wherein R³ R⁴ _;

R⁵ is independently selected from: H, -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Cio)cycloalkyl, -(C₆-Cio)aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, halo, and -CN; wherein said -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Cio)cycloalkyl, -(C₆- Cw)aryl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl group is optionally substituted with one or more group independently selected from: -(Ci- C₆)alkyl, -O(Ci-C₆)alkyl, halo, -CN, -OH, and -NH₂;

R⁶ is independently selected from: H, -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Ci₀)cycloalkyl, -(C₆-Cio)aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, halo, and -CN; wherein said -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Ci₀)cycloalkyl, -(C₆- Cw)aryl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl group is optionally substituted with one or more group independently selected from: -(Ci- C₆)alkyl, -O(Ci-C₆)alkyl, halo, -CN, -OH, and -NH₂;

R⁷ is independently selected from: H, -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Ci₀)cycloalkyl, -(C₆-Cio)aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, halo, and -CN; wherein said -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Ci₀)cycloalkyl, -(C₆- Cw)aryl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl group is optionally substituted with one or more group independently selected from: -(Ci- C₆)alkyl, -O(Ci-C₆)alkyl, halo, -CN, -OH, and -NH₂; p is an integer from 1 to 20; s is an integer from 1 to 20; q is an integer from 0 to 9; r is an integer from 0 to 18; p + 2q + r + s = 2 to 20; and wherein when q + r = 0, L is a direct bond.

In the present invention, oligomers may be prepared in a stepwise process from the compounds shown below. A significant advantage of this convergent approach is that an acid of formula (IV) may quickly be derivatised into different oligomers by performing an esterification reaction with a range of different compounds of formula (VI). As a person skilled in the art will appreciate, there are many different reagents and conditions that may be used to promote esterification reactions including, without limitation: acid, e.g. HCI; dicyclohexylcarbodiimide (DCC); diisopropylcarbodiimide (DIC); ethyl-(N’,N’- dimethylamino)propylcarbodiimide hydrochloride (EDC); (benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP); (benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP); (7-azabenzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP); bromotripyrrolidinophosphonium hexafluorophosphate; bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-CI); 0-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HBTU); 0-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU); O-(7- azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU); O-(7- azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TATU); O-(6- chlorobenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HCTU); O- [(ethoxycarbonyl)cyanomethylenamino]-N,N,N',N'-tetra methyluronium tetrafluoroborate (TOTU); 0-(N-succinimidyl)-1 ,1 ,3,3-tetramethyl-uronium tetrafluoroborate (TSTU); O-(5- norbornene-2,3-dicarboximido)-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TNTU); O- (1 ,2-dihydro-2-oxo-1-pyridyl-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TPTU); 3- (diethylphosphoryloxy)-1 ,2,3-benzotriazin-4(3H)-one (DEPBT); carbonyldiimidazole (CDI); and propylphosphonic anhydride (T3P).

A broad range of different compounds of formula (VI) may be used in the process of the present invention. In a preferred embodiment, the compound of formula (VI) is hydroxyethylmethacrylate (HEMA).

A range of protecting groups may be used to protect the alpha-alcohol of the acid of formula (IV). In particular, silyl ether protecting groups are preferred. As the skilled person will be aware, there are many different silyl protecting groups that may be used, including, without limitation: trimethylsilyl (TMS); triethylsilyl (TES); isopropyldimethylsilyl (IPDMS); diethylisopropylsilyl (DEIPS); f-butyldimethylsilyl (TBS); f-butyldiphenylsilyl (TBDPS); t- butyldiphenylsilyl (TBDPS); and triisopropylsilyl (TIPS). In a preferred embodiment the silyl protecting group is f-butyldiphenylsilyl (TBDPS).

As the skilled person will be aware, a range of different reagents may be used to deprotect the oligomer of formula (V). For example, the following reagents may be used, without limitation: tetrabutylammonium fluoride; pyridine (HF)_x; triethylamine trihydrofluoride; HF; tris(dimethylamino)sulfonium difluorotrimethylsilicate; ammonium fluoride; and HCI. With ordinary knowledge of the art, the skilled person would be able to select the most appropriate reagent for deprotecting the silyl protected alcohol group. Deprotecting reagents can also be used in combination with other reagents. For example, in one embodiment the reagents used to deprotect the oligomer of formula (V) are tetrabutylammonium fluoride and acetic acid.

After deprotection of the oligomer of formula (V), the resulting alcohol may be reacted with a compound of formula (VII) in an esterification reaction, similarly to the procedure described above. The esterification reaction could be a coupling of alcohol with a carboxylic acid, but it could also be a reaction of the alcohol with an activated carboxylic acid, for example an acyl chloride. In a preferred embodiment the compound of formula (VII) is methacryloyl chloride.

In yet another aspect the present invention provides an acid of formula (IV):

wherein:

L is a direct bond or a linker group selected from (la), and (lb):

R¹ and R² are independently H or -Me;

In yet another aspect the present invention provides an oligomer of formula (V):

wherein:

L is a direct bond or a linker group selected from (la), and (lb):

R¹ and R² are independently H or -Me;

R³ and R⁴ are independently H or -Me; and wherein R³ R⁴ _;

R⁵ is independently selected from: H, -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Cio)cycloalkyl, -(C₆- Cw)aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, halo, and -CN; wherein said -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Cio)cycloalkyl, -(C₆-Cio)aryl, 4- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl group is optionally substituted with one or more group independently selected from: -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, halo, -CN, -OH, and -NH₂;

R⁶ is independently selected from: H, -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Ci₀)cycloalkyl, -(C₆- Cw)aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, halo, and -CN; wherein said -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Ci₀)cycloalkyl, -(C₆-Cio)aryl, 4- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl group is optionally substituted with one or more group independently selected from: -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, halo, -CN, -OH, and -NH₂;

R⁷ is independently selected from: H, -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Ci₀)cycloalkyl, -(C₆- Cw)aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, halo, and -CN; wherein said -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Ci₀)cycloalkyl, -(C₆-Cio)aryl, 4- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl group is optionally substituted with one or more group independently selected from: -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, halo, -CN, -OH, and -NH₂; p is an integer from 1 to 20; s is an integer from 1 to 20; q is an integer from 0 to 9; r is an integer from 0 to 18; p + 2q + r + s = 2 to 20; and wherein when q + r = 0, L is a direct bond.

In some embodiments the oligomer as defined herein, or the acid as defined herein, wherein L, R¹, R², R⁵, R⁶, R⁷, p and s are as defined herein. In another aspect the present invention provides a process for preparing an oligomer as defined herein, the process comprising: a) performing an esterification of an acid of formula (IV):

V) wherein L, R¹, R², R⁵, R⁶, R⁷, p and s are as defined herein and PG is a protecting group, preferably a silyl ether protecting group; and b) deprotecting the oligomer of formula (V), and performing an esterification with a compound of formula (VII):

wherein R⁵, R⁶ and R⁷ are as defined herein, and wherein LG is a leaving group, preferably selected from

to provide an oligomer of formula (I). In another aspect the present invention provides a process for preparing an oligomer as defined herein, the process comprising: a) performing an esterification of an acid of formula (IV):

Active

The nanoparticle compositions provided by the present invention are particularly useful because they may further comprise an active agent, for example an active pharmaceutical ingredient, a cosmetic, or an agrochemical ingredient. In some embodiments the active agent is an active pharmaceutical ingredient, a cosmetic, or an agrochemical ingredient. In some embodiments the active agent is a prodrug of an active pharmaceutical ingredient or a prodrug of an agrochemical ingredient. In some embodiments the active agent is an active pharmaceutical ingredient or a prodrug of an active pharmaceutical ingredient. The active agent may be incorporated within the structure of the nanoparticle composition, for example it may be encapsulated, or adsorbed onto the nanoparticle composition. In some embodiments, the active agent is entirely encapsulated by the nanoparticle composition. In some embodiments, the active agent is entirely adsorbed onto the nanoparticle composition. In some embodiments, the active agent is encapsulated and adsorbed by the nanoparticle composition. The nanoparticle compositions comprising the active agent are therefore particularly useful because the active agent is released slowly over time - this would not be the case if the agent and nanoparticle were simply part of a mixture. As a person skilled in the art would appreciate, the nanoparticle compositions comprising an active agent of the present invention are particularly useful whether the active agent is encapsulated, adsorbed, or both encapsulated and adsorbed by the nanoparticle composition. Any of these options result in nanoparticle compositions comprising an active agent of the present invention with particularly useful extended release properties.

The spherical shape of the nanoparticle compositions of the present invention contributes towards many of their advantageous properties. Spherical nanoparticles have many different applications due to their high surface area to volume ratio. The spherical shape of the nanoparticles of the present invention is a significant advantage because in embodiments where the nanoparticle compositions comprise an active agent, the spherical shape means that a greater proportion of the active agent is encapsulated by the nanoparticles. Therefore, the nanoparticle compositions provided by the present invention have high encapsulation efficiencies. A high encapsulation efficiency is beneficial when the active agent is an active pharmaceutical ingredient because this results in a stronger therapeutic effect with reduced side effects. Likewise, a high encapsulation efficiency is also beneficial when the active agent is a cosmetic or an agrochemical ingredient because it allows greater control over the release of the active agent over time. In some embodiments, the encapsulation efficiency of a nanoparticle composition comprising an active agent is at least 20%, at least 30%, at least 40%, preferably at least 50%, more preferably at least 60%, most preferably at least 70%. The spherical shape of the nanoparticles of the present invention is also advantageous because this results in homogenous intramolecular interactions, for example hydrogen bonding and Van der Waals’ forces, between an active agent that is encapsulated by or adsorbed onto the surface of the nanoparticle compositions, and the nanoparticle compositions themselves.

By following the methods for preparing the nanoparticle compositions, nanospheres have been found to form spontaneously. The spontaneous formation of nanospheres is particularly important when the nanoparticle compositions of the present invention comprise an active agent, wherein the active agent is a pharmaceutical ingredient, cosmetic, or agrochemical ingredient, because the spontaneous formation of nanospheres results in a high encapsulation efficiency - the nanospheres spontaneously encapsulate the active agent in the methods of the present invention. These reliable methods to produce nanospheres and nanospheres comprising an active agent are a significant advantage of the present invention.

The nanoparticle compositions comprising an active agent, for example an active pharmaceutical ingredient, a cosmetic, or an agrochemical ingredient, provided by the present invention have highly tuneable active agent release profiles in aqueous or biological solution. The nanoparticle compositions comprising an active agent provide an extended release of the active agent over time. Due to the highly flexible and modular design of the nanoparticle compositions (deriving from oligomers), the nanoparticle compositions may be fine-tuned so that they release a certain proportion of the active agent within a certain period of time. This may either be a high, medium, or low proportion of the active agent depending on the desired application. In contrast, the applications of known PLGA nanoparticle compositions comprising an active agent are severely limited because these compositions are restricted to releasing only a very small amount of active agent in a certain period of time.

The nanoparticle compositions provided by the present invention have low polydispersity (PI) parameters. A low PI means that the nanoparticles are highly uniform in size. Therefore, the low PI is advantageous when the nanoparticle compositions of the present invention comprise an active agent, for example an active pharmaceutical ingredient, a cosmetic, or an agrochemical ingredient, because each nanoparticle comprising said agent will have similar properties. As a consequence of this, there is a greater degree of control over the pharmaceutical/agrochemical/cosmetic use of the nanoparticle compositions of the present invention. In some embodiments, the polydispersity of the nanoparticle composition is less than 0.4, less than 0.35, preferably less than 0.3, more preferably less than 0.25, most preferably less than 0.2.

The nanoparticle compositions provided by the present invention have negative

potentials. Negative ^-potentials are an advantageous property of the nanoparticle compositions of the present invention because in general, a ^-potential that is less negative than -15 mV suggests that the nanoparticles will start to agglomerate. When the ^-potential is equal to 0 mV, the nanoparticles will precipitate into a solid. It is desirable to have discrete nanoparticles in order to preserve the activity of the nanoparticle compositions of the present invention.

In some embodiments, the ^-potential of the nanoparticle composition is between 0 and -60 mV, preferably between -25 and -55 mV.

In some embodiments the composition further comprises an active agent, wherein the active agent is an active pharmaceutical ingredient, a cosmetic, or an agrochemical ingredient, wherein the active agent is stable in aqueous solution at temperatures up to 60 °C, preferably up to 70 °C, more preferably up to 80 °C. It may be the case that being adsorbed onto the surface of, or encapsulated by the nanoparticle provides an additional stabilising effect to the active agent and this makes it more resistant to degradation. “Stable” in this context may be used to refer to the proportion of the active agent that has degraded. As one of ordinary skill in the art will be aware, a number of analytical techniques may be used to determine the purity of a sample. These analytical techniques include, but are not limited to: NMR, for example ¹H NMR and ¹⁹F NMR; HPLC; SFC; GC; LC-MS; colourimetry; titration; and IR. For example, in some embodiments the amount of active agent that has degraded in aqueous solution at a given temperature is <30%. In some embodiments the amount of active agent that has degraded in aqueous solution at a given temperature is <20%. In some embodiments the amount of active agent that has degraded in aqueous solution at a given temperature is <10%. In some embodiments the amount of active agent that has degraded in aqueous solution at a given temperature is <5%. In preferred embodiments the amount of active agent that has degraded in aqueous solution at a given temperature is <1%.

In some embodiments the active agent is adsorbed and/or encapsulated by the nanoparticles. In this embodiment, the active agent is released slowly from the nanoparticles over a period of time. As a person skilled in the art would appreciate, the active agent would be released more quickly if it were simply part of a physical mixture comprising nanoparticles, so this is a significant benefit of the present invention. In embodiments where the active agent is an active pharmaceutical, a slower release of the active agent means that a reduction in dosage frequency is possible. This may reduce the frequency with which patients forget to take their medication and therefore help with patient compliance. Additionally, a slower release of the active pharmaceutical results in a lower peak concentration and avoids a “burst release”. The effect of this is that nanoparticle compositions comprising an active pharmaceutical result in fewer side effects in patients. The extended release of an active pharmaceutical is therefore a significant benefit of the present invention.

The nanoparticle compositions of the present invention may comprise a broad range of different active agents. It is also possible for the nanoparticle compositions to comprise one or more active agents. The one or more active agents may be adsorbed or encapsulated by the nanoparticles. Alternatively, one or more active agents may be encapsulated by the nanoparticles, and one or more active agents may also be adsorbed by the same nanoparticles. There may be mixtures of nanoparticles comprising one or more active agents as described previously, with other nanoparticles comprising one or more active agents, wherein the other nanoparticles comprising one or more active agents comprise one or more active agents that are different to the first. Alternatively, the other nanoparticles comprising one or more active agents may comprise either the same or different active agents, but the other nanoparticles comprising one or more active agents have a different structure to the first nanoparticles comprising one or more active agents.

In some embodiments the active agent is an active pharmaceutical agent. In some embodiments the active pharmaceutical agent is selected from the group of general drug categories consisting of: analgesics; antacids; antianxiety drugs; antiarrhythmics; antibacterials; antibiotics; anticoagulants and thrombolytics; anticonvulsants; antidepressants; antidiarrheals; antiemetics; antifungals; antihistamines; antihypertensives; antiinflammatories; antineoplastics; antipsychotics; antipyretics; antivirals; barbiturates; betablockers; bronchodilators; cold cures; corticosteroids; cough suppressants; cytotoxics; decongestants; diuretics; expectorant; hormones; hypoglycemics (oral); immunosuppressives; laxatives; muscle relaxants; sedatives; sex hormones e.g. male or female; sleeping drugs; tranquilizers; and vitamins. In a preferred embodiment the active pharmaceutical agent is an anti-inflammatory drug, for example a corticosteroid, and preferably a synthetic glucocorticoid, such as dexamethasone, betamethasone, or prednisolone, or a derivative thereof. In a preferred embodiment the active pharmaceutical agent is selected from the group consisting of: dexamethasone and derivatives thereof, e.g. dexamethasone acetate or dexamethasone disodium phosphate.

In some embodiments the active pharmaceutical agent is selected from the group consisting of: small molecules and biologic. In some embodiments the biologic is selected from the group consisting of: allergenics; antibodies, e.g. monoclonal and humanised monoclonal antibodies; blood; blood components; fusion proteins; gene therapies; cell therapies; proteins, e.g. recombinant proteins; somatic cells; tissues; and vaccines.

As a person of ordinary skill in the art will appreciate, toxicity issues associated with state of the art nanoparticles limits their use in combination with cosmetics. In contrast, the nanoparticles of the present invention comprise biocompatible glycolate and/or lactate moieties that can be metabolised in the body. The nanoparticles (either alone or in combination with cosmetics) therefore do not result in harmful effects either on the surface or after penetrating the skin of an individual. The nanoparticle compositions described herein therefore have particularly favourable properties that make them ideally suited for use in combination with an active agent, wherein the active agent is a cosmetic.

Many different active agents may be used in combination with the nanoparticles of the present invention, for example a cosmetic. In some embodiments the cosmetic is selected from the group consisting of: primer; foundation; fairness cream; humectant; emollient; electrolytes; concealer; anti-aging cream; moisturiser; setting powder; blemish balm cream; rouge; contour powder/cream; highlighter; sunscreen; eyeliner; mascara; eyeshadow; eyebrow powder; eyebrow gel; lipstick; lip liner; lip gloss; fragrance; deodorant; toothpaste; and anti-perspirant; or combinations thereof. In an embodiment the cosmetic is an antioxidant or a vitamin. For example, the antioxidant or vitamin may be selected from the group consisting of: amino acids, vitamin C, vitamin A, vitamin E, vitamin D, vitamin E, vitamin F, vitamin K, vitamin B, vitamin B1 , vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B7, vitamin B9, vitamin B12, resveratrol, coenzyme Q10, niacinamide, polyphenols, flavonoids, alpha-lipoic acid, folic acid, phytoene, biotin, alpha-glucosyl rutin, carnitine, carnosine, natural and/synthetic isoflavones, creatine, creatinine, taurine, B-alanine, glyceryl glucoside, liquorice extract, aloe vera, hyaluronic acid, aloe barbadensis leaf juice, niacinamide, dimethylmethoxy chromanol, hydroxyacetophenone, acorbic acid and its salts, hydroxymethoxyphenyl decanone, beta-aspartyl arginine, uric acid, urea, hydroxypinacolone retinoate, butyl hydroxytoluol (BHT), butylhydroxyanisol (BHA), hydroxyphenyl propamidobenzoic acid, ascorbyl palmitate, ascorbyl phosphate and salts thereof, tocopherol, tocopheryl acetate, ubiquinone-10, dilauryl thiodipropionate, pentaerythrityl tetra-di-t-butyl hydroxyhydrocinnamate, triethyl citrate, diethylhexyl syringylidene malonate, lactobacillus (ferment, filtrate, lysate), cannabinoids, cannabidiol and its extracts (cannabis sativa seed oil, cannabis sativa extract), cannabinol, hydroxyphenyl propamidobenzoic acid (dihydroavenanthramide D), green tea extract, Zingiber Officinalis (Ginger) root extract, tropolone, allantoin, or combinations thereof. The cosmetic may be selected without limitation from the group consisting of: dihydroxyacetone, 8-hexadecene-1 ,16-dicarboxylic acid, and (2- hydroxyethyl)urea.

In an embodiment the cosmetic is an electrolyte. Electrolyte components may be in the form of inorganic salt or organic salt, and also may be a low molecular weight compound or a high molecular weight compound. Components having water solubility and no skin irritancy are preferable. Preferably, an electrolyte component is a substance that dissociates into a cation and an anion in an aqueous solution or a polar solvent.

Electrolytes may be inorganic salts or organic salts. Examples of preferred electrolyte inorganic salts include inorganic salts such as sodium chloride, potassium chloride, calcium chloride, magnesium chloride, zinc chloride, aluminum chloride, calcium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, potassium sulfite, sodium sulfate, sodium hydrogensulfate, sodium sulfite, sodium hydrogensulfite, potassium sulfate, sodium sulfate, calcium sulfate, magnesium sulfate, zinc sulfate, aluminum sulfate, potassium phosphate, sodium phosphate, disodium hydrogenphosphate, and sodium dihydrogenphosphate.

Examples of preferred electrolyte organic salts that are low molecular weight compounds include glycyrrhizic acid salts such as dipotassium glycyrrhizic acid salt; a-hydroxy acid salts such as aminocaproic acid, citric acid, salicylic acid, lactic acid, glycolic acid, and tartaric acid; amino acids and derivatives thereof such as serine, glycine, asparagine, aspartic acid, tranexamic acid, lysine, threonine, alanine, thyrosin, valine, leucine, proline, arginine, threonine, cysteine, cysteine, methionine, tryptophan, glutamic acid, and pyrrolidone carboxylic acid; vitamins such as ascorbate, sodium ascorbate, potassium ascorbate, magnesium ascorbate, sodium ascorbate ester, ascorbic acid phosphoric ester magnesium, ascorbic acid phosphoric ester calcium, sodium ascorbyl sulfate, magnesium ascorbyl sulfate, calcium ascorbyl sulfate, ascorbic acid glucoside (2-O-a-D-glucopyranosyl-L-ascorbic acid), ascorbic acid glucosamine, dehydroascorbic acid, vitamin B2, vitamin B6 .vitamin B12, vitamin B13, biotin, pantothenic acid, niacin, folic acid, inositol, carnitine, thiamine, thiamine disulfide, fursultiamine, dicethiamine, bisbutythiamin, bisbentiamine, benfotiamine, thiamine monophosphate disulfide, cycotiamine, octotiamine, and prosultiamine; as well as disodium ethylenediaminetetraacetate, trisodium ethylenediaminetetraacetate, tetrasodium ethylenediaminetetraacetate, sodium benzoate, 2-hydroxy-4-methoxybenzophenone-5- sulfonate, adenosine-3'-5'-cyclic monophosphate, adenosine monophoshate, adenosine diphoshate, adenosine triphosphate and salts thereof; anionic surfactants such as fatty acid soaps (sodium laurate, sodium palmitate, sodium stearate, and the like), potassium lauryl sulfate, and alkyl sulfate triethanolamine ether; cationic surfactants such as stearyl chloride trimethylammonium, benzalkonium chloride, and lauryl amine oxide; ampholytic surfactants such as imidazoline-based ampholytic surfactants (2-cocoyl-2-imidazolinium hydroxide-1- carboxy ethyloxy disodium salt, and the like), betaine-based surfactants (alkyl betaine, amide betaine, sulfobetaine, and the like), and acyl methyl taurine.

Examples of preferred electrolyte organic salts that are high molecular weight compounds include hyaluronic acid, gellan gum, deacylation gellan gum, rhamsan gum, diutan gum, xanthan gum, carrageenan, xanthan gum, hexuronic acid, fucoidan, pectin, pectic acid, pectinic acid, heparan sulfate, heparin, heparan sulfate, keratosulfate, chondroitin sulfate, dermatan sulfate, rhamnan sulfate, and salts thereof; alginate derivatives such as sodium alginate and propylene glycol alginate ester; methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, carboxymethylcellulose and salts thereof such as sodium; cellulose derivatives such as methyl hydroxypropylcellulose, cellulose sodium sulfate, and dialkyl dimethylannmonium sulfate cellulose; chitosans, carboxyvinyl polymers, polyacrylic acids, and salts thereof such as sodium salts; an acrylic acid/(meth)acrylic acid ester copolymer, an acrylic acid/(meth)acrylic acid alkyl copolymer, cationized cellulose such as polyquaternium-10, a diallyl dimethylannmonium chloride/acrylamide copolymer such as polyquaternium-7, an acrylic acid/diallyl dimethylannmonium chloride copolymer such as polyquaternium-22, an acrylic acid/diallyl dimethylannmonium chloride/acrylamide copolymer such as polyquaternium-39, an acrylic acid/cationized (meth)acrylic acid ester copolymer, an acrylic acid/cationized (meth)acrylic acid amide copolymer, an acrylic acid/methyl acrylate/methacrylamidepropyl trimethylammonium chloride copolymer such as polyquaternium-47, a methacrylate chloride choline ester polymer, cationized dextran, cationized polysaccharides such as guar hydroxypropyl trimonium chloride, polyethyleneimine, and a copolymer of a 2-methacryloyloxyethyl phosphorylcholine polymer and a butyl (meth)acrylate copolymer such as polyquaternium-51.

In an embodiment the cosmetic is a moisturiser. For example, the moisturiser may be selected from the group consisting of: glycerin, ceramides, caprylyl glycol, D,L-panthenol, D- panthenol, vitamin A palmitate, vitamin E acetate, methylsilanetriol mannuronate, natural oils such as tallow oil, macadamia nut oil, borage oil, evening primrose oil, kukui nut oil, rice bran oil, tea tree oil, a medium chain fatty acid ester of glycerol, glycerol triheptanoate, glyceryl trioctanoate, glyceryl stearate, mineral water, silicones, silicone derivatives, butylene glycol, cetyl alcohol, dimethicone, dimyristyl tartrate, glucose, glycereth-26, glycerine, hydrolyzed milk protein, lactic acid, lactose and other sugars, laureth-8, lecithin, octoxyglycering, PEG- 12, PEG-135, PEG-150, PEG-20, PEG-8, pentylene glycol, hexylene glycol, phytantriol, polyquaternium-39, PPG-20 methyl glucose ether, propylene glycol, sodium hyaluronate, sodium lactate, sodium PCA, sorbitol, succinoglycan, synthetic beeswax, tri-C14-15 alkyl citrate, or mixtures thereof.

In an embodiment the cosmetic is an emollient. For example, the emollient may be selected from the group consisting of: benzoates, butylene glycol dicaprylate, caprylic triglyceride, cetyl alcohol, cetyl esters, cocoa butter, coconut, jojoba, sesame, almond, and other plant oils, isononyl isononanoate, lanolin, mineral oil, myristates, olive oil (oleic acid), palmitates, paraffin, petrolatum, shea butter, silicones, squalene, stearates, triethylhexanoin, triglycerides, or mixtures thereof.

In an embodiment the cosmetic is a humectant. For example, the humectant may be selected from the group consisting of: aloe vera, alpha-hydroxy acids (e.g., glycolic acid, sorbitol, sodium hyaluronate), butylene glycol, glycerin, hyaluronic acid (including low- and high-molecular weight hyaluronic acid), propanediol, propylene glycol, lactic acid, urea, or mixtures thereof. The cosmetic may be a hair product. For example, in some embodiments the cosmetic is selected from the group consisting of: hair shampoo; hair colour; hair serum; hair spray; and hair loss products.

The nanoparticles of the present invention absorb UV radiation. This useful advantage of the invention means that the nanoparticles are suitable for use as a sunscreen. The nanoparticles of the invention may be used either as the sunscreen, or in combination with another agent that is known to absorb UV radiation, for example as TiO₂. The cosmetic composition may comprise an inorganic sunscreen, e.g. TiO₂ and/or ZnO. The cosmetic composition may comprise an organic sunscreen, e.g. a cinnamic derivative. The organic sunscreen active may be selected from hydrophilic organic sunscreen, hydrophobic organic sunscreen, or mixtures thereof. Suitable examples of sunscreens may be found in the CTFA International Cosmetic Ingredient Dictionary and Handbook, 7th edition volume 2, pp.1672, edited by Wenning and Me Ewen (The Cosmetic, Toiletry, and Fragrance Association, Inc., Washington, D.C. 1997).

The organic sunscreen may be selected from cinnamic derivatives, alkyl (3,(3- diphenylacrylate derivatives, a-cyano p,|3-diphenylacrylate derivatives, anthranilate derivatives, benzophenone derivatives, camphor derivatives, dibenzoylmethane derivatives, p-aminobenzoic derivatives, salicylic derivatives, triazine derivatives, or mixtures thereof. The hydrophobic organic sunscreen may be selected from 4-(1 ,1 -dimethylethyl)-’'- methoxydibenzoylmethane, 4-isopropyldibenzoylmethane, 4-(1 ,1 -dimethylethyl)-’'- methoxydibenzoylmethane, 2-ethylhexyl-2-cyano-3,3-diphenylacrylate, avobenzene, oxybenzone, octinoxate, or mixtures thereof. In some embodiments the hydrophilic organic sunscreen is 2-phenylbenzimidaole-5-sulfonic acid.

Suitable examples of cinnamic derivative sunscreens may be found in the CTFA International Cosmetic Ingredient Dictionary and Handbook, 7th edition volume 2, pp.1672, edited by Wenning and Me Ewen (The Cosmetic, Toiletry, and Fragrance Association, Inc., Washington, D.C. 1997). The cinnamic derivative may be selected from 2-ethylhexyl-p- methoxycinnamate, diethanolamine methoxycinnamate, 2-ethoxyethyl-p-methoxycinnamate, or a mixture thereof. For instance, the cinnamic derivative may be 2-ethylhexyl-p- methoxycinnamate.

In some embodiments the cosmetic is used in combination with at least one of the group consisting of: emulsifier, chelating agent, pH adjusting agent, thickener, diluent, and preservatives.

In an embodiment the cosmetic is used in combination with an emulsifier. For example, the emulsifier may be selected from the group consisting of: behentrimonium chloride, behentrimonium methosulfate, carbomer, cetaryl alcohol, cetearyl olivate, cetearyl wheat straw glucosides, emulsifying wax-NF, glyceryl stearate, laureth-4, lecithin, polyethylene glycol (PEG) stearates (e.g., PEG-2 stearate, PEG-6 stearate, PEG-8 stearate, PEG-12 stearate, PEG-20 stearate, PEG-32 stearate, PEG-40 stearate, PEG-50 stearate, PEG-100 stearate, PEG-150 stearate), polysorbates (e.g., polysorbate 80), potassium cetyl sulfate, polyquaternium-37, propylene glycol, stearic acid, stearyl alcohol, sodium stearoyl lactylate, sorbitan olivate, and mixtures thereof.

In an embodiment the cosmetic is used in combination with a chelating agent. For example, the chelating agent may be selected from the group consisting of: ethylenediamine tetraacetic acid (EDTA) (e.g., Na₂-EDTA, Na -EDTA), gluconic acid, phytic acid, metaphosphoric acid, polyphosphoric acid, tetrahydroxypropyl ethylenediamine, and mixtures thereof.

In an embodiment the cosmetic is used in combination with a pH adjusting agent. For example, the pH adjusting agent may be selected from the group consisting of: inorganic acids (such as hydrochloric acid or sulfuric acid), organic acids (such as lactic acid, sodium lactate, citric acid, sodium citrate, succinic acid or sodium succinate), inorganic bases (such as potassium hydroxide or sodium hydroxide), and organic bases (such as triethanolamine, diisopropanolamine or triisopropanolamine), and mixtures thereof.

In an embodiment the cosmetic is used in combination with a thickener. For example, the thickener may be selected from the group consisting of: agar, gellan gum, guar gum, locust bean gum, carrageenan, xanthan gum, dextran, methyl cellulose, ethyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, carbomer, carboxyethyl cellulose, sodium alginate, propylene alginate glycol ester, dextran, polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, carboxyvinyl polymer, acrylic acid-alkyl methacrylate copolymer, sodium polyacrylate, polyethylene glycol, bentonite, dextrin fatty acid ester, pectin, hydroxyethyl acrylate-sodium acryloyldimethyl taurate copolymer, dimethyl distearyl ammonium hectorite, ammonium acryloyldimethyl taurate-vinylpyrrolidone copolymer, ammonium acryloyldimethyl taurate-beheneth-25 methacrylate crosspolymer ammonium acryloyldimethyltaurate-steareth-25 methacrylate crosspolymer, polyethylene glycol distearate, polyquaternium-37, ethylene glycol triisostearate, and mixtures thereof.

In an embodiment the cosmetic is used in combination with a diluent. For example, the diluent may be selected from the group consisting of: water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (for example, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, 1 ,3- butanediol, and mixtures thereof. In an embodiment the cosmetic is used in combination with a preservative. For example, the preservative may be selected from the group consisting of: parabens (e.g., methylparaben, propylparaben, butylparaben), phenoxyethanol, benzoic acid/sodium benzoate, sorbic acid/potassium sorbate, levulinic acid, anisic acid, isothiazolinones, gluconolactone sodium benzoate, phenylpropanol ethylhexylglycerin, caprylyl glycol, benzyl alcohol, caprylyl glycol ethylhexylglycerin, and mixtures thereof.

In some embodiments the active agent is an agrochemical ingredient. In some embodiments the agrochemical ingredient is selected from the group consisting of: algaecides; fertilisers; fungicides; herbicides; insecticides; molluscicides; nematicides; plant growth regulators; rodenticides; and soil conditioners. Similarly to the pharmaceutical and cosmetic applications described above, it is desirable for the nanoparticles that comprise an agrochemical to be biocompatible and non-toxic. For example, if the nanoparticles comprising an agrochemical are applied to plants that are to be later consumed by humans or animals, it is important that there are no harmful residues or degradants in the plants when they are later consumed. The nanoparticles of the present invention therefore particularly useful because they comprise biocompatible glycolate and/or lactate moieties that can be metabolised.

In some embodiments the active ingredient has a molecular weight (MW) of < 20000 Daltons. In some embodiments the active ingredient has a molecular weight (MW) of < 15000 Daltons. In some embodiments the active ingredient has a molecular weight (MW) of < 10000 Daltons, preferably < 6000 Daltons, more preferably < 900 Daltons, most preferably < 500 Daltons. A wide range of different classes of active agent may be adsorbed/encapsulated by the nanoparticles, and these may have a wide range of molecular weights. For example, small molecules may typically have molecular weights of < 500 Daltons, but biologies, for example peptides, may typically have molecular weights of < 10000 Daltons. The wide variety of different active agents that are tolerated by the invention is a significant benefit.

The nanoparticle compositions of the present invention may be prepared following the methods described herein. In the embodiment described below, an aqueous solution is used in step ii). As a person skilled in the art will appreciate, the ability to use water as a solvent is highly beneficial from environmental, cost, and practical considerations.

In some embodiments the method for preparing a nanoparticle composition by precipitation polymerisation further comprises the following preceding steps for preparation of the oligomer of formula (I): a) performing an esterification of an acid of formula (IV):

wherein L, R¹, R², p and s are as defined herein and PG is a protecting group, preferably a silyl ether protecting group; with a compound of formula (VI):

wherein L, R¹, R², R⁵, R⁶, R⁷, p and s are as defined herein and PG is a protecting group, preferably a silyl ether protecting group; and deprotecting the oligomer of formula (V) and performing an esterification with a compound of formula (VII):

wherein R⁵, R⁶ and R⁷ are as defined herein, and wherein LG is a leaving group, preferably selected from -F, -Cl, -Br, -OH, -OMe, -OCF₃,

b) to provide an oligomer of formula (I).

In some embodiments the oligomer of formula (I) is obtained from the oligomerisation of lactic acid and glycolic acid monomers, or derivatives thereof.

In some embodiments the ratio of lactic acid monomer units to glycolic acid monomer units, or derivatives thereof, is from 0.5 to 2.0 to 1 .0, preferably from 0.8 to 1 .2.

In some embodiments: a. the lactic acid monomer units are L-lactic acid monomer units; b. the lactic acid monomer units are D-lactic acid monomer units; or c. the lactic acid monomer units are L-lactic acid monomer units and D-lactic acid monomer units in a 1 :1 ratio.

In some embodiments the method further comprises providing an active agent in the mixture of step i) and obtaining a nanoparticle composition in step iii) comprising encapsulated active agent; wherein the active agent is an active pharmaceutical ingredient, a cosmetic, or an agrochemical ingredient, wherein the active agent is stable in aqueous solution at temperatures up to 60 °C, preferably up to 70 °C, more preferably up to 80 °C.

In some embodiments the water-miscible organic solvent in step i) comprises tetra hydrofuran (THF), dioxane, or acetonitrile, preferably tetrahydrofuran (THF). As a person skilled in the art would appreciate, it may be possible to use other water-miscible organic solvents in the method used to prepare the oligomer of formula (I). In some embodiments, the solvent used in step i) comprises a mixture of water-miscible solvents. In a preferred embodiment, the solvent used in step i) is THF and water.

Medical uses

In yet another aspect the present invention provides a nanoparticle composition comprising an active pharmaceutical ingredient, as defined herein, for use in therapy. In some embodiments the use in therapy is to treat a disease or condition. The nanoparticle compositions provided by the present invention are particularly useful because they may further comprise an active agent, for example an active pharmaceutical ingredient. The active agent may be incorporated within the structure of the nanoparticle composition, for example it may be encapsulated, or adsorbed onto its surface. The nanoparticle compositions comprising the active agent are therefore particularly useful because the active agent is released slowly over time. As a consequence of this, the nanoparticle compositions comprising an active pharmaceutical ingredient are particularly useful in therapy. As a person skilled in the art would appreciate, the nanoparticle compositions comprising an active pharmaceutical ingredient of the present invention are particularly useful in therapy whether the active pharmaceutical ingredient is encapsulated, adsorbed, or both encapsulated and adsorbed by the nanoparticle composition. Any of these options result in nanoparticle compositions comprising an active pharmaceutical ingredient of the present invention with particularly useful extended release properties.

The spherical shape of the nanoparticle compositions of the present invention contributes towards many of their advantageous properties. Spherical nanoparticles have many different applications due to their high surface area to volume ratio. The spherical shape of the nanoparticles of the present invention is a significant advantage because in embodiments where the nanoparticle compositions comprise an active pharmaceutical ingredient, the spherical shape means that a greater proportion of the active agent is encapsulated by the nanoparticles. Therefore, the nanoparticle compositions provided by the present invention have high encapsulation efficiencies. A high encapsulation efficiency is beneficial when the active agent is an active pharmaceutical ingredient because this results in a stronger therapeutic effect with reduced side effects. In some embodiments, the encapsulation efficiency of a nanoparticle composition comprising an active agent is at least 20%, at least 30%, at least 40%, preferably at least 50%, more preferably at least 60%, most preferably at least 70%.

The spherical shape of the nanoparticles of the present invention is also advantageous because this results in homogenous intramolecular interactions, for example hydrogen bonding and Van der Waals’ forces, between an active pharmaceutical ingredient that is encapsulated by or adsorbed onto the surface of the nanoparticle compositions, and the nanoparticle compositions themselves.

In preferred embodiments the nanoparticle composition comprises nanospheres. Following the methods of the present invention that are described herein, nanospheres are formed spontaneously. The spontaneous formation of nanospheres is particularly important when the nanoparticle compositions of the present invention comprise an active pharmaceutical ingredient, because the spontaneous formation of nanospheres results in a high encapsulation efficiency - the nanospheres spontaneously encapsulate the active pharmaceutical ingredient in the methods of the present invention. These reliable methods to produce nanospheres and nanospheres comprising an active pharmaceutical ingredient are a significant advantage of the present invention.

In many cases, an extended release of the active pharmaceutical ingredient is desirable to avoid rapid changes in concentration. Extended release of the pharmaceutical ingredient also reduces the likelihood of undesired side effects. There are many common side effects of medications that may be avoided or minimised by administering extended release formulations of active pharmaceutical ingredients. Some common side effects include: gastrointestinal adverse events; loss of appetite; nausea; vomiting; abdominal distension; dyspepsia; gingival pain; dry lip; lower abdominal pain; stomach discomfort; toothache; upper abdominal pain; diarrhoea; peptic ulcers; gastrointestinal bleeding; constipation; and upset stomach.

As a person skilled in the art will appreciate, there are many medical indications for which it is necessary for the drug concentration to be above a certain concentration to prevent resistance. This is particularly important when treating viral, fungal, and/or bacterial conditions. The nanoparticle compositions comprising an active pharmaceutical ingredient of the present invention are therefore particularly useful in treating these conditions because they are designed to promote an extended release of the active pharmaceutical ingredient. Examples of viral conditions include: respiratory viral diseases; flu; common cold; respiratory syncytial virus infection; adenovirus infection; parainfluenza virus infection; severe acute respiratory syndrome (SARS); gastrointestinal viral diseases; norovirus; rotavirus; astrovirus; exanthematous viral diseases; measles; rubella; shingles; roseola; smallpox; fifth disease; chikungunya virus infection; hepatic viral diseases; hepatitis A, B, C, D, E; cutaneous viral diseases; warts; oral herpes; genital herpes; molluscum contagiosum; hemorrhagic viral diseases; ebola; lassa fever; coronavirus; dengue fever; yellow fever; marburg hemorrhagic fever; Crimean-Congo hemorrhagic fever; neurologic viral diseases; polio; viral meningitis; viral encephalitis; rabies; HIV/AIDS; and sexually transmitted infections. Examples of bacterial conditions include: skin and deep tissue infections; impetigo; cellulitis; MRSA; erysipelas; necrotising fasciitis; bacterial folliculitis; ‘hot tub’ folliculitis; erythrasma; pneumonia; lyme disease; meningitis; chlamydia; strep throat; bacterial vaginosis; and tuberculosis. Examples of fungal conditions include: fungal nail infections; ringworm; vaginal candidiasis; Candida infections of the mouth, throat, and oesophagus; blastomycosis; cryptococcus gattii infection; paracoccidioidomycosis; coccidioidomycosis (valley fever); histoplasmosis; aspergillosis; Candida auris infection; Invasive candidiasis; pneumocystis pneumonia (PCP); candidiasis; cryptococcus neoformans infection; mucormycosis; talaromycosis; fungal eye infections; sporotrichosis; mycetoma; and healthcare-associated fungal meningitis.

There are many other medical conditions where an extended release of the active pharmaceutical ingredient is beneficial, for example in the treatment of neurological diseases. In particular, extended release drug formulations can result in increased patient compliance. This is particularly important for neurological diseases because symptoms can change significantly over a relatively short amount of time. In some cases, patients either forget or are unable to take a subsequent dose at the correct time. Examples of neurological diseases include: Parkinson’s disease; Alzheimer’s disease; Huntington’s disease; ALS; multiple sclerosis; neurodegenerative diseases; dementias; cerebrovascular conditions; movement disorders; cranial nerve disorders; neuropsychiatric disorder.

The nanoparticles comprising an active pharmaceutical agent are particularly useful in treating nausea. In some embodiments the disease or condition is nausea. Nausea may have several different symptoms, for example: diarrhoea; vomiting; headache; high temperature; heartburn; bloating after eating; sensitivity to light or sound; and dizziness. The nausea itself may be a symptom of: excessive consumption of food or alcohol; digestive system diseases; infectious diseases; pregnancy; side effects from medication; anaesthesia; chemotherapy; and radiotherapy. In a preferred embodiment the nausea is a symptom of chemotherapy and/or radiotherapy.

The nanoparticles comprising an active pharmaceutical agent are particularly useful in treating inflammatory diseases. In some embodiments the disease or condition is an inflammatory disease, for example: inflammation, inflammatory bowel disease (IBD) arthritis, rheumatoid arthritis, spondylarthropathies, gouty arthritis, osteoarthritis, juvenile arthritis, and other arthritic conditions, systemic lupus erthematosus (SLE), skin-related conditions, eczema, Sjogren's syndrome, burns, dermatitis, neuroinflammation, allergy pain, autoimmune myositis, neuropathic pain, fever, pulmonary disorders, lung inflammation, adult respiratory distress syndrome, pulmonary sarcoisosis, asthma, silicosis, chronic pulmonary inflammatory disease, and chronic obstructive pulmonary disease (COPD), cardiovascular disease, arteriosclerosis, myocardial infarction (including post-myocardial infarction indications), thrombosis, congestive heart failure, cardiac reperfusion injury, as well as complications associated with hypertension and/or heart failure such as vascular organ damage, restenosis, cardiomyopathy, stroke including ischemic and hemorrhagic stroke, reperfusion injury, renal reperfusion injury, ischemia including stroke and brain ischemia, and ischemia resulting from cardiac/coronary bypass, neurodegenerative disorders, liver disease and nephritis, gastrointestinal conditions, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, ulcerative diseases, gastric ulcers, viral and bacterial infections, sepsis, septic shock, gram negative sepsis, malaria, meningitis, HIV infection, opportunistic infections, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), pneumonia, herpes virus, myalgias due to infection, influenza, autoimmune disease, graft vs. host reaction and allograft rejections, treatment of bone resorption diseases, osteoporosis, multiple sclerosis, acute gout, pneumonitis, myocarditis, pericarditis, myositis, eczema, alopecia, vitiligo, bullous skin diseases, atherosclerosis, depression, retinitis, uveitis, scleritis, hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis, Addison's disease, hypophysitis, thyroiditis, type I diabetes, giant cell arteritis, nephritis including lupus nephritis, vasculitis with organ involvement such as glomerulonephritis, vasculitis including giant cell arteritis, Wegener's granulomatosis, Polyarteritis nodosa, Behcet's disease, Kawasaki disease, Takayasu's Arteritis, vasculitis with organ involvement, acute rejection of transplanted organs, endotoxaemia, systemic inflammatory response syndrome (SIRS), multiorgan dysfunction syndrome, toxic shock syndrome, acute lung injury, ARDS (adult respiratory distress syndrome), acute renal failure, fulminant hepatitis, burns, acute pancreatitis, postsurgical syndromes, sarcoidosis, Herxheimer reactions, encephalitis, myelitis, SIRS associated with viral infections such as influenza, herpes zoster, herpes simplex, coronavirus or dry eye syndrome (or keratoconjunctivitis sicca (KCS)).

The nanoparticles comprising an active pharmaceutical agent are particularly useful in treating cardiovascular diseases. In some embodiments the disease or condition is a cardiovascular disease, for example: congestive heart failure, stroke, acute coronary artery disease, arrhythmia, asymmetric septal hypertrophy (e.g., left ventricular hypertrophy with resultant diastolic dysfunction), cardiomyopathy, valvular dysfunction, pericarditis, atherosclerosis, or myocardial infarction.

The nanoparticles comprising an active pharmaceutical agent are particularly useful in treating dermatological diseases. In some embodiments the disease or condition is a dermatological disease, for example: acne vulgaris, adult eczema, alopecia, allergic contact dermatitis, allergic dermatitis, allergic contact eczema, asteatotic eczema, atopic eczema, hand eczema, atopic dermatitis, childhood eczema, chronic dermatitis of hands or feet, contact dermatitis, contact eczema, discoid eczema, drug-induced skin reactions, dermatitis herpetiformis, discoid lupus erythematosus, epidermolysis bullosa, erythroderma, erythema nodosum, erythema multiforme, hand eczema, hand and foot dermatitis, ichthyosis vulgaris, infantile eczema, insect bite inflammation, keratoconus, keratosis pilaris, lichen simplex chronicus, lichen planus, nummular dermatitis, melanomas, over-treatment dermatitis, pemphigus, pemphigoid, photodermatoses, pityriasis rosea, pyoderma gangrenosum, pompholyx, psoriasis, prurigo nodularis, rosacea, scabies, seborrheic dermatitis, seborrhea, scleroderma, Sjogren's Disease, stasis dermatitis, subacute cutaneous lupus erythematosus, sunburn, systemic lupus erythematosus, vitiligo and urticaria.

The nanoparticles comprising an active pharmaceutical agent are particularly useful in treating neurological diseases. In some embodiments the disease or condition is a neurological disease, for example: Alzheimer's disease (AD), Parkinson Disease (PD), dementia with Lewy bodies (DLB), multi-infarct dementia (MID), vascular dementia (VD), schizophrenia and/or depression.

The nanoparticles comprising an active pharmaceutical agent are particularly useful in treating metabolic diseases. In some embodiments the disease or condition is a metabolic disease, for example: overweight, weight gain, obesity, non-alcoholic fatty liver disease, diabetes, insulin-resistance, alcoholic fatty liver disease, dyslipidemia, steatosis (e.g., liver steatosis, heart steatosis, kidney steatosis, muscle steatosis), abeta-lipoproteinemia, glycogen storage disease, Weber-Christian disease, lipodystrophy; a liver disease, liver inflammation, hepatitis, steatohepatitis, Hepatitis C, Genotype 3 Hepatitis C, Alpha 1- antitrypsin deficiency, acute fatty liver of pregnancy, Wilson disease; a kidney disease; a heart disease, hypertension, ischemia, heart failure, cardiomyopathy; poisoning; HIV; a neurodegenerative disease, Parkinson's disease, Alzheimer's disease; cancer, physical exercise, high cholesterol, an eating disorder, anorexia, starvation, malnutrition, total parenteral nutrition, severe weight loss, underweight, re-feeding syndrome; gastrointestinal surgery-mediated metabolic alterations, jejuno-ilial bypass, gastric bypass; inflammatory/infectious conditions, jujunal diverticulosis with bacterial overgrowth, or inflammatory bowel disease.

The nanoparticles comprising an active pharmaceutical agent are particularly useful in treating genetic diseases. In some embodiments the disease or condition is a genetic disease, for example: cystic fibrosis, polycystic kidney disease, Wilson's disease, amyotrophic lateral sclerosis (or ALS or Lou Gehrig's Disease), Duchenne muscular dystrophy, p thalassemia, Becker muscular dystrophy, Gaucher's disease, Parkinson's disease, Alzheimer's disease, Huntington's disease, Charcot-Marie-Tooth syndrome, Zellweger syndrome, autoimmune polyglandular syndrome, Marfan's syndrome, Werner syndrome, adrenoieukodystrophy (or ALD), Menkes syndrome, malignant infantile osteopetrosis, spinocerebellar ataxia, spinal muscular atrophy (or SMA)i, obesity, glucose galactose malabsorption, dystrophin Kobe, osteogenesis imperfect, Merosin-deficient congenital muscular dystrophy type 1 A, graft- versus-host disease, or spinal muscular atrophy.

The nanoparticles comprising an active pharmaceutical agent are particularly useful in treating cancer. In some embodiments the disease or condition is cancer, for example: human sarcoma or carcinoma, selected from the group consisting of fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, colorectal cancer, anal carcinoma, esophageal cancer, gastric cancer, hepatocellular cancer, bladder cancer, endometrial cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, stomach cancer, atrial myxomas, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, thyroid and parathyroid neoplasms, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, non-small- cell lung cancer, bladder carcinoma, epithelial carcinoma, glioma, pituitary neoplasms, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, schwannomas, oligodendroglioma, meningioma, spinal cord tumors, melanoma, neuroblastoma, pheochromocytoma, Types 1-3 endocrine neoplasia, retinoblastoma; leukemia, selected from the group consisting of acute lymphocytic leukemia, acute myelocytic leukemia; chronic leukemia, polycythemia vera, lymphoma, multiple myeloma, Waldenstrobm's macroglobulinemia, heavy chain disease, T-cell leukemias, B cell leukemia; mixed cell leukemias, myeloid leukemias, neutrophilic leukemia, eosinophilic leukemia, monocytic leukemia, myelomonocytic leukemia, Naegeli-type myeloid leukemia, or nonlymphocytic leukemia.

The nanoparticle compositions of the present invention are particularly useful in therapy because they are able to be taken up by cells, for example HeLa cells. This is particularly beneficial because it means that nanoparticle compositions comprising an active pharmaceutical agent can be taken up by cells. The active pharmaceutical agent can then be delivered to the inside of the cell, thereby resulting in a therapeutic effect.

In yet another aspect the present invention provides a nanoparticle composition comprising an active pharmaceutical agent as defined herein, wherein the active pharmaceutical ingredient is an anti-inflammatory drug, preferably a synthetic glucocorticoid, such as dexamethasone, betamethasone, or prednisolone, for use in treating nausea in a subject, for example where the nausea is a symptom of chemotherapy and/or radiotherapy. Pharmaceutical compositions

As will be understood by the skilled person, the nanoparticle compositions comprising an active pharmaceutical agent may be formulated into pharmaceutical compositions. The present invention provides pharmaceutical compositions comprising a nanoparticle composition wherein the composition further comprises an active agent, as described herein, wherein the active agent is an active pharmaceutical ingredient, as described herein, and at least one pharmaceutically acceptable excipient, e.g. for use according to the methods disclosed herein. The pharmaceutically acceptable excipient can be any such excipient known in the art including those described in, for example, Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). Pharmaceutical compositions of the nanoparticle compositions comprising an active agent presently disclosed may be prepared by conventional means known in the art including, for example, mixing at least one presently disclosed nanoparticle composition comprising an active agent with a pharmaceutically acceptable excipient.

Thus, in one aspect the present invention provides a pharmaceutical dosage form comprising a nanoparticle composition comprising an active agent as described herein and a pharmaceutically acceptable excipient, wherein the dosage form is formulated to provide, when administered (e.g. when administered orally), an amount of said nanoparticle composition comprising an active agent sufficient to treat a disease or disorder as described herein.

A pharmaceutical composition or dosage form of the invention can include an agent and another carrier, e.g. compound or composition, inert or active, such as a detectable agent, label, adjuvant, diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant or the like. Carriers also include pharmaceutical excipients and additives, for example, proteins, peptides, amino acids, lipids, and carbohydrates (e.g. sugars, including monosaccharides, di-, tri-, tetra-, and oligosaccharides; derivatized sugars such as alditols, aldonic acids, esterified sugars and the like; and polysaccharides or sugar polymers), which can be present singly or in combination, comprising alone or in combination 1 to 99.99% by weight or volume. Exemplary protein excipients include serum albumin such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like. Representative amino acid/antibody components, which can also function in a buffering capacity, include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and the like. Carbohydrate excipients are also intended within the scope of this invention, examples of which include but are not limited to monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol) and myoinositol.

Carriers which may be used include a buffer or a pH adjusting agent; typically, the buffer is a salt prepared from an organic acid or base. Representative buffers include organic acid salts such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid; Tris, tromethamine hydrochloride, or phosphate buffers. Additional carriers include polymeric excipients/additives such as polyvinylpyrrolidones, ficolls (a polymeric sugar), dextrates (e.g. cyclodextrins, such as 2- hydroxypropyl-p-cyclodextrin), polyethylene glycols, flavoring agents, antimicrobial agents, sweeteners, antioxidants, antistatic agents, surfactants (e.g. polysorbates such as “TWEEN 20” and “TWEEN 80”), lipids (e.g. phospholipids, fatty acids), steroids (e.g. cholesterol), and chelating agents (e.g. EDTA).

The present invention also provides pharmaceutical compositions, and kits comprising said compositions, which contain at least one nanoparticle composition comprising an active agent and at least one further pharmaceutically-active agent. These pharmaceutical compositions and kits may be adapted to allow simultaneous, subsequent and/or separate administration of the nanoparticle composition comprising an active agent and the further active agent. For example, the nanoparticle composition comprising an active agent and the further active agent may be formulated in separate dosage forms, e.g. in separate tablets, capsules, lyophilizates, suspensions or liquids, or they may be formulated in the same dosage form, e.g. in the same tablet, capsule, lyophilizate, suspension or liquid. Where the nanoparticle composition comprising an active agent and the further active agent are formulated in the same dosage form, the nanoparticle composition comprising an active agent and the further active agent may be present substantially in admixture, e.g. within the core of a tablet or capsule, or they may be present substantially in discrete regions of the dosage form, e.g. in separate layers or areas of the same tablet or capsule. In one embodiment, the pharmaceutical dosage form comprises a further agent which is capable of treating a disease or condition as described herein.

In a further aspect the present invention provides a pharmaceutical composition comprising: (i) a nanoparticle composition comprising an active agent as described herein; (ii) a further active agent; and (iii) a pharmaceutically acceptable excipient. In another embodiment, the further active agent is an agent which is capable of treating or preventing a disease or condition, as described herein, for example, when administered orally to a subject. In another embodiment, the further active agent is an agent which is capable of treating or preventing a disease or condition, as described herein, for example, when administered intravenously to a subject.

The presently disclosed nanoparticle compositions comprising an active agent and pharmaceutical compositions can be used in an animal or human. Thus, a presently disclosed compound can be formulated as a pharmaceutical composition for oral, buccal, parenteral (e.g. intravenous, intramuscular or subcutaneous), topical, rectal or intranasal administration or in a form suitable for administration by inhalation or insufflation. In particular embodiments, the nanoparticle composition comprising an active agent or pharmaceutical composition is formulated for systemic administration, e.g. via a non-parenteral route. In one embodiment, the nanoparticle composition comprising an active agent or pharmaceutical composition is formulated for oral administration, e.g. in solid, liquid or suspension form. Such modes of administration and the methods for preparing appropriate pharmaceutical compositions are described, for example, in Gibaldi’s Drug Delivery Systems in Pharmaceutical Care (1st ed., American Society of Health-System Pharmacists 2007).

The pharmaceutical compositions can be formulated so as to provide an extended release of the active ingredient therein using, for example, hydroxypropyl methyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. The pharmaceutical compositions can also optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner, e.g. by using an enteric coating. Examples of embedding compositions include polymeric substances and waxes. The nanoparticle composition comprising an active agent can also be in micro-encapsulated form, if appropriate, with one or more pharmaceutically acceptable carriers, excipients, or diluents well known in the art (see, e.g., Remington’s). The nanoparticle compositions comprising an active agent presently disclosed may be formulated for sustained delivery according to methods well known to those of ordinary skill in the art. Examples of such formulations can be found in United States Patents 3,119,742; 3,492,397; 3,538,214; 4,060,598; and 4,173,626.

In solid dosage forms for oral administration (e.g. capsules, tablets, pills, dragees, powders, granules and the like), the nanoparticle composition comprising an active agent is mixed with one or more pharmaceutically acceptable carriers, excipients, or diluents, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, microcrystalline cellulose, calcium phosphate and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, pregelatinized maize starch, polyvinyl pyrrolidone, hydroxypropyl methylcellulose, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, sodium starch glycolate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, sodium lauryl sulphate, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, silica, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets, and pills, the pharmaceutical compositions can also comprise buffering agents. Solid compositions of a similar type can also be prepared using fillers in soft and hard-filled gelatin capsules, and excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

A tablet can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (for example, gelatin or hydroxypropyl methyl cellulose), lubricants, inert diluents, preservatives, disintegrants (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-actives, and/ or dispersing agents. Molded tablets can be made by molding in a suitable machine a mixture of the powdered nanoparticle composition comprising an active agent moistened with an inert liquid diluent. The tablets and other solid dosage forms, such as dragees, capsules, pills, and granules, can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the art.

In embodiments, the pharmaceutical compositions are administered orally in a liquid form. Liquid dosage forms for oral administration of a nanoparticle composition comprising an active agent include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. Liquid preparations for oral administration may be presented as a dry product for constitution with water or other suitable vehicle before use. In addition to the nanoparticle composition comprising an active agent, the liquid dosage forms can contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, oils (e.g. cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, the liquid pharmaceutical compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents, and the like. Suspensions, in addition to the nanoparticle composition comprising an active agent can contain suspending agents such as, but not limited to, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. Suitable liquid preparations may be prepared by conventional means with a pharmaceutically acceptable additive(s) such as a suspending agent (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g. lecithin or acacia); nonaqueous vehicle (e.g. almond oil, oily esters or ethyl alcohol); and/or preservative (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid). The nanoparticle compositions comprising an active agent can also be administered as a bolus, electuary, or paste.

For buccal administration, the composition may take the form of tablets or lozenges formulated in a conventional manner.

In some embodiments the pharmaceutical compositions are administered by non-oral means such as by topical application, transdermal application, injection, eye drops, aerosol, and the like. In related embodiments, the pharmaceutical compositions are administered parenterally by injection, infusion, or implantation (e.g. intravenous, intramuscular, intraarterial, subcutaneous, and the like).

Presently disclosed nanoparticle compositions comprising an active agent may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g. in ampules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain a formulating agent such as a suspending, stabilizing and/or dispersing agent recognized by those of skill in the art. Alternatively, the nanoparticle composition comprising an active agent may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use. The pharmaceutical compositions may be administered directly to the central nervous system. Accordingly, in certain embodiments the compositions are administered directly to the central nervous system so as to avoid the blood brain barrier. In some embodiments, the composition can be administered via direct spinal cord injection. In embodiments, the composition is administered by intrathecal injection. In some embodiments, the composition is administered via intracerebroventricular injection. In embodiments, the composition is administered into a cerebral lateral ventricle. In embodiments, the composition is administered into both cerebral lateral ventricles. In additional embodiments, the composition is administered via intrahippocampal injection. The compositions may be administered in one injection or in multiple injections. In other embodiments, the composition is administered to more than one location (e.g. to two sites in the central nervous system).

The pharmaceutical compositions can be in the form of sterile injections. The pharmaceutical compositions can be sterilized by, for example, filtration through a bacteria- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. To prepare such a composition, the nanoparticle composition comprising an active agent is dissolved or suspended in a parenterally acceptable liquid vehicle. Exemplary vehicles and solvents include, but are not limited to, water, water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1 ,3-butanediol, Ringer’s solution and isotonic sodium chloride solution. The pharmaceutical composition can also contain one or more preservatives, for example, methyl, ethyl or n-propyl p-hydroxybenzoate. To improve solubility, a dissolution enhancing or solubilizing agent can be added or the solvent can contain 10-60% w/w of propylene glycol or the like.

The pharmaceutical compositions can contain one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders, which can be reconstituted into sterile injectable solutions or dispersions just prior to use. Such pharmaceutical compositions can contain antioxidants; buffers; bacteriostats; solutes, which render the formulation isotonic with the blood of the intended recipient; suspending agents; thickening agents; preservatives; and the like.

Examples of suitable aqueous and nonaqueous carriers, which can be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Controlled release parenteral compositions can be in form of aqueous suspensions, nanoparticle composition comprising an active agent in microspheres, nanoparticle composition comprising an active agent in microcapsules, nanoparticle composition comprising an active agent in magnetic microspheres, oil solutions, oil suspensions, emulsions, or the nanoparticle composition comprising an active agent can be incorporated in biocompatible carrier(s), nanoparticles, implants or infusion devices. Materials for use in the preparation of microspheres and/or microcapsules include, but are not limited to, biodegradable/bioerodible polymers such as polyglactin, poly-(isobutyl cyanoacrylate), poly(2- hydroxyethyl-L-glutamine) and poly(lactic acid). Biocompatible carriers which can be used when formulating a controlled release parenteral formulation include carbohydrates such as dextrans, proteins such as albumin, lipoproteins or antibodies. Materials for use in implants can be non-biodegradable, e.g. polydimethylsiloxane, or biodegradable such as, e.g., poly(caprolactone), poly(lactic acid), poly(glycolic acid) or poly(ortho esters).

For topical administration, a presently disclosed nanoparticle composition comprising an active agent may be formulated as an ointment or cream. Presently disclosed nanoparticle compositions comprising an active agent may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, presently disclosed nanoparticle compositions comprising an active agent may be conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the presently disclosed nanoparticle composition comprising an active agent. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a presently disclosed nanoparticle composition comprising an active agent and a suitable powder base such as lactose or starch.

Generally, the nanoparticle composition comprising an active agent and pharmaceutical compositions thereof described herein are administered in an effective amount or quantity sufficient to treat or prevent a disease or condition in a subject in need thereof. Typically, the dose can be adjusted within this range based on, e.g., age, physical condition, body weight, sex, diet, time of administration, and other clinical factors. Determination of an effective amount is well within the capability of those skilled in the art.

As the skilled person will be aware, the nanoparticle compositions comprising an agrochemical ingredient may be formulated into agrochemical compositions. Many of the pharmaceutically acceptable excipients described above are also appropriate for use in agrochemical compositions. In particular, the following non-limiting list of solubilizing media may be used in the agrochemical compositions of the present invention: paraffins selected from octane, nonane, decane, undecane, dodecane, tridecane, tetradecane, pentadecane, hexadecane, hepta-decane, octa-decane, nona-decane, eicosane, heneicosane, docosane, tricosane, tetracosane, pentacosane, and branched chain isomers thereof; petroleum, ketones (e.g. acetophenone, cyclohexanone); aromatic ethoxylate compounds selected from di- or tri-styrylphenol ethoxylates and their derivates, such as phosphates and sulphates and salts thereof. Examples of the one or more di- or tri-styrylphenol ethoxylates or derivatives thereof include, but are not limited to, ethoxylated tristyrylphenol, sulphates and phosphates of polyarylphenol ethoxylates. These sulphates and phosphates being used either in their acid forms, or as salts, such as ammonium, triethanolamine, etc. Examples of such products include: Soprophor BSU', 'Soprophor S25', Soprophor TS/10, Soprophor 4D384, Soprophor 3D33, Soprophor FL, etc; vegetable oils (e.g. olive oil, kapok oil, castor oil, papaya oil, camellia oil, palm oil, sesame oil, com oil, rice bran oil, peanut oil, cotton seed oil, soybean oil, rapeseed oil, linseed oil, tung oil, sunflower oil, safflower oil, tall oil); alkyl ester of vegetable oils (e.g. rapeseed oil methyl ester or rapeseed oil ethyl ester, rapeseed oil propyl esters, rapeseed oil butyl esters, tall oil fatty acids esters etc.); diesel, mineral oil, fatty acid amides (e.g. C1-C3 amines, alkylamines or alkanolamines with C6-C18 carboxylic acids), fatty acids, alkyl esters of fatty acids (e.g. C1-C4 monohydric alcohol esters of Cs to C22 fatty acids such as methyl oleate, ethyl oleate), modified vegetable oils, methanol, ethanol, propylene glycol, isopropanol, and 1 ,3-propanediol, glycerine, derivatives thereof or a combination thereof.

The agrochemical composition of the invention may further comprise a rheological modifier. Examples of rheological modifiers suitable for use in agrochemical compositions include but are not limited to: hydrophobic silica, hydrophilic silica, hydrophobic fumed silica (Aerosil R 972, Cabosil TS 610, Cabosil TS 720, HDK, Aerosil R 812), hydrophilic fumed silica (Cab-O-Sil M-5), silica gels, silicates, talc, kaolin, montmorillonite, attapulgite, pumice, sepiolite, bentonite, limestone, lime, chalk, clay, dolomite, diatomaceous earth, calcite, calcium sulfate, magnesium sulfate, magnesium sulfate, magnesium oxide, sand, ammonium sulfate, ammonium phosphate, ammonium nitrate, ureas, cereal meal, tree bark meal, wood meal, nutshell meal, and cellulose powders.

The agrochemical composition of the invention may further comprise one or more nonionic surfactant or dispersing agents (also known as emulsifiers) and/or at least one or more anionic surfactant or dispersing agents. Suitable non-ionic surfactants or dispersing agents include all substances of this type that can normally be used in agrochemical compositions. Non-ionic dispersing agents include but not limited to phosphate esters of tristyrylphenol ethoxylates (e.g., SOPROPHOR 3D33, SOPROPHOR BSU, ethoxylated triglycerides, ethoxylated aliphatic alcohols, polyalkylene oxide block copolymers of a simple primary alcohol (e.g. ethylene oxide-propylene oxide block copolymers of butanol) such as Atlas™ G-5000, Termul™ 5429 or Tergitol™XJ, XD or XH; polyisobutene succinic anhydride-polyethylene glycol such as Atlox™ 4914; polyoxyethylenepolyoxypropylene (EO/PO) block copolymers (e.g., PLURONIC F108, ATLOX 4912, ATLAS G-5000, SYNPERONIC PE Series copolymers) and ethylene oxidepropylene oxide based acrylic acid graft copolymers such as methyl methacrylate graft copolymers (e.g., ATLOX 4913).

Anionic dispersing agents include but not limited to alkylnaphthalene sulfonates and their formaldehyde condensates (e.g., MORWET D425), polyalkylaryl sulfonates (e.g., SUPRAGIL MNS90), polymerized fatty acids (e.g., ATLOX LP-1 (12-hydroxyoctadecanoic acid homopolymer, octadecanoate), ricinoleic acid homopolymer), lignin sulfonates (e.g., ammonium lignosulfonate or sodium lignosulfonate), polyphenol sulfonates and the salts of polyacrylic acids. A further preferred group of anionic surfactants or dispersants includes the following salts that are of low solubility in vegetable oil: salts of polystyrenesulphonic acids, salts of polyvinylsulphonic acids, salts of naphthalenesulphonic acid-formaldehyde condensation products, salts of condensation products of naphthalenesulphonic acid, phenolsulphonic acid and formaldehyde, and salts of lignosulphonic acid.

Other emulsifiers that may be added to the present composition include but not limited to polysaccharide ethers, polyglycosides, fatty acids, fatty alcohols, amine oxides, water- soluble cellulose derivatives, alkyl sulfonates, ethoxylated alkyl phenols, alkanaolamides, betaines, zwiterionics, carboxylated alcohols, carboxylic acids, ethoxylated alcohols, and derivatives thereof. In certain embodiments, a composition provided herein further comprises emulsifiers, such as lauryl alcohol (e.g., Laureth-7), fatty acid diethanolamine (e.g., cocamide DEA), ammonium methyl sulfate and fatty alcohol ethoxylate (e.g., Steposol DG, Steposol ME), Tomadyne 100 surfactant, linear alcohol (C12-15) ethoxylate, POE-7, POE-3, sodium branched dodecyl benzene sulfonate, or mixtures thereof.

The agrochemical composition of the invention may further comprise one or more spreading agents. Spreading agents include but not limited to: ethylene oxide/propylene oxide block copolymers, alcohol ethoxylates (such as Brij 010 and Brij 02), alkyl polysaccharides (such as Atplus 435 or AL2575), polyethoxylated alcohols/fatty alcohols (such as Synperonic A7, Etocas 35), alkyl phenyl ethoxylates (such as Agral 90), polyethoxylated nonyl phenyl ether carboxylic acid (such as Sandopan MA-18), tallow amine ethoxylates, oil based derivatives (either mineral or vegetable) (such as Atplus 411 F and Atplus 463), sorbitol, ethoxylated Sorbitan derivatives (such as one of the Tween series of surfactants such as Tween 20, or Ariatone TV), acetylenic diol derivatives (such as one of the Surfynol series), esters of alkoxylated diethylethanolamine (such as Atlox 4915), and polyethyleneglycol.

Other ingredients, such as adhesives, neutralizers, thickeners, binders, sequestrates, biocides, stabilizers, buffers preservatives, antioxidants or anti-freeze agents, may also be added to the agrochemical composition in order to increase the stability, density, and viscosity of the described composition. Further, the agrochemical composition herein may be used in conjunction with one or more other agrochemicals to control a wider variety of undesirable pests.

Cosmetic compositions

As the skilled person will be aware, the nanoparticle compositions comprising a cosmetic may be formulated into cosmetic compositions. Many of the pharmaceutically acceptable excipients described above are also appropriate for use in cosmetic compositions. In particular, the following non-limiting list of excipients may be used in the cosmetic compositions of the present invention: lubricating agents; wetting agents; emulsifying agents; viscosity increasing agents; granulating agents; disintegrating agents; binding agents; osmotic active agents; suspending agents; preserving agents; sweetening agents; flavouring agents; adsorption enhancers (e.g. surface penetrating agents, e.g. bile salts, lecithins, surfactants, fatty acids, chelators); browning agents; organic solvent; antioxidant; stabilizing agents; emollients; silicone; alpha-hydroxy acid; demulcent; anti-foaming agent; moisturizing agent; fragrance; ionic or non-ionic thickeners; surfactants; filler; ionic or non-ionic thickener; sequestrant; polymer; propellant; alkalinizing or acidifying agent; opacifier; colouring agents and fatty compounds and the like. Some of these components are described in more detail below.

The cosmetic compositions may be for topical use. Topical compositions include: gels; creams; ointments; sprays; lotions; salves; sticks; soaps; powders; films; aerosols; drops; foams; solutions; emulsions; suspensions; dispersions e.g. non-ionic vesicle dispersions; milks and any other conventional cosmetic forms in the art.

The cosmetic composition of the invention may further comprise stabilising agents, preservatives and anti-microbials. Examples of stabilising agents, preservatives and antimicrobials suitable for use in cosmetic compositions include but are not limited to: salts or nonelectrolytes; acetate; SDS; EDTA; citrate or acetate buffers; mannitol; glycine; polysorbate; benzyl alcohol; and urea.

The cosmetic composition of the invention may further comprise one or more polysaccharides. Examples of polysaccharides include but are not limited to: any one or more of anionic polysaccharides (e.g. alginic acid; pectin; xanthan gum; hyaluronic acid; chondroitin sulfate; gum arabic; gum karaya; gum tragacanth; carboxymethyl-chitin; cellulose gum; glycosaminoglycans); cationic polysaccharides (e.g. chitosan; acetylated chitosan; cationic guar gum; cationic hydroxyethylcellulose (HEC)); nonionic polysaccharides (e.g. starch; dextrins; guar gum; cellulose ethers such as hydroxyethylcellulose, methylcellulose and nitrocellulose); amphoteric polysaccharides (e.g. carboxymethylchitosan; N-hydroxy- dicarboxyethyl-chitosan; modified potato starch) and hydrophobic polysaccharides (e.g. cetyl hydroxyethylcellulose; and polyquaternium-24).

The cosmetic composition of the invention may further comprise a skin-conditioning agent. Examples of skin-conditioning agents include but are not limited to: humectants, exfoliants, emollients or mixtures thereof. Humectants includes polyhydric alcohols such as glycerine, propylene glycol, dipropylene glycol, polypropylene glycol, polyethylene glycol, sorbitol, hydroxypropyl sorbitol, hexylene glycol, 1 ,3-butylene glycol, 1 ,2,6-hexanetriol, ethoxylated glycerin, propoxylated glycerine or mixtures thereof.

The cosmetic composition of the invention may further comprise antioxidants. Examples of antioxidants that may be combined with the composition of the invention include but are not limited to amino acids; vitamins; minerals; carotenoids; peptides; thiols; sulfoximine compounds; chelators; unsaturated fatty acids; phenolic compounds; plant extracts; stilbenes; uric acid; mannose; chlorogenic acid; imidazoles (e.g. urocanic acid); furfurylidenesorbitol; ubiquinone; ubiquinol; plastoquinone; phytosterols and derivatives thereof (e.g. salts; esters; ethers; sugars; nucleotides; nucleosides; peptides and/or lipid derivatives); some of which are described above.

The cosmetic composition of the invention may further comprise extracts. Extracts that may be incorporated in the cosmetic composition include, but are not limited to plant extracts, which may comprise phenolic compounds such as, for example: flavonoids (e.g., glycosyl rutin; ferulic acid; caffeic acid); furfurylidene glucitol; butylated hydroxytoluene; butylated hydroxyanisole; nordihydroguaiaretic resin acid; nordi-hydroguaiaretic acid; trihydroxybutyrophenone and derivatives thereof.

Aarochemical uses

In yet another aspect the present invention provides the use of a nanoparticle composition comprising an agrochemical ingredient, as defined herein, as a controlled release agrochemical composition. The nanoparticles of the present invention therefore particularly useful because they can deliver a steady amount of the agrochemical over an extended period of time. This results in improved outcomes, whether it is the treatment of a fungal disease, or the delivery of a fertiliser. As described herein, the nanoparticle compositions comprise biocompatible glycolate and/or lactate moieties that can be metabolised. The nanoparticle can deliver the agrochemical to the plant where it can cause the intended effect, for example treating a fungal disease. The nanoparticle then degrades into harmless degradants. As a result of this, the nanoparticles comprising an agrochemical ingredient are suitable for use, for example, on plants that will be consumed by humans or animals.

As a person skilled in the art would appreciate, the nanoparticle compositions comprising an agrochemical ingredient of the present invention are particularly useful whether the agrochemical ingredient is encapsulated, adsorbed, or both encapsulated and adsorbed by the nanoparticle composition. Any of these options result in nanoparticle compositions comprising an agrochemical ingredient of the present invention with particularly useful extended release properties.

The spherical shape of the nanoparticle compositions of the present invention contributes towards many of their advantageous properties. Spherical nanoparticles have many different applications due to their high surface area to volume ratio. The spherical shape of the nanoparticles of the present invention is a significant advantage because in embodiments where the nanoparticle compositions comprise an agrochemical ingredient, the spherical shape means that a greater proportion of the agrochemical ingredient is encapsulated by the nanoparticles. Therefore, the nanoparticle compositions provided by the present invention have high encapsulation efficiencies. A high encapsulation efficiency is beneficial when the active agent is an agrochemical ingredient because this results in a stronger effect with reduced side effects. In addition, a high encapsulation efficiency results in the extended release profile of the nanoparticle compositions comprising an agrochemical of the present invention that is particularly important for agrochemicals since it is desirable for there to be as long a period between applications to crops as possible. In some embodiments, the encapsulation efficiency of a nanoparticle composition comprising an agrochemical ingredient is at least 20%, at least 30%, at least 40%, preferably at least 50%, more preferably at least 60%, most preferably at least 70%.

The spherical shape of the nanoparticles of the present invention is also advantageous because this results in homogenous intramolecular interactions, for example hydrogen bonding and Van der Waals’ forces, between an agrochemical ingredient that is encapsulated by or adsorbed onto the surface of the nanoparticle compositions, and the nanoparticle compositions themselves.

In preferred embodiments the nanoparticle composition comprises nanospheres. Following the methods of the present invention that are described herein, nanospheres are formed spontaneously. The spontaneous formation of nanospheres is particularly important when the nanoparticle compositions of the present invention comprise an agrochemical ingredient, because the spontaneous formation of nanospheres results in a high encapsulation efficiency - the nanospheres spontaneously encapsulate the agrochemical ingredient in the methods of the present invention. These reliable methods to produce nanospheres and nanospheres comprising an agrochemical ingredient are a significant advantage of the present invention.

A number of applications are possible with the nanoparticle compositions comprising an agrochemical ingredient, for example the composition could be used as: an algaecide; a fertiliser; a fungicide; a herbicide; an insecticide; a molluscicide; a nematicide; a plant growth regulator; a rodenticide; and a soil conditioner.

The nanoparticle compositions comprising an agrochemical ingredient of the invention may be active against a wide variety of chewing, boring and sucking insects, e.g. aphids, thrips, lepidopterous larvae, sawflies, leafminers, leafhoppers, cutworms, whiteflies, soil insects, termites and some species of biting insects, such as rice water weevil on colarado beetle etc. In addition, the nanoparticle compositions comprising an agrochemical ingredient of the invention may useful for the control of agricultural pests, or hygienic pests, for example pests that affect growing plants including: cotton; paddy; rice forage crops; sugarcane; cole crops; leafy vegetables; tobacco; tomatoes; potatoes; flowering ornamentals; vine crops and fruit trees.

The nanoparticle compositions comprising an agrochemical ingredient of the invention may be use in a method of controlling or preventing unwanted pests on plants or propagation material thereof, said method comprising applying an agrochemically effective amount of the composition according to the present invention to the pests or to their locus.

The nanoparticle compositions comprising an agrochemical ingredient of the invention may be delivered either alone or in combination with other active (e.g., fertilisers) or inactive substances and may be applied by, for example, spraying, injection (e.g. microinjection), through plants, pouring, dipping, in the form of concentrated liquids, gels, solutions, suspensions, sprays, powders, pellets, briquettes, bricks and the like, formulated to deliver an effective concentration of the nanoparticle compositions comprising an agrochemical ingredient of the invention. Amounts and locations for application of the compositions comprising an agrochemical ingredient of the invention described herein may be determined by a person skilled in the art, and are generally influenced by the habitat of the plant, the lifecycle stage at which the plant can be targeted by the composition, the site where the application is to be made, and the physical and functional characteristics of the composition comprising an agrochemical ingredient of the invention.

Cosmetic uses

In yet another aspect the present invention provides the non-therapeutic use of a nanoparticle composition comprising a cosmetic, as defined herein, as a controlled release cosmetic composition. The nanoparticles of the present invention therefore particularly useful because they can deliver a steady amount of the cosmetic over an extended period of time. This results in improved outcomes, for example whether it is the controlled release of a moisturiser or a deodorant.

As a person skilled in the art would appreciate, the nanoparticle compositions comprising a cosmetic of the present invention are particularly useful whether the cosmetic is encapsulated, adsorbed, or both encapsulated and adsorbed by the nanoparticle composition. Any of these options result in nanoparticle compositions comprising a cosmetic of the present invention with particularly useful extended release properties.

The spherical shape of the nanoparticle compositions of the present invention contributes towards many of their advantageous properties. Spherical nanoparticles have many different applications due to their high surface area to volume ratio. The spherical shape of the nanoparticles of the present invention is a significant advantage because in embodiments where the nanoparticle compositions comprise a cosmetic, the spherical shape means that a greater proportion of the cosmetic is encapsulated by the nanoparticles. Therefore, the nanoparticle compositions provided by the present invention have high encapsulation efficiencies. A high encapsulation efficiency is beneficial when the active agent is a cosmetic because this results in an extended release of the cosmetic. In some embodiments, the encapsulation efficiency of a nanoparticle composition comprising a cosmetic is at least 20%, at least 30%, at least 40%, preferably at least 50%, more preferably at least 60%, most preferably at least 70%.

The spherical shape of the nanoparticles of the present invention is also advantageous because this results in homogenous intramolecular interactions, for example hydrogen bonding and Van der Waals’ forces, between a cosmetic that is encapsulated by or adsorbed onto the surface of the nanoparticle compositions, and the nanoparticle compositions themselves.

In preferred embodiments the nanoparticle composition comprises nanospheres. Following the methods of the present invention that are described herein, nanospheres are formed spontaneously. The spontaneous formation of nanospheres is particularly important when the nanoparticle compositions of the present invention comprise a cosmetic, because the spontaneous formation of nanospheres results in a high encapsulation efficiency - the nanospheres spontaneously encapsulate the cosmetic in the methods of the present invention. These reliable methods to produce nanospheres and nanospheres comprising a cosmetic are a significant advantage of the present invention.

The nanoparticle composition comprising a cosmetic as described herein have a larger number of different applications, for example as: primer; foundation; fairness cream; concealer; anti-aging cream; moisturiser; setting powder; blemish balm cream; rouge; contour powder/cream; highlighter; sunscreen; eyeliner; mascara; eyeshadow; eyebrow powder; eyebrow gel; lipstick; lip liner; lip gloss; fragrance; deodorant; toothpaste; anti-perspirant; hair shampoo; hair colour; hair serum; hair spray; and hair loss products.

As described herein, the nanoparticle compositions comprise biocompatible glycolate and/or lactate moieties that can be metabolised. The nanoparticle can deliver the cosmetic where it can cause the intended effect, for example acting as a moisturiser. The nanoparticle then degrades into harmless degradants. As a result of this, the nanoparticles comprising a cosmetic are suitable for use, for example, in humans.

The non-therapeutic use of a nanoparticle composition comprising a cosmetic, as defined herein generally comprises administering to the skin of a subject a cosmetically effective amount of the composition as described herein. In other embodiments, the composition is administered to another region of the body, such as the hair, fingernails, or toenails.

Having been generally described herein, the follow non-limiting examples are provided to further illustrate this invention.

EXAMPLES

General information and instrumentation

Commercial reagents were used as supplied. All non-aqueous reactions were carried-out under nitrogen gas atmosphere with flame-dried glassware, using standard techniques. Anhydrous solvents were obtained by filtration through drying columns (CH₂CI₂ and THF) or used as supplied (EtOAc). Deionized water was obtained from a Sartorius Arium® water purification system and was filtered through 0.2 pm Acrodisc® syringe filters prior use. Deionized water used for nanoprecipitation polymerizations was deoxygenated by passing through nitrogen gas over 1 h. Nanoparticle suspensions were purified using Amicon® Ultra- 15 centrifugal filter units with a 30 kDa MWCO. Dexamethasone release was assayed in Amicon® Ultra 0.5 centrifugal filter devices with a 100 kDa MWCO. Flash column chromatography was performed using 230-400 mesh silica, with the indicated solvent system according to standard techniques. Analytical thin-layer chromatography (TLC) was performed on precoated, aluminum silica gel sheets. Visualization of the developed chromatogram was performed by UV absorbance (254 nm) and staining with basic potassium permanganate stain. Infrared spectra (v_max, FTIR ATR) were recorded in reciprocal centimeters (cm^-1) on an Agilent Cary 630 FTIR spectrometer. Nuclear magnetic resonance spectra were recorded on 400 MHz spectrometers. Chemical shifts for ¹H NMR spectra are recorded in parts per million from tetramethylsilane with the solvent resonance as the internal standard (CHCI₃: 5= 7.27 ppm, H₂O: 5=4.79 ppm, DMSO: 5= 2.50 ppm). Data is reported as follows: chemical shift (multiplicity [s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, multiplet and br = broad], coupling constant (in Hz) and integration). ¹³C NMR spectra were recorded with complete proton decoupling. Chemical shifts are reported in parts per million from tetramethylsilane with the solvent resonance as the internal standard (¹³CDCI₃: 6= 77.0 ppm). For clarity NMR spectra are displayed as follows: ¹H NMR spectra are displayed between 10 ppm and 0 ppm; ¹³C NMR spectra are displayed between 210 ppm and 0 ppm. Quantitation of dexamethasone was performed by measurement of absorbance on an Agilent Cary 60 UV- Vis spectrophotometer. Particle size as z-average mean diameter, PI and ^-potential were determined by DLS analysis of aqueous suspensions performed at 25°C using a Malvern Zetasizer Ultra instrument. For size analysis, samples were prepared by mixing 40-50 pL of nanoparticle dispersions with the appropriate dispersant (1 ml_). Measurements were performed using polystyrene cuvettes at 25 °C, measuring the scattered light at an angle of 173°. The samples were then transferred to a folded capillary cell for ^-potential determination, performing the measurements at 25 °C. Nanoparticles were imaged directly using a JEM- 21 OOPIus transmission electron microscope.

Commercial reagents

Commercial reagents used in the examples herein were purchased from the following suppliers:

2-hydroxyethyl methacrylate (HEMA) - Sigma-Aldrich /V-(3-Dimethylaminopropyl)-/V-ethylcarbodiimide hydrochloride (EDC HCI) - Sigma-Aldrich 4-Dimethylaminopyridine (DMAP) - Sigma-Aldrich

Tetrabutylammonium fluoride (TBAF) 1.0 M solution in THF - Sigma-Aldrich

Acetic acid (glacial) - Fluorochem

Methacryloyl chloride - Sigma-Aldrich

Triethylamine - Sigma-Aldrich

PEG diacrylate 700 (PEGDA700) - Fluorochem

2,2'-Azobis(2-methylpropionitrile) (AIBN) - Sigma-Aldrich

Dexamethasone - Sigma-Aldrich

PLGA-PEG-based nanoparticles were prepared from commercially available PLGA-PEG- COOH (LA:GA 50:50, MW 50kDa-5kDa) polymer - PolySciTech.

General procedures

General Procedure A: Synthesis of precisely sequenced O LG ADM As

OLGADMAs used to prepare the nanoparticles of the invention may be prepared by the route shown below (Scheme 1).

Scheme 1. General synthesis of precisely sequenced OLGADMAs from acids 1.

Synthesis of carboxylic acids 1 :

Carboxylic acids 1 as shown in Scheme 1 were synthesized according to the synthetic procedures shown below.

HO-G-COOBn:

DBU (0.17 ml_, 1 .1 mmol) was added dropwise to a mixture of glycolic acid (0.09 g, 1.2 mmol) and benzyl bromide (0.12 ml_, 1.0 mmol) in acetonitrile (1 mL) at 0 °C. The reaction mixture was warmed to 70 °C, left stirring for 5h and then poured into ice cold water (10 mL). The aqueous phase was extracted with ethyl acetate (3 x 10 mL) and the combined organic extracts washed with aq. HCI (1 M, 10 mL), ice cold water (2 x mL), dried over Na₂SO and concentrated in vacuo to afford the desired compound.

HO-L-COOBn:

DBU (3.30 mL, 22.0 mmol) was added dropwise to a mixture of L-lactic acid (>85% solution in water, 2.5 g, >24 mmol) and benzyl bromide (2.38 mL, 20.0 mmol) in acetonitrile (20 mL) at 0 °C. The reaction mixture was warmed to 70 °C, left stirring for 2 h 45 min and then poured into ice cold water (20 mL). The aqueous phase was extracted with ethyl acetate (2 x 20 mL) and the combined organic extracts washed with aq. HCI (10%, 20 mL), brine (20 mL), dried over Na₂SO and concentrated in vacuo. The crude mixture was purified by vacuum distillation (165 °C at 0.22 mmHg) to afford the desired compound.

TBDPSO-G-COOH:

TBDPS chloride (6.24 mL, 24.0 mmol) was added dropwise to a solution of methyl glycolate (1 .54 mL, 20.0 mmol) and imidazole (2.7 g, 40 mmol) in dichloromethane (80 mL) at 0°C. The reaction mixture was warmed to rt, left stirring for 2h and then quenched by addition of aq. HCI (1 M, 50 mL). The organic phase was washed with water (2 x 100 mL), dried over Na₂SO₄ and concentrated in vacuo. The resulting crude mixture was dissolved in THF (180 mL) and aq. NaOH (1 M, 80 mL, 80 mmol) was added to the solution at 0°C. The mixture was then warmed to rt and stirred for 4 h. Water (100 mL) was added upon reaction completion and the THF removed by concentration in vacuo. The aqueous phase was washed with diethyl ether (2 x 100 ml_), acidified with aq. HCI (1 M, 50 mL) until reaching pH 2 and extracted with ethyl acetate (3 x 50 mL). The organic phase was dried over Na₂SO₄ and concentrated in vacuo to afford the desired compound.

TBDPSO-L-COOH: TBDPS chloride (6.24 mL, 24.0 mmol) was added dropwise to a solution of methyl L-lactate (1.91 mL, 20.0 mmol) and imidazole (2.72 g, 40.0 mmol) in dichloromethane (80 mL) at 0 °C. The reaction mixture was warmed to rt, left stirring for 1 h and then quenched by addition of 10% aq. HCI (50 mL). The organic phase was washed with brine (2 x 50 mL), dried over Na₂SO₄ and concentrated in vacuo. The resulting crude mixture was dissolved in THF (100 mL), aq. NaOH (1 M, 80 mL, 80 mmol) was added and the mixture was stirred 32 h at rt. Upon completion, water (100 mL) was added and the THF removed by concentration in vacuo. The aqueous phase was washed with diethyl ether (2 x 100 mL), acidified with 10% aq. HCI (50 mL) to reach pH 2 and extracted with ethyl acetate (3 x 50 mL). The organic phase was dried over Na₂SO₄ and concentrated in vacuo to afford the desired compound. TBDPSO-(GL)₂-COOH:

TBDPSO-G₂L₂-COOH:

5 TBDPSO-(LG)₃-COOH:

Ester synthesis - a):

EDC HCI (1 .3 equiv) was added to a solution of acid (1 equiv), alcohol (1 .2 equiv) and DMAP (0.5 equiv) in dichloromethane. The mixture was left stirring overnight at rt and then concentrated in vacuo. Purification by flash chromatography (ethyl acetate/hexane) afforded the desired compounds.

Catalytic hydrogenation - b):

A mixture of benzyl ester and Pd/C (5 wt. %) in ethyl acetate was left stirring under hydrogen gas (atmospheric pressure) overnight. The system was then purged with nitrogen gas and the mixtures filtered through a short plug of celite, eluting with dichloromethane. The resulting solution was concentrated in vacuo to afford the desired acids.

Silyl ether cleavage - c):

TBAF (1 .5 equiv) was added to a cold solution of silyl ether and glacial acetic acid (3 equiv) in THF and left stirring at 0 °C. The reaction was monitored by TLC, warming to room temperature if necessary. Upon completion, the reaction mixture was mixed with brine, extracted three times with diethyl ether, dried over Na₂SO₄ and concentrated in vacuo. Purification by flash chromatography (ethyl acetate/hexane or diethyl ether/hexane) afforded the desired alcohols.

Synthesis of ethyl methacrylates 2:

Ethyl methacrylates 2 were prepared from the carboxylic acid 1 following the ester synthesis

- a) procedure described above, but with the alcohol substituted for HEMA (1 .3 equiv).

Synthesis of alcohols 3:

Alcohols 3 were prepared from the ethyl methacrylate 2 following the silyl ether cleavage - c) procedure described above.

Synthesis of OLGADMAs: Methacryloyl chloride (2 or 3 equiv) was added to a cold solution of alcohol 3 and triethylamine (4 equiv) in dichloromethane at 0 °C. The reaction was monitored by TLC, warming to room temperature if necessary. Upon completion, the reaction mixture was partitioned between brine and dichloromethane, extracted with dichloromethane, dried over Na₂SO₄ and concentrated in vacuo. Purification by flash chromatography (ethyl acetate/hexane) afforded the desired OLGADMAs.

General Procedure B: Synthesis of OLGADMA-based nanoparticles

OLGADMA-based nanoparticles were prepared by quick injection of a THF solution of OLGADMA and PEG diacrylate Mn700 (PEGDA700) (1 :1 weight ratio) and AIBN (20 wt. % of total reagents) into water at 70 °C, stirring at 1000 rpm, with the system open to air and under N₂ gas flow (Scheme 2). The reaction mixture was immediately purged with N₂ gas for 5 minutes and then left under N₂ gas atmosphere for a further 10 min. The reaction mixtures were then exposed to air and cooled in an ice bath for 2 minutes. The resulting suspensions were purified by ultrafiltration (MWCO 30 kDa), via two centrifugations at 3200 ref for 5 minutes, passing through water (12 ml_). NP suspensions were obtained by diluting the retentate (< 0.5 mL) to a final volume of 5 mL with deionized water, mixed manually to achieve re-suspension, and stored at 4 °C. Examples of typical reactions compositions are reported in the supplementary information section.

Safety note: There may be potential hazards deriving from a quick injection of substantial quantities of an organic solution of AIBN (H242) into water at 70 °C. Unwanted events were not observed in any of the reactions. The highest amount of AIBN used was 4 mg per reaction.

Scheme 2. Synthesis of OLGADMA-based nanoparticles

General Procedure C: Synthesis of OLGADMA-based nanoparticles incorporating a drug

OLGADMA-based nanoparticles incorporating a drug were prepared by following General Procedure B, with the modification that a THF solution of OLGADMA, PEG diacrylate Mn700 (PEGDA700) and the drug (1 :1 :0.75 weight ratio) and AIBN (20 wt. % of total reagents) was used instead of a THF solution of OLGADMA and PEGDA700 (1 :1 weight ratio) and AIBN (20 wt. % of total reagents). General Procedure D: Synthesis of PLGA-PEG-COOH-based nanoparticles

PLGA-PEG-COOH-based nanoparticles were prepared by quick injection of a THF solution of commercially available PLGA-PEG-COOH (LA:GA 50:50, 50kDa-5kDa) into water at 70 °C, stirring at 1000 rpm, with the system open to air and under N₂ gas flow. The reaction mixture was immediately purged with N₂ gas for 5 minutes and then left under N₂ gas atmosphere for a further 10 minutes. The mixtures were then exposed to air and cooled in an ice bath for 2 minutes. The crude mixtures were then purified and stored following the procedure given by General Procedure B.

General Procedure E: Synthesis of PLGA-PEG-COOH-based nanoparticles incorporating a drug

PLGA-PEG-COOH-based nanoparticles incorporating a drug were prepared following General Procedure D, with the modification that a THF solution of PLGA-PEG-COOH and drug (1 :0.375 weight ratio) was used instead of a THF solution of PLGA-PEG-COOH.

The nanoparticles (NPs) prepared in this work are designated with NP followed by the type of OLGADMA used for the synthesis or PLGA-PEG (e.g. NP4Aa denotes NPs prepared using OLGADMA 4Aa). Analogously, dexamethasone-loaded NPs prepared in this work are designated with DNP followed by the type of OLGADMA used for the preparation or PLGA- PEG (e.g. DNP4Aa denotes dexamethasone-loaded NPs prepared using OLGADMA 4Aa). Example 1 - Synthesis of precisely sequenced OLGADMAs

This example provides a method for preparing example oligomers of the present invention that may be used to prepare the nanoparticle compositions of the present invention and nanoparticle compositions comprising an active agent of the present invention. Precisely sequenced OLGADMAs were synthesised following General Procedure A. The compounds were prepared using non-racemic L-lactate derivatives. The ratio of lactate to glycolate units was maintained at 1 . OLGADMAs with alternating (A) and block (B) sequences comprising of tetramers (4), hexamers (6) and octamers (8) were prepared. Tetramers were prepared in both directions of the sequence relative to the end groups and are further designated with a or b. The precisely sequenced OLGADMAs are shown in Table 1 above.

OLGADMAs were obtained as water-insoluble oils at room temperature.

A number of compounds were synthesised during preparation of the precisely sequenced OLGADMAs. These compounds were characterised as shown below:

Appearance: colorless oil; Yield: 76%; R_f = 0.23 (50% Et₂O/hexane); IR (film)/cnr¹ 3451 (br. OH), 1736 (C=O), 1498, 1453, 1192, 1084, 991 , 738, 697; The observed spectroscopic data (¹H NMR and ¹³C NMR) for this compound was consistent with that previously reported.¹

Appearance: colorless oil; Yield: 41%; R_f = 0.69 (50% ethyl acetate/hexane); IR (film)/cnr¹ 3462 (br. OH), 2982, 1737 (C=O), 1498, 1453, 1375, 1264, 1215, 1126, 1043, 954, 753, 701 ; The observed spectroscopic data (¹H NMR and ¹³C NMR) for this compound was consistent with that previously reported.¹

Appearance: colorless oil; Yield: 55%; IR (film)/cnT¹3071 , 2929, 2855, 1726 (s. C=O), 1587, 1472, 1427, 1390, 1364, 1244, 1136, 1110, 998, 939, 820, 738, 697. The observed spectroscopic data (¹H NMR and ¹³C NMR) was consistent with that previously reported.¹ o T8DPSO.. Ji . OH TBDPSO-L-COOH

Appearance: colorless oil; Yield: 59%; IR (film)/cnr¹ 3071 , 2933, 2892, 2859, 1722 (s. C=O), 1472, 1427, 1364, 1300, 1244, 1140, 1110, 1058, 969, 823, 786, 738, 701. The observed spectroscopic data (¹H NMR and ¹³C NMR) was consistent with that previously reported.¹

Appearance: colorless oil, Yield: 62%, Characterization: R_f= 0.18 (5% EtOAc/hexane); IR (film)/cm-¹ 3041 , 2937, 2855, 1751 (C=O), 1453, 1267, 1192, 1133, 820, 700, 506; ¹H NMR (400 MHz, CDCI₃) 6 7.73 - 7.67 (m, 4H), 7.48 - 7.31 (m, 11 H), 5.24 - 5.14 (m, 3H), 4.37 (d, J = 16.8 Hz, 1 H), 4.31 (d, J = 16.7 Hz, 1 H), 1.46 (d, J = 7.1 Hz, 3H), 1.10 (s, 9H); ¹³C NMR (101 MHz, CDCI3) 6 170.6, 170.3, 135.6, 135.5, 135.2, 132.7, 129.9, 128.6, 128.4, 128.1 , 127.8, 68.7, 67.0, 62.0, 26.6, 19.2, 16.9.

Appearance: colorless oil, Yield: 74%, Characterization: R_f= 0.30 (5% EtOAc/hexane); IR (film)Zcm-¹ 3071 , 2933, 2858, 1759 (C=O), 1427, 1394, 1177, 1133, 969, 782, 741 , 700; ¹H NMR (400 MHz, CDCI3) 5 7.72 - 7.65 (m, 4H), 7.48 - 7.28 (m, 11 H), 5.18 (s, 2H), 4.62 (d, J = 15.9 Hz, 1 H), 4.47 (d, J = 15.9 Hz, 1 H), 4.39 (q, J = 6.8 Hz, 1 H), 1.41 (d, J = 6.8 Hz, 3H), 1.10 (s, 9H); ¹³C NMR (101 MHz, CDCI3) 5 173.1 , 167.3, 135.9, 135.7, 135.0, 133.4, 133.0, 129.8, 128.6, 128.5, 128.4, 127.6, 127.6, 68.7, 67.0, 60.6, 26.8, 21.2, 19.2; HRMS (TOF MS ES+) m/z calcd for C₂8H32O₅NaSi⁺ [M+Na]⁺: 499.1917; Found: 499.1909.

Appearance: colorless oil, Yield: 78%, Characterization: Ry= 0.15 (5% EtOAc/hexane); IR (film)Zcm'¹ 3071 , 2929, 2855, 1755 (C=O), 1472, 1427, 1267, 1133, 823, 738, 697; ¹H NMR (400 MHz, CDCI3) 6 7.73 - 7.67 (m, 4H), 7.48 - 7.32 (m, 11 H), 5.20 (s, 2H), 4.68 (s, 2H), 4.37 (s, 2H), 1.10 (s, 9H); ¹³C NMR (101 MHz, CDCI3) 6 170.6, 167.3, 135.5, 135.0, 134.8, 132.6, 129.9, 128.6, 128.5, 128.4, 127.8, 67.1 , 61.9, 60.7, 26.6, 19.2; HRMS (TOF MS ES+) m/z calcd for C₂7H3o0₅NaSi⁺ [M+Na]⁺: 485.1760; Found: 485.1742.

Appearance: colorless oil, Yield: 57%, Characterization: Ry= 0.20 (5% EtOAc/hexane); IR (film)/cm-¹3071 , 2933, 2858, 1751 (C=O), 1587, 1453, 1427, 1267, 1185, 1129, 972, 823, 738, 700; ¹H NMR (400 MHz, CDCI₃) 6 7.73 - 7.64 (m, 4H), 7.50 - 7.27 (m, 11 H), 5.17 (d, J = 12.3 Hz, 1 H), 5.11 (d, J = 12.3 Hz, 1 H) 4.99 (q, J = 7.1 Hz, 1 H), 4.33 (q, J = 6.7 Hz, 1 H), 1.38 (d, J = 6.7 Hz, 3H), 1.34 (d, J = 7.1 Hz, 3H), 1.10 (s, 9H); ¹³C NMR (101 MHz, CDCI3) 6 173.1 , 170.3, 135.9, 135.7, 135.2, 133.4, 133.1 , 129.8, 128.6, 128.4, 128.2, 127.6, 127.5, 68.5, 67.0, 26.8, 21.1 , 19.2, 16.7; HRMS (TOF MS ES+) m/z calcd for C₂9H340₅SiNa⁺ [M+Na]⁺: 513.2073; Found: 513.2070.

Appearance: colorless oil, Yield: 20%, Characterization: Ry= 0.40 (30% EtOAc/hexane); IR (film)/cm-¹3071 , 2929, 2855, 1755 (C=O), 1587, 1423, 1394, 1267, 1170, 1133, 1073, 823; ¹H NMR (400 MHz, CDCI₃) 6 7.73 - 7.66 (m, 4H), 7.49 - 7.32 (m, 11 H), 5.21 (s, 2H), 4.75 (s, 2H), 4.73 (s, 2H), 4.37 (s, 2H), 1.10 (s, 9H); ¹³C NMR (101 MHz, CDCI3) 6 170.5, 166.9, 135.5, 134.9, 132.6, 129.9, 128.7, 128.6, 128.4, 127.8, 67.3, 61.8, 61.1 , 60.3, 26.6, 19.2; HRMS (TOF MS ES+) m/z calcd for C₂9H₃₂O₇NaSi⁺ [M+Na]⁺: 543.1815; Found: 543.1811.

Appearance: colorless oil, Yield: 91%, Characterization: Ry= 0.23 (10% EtOAc/hexane); IR (film)Zcm-¹ 3068, 2930, 2856, 1750 (C=O), 1588, 1452, 1184, 1127, 1091 , 971 , 738, 698; ¹H NMR (400 MHz, CDCI3) 6 7.73 - 7.64 (m, 4H), 7.53 - 7.28 (m, 11 H), 5.22 - 5.10 (m, 3H), 4.95 (q, J = 7.1 Hz, 1 H), 4.33 (q, J = 6.7 Hz, 1 H), 1.51 (d, J = 7.1 Hz, 3H), 1.42 (d, J = 6.7 Hz, 3H), 1.34 (d, = 7.1 Hz, 3H), 1.10 (s, 9H); ¹³C NMR (101 MHz, CDCI3) 6 173.1 , 170.1 , 169.9, 136.0, 135.7, 135.1 , 133.4, 133.1 , 129.8, 128.6, 128.5, 128.2, 127.6, 127.6, 69.1 , 68.5, 68.2, 67.1 , 26.8, 21.1, 19.2, 16.8, 16.5; HRMS (TOF MS ES+) m/z calcd for C₃2H38O₇NaSi⁺ [M+Na]⁺: 585.2285; Found: 585.2293.

Appearance: colorless oil, Yield: 84%, Characterization: Ry= 0.26 (20% EtOAc/hexane); IR (film)/cm-¹3041, 2987, 2855, 1751 (C=O), 1453, 1267, 1177, 1088, 820, 700; ¹H NMR (400 MHz, CDCI3) 67.73 -7.67 (m, 4H), 7.48-7.31 (m, 11H), 5.26-5.14 (m, 4H), 4.87 (d, J = 16.0 Hz, 1H), 4.63 (d, J= 16.0 Hz, 1H), 4.38 (d, J = 16.8 Hz, 1H), 4.31 (d, J= 16.8 Hz, 1H), 1.53 (d, J = 7.1 Hz, 3H), 1.53 (d, J = 7.1 Hz, 3H), 1.09 (s, 9H); ¹³C NMR (101 MHz, CDCI3) 6

170.6, 169.8, 166.6, 135.6, 135.5, 135.1, 132.7, 129.9, 128.6, 128.5, 128.2, 127.8, 69.5, 68.4, 67.2, 61.9, 60.7, 26.6, 19.2, 16.8, 16.8.

Appearance: colorless oil, Yield: 89%, Characterization: Ry= 0.24 (15% EtOAc/hexane); IR (film)Zcnr¹3069,2933,2857, 1753 (C=O), 1451, 1424, 1277, 1174, 1128, 1101 , 969, 740, 701 , 611 , 507; ¹H NMR (400 MHz, CDCI3) 67.71 - 7.65 (m, 4H), 7.49 - 7.31 (m, 11 H), 5.24 (q, J = 7.1 Hz, 1H), 5.19 (s, 2H), 4.80 (d, J= 15.9 Hz, 1H), 4.68 (d, J= 16.0 Hz, 1H), 4.62 (d, J = 15.9 Hz, 1H), 4.45 (d, J= 16.0 Hz, 1H), 4.38 (q, J= 6.8 Hz, 1H), 1.53 (d, J= 7.1 Hz, 3H), 1.43 (d, J = 6.8 Hz, 3H), 1.10 (s, 9H); ¹³C NMR (101 MHz, CDCI3) 6173.0, 169.5, 166.9, 166.8, 135.9, 135.7, 134.8, 133.4, 132.9, 129.8, 128.7, 128.5, 127.7, 127.6, 69.0, 68.6, 67.3, 61.1, 60.1, 26.8, 21.3, 19.2, 16.7; HRMS (TOF MS ES+) m/z calcd for C₃₃H38O₉NaSi⁺ [M+Na]⁺: 629.2183; Found: 629.2181.

Appearance: colorless oil, Yield: 97%, Characterization: Ry= 0.26 (20% EtOAc/hexane); IR (film)Zcm-¹3069, 2931, 2857, 1752 (C=O), 1451, 1173, 970; ¹H NMR (400 MHz, CDCI3) 67.74 -7.67 (m, 4H), 7.47-7.33 (m, 11H), 5.25-5.13 (m, 4H), 4.77 (d, J= 16.1 Hz, 1H), 4.66 (d, J= 16.1 Hz, 1H), 4.37 (d, J= 16.8 Hz, 1H), 4.37 (d, J= 16.8, 1H), 1.54 (d, J= 7.1 Hz, 3H), 1.52 (d,J= 7.1 Hz, 3H), 1.10 (s, 9H); ¹³CNMR(101 MHz, CDCI3) 6170.5, 169.9, 169.5, 166.9, 135.5, 135.0, 132.6, 132.6, 129.9, 128.6, 128.5, 128.2, 127.8, 69.3, 69.1, 67.2, 61.8, 60.4,

26.6, 19.2, 16.7, 16.6; HRMS (TOF MS ES+) m/z calcd for C33H₄₂NO₉Si⁺ [M+NH₄]⁺: 624.2629; Found: 624.2637.

Appearance: colorless oil, Yield: 86%, Characterization: Ry = 0.25 (30% Et₂O/hexane); IR (film)/cm-¹3070, 2931, 2857, 1750 (C=O), 1451, 1170, 971, 702; ¹H NMR (400 MHz, CDCI3) 67.72-7.66 (m, 4H), 7.50 - 7.32 (m, 11H), 5.20 (s, 2H), 5.01 (q, J=7.1 Hz, 1H), 4.85 (d, J = 16.1 Hz, 1H), 4.79-4.63 (m, 3H), 4.35 (q, J= 6.7 Hz, 1H), 1.45 - 1.39 (m, 6H), 1.10 (s, 9H); ¹³C NMR (101 MHz, CDCI3) 6173.1, 169.8, 166.8, 166.6, 136.0, 135.7, 134.8, 133.4, 133.0, 129.8, 128.7, 128.6, 128.4, 127.6, 127.6, 68.5, 68.3, 67.3, 61.1, 60.5, 26.8, 21.1, 19.2, 16.6; HRMS (TOF MS ES+) m/z calcd for C₃₃H₃₈O₉NaSi⁺ [M+Na]⁺: 629.2183; Found: 629.2194.

Appearance: colorless oil, Yield: 81%, Characterization: Ry= 0.25 (30% EtOAc/hexane); IR (film)/cm-¹3069, 2932, 2857, 1759 (C=O), 1588, 1424, 1394, 1270, 1165, 1136, 822, 703; ¹H NMR (400 MHz, CDCI3) 67.72 - 7.67 (m, 4H), 7.48 - 7.35 (m, 11 H), 5.21 (s, 2H), 4.81 (s, 2H), 4.75 (s, 2H), 4.74 (s, 2H), 4.37 (s, 2H), 1.10 (s, 9H); ¹³C NMR (101 MHz, CDCI3) 6170.5,

166.8, 166.8, 166.5, 135.5, 134.8, 132.6, 129.9, 128.6, 128.6, 128.4, 127.8, 67.3, 61.8, 61.2, 60.7, 60.2, 26.6, 19.2; HRMS (TOF MS ES+) m/z calcd forC₃iH₃40₉NaSi⁺[M+Na]⁺: 601.1870; Found: 601.1862.

Appearance: colorless oil, Yield: 63%, Characterization: Ry= 0.32 (15% EtOAc/hexane); IR (film)/cm-¹3069, 290, 2931, 2856, 1751 (C=O), 1452, 1184, 1128, 1093, 702; ¹H NMR (400 MHz, CDCI₃) 67.74 - 7.65 (m, 4H), 7.46 - 7.31 (m, 11 H), 5.23 - 5.10 (m, 4H), 4.95 (q, J = 7.1 Hz, 1H), 4.33 (q, J = 6.7 Hz, 1H), 1.52 (d, J= 7.1 Hz, 3H), 1.51 (d, J= 7.1 Hz, 3H), 1.42 (d, J = 6.7 Hz, 3H), 1.40 (d, J = 7.1 Hz, 3H), 1.10 (s, 9H); ¹³C NMR (101 MHz, CDCI₃) 6173.1,

169.9, 169.7, 135.9, 135.7, 135.1, 133.4, 133.0, 129.8, 128.6, 128.5, 128.2, 127.6, 127.6, 69.2, 68.8, 68.5, 68.2, 67.2, 26.8, 21.1, 19.2, 16.7, 16.6; HRMS (TOF MS ES+) m/z calcd for C₃₅H₄2O₉NaSi⁺ [M+Na]⁺: 657.2496; Found: 657.2501.

Appearance: colorless oil, Yield: 68%, Characterization: Ry= 0.49 (30% EtOAc/hexane); IR (film)/cm-¹3069,2931,2857, 1758 (C=O), 1588, 1452, 1424, 1389, 1175, 1131, 1101,703; ¹H NMR (400 MHz, CDCI₃) 67.71 -7.64 (m, 4H), 7.49-7.31 (m, 11H), 5.29 - 5.17 (m, 4H), 4.86 (d, J= 16.1 Hz, 1H), 4.82 (d, J= 15.9 Hz, 1H), 4.68 (d, J= 16.0 Hz, 1H), 4.66-4.60 (m, 2H), 4.45 (d, J= 16.0 Hz, 1H), 4.38 (q, J = 6.7 Hz, 1H), 1.56 (d, J = 7.1 Hz, 3H), 1.56 (d, J= 7.1

Hz, 3H), 1.43 (d, J= 6.7 Hz, 3H), 1.10 (s, 9H); ¹³C NMR (101 MHz, CDCI₃) 6173.0, 169.5, 169.4, 166.9, 166.8, 166.4, 135.9, 135.7, 134.8, 133.4, 132.9, 129.8, 128.6, 128.5, 127.6, 127.6, 69.3, 69.2, 68.9, 68.6, 67.3, 61.1 , 60.8, 60.2, 26.8, 21.2, 19.2, 16.7, 16.7; HRMS (TOF MS ES+) m/z calcd for C₃8H₄40i₃NaSi⁺ [M+Na]⁺: 759.2449; Found: 759.2456.

Appearance: colorless oil, Yield: 70%, Characterization: R₇= 0.42 (30% EtOAc/hexane); IR (film)Zcm'¹3069, 2934, 2857, 1754 (C=O), 1452, 1425, 1387, 1269, 1184, 1133, 1094, 703; ¹H NMR (400 MHz, CDCI₃) 6 7.72 - 7.67 (m, 4H), 7.48 - 7.31 (m, 11 H), 5.25 - 5.11 (m, 5H), 4.82 (d, J = 16.1 Hz, 1 H), 4.79 - 4.68 (m, 3H), 4.37 (s, 2H), 1.60 (d, J = 7.1 Hz, 3H), 1.54 (d, J = 7.1 Hz, 3H), 1.53 (d, J = 7.1 Hz, 3H), 1.09 (s, 9H); ¹³C NMR (101 MHz, CDCI₃) 6 170.5, 169.9,

169.5, 169.4, 166.8, 166.5, 135.6, 132.6, 129.9, 128.6, 128.5, 128.2, 127.8, 69.3, 69.1 , 67.2,

61.8, 60.8, 60.3, 26.6, 19.2, 16.7, 16.7, 16.6.

Appearance: colorless oil, Yield: 81%, Characterization: R₇= 0.57 (35% EtOAc/hexane); IR (film)Zcm-¹ 3070, 2927, 2856, 1753 (C=O), 1588, 1451 , 1423, 1387, 1275, 1171 , 1128, 1091 , 740, 701 ; ¹H NMR (400 MHz, CDCI₃) 6 7.72 - 7.64 (m, 4H), 7.48 - 7.32 (m, 11 H), 5.31 - 5.18 (m, 5H), 4.92 - 4.79 (m, 3H), 4.73 - 4.60 (m, 4H), 4.46 (d, J = 16.0 Hz, 1H), 4.38 (q, J = 6.7 Hz, 1 H), 1.59 (d, J = 7.1 Hz, 3H), 1.57 (d, J = 7.1 Hz, 3H), 1.56 (d, J = 7.1 Hz, 3H), 1.43 (d, J = 6.7 Hz, 3H), 1.10 (s, 9H); ¹³C NMR (101 MHz, CDCI₃) 6 173.0, 169.5, 169.4, 169.4, 166.9,

166.8, 166.5, 166.4, 135.9, 135.7, 134.8, 133.4, 132.9, 129.8, 128.6, 128.5, 127.6, 127.6, 69.2, 69.1 , 68.9, 68.6, 67.3, 61.1 , 60.8, 60.7, 60.2, 26.8, 21.3, 19.2, 16.7; HRMS (TOF MS ES+) m/z calcd for C₄₃H₅oOi₇NaSi⁺ [M+Na]⁺: 889.2715; Found: 889.2730.

Appearance: colorless oil, Yield: 45 %, Characterization: R? = 0.43 (35% EtOAc/hexane); IR (film)Zcm-¹ 3069. 2938, 2857, 1752 (C=O), 1451 , 1424, 1391 , 1158, 1128, 1089, 740, 703; ¹H NMR (400 MHz, CDCI₃) 6 7.72 - 7.65 (m, 4H), 7.47 - 7.33 (m, 11 H), 5.26 - 5.19 (m, 3H), 5.15 (q, J = 7.1 Hz, 1 H), 4.95 (q, J= 7.1 Hz, 1 H), 4.92 - 4.64 (m, 8H), 4.33 (q, J = 6.7 Hz, 1 H), 1.59 (d, J = 8.2 Hz, 3H), 1.57 (d, J = 8.1 Hz, 3H), 1.42 (d, J = 6.8 Hz, 3H), 1.40 (d, J = 7.1 Hz, 3H), 1.10 (s, 9H); ¹³C NMR (101 MHz, CDCI₃) 6 173.1 , 170.0, 169.7, 169.5, 166.8, 166.4,

166.4, 166.3, 135.9, 135.7, 134.8, 133.4, 133.0, 129.8, 128.7, 128.4, 127.6, 127.6, 68.9, 68.8,

68.4, 68.2, 67.4, 61.2, 60.8, 60.7, 60.6, 26.8, 21.1 , 19.2, 16.7, 16.6, 16.6; HRMS (TOF MS

ES+) m/z calcd for C₄3H₅oOi₇NaSi⁺ [M+Na]⁺: 889.2715; Found: 889.2733.

Appearance: colorless oil, Yield: 93%, Characterization: Ry = 0.17 (60% Et₂O/hexane); IR (film)/cm-¹ 3473 (br, OH), 2944, 1744 (C=O), 1453, 1267, 1192, 1095, 745; ¹H NMR (400 MHz, CDCI3) 5 7.43 - 7.32 (m, 5H), 5.26 (q, J = 7.1 Hz, 1 H), 5.23 - 5.16 (m, 2H), 4.30 (d, J = 17.4 Hz, 1 H), 4.24 (d, J = 17.4 Hz, 1 H), 2.32 (br, 1 H), 1.55 (d, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCI3) 5 172.7, 170.0, 135.0, 128.6, 128.5, 128.1 , 69.4, 67.2, 60.5, 16.8.

Appearance: colorless oil, Yield: 93%, Characterization: Ry= 0.16 (30% EtOAc/hexane); IR (film)Zcm'¹ 3488 (br, OH), 3034, 2985, 2944, 1744 (C=O), 1453, 1278, 1181 , 1125, 752, 700; ¹H NMR (400 MHz, CDCI3) 5 7.44 - 7.31 (m, 5H), 5.21 (s, 2H), 4.80 (d, J = 15.9 Hz, 1 H), 4.71 (d, J = 15.9 Hz, 1 H), 4.42 (q, J = 6.9 Hz, 1 H), 2.16 (br, 1 H), 1.48 (d, J = 7.0 Hz, 3H); ¹³C NMR (101 MHz, CDCI3) 5 175.1 , 167.1 , 134.8, 128.7, 128.5, 67.3, 66.7, 61.2, 20.3.

Appearance: colorless oil, Yield: 90%, Characterization: Ry= 0.20 (40% EtOAc/hexane); IR (film)/cm-¹ 3309 (br, OH), 2952, 1744 (C=O), 1580, 1431 , 1401 , 1200, 1092, 1039, 700; ¹H NMR (400 MHz, CDCI₃) 6 7.45 - 7.31 (m, 5H), 5.22 (s, 2H), 4.78 (s, 2H), 4.31 (s, 2H), 2.33 (br, 1 H); ¹³C NMR (101 MHz, CDCI3) 5 172.7, 167.1 , 134.8, 128.7, 128.4, 67.4, 61.1 , 60.4; HRMS (APCI) m/z calcd for CnHnOs’ [M-H]" 223.0612; Found: 223.0611 .

Appearance: colorless oil, Yield: 64%, Characterization: Ry= 0.12 (30% EtOAc/hexane); IR (film)Zcm-¹ 3490 (br, OH), 2987, 2939, 1737 (C=O), 1498, 1452, 1266, 1188, 1122, 1092, 1042, 743, 697; ¹H NMR (400 MHz, CDCI₃) 5 7.44 - 7.31 (m, 5H), 5.31 - 5.13 (m, 3H), 4.35 (q, J = 7.0 Hz, 1 H), 2.55 (br, 1 H), 1.55 (d, J = 7.1 Hz, 3H), 1.45 (d, J = 6.9 Hz, 3H); ¹³C NMR (101 MHz, CDCI3) 5 175.1 , 170.0, 135.0, 128.6, 128.5, 128.2, 69.4, 67.2, 66.7, 20.4, 16.8; HRMS

(TOF MS ES+) m/z calcd for Ci3Hi₆O₅Na⁺ [M+Na]⁺: 275.0895; Found: 275.0900.

Appearance: colorless oil, Yield: 88%, Characterization: Ry= 0.20 (30% EtOAc/hexane); IR (film)Zcm-¹ 3490 (br, OH), 2917, 2849, 1737 (C=O), 1495, 1462, 1239, 1091 , 740; ¹H NMR (400 MHz, CDCI₃) 6 7.43 - 7.31 (m, 5H), 5.25 - 5.12 (m, 4H), 4.36 (q, J = 6.9 Hz, 1 H), 2.65 (s, 1 H), 1.55 (d, J = 7.1 Hz, 3H), 1.55 (d, J = 7.1 Hz, 3H), 1.50 (d, J = 6.9 Hz, 3H); ¹³C NMR (101 MHz, CDCI3) 6 175.1 , 169.9, 169.6, 128.6, 128.5, 128.3, 69.3, 69.1 , 67.2, 66.7, 20.5, 16.8, 16.7; HRMS (TOF MS ES+) m/z calcd for CI₆H₂IO₇ ⁺ [M+H]⁺: 325.1287; Found: 325.1286.

Appearance: colorless oil, Yield: 89%, Characterization: Ry= 0.25 (30% EtOAc/hexane); IR (film)/cm-¹ 3514 (br, OH), 2926. 2851 , 1751 (C=O), 1587, 1349, 1278. 1177, 1133, 1099, 752, 700; ¹H NMR (400 MHz, CDCI3) 6 7.43 - 7.32 (m, 5H), 5.28 (q, J = 7.1 Hz, 1 H), 5.20 (s, 2H), 4.87 (d, J = 16.0 Hz, 1 H), 4.82 (d, J = 15.9 Hz, 1 H), 4.72 (d, J = 16.1 Hz, 1 H), 4.64 (d, J = 15.9 Hz, 1 H), 4.42 (q, J = 6.9 Hz, 1 H), 2.35 (br, 1 H), 1.58 (d, J = 7.1 Hz, 3H), 1.50 (d, J = 6.9 Hz, 3H); ¹³C NMR (101 MHz, CDCI3) 5 174.9, 169.4, 166.9, 166.6, 134.8, 128.7, 128.5, 69.2, 67.3, 66.7, 61.1 , 60.8, 20.3, 16.7; HRMS (TOF MS ES+) m/z calcd for Ci7H₂o0₉Na⁺ [M+Na]⁺: 391.1005; Found: 391.1006.

Appearance: colorless oil, Yield: 60%, Characterization: Ry= 0.28 (55% EtOAc/hexane); IR (film)/cm-¹ 3500 (br, OH), 2953, 1743 (C=O), 1422, 1394, 1273, 1154, 1095, 1074, 737, 697; ¹H NMR (400 MHz, CDCI3) 5 7.43 - 7.32 (m, 5H), 5.21 (s, 2H), 4.86 (s, 2H), 4.84 (s, 2H), 4.75 (s, 2H), 4.32 (s, 2H), 2.18 (br, 1 H); ¹³C NMR (101 MHz, CDCI₃) 5 172.6, 166.8, 166.6, 166.5, 134.8, 128.7, 128.4, 67.4, 61.2, 60.8, 60.7, 60.4; HRMS (TOF MS ES+) m/z calcd for Ci₅Hi6O₉Na⁺ [M+Na]⁺: 363.0692; Found: 363.0701.

Appearance: colorless oil, Yield: 100%, Characterization: IR (film)/cnr¹ broad OH vibration, 3049, 2937, 2862, 1745 (C=O), 1729 (C=O), 1431 , 1192, 1140, 820, 700; ¹H NMR (400 MHz, CDCI3) 5 7.73 - 7.67 (m, 4H), 7.46 - 7.37 (m, 6H), 5.15 (q, J = 7.1 Hz, 1 H), 4.38 (d, J = 16.9 Hz, 1 H), 4.33 (d, J = 16.9 Hz, 1 H), 1.51 (d, J = 7.1 Hz, 3H), 1.10 (s, 9H); ¹³C NMR (101 MHz, CDCI3) 5 176.1 , 170.6, 135.6, 135.5, 132.6, 132.6, 129.9, 127.8, 68.2, 61.9, 26.6, 19.2, 16.7; HRMS (APCI) m/z calcd for C₂iH₂₅O₅Si- [M-H]" 385.1477; Found: 385.1465.

Appearance: colorless oil, Yield: 95%, Characterization: IR (film)/cnr¹ broad OH vibration visible, 3069, 2932, 2857, 1728 (C=O), 1588, 1424, 1132, 1105, 820, 738, 698, 609, 504, 483; ¹H NMR (400 MHz, CDCI3) 5 7.73 - 7.64 (m, 4H), 7.49 - 7.34 (m, 6H), 4.60 (d, J = 16.4 Hz, 1H), 4.50 (d, J = 16.4 Hz, 1 H), 4.40 (q, J = 6.8 Hz, 1 H), 1.43 (d, J = 6.8 Hz, 3H), 1.10 (s, 9H); ¹³C NMR (101 MHz, CDCI3) 5 173.0, 172.4, 135.9, 135.7, 133.4, 132.9, 129.8, 127.7, 127.6, 68.6, 60.0, 26.8, 21.2, 19.2; HRMS (TOF MS ES+) m/z calcd for C₂iH₂₆O₅NaSi⁺ [M+Na]⁺: 409.1447; Found: 409.1461.

Appearance: colorless oil, Yield: 100%, Characterization: IR (film)/cnr¹ broad OH vibration visible, 3071 , 2929, 2855, 1763 (C=O), 1729 (C=O), 1580, 1431 , 1259, 1200, 1110, 931 , 805, 700; ¹H NMR (400 MHz, CDCI₃) 5 7.75 - 7.66 (m, 4H), 7.47 - 7.37 (m, 6H), 4.69 (s, 2H), 4.38 (s, 2H), 1.10 (s, 9H); ¹³C NMR (101 MHz, CDCI3) 5 171.8, 170.6, 135.5, 134.8, 132.6, 130.0,

127.8, 61.8, 60.0, 26.6, 19.2; HRMS (TOF MS ES+) m/z calcd for C₂oH₂40₅NaSi⁺ [M+Na]⁺: 395.1291 ; Found: 395.1291.

Appearance: colorless oil, Yield: 100%, Characterization: IR (film)Zcnr¹ broad OH vibration observed, 3071 , 2933, 2858, 1763 (C=O), 1722 (C=O), 1587, 1461 , 1427, 1185, 1107, 972, 909, 820, 734, 700; ¹H NMR (400 MHz, CDCI₃) 5 7.72 - 7.66 (m, 4H), 7.47 - 7.34 (m, 6H), 4.95 (q, J = 7.1 Hz, 1 H), 4.34 (q, J = 6.7 Hz, 1 H), 1.42 (d, J = 6.7 Hz, 3H), 1.39 (d, J = 7.2 Hz, 3H), 1.10 (s, 9H); ¹³C NMR (101 MHz, CDCI3) 5 176.1 , 173.1 , 136.0, 135.7, 133.4, 133.0,

129.8, 127.6, 127.6, 68.5, 68.1 , 26.8, 21.1 , 19.2, 16.6; HRMS (TOF MS ES+) m/z calcd for C₂₂H₂₈O₅NaSi⁺ [M+Na]⁺: 423.1604; Found: 423.1598.

Appearance: colorless oil, Yield: 100%, Characterization: IR (film)/cnr¹ broad OH vibration observed, 3071 , 2933, 2858, 1763 (C=O), 1722 (C=O), 1587, 1461 , 1427, 1185, 1107, 972, 909, 820, 734, 700; ¹H NMR (400 MHz, CDCI3) 5 7.72 - 7.66 (m, 4H), 7.47 - 7.34 (m, 6H), 4.95 (q, J = 7.1 Hz, 1 H), 4.34 (q, J = 6.7 Hz, 1 H), 1.42 (d, J = 6.7 Hz, 3H), 1.39 (d, J = 7.2 Hz, 3H), 1.10 (s, 9H); ¹³C NMR (101 MHz, CDCI3) 5 176.1 , 173.1 , 136.0, 135.7, 133.4, 133.0,

Appearance: colorless oil, Yield: 98%, Characterization: IR (film)/cnr¹ broad OH vibration observed, 2926, 2849, 1721(C=O), 1423, 1102, 1082, 809; ¹H NMR (400 MHz, CDCI₃) 57.72 -7.66 (m, 4H), 7.49-7.35 (m, 6H), 4.75 (s, 2H), 4.74 (s, 2H), 4.38 (s, 2H), 1.10 (s, 9H); ¹³C NMR (101 MHz, CDCI3) 5171.0, 170.6, 166.8, 135.6, 132.6, 130.0, 127.8, 61.8, 60.4, 60.3,

26.6, 19.2; HRMS (TOF MS ES+) m/z calcd for C22H₂6O₇NaSi⁺ [M+Na]⁺: 453.1346; Found: 453.1351.

Appearance: yellowish oil, Yield: 99%, Characterization: IR (film)/cnr¹ broad OH vibration observed, 3069, 2932, 1744 (C=O), 1590, 1185, 1130, 740, 702 ; ¹H NMR (400 MHz, CDCI3) 57.76 - 7.66 (m, 4H), 7.47 - 7.37 (m, 6H), 5.25 - 5.13 (m, 2H), 4.88 (d, J = 16.1 Hz, 1 H), 4.64 (d, J= 16.1 Hz, 1H), 4.38 (d, J= 16.8, 1H), 4.32 (d, J= 16.9 Hz, 1H), 1.57 (d, J= 7.2 Hz, 3H), 1.53 (d,J= 7.1 Hz, 3H), 1.09 (s, 9H); ¹³CNMR(101 MHz, CDCI3) 6175.2, 170.7, 169.9, 166.6,

135.6, 135.5, 132.6, 129.9, 127.8, 68.9, 68.4, 61.9, 60.7, 26.6, 19.2, 16.8, 16.6; HRMS (APCI) m/z calcd for C26H₃iO₉Si- [M-H]" 515.1743, Found: 515.1730.

Appearance: colorless oil, Yield: 100%, Characterization: IR (film)Zcnr¹3069, 2991, 2932, 2857, 1755 (C=O), 1588, 1452, 1376, 1187, 1129, 095, 703; ¹H NMR (400 MHz, CDCI3) 5 7.73 - 7.65 (m, 4H), 7.49 - 7.34 (m, 6H), 5.16 (q, J = 7.1 Hz, 2H), 4.95 (q, J = 7.1 Hz, 1H), 4.34 (q, J=6.7Hz, 1H), 1.56 (d, J=7.1 Hz, 3H), 1.56 (d, J=7.1 Hz, 3H), 1.42 (d, J = 6.8Hz, 3H), 1.40 (d, J= 7.2 Hz, 3H), 1.10 (s, 9H); ¹³C NMR (101 MHz, CDCI3) 6174.9, 173.2, 170.0,

169.6, 135.9, 135.7, 133.4, 133.0, 129.8, 127.6, 127.6,68.8,68.7,68.5,68.3,26.8,21.1, 19.2,

16.6, 16.6; HRMS (TOF MS ES+) m/z calcd for C₂8H₃6O₉NaSi⁺ [M+Na]⁺: 567.2026; Found: 567.2033.

Appearance: yellowish oil, Yield: 97%, Characterization: IR (film)/cnr¹ broad OH vibration, 3071, 2929, 2858, 1763 (C=O), 1427, 1185, 1133, 1110, 704; ¹H NMR (400 MHz, CDCI3) 5 7.71 -7.63 (m, 4H), 7.50-7.34 (m, 6H), 5.24 (q, J= 7.1 Hz, 1H), 4.80 (d, J= 16.4 Hz, 1H), 4.73-4.61 (m, 2H), 4.46 (d, J= 16.0 Hz, 1H), 4.39 (q, J = 6.8 Hz, 1H), 1.56 (d, J= 7.1 Hz, 3H), 1.43 (d, J= 6.8 Hz, 3H), 1.10 (s, 9H); ¹³C NMR (101 MHz, CDCI3) 6173.1, 171.0, 169.4, 166.9, 135.9, 135.7, 133.4, 132.9, 129.8, 127.7, 127.6,69.0,68.6,60.5,60.3,26.8,21.3, 19.2, 16.7; HRMS (TOF MS ES+) m/z calcd for C₂₆H₃₂O₉NaSi [M+Na]⁺: 539.1713, Found: 539.1709.

Appearance: yellowish oil, Yield: 94%, Characterization: IR (film)/cnr¹ broad OH vibration observed, 3070, 2932, 2857, 1744 (C=O), 1589, 1426, 1186, 1131 , 1102, 821 , 741 , 703; ¹H NMR (400 MHz, CDCI3) 5 7.75 - 7.64 (m, 4H), 7.49 - 7.35 (m, 6H), 5.28 - 5.14 (m, 2H), 4.77 (d, J = 16.1 Hz, 1 H), 4.67 (d, J = 16.1 Hz, 1 H), 4.37 (d, J = 16.7 Hz, 1 H), 4.37 (d, J = 16.7 Hz, 1 H), 1.57 (d, J = 7.1 Hz, 6H), 1.09 (s, 9H); ¹³C NMR (101 MHz, CDCI3) 6 175.2, 170.6, 169.4, 166.9, 135.5, 132.6, 129.9, 127.8, 69.1 , 68.7, 61.8, 60.4, 26.6, 19.2, 16.6; HRMS (TOF MS ES+) m/z calcd for C26H₃6NO₉Si⁺ [M+NH₄]⁺: 534.2159, Found: 534.2155.

Appearance: yellowish oil, Yield: 100%, Characterization: IR (film)Zcnr¹ broad OH vibration, 3329, 2931 , 2855, 1760, 1587, 1425, 1176, 1131 , 108, 972, 704, 507; ¹H NMR (400 MHz, CDCI3) 6 7.74 - 7.62 (m, 4H), 7.49 - 7.32 (m, 6H), 5.01 (q, J = 7.1 Hz, 1 H), 4.84 (d, J = 16.2 Hz, 1 H), 4.80 - 4.63 (m, 3H), 4.35 (q, J = 6.7 Hz, 1 H), 1.44 - 1.40 (m, 6H), 1.10 (s, 9H); ¹³C NMR (101 MHz, CDCI3) 5 173.2, 171.4, 169.9, 166.6, 136.0, 135.7, 133.4, 133.0, 129.8, 127.6, 127.6, 68.5, 68.3, 60.5, 26.8, 21.1 , 19.2, 16.6; HRMS (APCI) m/z calcd for C₂₆H₃iO₉Si- [M-H]- : 515.1743, Found: 515.1732.

Appearance: yellowish oil, Yield: 90%, Characterization: IR (film)/cnr¹ broad OH vibration visible, 3069, 2930, 2855, 1750 (C=O), 1589, 1454, 1384, 1130, 702; ¹H NMR (400 MHz, CDCI₃) 5 7.71 - 7.65 (m, 4H), 7.49 - 7.33 (m, 6H), 5.31 - 5.20 (m, 2H), 4.87 (d, J = 16.1 Hz, 1H), 4.81 (d, J = 16.3 Hz, 1H), 4.72 - 4.61 (m, 3H), 4.46 (d, J = 16.0 Hz, 1 H), 4.39 (q, J = 6.7 Hz, 1 H), 1.59 (d, J = 7.1 Hz, 3H), 1.57 (d, J = 7.0 Hz, 3H), 1.43 (d, J = 6.8 Hz, 3H), 1.10 (s, 9H); ¹³C NMR (101 MHz, CDCI3) 5 173.1 , 171.5, 169.5, 169.3, 166.9, 166.5, 135.9, 135.7, 133.3, 132.9, 129.8, 127.7, 127.6, 69.2, 68.9, 68.6, 60.8, 60.6, 60.3, 26.8, 21.2, 19.2, 16.7, 16.7; HRMS (TOF MS ES+) m/z calcd for C₃iH₄2NOi₃Si⁺ [M+NH₄]⁺: 664.2425, Found: 664.2437.

Appearance: yellowish oil, Yield: 100%, Characterization: IR (film)/cnr¹ broad OH vibration observable, 3070, 2928, 2856, 1747 (C=O), 1589, 1454, 1426, 1385, 1191 , 1132, 1108, 821 , 704; ¹H NMR (400 MHz, CDCI3) 5 7.73 - 7.65 (m, 4H), 7.48 - 7.36 (m, 6H), 5.26 - 5.14 (m, 3H), 4.81 (d, J = 16.1 Hz, 1 H), 4.77 - 4.67 (m, 3H), 4.37 (s, 2H), 1.60 (d, J = 7.1 Hz, 3H), 1.59 (d, J = 7.1 Hz, 3H), 1.57 (d, J = 7.2 Hz, 3H), 1.09 (s, 9H); ¹³C NMR (101 MHz, CDCI3) 6 174.4, 170.6, 169.5, 169.5, 166.8, 166.5, 135.5, 132.6, 129.9, 127.8, 69.3, 69.1 , 68.7, 61.8, 60.8, 60.3, 26.6, 19.2, 16.6, 16.6; HRMS (TOF MS ES+) m/z calcd for C₃8H₄40i₃NaSi⁺ [M+Na]⁺: 759.2449, Found: 759.2455.

Appearance: yellowish oil, Yield: 99%, Characterization: IR (film)Zcnr¹ broad OH vibration visible, 2926, 2855, 1751 (C=O), 1588, 1452, 1423, 1275, 1171 , 1128, 1092, 741 , 702; ¹H NMR (400 MHz, CDCI3) 5 7.70 - 7.65 (m, 4H), 7.48 - 7.34 (m, 6H), 5.32 - 5.19 (m, 3H), 4.91 - 4.79 (m, 3H), 4.72 - 4.61 (m, 4H), 4.46 (d, J = 16.0 Hz, 1 H), 4.38 (q, J = 6.7 Hz, 1 H), 1.59 (d, J = 7.1 Hz, 6H), 1.56 (d, J = 7.1 Hz, 3H), 1.42 (d, J = 6.7 Hz, 3H), 1.10 (s, 9H); ¹³C NMR (101 MHz, CDCI3) 5 173.1 , 171.1 , 169.5, 169.4, 169.3, 166.9, 166.5, 166.5, 135.9, 135.7, 133.4, 132.9, 129.8, 127.7, 127.6, 69.2, 69.1 , 69.0, 68.6, 60.8, 60.8, 60.5, 60.3, 26.8, 21.3, 19.2, 16.7, 16.7; HRMS (TOF MS ES+) m/z calcd for C36H₄40i₇NaSi⁺ [M+Na]⁺: 799.2245; Found: 799.2250.

Appearance: yellowish oil, Yield: 96%, Characterization: IR (film)/cnr¹ 3071 , 2953, 2857, 1758 (C=O), 1425, 1165, 1131 , 1095, 705; ¹H NMR (400 MHz, CDCI3) 6 7.76 - 7.62 (m, 4H), 7.48 - 7.31 (m, 6H), 5.22 (q, J= 7.1 Hz, 1H), 5.16 (q, J = 7.1 Hz, 1 H), 4.95 (q, J = 7.1 Hz, 1 H), 4.91 - 4.81 (m, 5H), 4.79 - 4.68 (m, 3H), 4.33 (q, J = 6.7 Hz, 1 H), 1 .59 (d, J = 7.2 Hz, 3H), 1.57 (d, J = 7.2 Hz, 4H), 1.42 (d, J = 6.8 Hz, 3H), 1.39 (d, J = 7.1 Hz, 3H), 1.09 (s, 9H); ¹³C NMR (101 MHz, CDCI3) 6 173.3, 170.6, 170.0, 169.7, 169.5, 166.5, 166.4, 166.4, 135.9, 135.7, 133.4, 133.0, 129.8, 127.6, 127.6, 68.9, 68.8, 68.5, 68.3, 60.8, 60.7, 60.6, 26.8, 21.1 , 19.2,

16.6, 16.6, 16.5; HRMS (TOF MS ES+) m/z calcd for C₃6H₄40i₇NaSi⁺ [M+Na]⁺: 799.2245;

Found: 799.2256.

TBDPSO-(GL)₂-ethyl methacrylate

Appearance: colorless oil, Yield: 68%, Characterization: R₇= 0.20 (20% EtOAc/hexane); IR (film)Zcm-¹ 3080, 2952, 2862, 1759 (C=O), 1720 (C=O), 1640, 1453, 1274, 1095, 946, 820, 700; ¹H NMR (400 MHz, CDCI3) 5 7.74 - 7.65 (m, 4H), 7.48 - 7.35 (m, 6H), 6.16 - 6.09 (m, 1H), 5.63 - 5.58 (m, 1 H), 5.23 - 5.13 (m, 2H), 4.87 (d, J = 16.0 Hz, 1H), 4.63 (d, J = 16.0 Hz, 1H), 4.51 - 4.27 (m, 6H), 1.98 - 1.91 (m, 3H), 1.53 (d, J = 7.1 , 3H), 1.52 (d, J = 7.1 Hz, 3H),

1.09 (s, 9H); 13C NMR (101 MHz, CDCI3) 6 170.6, 169.8, 169.8, 167.0, 166.6, 135.7, 135.6, 135.5, 132.6, 129.9, 127.8, 126.2, 69.3, 68.4, 63.1 , 61.9, 61.9, 60.7, 26.6, 19.2, 18.2, 16.8,

16.7. TBDPSO-(LG)₂-ethyl methacrylate

Appearance: colorless oil, Yield: 89%, Characterization: Ry= 0.25 (30% EtOAc/hexane); IR (film)/cm-¹ 3048, 2931 , 2857, 1728 (C=O), 1588, 1468, 1426, 1136, 1109, 820, 700; ¹H NMR (400 MHz, CDCI₃) 6 7.71 - 7.64 (m, 4H), 7.48 - 7.34 (m, 6H), 6.15 - 6.11 (m, 1 H), 5.61 (quint, J = 1.6 Hz, 1 H), 5.24 (q, J = 7.1 Hz, 1 H), 4.79 (d, J = 15.9 Hz, 1 H), 4.68 (d, J = 16.0 Hz, 1 H), 4.61 (d, J = 16.0 Hz, 1 H), 4.50 - 4.33 (m, 6H), 1.97 - 1.93 (m, 3H), 1.56 (d, J = 7.1 Hz, 3H), 1.43 (d, J= 6.8 Hz, 3H), 1.10 (s, 9H); ¹³C NMR (101 MHz, CDCI3) 6 173.0, 169.5, 167.0, 166.9, 166.8, 135.9, 135.7, 133.4, 132.9, 129.8, 127.7, 127.6, 126.3, 69.0, 68.6, 63.1 , 62.0, 60.9,

60.2, 26.8, 21.3, 19.2, 18.2, 16.7; HRMS (TOF MS ES+) m/z calcd for C₃2H₄oOiiNaSi⁺ [M+Na]⁺: 651.2238, Found: 651.2240.

TBDPSO-G₂L2-ethyl methacrylate

Appearance: colorless oil, Yield: 70%, Characterization: Ry= 0.30 (25% EtOAc/hexane); IR (film)Zcm'¹3071 , 2933, 2855, 1751(C=O), 1720 (C=O), 1636, 1453, 1129, 1095, 823, 741 , 700, 611 ; ¹H NMR (400 MHz, CDCI3) 6 7.75 - 7.63 (m, 4H), 7.51 - 7.33 (m, 6H), 6.16 - 6.09 (m, 1H), 5.61 (quint, J = 1.5 Hz, 1 H), 5.31 - 5.11 (m, 2H), 4.77 (d, J = 16.1 Hz, 1 H), 4.66 (d, J =

16.1 Hz, 1 H), 4.53 - 4.29 (m, 6H), 1.97 - 1.93 (m, 3H), 1.57 (d, J = 7.1 Hz, 3H), 1.54 (d, J =

7.1 Hz, 3H), 1.09 (s, 9H); ¹³C NMR (101 MHz, CDCI3) 6 170.5, 169.9, 169.4, 167.0, 166.9,

135.7, 135.5, 132.6, 129.9, 127.8, 126.3, 69.1 , 69.0, 63.0, 62.0, 61.8, 60.3, 26.6, 19.2, 18.2,

16.7, 16.6. TBDPSO-L₂G₂-ethyl methacrylate

Appearance: colorless oil, Yield: 72%, Characterization: Ry = 0.33 (50% Et₂O/hexane); IR (film)/cm-¹ 3070, 2934, 2956, 2858, 1759 (C=O), 1722 (C=O), 1636, 1425, 1159, 1130. 1107, 972, 704, 508; ¹H NMR (400 MHz, CDCI₃) 6 7.73 - 7.64 (m, 4H), 7.49 - 7.33 (m, 6H), 6.16 - 6.09 (m, 1 H), 5.61 (quint, J = 1.6 Hz, 1 H), 5.01 (q, J = 7.1 Hz, 1 H), 4.84 (d, J = 16.1 Hz, 1 H), 4.77 - 4.64 (m, 3H), 4.46 - 4.40 (m, 2H), 4.39 - 4.31 (m, 3H), 1.97 - 1 .93 (m, 3H), 1 .46 - 1 .39 (m, 6H), 1.10 (s, 9H); ¹³C NMR (101 MHz, CDCI3) 6 173.0, 169.8, 167.0, 166.8, 166.6, 135.9,

135.7, 133.4, 133.0, 129.8, 127.6, 127.6, 126.3, 68.5, 68.2, 63.2, 61.9, 60.9, 60.5, 26.8, 21.1 , 19.2, 18.2, 16.6; HRMS (TOF MS ES+) m/z calcd for C₃₂H₄iOnSi⁺ [M+H]⁺: 629.2418, Found: 629.2429. TBDPSO-(LG)₃-ethyl methacrylate

Appearance: colorless oil, Yield: 58%, Characterization: Ry = 0.55 (70% Et₂O/hexane); IR (film)/cm-¹ 3071 , 2992, 2955, 2858, 1761 , 1722, 1636, 1425, 1173, 1132, 1102, 705, 509; ¹H NMR (400 MHz, CDCI₃) 6 7.73 - 7.63 (m, 4H), 7.51 - 7.33 (m, 6H), 6.13 (quint, J = 1.1 Hz, 1H), 5.62 (quint, J = 1.6 Hz, 1 H), 5.31 - 5.19 (m, 2H), 4.87 (d, J = 16.0 Hz, 1 H), 4.80 (d, J = 16.0 Hz, 1 H), 4.72 - 4.58 (m, 3H), 4.49 - 4.33 (m, 6H), 1.97 - 1.92 (m, 3H), 1.59 (d, J = 7.1 Hz, 3H), 1.57 (d, J = 7.1 Hz, 3H), 1.43 (d, J = 6.7 Hz, 3H), 1.10 (s, 9H); ¹³C NMR (101 MHz, CDCI3) 6 173.0, 169.5, 169.4, 167.0, 166.8, 166.5, 135.9, 135.7, 133.4, 132.9, 129.8, 127.7, 127.6, 126.3, 69.2, 68.9, 68.6, 63.2, 62.0, 60.9, 60.7, 60.2, 26.8, 21.3, 19.2, 18.2, 16.7, 16.7; HRMS (TOF MS ES+) m/z calcd for C₃7H₅oNOi₅Si⁺ [M+HH₄]⁺: 776.2950, Found: 776.2955.

TBDPSO-GsLs-ethyl methacrylate

Appearance: colorless oil, Yield: 73%, Characterization: Ry= 0.24 (35% EtOAc/hexane); IR (film)/cm-¹ 3069, 2952, 2857, 1755 (C=O), 1721 (C=O), 1451 , 1425, 1382, 1169, 1133, 1094, 704; ¹H NMR (400 MHz, CDCI3) 6 7.72 - 7.67 (m, 4H), 7.48 - 7.36 (m, 6H), 6.15 - 6.11 (m, 1H), 5.61 (quint, J = 1.6 Hz, 1 H), 5.26 - 5.12 (m, 3H), 4.86 - 4.70 (m, 4H), 4.49 - 4.34 (m, 6H), 1 .98 - 1 .93 (m, 3H), 1 .60 (d, J = 7.1 , 3H), 1 .59 (d, J = 7.1 Hz, 3H), 1 .53 (d, J = 7.1 Hz, 3H), 1.09 (s, 9H); 13C NMR (101 MHz, CDCI3) 6 170.5, 169.9, 169.5, 169.4, 167.0, 166.8, 166.5, 135.5, 132.6, 129.9, 127.8, 126.2, 69.2, 69.1 , 69.1 , 63.0, 62.0, 61.8, 60.8, 60.2, 26.6,

19.2, 18.2, 16.7, 16.6, 16.6; HRMS (TOF MS ES+) m/z calcd for C₃7H₄60i₅NaSi⁺ [M+Na]⁺: 781.2504, Found: 781.2492. TBDPSO-(LG)₄-ethyl methacrylate

Appearance: colorless oil, Yield: 69%, Characterization: Ry = 0.62 (8% MeCN/CH₂CI₂); IR (film)Zcm-¹ 3080, 2992, 2954, 2857, 1753 (C=O), 1720 (C=O), 1635, 1423, 1277, 1169, 1128, 1093, 964, 742, 704, 612, 508; ¹H NMR (400 MHz, CDCI3) 6 7.71 - 7.64 (m, 4H), 7.47 - 7.34 (m, 6H), 6.16 - 6.11 (m, 1 H), 5.62 (quint, J = 1.6 Hz, 1 H), 5.32 - 5.18 (m, 3H), 4.92 - 4.58 (m, 7H), 4.49 - 4.34 (m, 6H), 1.95 (dd, J = 1.6, 1.0 Hz, 3H), 1.59 (d, J = 7.1 Hz, 6H), 1.56 (d, J = 7.1 Hz, 3H), 1.42 (d, J= 6.8 Hz, 3H), 1.10 (s, 9H); ¹³C NMR (101 MHz, CDCI3) 6 173.0, 169.5, 169.4, 167.0, 166.8, 166.5, 166.4, 135.9, 135.7, 133.4, 132.9, 129.8, 127.6, 127.6, 126.3,

69.2, 69.1 , 68.9, 68.6, 63.1 , 62.0, 60.9, 60.8, 60.7, 60.2, 26.8, 21.3, 19.2, 18.2, 16.7; HRMS

(TOF MS ES+) m/z calcd for C₄₂H₅₂0i₉NaSi⁺ [M+Na]+: 911 .2770, Found: 911 .2783. TBDPSO-L₄G₄-ethyl methacrylate

Appearance: colorless oil, Yield: 75%, Characterization: Ry = 0.60 (8% MeCN/CH₂CI₂); IR (film)/cm-¹3071, 2928, 2857, 1757 (C=O), 1722 (C=O), 1636, 1451, 1425, 1384, 1158, 1130, 1093, 705; ¹H NMR (400 MHz, CDCI₃) 67.72 - 7.65 (m, 4H), 7.49 - 7.33 (m, 6H), 6.16-6.12 (m, 1H), 5.62 (quint, J = 1.6 Hz, 1H), 5.22 (q, J= 7.1 Hz, 1H), 5.16 (q, J= 7.1 Hz, 1H), 4.95 (q, J= 7.1 Hz, 1H), 4.89 (d, J= 16.1 Hz, 1H), 4.85-4.73 (m, 6H), 4.69 (d, J= 16.1 Hz, 1H), 4.48-4.40 (m, 2H), 4.40-4.30 (m, 3H), 1.95 (dd, J= 1.6, 1.0 Hz, 3H), 1.59 (d, J= 7.1 Hz, 3H), 1.57 (d, J= 7.1 Hz, 3H), 1.42 (d, J = 6.7 Hz, 3H), 1.40 (d, J = 7.1 Hz, 3H), 1.09 (s, 9H); ¹³C NMR (101 MHz, CDCI₃) 6173.1, 169.9, 169.7, 169.5, 167.0, 166.7, 166.4, 166.4, 166.3, 135.9, 135.7, 133.4, 133.0, 129.8, 127.6, 127.5, 126.3,68.9,68.8,68.4,68.2,63.2,61.9,61.0, 60.8, 60.7, 60.6, 26.8, 21.1, 19.2, 18.2, 16.7, 16.6, 16.5; HRMS (TOF MS ES+) m/z calcd for C₄₂H₅₂0i₉NaSi⁺ [M+Na]⁺: 911.2770, Found: 911.2791. HO-(GL)₂-ethyl methacrylate

Appearance: colorless oil, Yield: 86%, Characterization: Ry= 0.24 (50% EtOAc/hexane); IR (film)/cm-¹3503 (br. OH), 2959, 1751 (C=O), 1720 (C=O), 1640, 1453, 1177, 1095; ¹H NMR (400 MHz, CDCI3) 66.15-6.11 (m, 1H), 5.63-5.59 (m, 1H), 5.30 (q, J= 7.1 Hz, 1H), 5.19 (q, J= 7.1 Hz, 1H), 4.87 (d, J= 16.0 Hz, 1H), 4.67 (d, J= 16.0 Hz, 1H), 4.52-4.42 (m, 1H), 4.42-4.22 (m, 5H), 2.56-2.17 (br, 1H), 1.98- 1.92 (m, 3H), 1.61 (d, J = 7.1 Hz, 3H), 1.53 (d, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCI3) 5172.6, 169.7, 169.6, 167.0, 166.4, 135.8,

126.2, 69.4, 69.0, 63.1, 62.0, 60.8, 60.5, 18.2, 16.8, 16.8; HRMS (TOF MS ES+) m/z calcd for CI₆H₂₃0II⁺ [M+H]⁺: 391.1240; Found: 391.1228. HO-(LG)₂-ethyl methacrylate

Appearance: colorless oil, Yield: 76%, Characterization: Ry= 0.37 (60% EtOAc/hexane); IR (film)/cm-¹3500 (br. OH), 2986, 2957, 1750 (C=O), 1719 (C=O), 1635, 1451, 1384, 1292, 1169, 1128, 1096, 950; ¹H NMR (400 MHz, CDCI3) 66.16 - 6.09 (m, 1H),5.60 (quint, J= 1.6 Hz, 1H), 5.26 (q, J= 7.1 Hz, 1H), 4.86 (d, J= 16.0 Hz, 1H), 4.79 (d, J= 15.9 Hz, 1H), 4.72 (d, J= 16.0 Hz, 1H), 4.62 (d, J= 16.0 Hz, 1H), 4.46-4.33 (m, 5H), 3.34-2.44 (br, 1H), 1.94 (t, J= 1.2 Hz, 3H), 1.59 (d, J= 7.1 Hz, 3H), 1.49 (d, J= 7.0 Hz, 3H); ¹³C NMR (101 MHz, CDCI3) 5 174.8, 169.4, 167.0, 166.8, 166.6, 135.7, 126.3, 69.1, 66.7, 63.1, 62.0, 60.9, 60.8, 20.3,

18.2, 16.7; HRMS (TOF MS ES+) m/z calcd for Ci₆H₂₂0nNa⁺ [M+Na]⁺: 413.1060, Found: 413.1066. HO-G₂l-2-ethyl methacrylate

Appearance: colorless oil, Yield: 84%, Characterization: Ry= 0.20 (50% EtOac/hexane); IR (film)/cm-¹3503 (br, OH), 2952, 1744 (C=O), 1720 (C=O), 1640, 1453, 1386, 1162, 1088, 954; ¹H NMR (400 MHz, CDCI3) 66.18 - 6.08 (m, 1 H), 5.61 (quint, J = 1.6 Hz, 1 H), 5.28 - 5.14 (m, 2H), 4.86 (d, J = 16.1 Hz, 1 H), 4.78 (d, J = 16.0 Hz, 1 H), 4.50 - 4.29 (m, 6H), 2.22 (s, 1 H), 1.95 (dd, J = 1.6, 1.0 Hz, 3H), 1.60 (d, J = 7.1 Hz, 3H), 1.54 (d, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCI3) 5 172.6, 169.8, 169.3, 167.0, 166.6, 135.8, 126.3, 69.3, 69.2, 63.0, 62.0, 60.8,

60.4, 18.2, 16.7, 16.7.

HO-L₂G2-ethyl methacrylate

Appearance: colorless oil, Yield: 60%, Characterization: Ry = 0.28 (70% Et₂O/hexane); IR (film)/cm-¹ 3500 (br, OH), 2987, 2958, 1753, 1720, 1635, 1388, 1295, 1166, 1129, 1097, 943; ¹H NMR (400 MHz, CDCI3) 66.16 - 6.10 (m, 1 H), 5.61 (quint, J = 1.6 Hz, 1 H), 5.32 - 5.23 (m, 1H), 4.89 (d, J = 16.1 Hz, 1 H), 4.79 - 4.68 (m, 3H), 4.50 - 4.29 (m, 5H), 2.87 - 2.70 (m, 1 H), 1.95 (t, J = 1.3 Hz, 3H), 1.61 (d, J = 7.1 Hz, 3H), 1.50 (d, J = 6.9 Hz, 3H); ¹³C NMR (101 MHz, CDCI3) 5 175.0, 169.5, 167.0, 166.8, 166.5, 135.7, 126.3, 69.0, 66.7, 63.2, 61.9, 61.0, 60.7,

20.4, 18.2, 16.7; HRMS (TOF MS ES+) m/z calcd for CI₆H₂₃0II⁺ [M+H]⁺: 391.1240, Found: 391.1226.

HO-(LG)₃-ethyl methacrylate

Appearance: colorless oil, Yield: 82%, Characterization: Ry= 0.22 (50% EtOAc/hexane); IR (film)/cm-¹ 3531 (br, OH), 2993, 2957, 1755 (C=O), 1720 (C=O), 1635, 1386, 1279, 1176, 1130, 1096, 955; ¹H NMR (400 MHz, CDCI₃) 6 6.17 - 6.10 (m, 1 H), 5.63 - 5.56 (m, 1 H), 5.33 - 5.22 (m, 2H), 4.94 - 4.57 (m, 6H), 4.47 - 4.32 (m, 5H), 2.75 (d, J = 5.3 Hz, 1 H), 1 .95 (s, 3H), 1.60 (d, J = 7.2 Hz, 3H), 1 .59 (d, J = 7.0 Hz, 3H), 1 .50 (d, J = 7.0 Hz, 3H); ¹³C NMR (101 MHz, CDCI3) 6 174.9, 169.4, 167.0, 166.8, 166.6, 166.4, 135.7, 126.3, 69.2, 69.1 , 66.7, 63.2, 62.0,

60.9, 60.8, 60.8, 20.3, 18.2, 16.7, 16.7; HRMS (ES+) m/z calcd for C₂iH280i₅Na⁺ [M+Na]⁺: 543.1326, Found: 543.1334.

HO-GsLs-ethyl methacrylate

Appearance: colorless oil, Yield: 75%, Characterization: Ry= 0.24 (50% EtOAc/hexane); IR (film)Zcm'¹ 3520 (br, OH), 2993, 2952, 1750 (C=O), 1720 (C=O), 1633, 1386, 1176, 954; ¹H NMR (400 MHz, CDCI3) 5 6.16 - 6.10 (m, 1 H), 5.61 (quint, J = 1.6 Hz, 1 H), 5.28 - 5.13 (m, 3H), 4.91 - 4.72 (m, 4H), 4.50 - 4.25 (m, 6H), 1.95 (t, J = 1.3 Hz, 3H), 1.60 (d, J = 7.1 , 3H), 1.59 (d, J = 7.1 Hz, 3H), 1.53 (d, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCI₃) 6 172.6, 169.9,

169.5, 169.4, 167.0, 166.6, 166.4, 135.8, 126.2, 69.3, 69.1 , 69.1 , 63.0, 62.0, 60.9, 60.7, 60.4, 18.2, 16.7, 16.6, 16.6.

HO-(LG)₄-ethyl methacrylate

Appearance: colorless oil, Yield: 76%, Characterization: Ry= 0.27 (60% EtOAc/hexane); IR (film)/cm-¹ 3501 (br, OH), 2993, 2953, 2925, 1756 (C=O), 1720 (C=O), 1635, 1385, 1175, 1130, 1095, 956; ¹H NMR (400 MHz, CDCI3) 6 6.16 - 6.05 (m, 1 H), 5.65 - 5.54 (m, 1 H), 5.30 - 5.22 (m, 3H), 4.92 - 4.59 (m, 8H), 4.45 - 4.33 (m, 5H), 2.64 - 2.37 (br, 1 H), 1 .97 - 1 .90 (m, 3H), 1.62 - 1.57 (m, 9H), 1.49 (d, J = 7.0 Hz, 3H); ¹³C NMR (101 MHz, CDCI3) 5 174.9, 169.4, 167.0, 166.8, 166.6, 166.4, 135.7, 126.3, 69.1 , 69.1 , 66.7, 63.1 , 62.0, 60.9, 60.8, 20.3, 18.2, 16.7, 16.7; HRMS (TOF MS ES+) m/z calcd for C₂6H₃40i₉Na⁺ [M+Na]⁺: 673.1592, Found: 673.1584.

HO-L₄G₄-ethyl methacrylate

Appearance: colorless oil, Yield: 82%, Characterization: Ry= 0.18 (55% EtOAc/hexane); IR (film)Zcm'¹ 3460 (br, OH), 1745 (C=O), 1720 (C=O), 1634, 1167, 720 ; ¹H NMR (400 MHz, CDCI3) 5 6.13 (quint, J = 1.0 Hz, 1 H), 5.62 (quint, J = 1.6 Hz, 1H), 5.31 - 5.13 (m, 3H), 4.97 - 4.66 (m, 8H), 4.46 - 4.42 (m, 2H), 4.40 - 4.33 (m, 3H), 1 .95 (dd, J = 1 .6, 1 .0 Hz, 3H), 1 .64 - 1.57 (m, 9H), 1.50 (d, J = 6.9 Hz, 3H); ¹³C NMR (101 MHz, CDCI3) 5 169.9, 169.5, 169.4,

167.3, 167.0, 166.6, 166.5, 135.8, 135.2, 127.2, 126.3, 69.3, 69.2, 69.1 , 63.1 , 62.1 , 60.9, 60.7,

60.5, 18.2, 18.2, 16.7, 16.7, 16.6; HRMS (TOF MS ES+) m/z calcd for C26H₃40i₉Na⁺ [M+Na]⁺: 673.1592, Found: 673.1577.

Appearance: colorless oil, Yield: 95%, Characterization: R? = 0.3 (30% EtOAc/hexane); IR (film)Zcm-¹ 2990, 2959, 1752 (C=O), 1722 (C=O), 1640, 1453, 1148, 909, 730; ¹H NMR (400 MHz, CDCI3) 5 6.24 - 6.21 (m, 1 H), 6.13 - 6.12 (m, 1 H), 5.66 (quint, J = 1.6 Hz, 1 H), 5.61 (quint, J = 1.6 Hz, 1 H), 5.27 (q, J = 7.1 Hz, 1 H), 5.18 (q, J = 7.0 Hz, 1 H), 4.91 - 4.79 (m, 2H), 4.74 (d, J = 16.2 Hz, 1 H), 4.64 (d, J = 16.0 Hz, 1 H), 4.50 - 4.41 (m, 1 H), 4.40 - 4.33 (m, 3H), 2.00 - 1.96 (m, 3H), 1.96 - 1.93 (m, 3H), 1.62 - 1.57 (m, 3H), 1.52 (d, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCI3) 5 169.7, 169.5, 167.2, 167.0, 166.5, 166.5, 135.8, 135.2, 127.0, 126.2,

69.3, 68.9, 63.1 , 61.9, 60.8, 60.6, 18.2, 18.2, 16.7; HRMS (ES+) m/z calcd for C₂oH260i₂Na⁺ [M+Na]⁺: 481.1316, Found: 481.1327.

Appearance: colorless oil, Yield: 68%, Characterization: Ry = 0.19 (30% EtOAc/hexane); IR (film)/cm-¹2991 , 2957, 1753 (C=O), 1717 (C=O), 1635, 1451, 1381, 1288, 1155, 1090, 943, 813; ¹H NMR (400 MHz, CDCI₃) 66.23-6.20 (m, 1H), 6.14-6.12 (m, 1H), 5.65 (quint, J = 1.5 Hz, 1H), 5.61 (quint, J = 1.5 Hz, 1H), 5.30-5.18 (m, 2H), 4.90 (d, J= 16.1 Hz, 1H), 4.80 (d, J= 16.0 Hz, 1H), 4.65 (d, J= 16.0 Hz, 1H), 4.62 (d, J= 16.0 Hz, 1H), 4.45-4.41 (m, 2H), 4.38 - 4.35 (m, 2H), 1.98 - 1.96 (m, 3H), 1.96 - 1.93 (m, 3H) , 1.62 (d, J = 7.1 Hz, 3H), 1.59 (d, J= 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCI3) 6170.25, 169.42, 166.99, 166.85, 166.61, 135.75, 135.42, 126.70, 126.27,69.10,68.49,63.14,61.98,60.93,60.66, 18.21, 18.12, 16.86, 16.73; HRMS (TOF MS ES+) m/z calcd for C₂oH₂60i₂Na⁺ [M+Na]+: 481.1322, Found: 481.1308.

Appearance: colorless oil, Yield: 80%, Characterization: Ry = 0.24 (30% EtOAc/hexane); IR (film)Zcm'¹ 2991, 2952, 1752 (C=O), 1722 (C=O), 1640, 1453, 1274, 1140, 946, 812; ¹H NMR (400 MHz, CDCI3) 66.24 -6.22 (m, 1H), 6.14-6.11 (m, 1H), 5.67 (quint, J= 1.6 Hz, 1H), 5.61 (quint, J= 1.6 Hz, 1H), 5.27-5.12 (m, 2H), 4.88-4.71 (m, 4H), 4.50-4.30 (m, 4H), 1.98 (dd, J = 1.6, 1.0 Hz, 3H), 1.94 (dd, J = 1.6, 1.0 Hz, 3H), 1.58 (d, J= 7.1 Hz, 3H), 1.53 (d, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCI3) 6169.8, 169.3, 167.2, 166.9, 166.5, 166.5, 135.7, 135.2, 127.1, 126.2, 69.2, 69.2, 63.0, 62.0, 60.7, 60.5, 18.2, 18.2, 16.7, 16.6; HRMS (ES+) m/z calcd for C₂₀H₂₆Oi₂Na⁺ [M+Na]⁺: 481.1316, Found: 481.1326.

Appearance: colorless oil, Yield: 52%, Characterization: Ry = 0.22 (25% EtOAc/hexane); IR (film)Zcm-¹2991, 2956, 1756 (C=O), 1719 (C=O), 1635, 1451, 1292, 1156, 1129, 1095, 946, 614; ¹H NMR (400 MHz, CDCI3) 66.21 (s, 1H), 6.14 (s, 1H), 5.66-5.64 (m, 1H), 5.63-5.60 (m, 1H), 5.26 (q, J = 7.0 Hz, 1H), 5.17 (q, J = 7.1 Hz, 1H), 4.89 (d, J = 16.1 Hz, 1H), 4.78 - 4.66 (m, 3H), 4.46 - 4.40 (m, 2H), 4.40 - 4.35 (m, 2H), 1.99 - 1.96 (m, 3H), 1.96 - 1.94 (m, 3H), 1.62 (d, J = 7.0 Hz, 6H); ¹³C NMR (101 MHz, CDCI3) 6170.2, 169.6, 167.0, 166.7, 166.7, 166.5, 135.7, 135.4, 126.6, 126.3, 68.7, 68.5, 63.2, 61.9, 60.9, 60.6, 18.2, 18.1, 16.7, 16.7; HRMS (TOF MS ES+) m/z calcd for C₂₀H₂₇OI₂ ⁺ [M+H]⁺: 459.1503, Found: 459.1519.

Appearance: colorless oil, Yield: 51%, Characterization: R?= 0.21; IR (film)/cnr¹2993, 2956, 1758 (C=O), 1721 (C=O), 1636, 1452, 1288, 1165, 1130, 1095, 951; ¹H NMR (400 MHz, CDCI₃) 66.22 (s, 1H), 6.13 (s, 1H), 5.67-5.60 (m, 2H), 5.33-5.18 (m, 3H), 4.93-4.77 (m, 3H), 4.71 - 4.58 (m, 3H), 4.46 - 4.40 (m, 2H), 4.39 - 4.35 (m, 2H), 1.98 - 1.96 (m, 3H), 1.96 -1.94 (m, 3H), 1.64-1.58 (m, 9H); ¹³C NMR (101 MHz, CDCI3) 6170.3, 169.4, 169.4, 167.0, 166.8, 166.6, 166.4, 135.7, 135.4, 126.7, 126.3, 69.2, 69.1, 68.5, 63.2, 62.0, 60.9, 60.8, 60.7, 18.2, 18.1, 16.9, 16.7; HRMS (TOF MS ES+) m/z calcd for C₂5H₃30I₆ ⁺ [M+H]⁺: 589.1763, Found: 589.1785.

Appearance: colorless oil, Yield: 55%, Characterization: Ry= 0.20 (40% EtOAc/hexane); IR (film)/cm-¹2922, 2855, 1751 (C=O), 1720 (C=O), 1640, 1453, 1379, 1140, 954, 812; ¹H NMR (400 MHz, CDCI3) 66.24 (quint, J = 1.0 Hz, 1H), 6.16-6.11 (m, 1H), 5.68 (quint, J = 1.6 Hz, 1H), 5.61 (quint, J= 1.6 Hz, 1H), 5.26-5.12 (m, 3H), 4.88-4.73 (m, 6H), 4.49-4.40 (m, 1H), 4.39-4.32 (m, 3H), 1.99 (dd, J = 1.6, 1.0 Hz, 3H), 1.95 (dd, J = 1.6, 1.0 Hz, 3H), 1.60 (d, J = 7.1 Hz, 3H), 1.59 (d, J = 7.1 Hz, 3H), 1.53 (d, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCI3) 6169.9, 169.5, 169.4, 167.0, 166.5, 166.4, 135.8, 135.2, 127.1, 126.2, 69.3, 69.1, 69.1, 63.0, 62.0, 60.9, 60.6, 60.5, 18.2, 18.2, 16.7, 16.6, 16.6; HRMS (TOF MS ES+) m/z calcd for C₂5H₃20i₆Na⁺ [M+Na]⁺: 611.1588, Found: 611.1575.

Appearance: colorless oil, Yield: 51%, Characterization: Ry= 0.43 (45% EtOAcZ hexane); IR (film)Zcm-¹2922, 2855, 1759 (C=O), 1722 (C=O), 1640, 1453, 1174, 1095, 954; ¹H NMR (400 MHz, CDCI3) 66.25-6.17 (m, 1H), 6.16-6.09 (m, 1H), 5.66-5.63 (m, 1H), 5.63-5.60 (m, 1H), 5.30-5.16 (m, 4H), 4.93-4.85 (m, 3H), 4.80 (d, J= 15.9 Hz, 1H), 4.69-4.59 (m, 4H), 4.46 - 4.40 (m, 2H), 4.39 - 4.34 (m, 2H), 1.97 (t, J = 1.3 Hz, 3H), 1.95 (t, J = 1.3 Hz, 3H), 1.63 -1.58 (m, 12H); ¹³CNMR(101 MHz, CDCI₃) 6170.2, 169.4, 169.4, 167.0, 166.8, 166.6, 166.6, 166.4, 166.4, 135.7, 135.4, 126.7, 126.3, 69.2, 69.1, 69.0, 68.5, 63.1, 62.0, 60.9, 60.8, 60.6, 18.2, 18.1, 16.8, 16.7; HRMS (TOF MS ES+) m/z calcd for C₃oH₄₂N0₂o⁺ [M+NH₄]⁺: 736.2300, Found: 736.2309.

Appearance: colorless oil, Yield: 30%, Characterization: Ry = 0.58 (60% EtOAc/hexane); IR (film)Zcm-¹2921, 2852, 1752 (C=O), 1718 (C=O), 1635, 1454, 1379, 1292, 1155, 1128, 1084, 947, 732; ¹H NMR (400 MHz, CDCI3) 66.25-6.18 (m, 1H), 6.16-6.10 (m, 1H), 5.64 (quint, J = 1.5 Hz, 1 H), 5.62 (quint, J = 1.6 Hz, 1 H), 5.28 - 5.13 (m, 4H), 4.92 - 4.68 (m, 8H), 4.47 - 4.41 (m, 2H), 4.41 - 4.35 (m, 2H), 1 .97 (t, J = 1 .3 Hz, 3H), 1 .95 (t, J = 1 .3 Hz, 3H), 1 .64 - 1 .56 (m, 12H); ¹³C NMR (101 MHz, CDCI₃) 6 170.4, 169.8, 169.6, 169.5, 166.7, 166.4, 166.4, 166.3,

135.8, 135.4, 126.6, 126.3, 68.9, 68.8, 68.5, 63.2, 61.9, 61.1 , 60.8, 60.7, 60.6, 18.2, 18.1 ,

16.8, 16.7, 16.6, 16.6; HRMS (TOF MS ES+) m/z calcd for C₃oH₃80₂oNa⁺ [M+Na]⁺: 741.1854, Found: 741.1853.

Example 2 - Synthesis of OLGADMA-based nanoparticles

This example provides a method for preparing example nanoparticle compositions of the present invention. A selection of OLGADMA-based nanoparticles were prepared by following General Procedure B and using the OLGADMAs shown in Table 3.

Table 3. Precisely sequenced OLGADMAs used to prepare OLGADMA-based nanoparticles

OLGADMA-based nanoparticles were synthesized via nanoprecipitation polymerizations using the components presented in Table 4.

Table 4. Components used to prepare OLGADMA-based nanoparticles

The successful polymerization of OLGADMAs was confirmed via FTIR analysis of lyophilized NPs (Fig. 14). The conversion of methacrylates can be evidenced by the absence of the vinyl C=C stretch in the spectra of NPs, as seen in the FTIR spectrum of NP4Aa (FIG. 1). Furthermore, the conjugated carbonyl stretch visible in the FTIR spectra of the starting materials is absent in the spectrum of the NPs. The two distinct vibrations in the carbonyl stretch region belonging to oc-hydroxy acid esters and those deriving from (meth)acrylic esters respectively, are superimposed in a single broad vibration in the FTIR spectrum of the NPs. A prominent stretch vibration of the nitrile group deriving from the initiator AIBN could not be detected by FTIR in any of the NPs prepared. Relative to the carbonyl stretches, the characteristic C-H stretches present in the FTIR spectrum of PEGDA700 and the physical mixture of the starting materials are less intense in the spectrum of the NP. This was suggestive of a sub-quantitative incorporation of PEGDA700 into the NP structure. See Example 8 for quantification of the PEG content of the prepared NPs.

Example 3 - Monitoring the synthesis of OLGADMA-based nanoparticles by NMR spectroscopy and dynamic light scattering

This example shows the spontaneous formation of nanoparticles in a nanoprecipitation reaction from oligomers of the present invention. The nanoprecipitation polymerization reaction was monitored over 6 h via ¹H NMR spectroscopy and dynamic light scattering (DLS), using a mixture of compound 4Aa and PEGDA700 under the conditions of General Procedure B (FIG. 2).

Samples (0.2 mL) of the reaction mixture were taken at determined time points, quickly diluted into ice cold deionized water (0.6 mL) with exposure to air and analyzed by DLS. The so-prepared suspensions were then freeze-dried for 48 h, dissolved in deuterated DMSO (0.75 mL) and analyzed by ¹H NMR.

The reaction appeared to be a fast process, with no starting materials detectable by ¹H NMR after 15 min of reaction. The polymeric NP itself was not detected by ¹H NMR, possibly due to factors such as concentration, poor solvation, and densely crosslinked structure. At reaction times longer than 15 min, the presence of a hypothetical PEG species becomes NMR-visible as a resonance of increasing intensity at 3.51 ppm. The simultaneous DLS analysis of the crude reaction mixture denotes a gradual and time-dependent increase in NP size. These observations could be indicative of the existence of an initial NP formation step followed by swelling of the NPs caused by hydrolytic degradation in water at 70 °C, and thus the reaction time was limited to 15 min throughout. Example 4 - Synthesis of drug-loaded OLGADMA-based nanoparticles

This example provides a method for preparing nanoparticle compositions comprising an active agent of the present invention. Drug-loaded OLGADMA-based nanoparticles were prepared by following General Procedure C, using dexamethasone as the drug, and the

nanoparticles

Drug-loaded OLGADMA-based nanoparticles were synthesized via nanoprecipitation polymerizations using the components presented in Table 6.

Table 6. Components used to prepare drug-loaded OLGADMA-based nanoparticles Dexamethasone is poorly soluble in water (89 pg/mL at 25°C) and its administration via injection is achieved using the inactive phosphate form as a prodrug. It was envisaged that the encapsulation of dexamethasone within OLGADMA NPs would facilitate a pseudosolubilization of substantial quantities of the drug, which could then be slowly released from the NPs. Dexamethasone was encapsulated in situ, via solubilization into the THF solution used for nanoprecipitation polymerization.

The chemical stability of dexamethasone during the nanoprecipitation polymerization was confirmed as the drug could be recovered qualitatively and quantitatively after being subjected to the reaction conditions (FIG. 18). The procedure for investigating the stability of dexamethasone under typical reaction conditions is outlined below:

A solution of dexamethasone (6 mg) and AIBN (4 mg) in THF (1.6 mL) was quickly injected into water (4.8 mL) at 70 °C, stirring at 1000 rpm, with the system open to air and under N₂ gas flow. The mixture was immediately subjected to nitrogen gas bubbling for 5 minutes and then left under nitrogen gas atmosphere for a further 10 min. The mixture was then opened to air, cooled in an ice bath for 2 minutes and freeze-dried for 48 h. The lyophilizates were subjected to ¹H NMR analysis (FIG. 18).

Furthermore, the ¹H NMR analysis of the freeze-dried combined filtrates obtained during drug release assays of DNP4Aa confirmed the release of structurally intact dexamethasone (FIG. 19). The successful polymerization of OLGADMAs loaded with dexamethasone was confirmed via FTIR analysis (Fig. 15). The presence of dexamethasone in NP suspensions was confirmed by FTIR analysis where vibrations characteristic of the drug are observable (FIG. 3). A comparison of DNP4Bb, and a physical mixture obtained by grinding of NP4Bb and dexamethasone solid reveals differences between the FTIR spectra. This is suggestive of alternative or stronger drug-polymer interactions in the drug-containing DNP4Bb compared to a mere physical mixture of empty nanoparticles N4Bb and the drug. This example shows that a variety of different oligomers of the invention may be used to prepare nanoparticles of the invention comprising a drug.

Example 5 - Synthesis of drug-loaded OLGADMA-based nanoparticles of varying sizes

The ability to tune the size of drug-loaded NPs is highly desirable for drug delivery applications. This example shows how the methods and processes of the present invention may be fine-tuned to provide nanoparticles of varying sizes. Dexamethasone-loaded OLGADMA-based NPs with sizes ranging from 105 to 313 nm were synthesized from 4Aa and PEGDA700 by varying the duration of the nitrogen purging step of the nanoprecipitation polymerization following General Procedure C. Particularly, longer purging of the reaction mixture was found to induce the formation of smaller dexamethasone-loaded OLGADMA- based NPs. The NPs presented in this work were prepared according to standard conditions (5 min purging time). Fives sizes of dexamethasone-loaded OLGADMA-based NPs were prepared from 4Aa by variation of the duration of the nitrogen gas purging step described in the nanoprecipitation polymerization protocol. The quantitative reaction compositions were identical, the total reaction time was kept at 15 minutes, and the obtained reaction mixtures were subjected standard purification conditions. The analysis of the obtained NP suspensions is described in Table 7.

Tab e 7. Analysis of dexamethasone-loaded OLGADMA-based NPs prepared from 4Aa with variations of the duration of the N₂ purge step of nanoprecipitation polymerization.

Example 6 - Synthesis of PLGA-PEG-COOH nanoparticles

This example provides a procedure for preparing PLGA-PEG-COOH nanoparticles that are useful for comparison with the nanoparticle compositions of the present invention. PLGA-PEG-COOH nanoparticles were prepared from commercially available PLGA-PEG- COOH polymer (LA:GA 50:50, 50kDa-5kDa) following General Procedure D. The copolymer was chosen for comparison with OLGADMA-based NPs due to its 1 :1 lactate/glycolate ratio and the content of PEG. Intensity-weighted size distributions and corresponding correlation functions are presented in FIG. 13.

Example 7 - Synthesis of drug-loaded PLGA-PEG-COOH nanoparticles

This example provides a procedure for preparing PLGA-PEG-COOH nanoparticles comprising a drug that are useful for comparison with the nanoparticle compositions comprising a drug of the present invention. Drug-loaded PLGA-PEG-COOH nanoparticles were prepared by following General Procedure E, using dexamethasone as the drug. The copolymer was chosen for comparison with OLGADMA-based NPs due to its 1 :1 lactate/glycolate ratio and the content of PEG. Intensity-weighted size distributions and corresponding correlation functions are presented in FIG. 13.

Example 8 - Characterization of nanoparticles

This example shows how nanoparticles may be characterised in terms of their physical properties. The NPs of Example 2, 4, 6, and 7 were characterized in terms of size, polydispersity, ^-potential, encapsulation efficiency and drug-loading efficiency (FIG. 4). The size of OLGADMA-based NPs, measured by DLS and expressed as z-average mean diameter, ranged from 172 to 366 nm. Dexamethasone-loaded OLGADMA NPs had sizes ranging from 199 to 321 nm. In comparison, both NP-PLGA-PEG and DNP-PLGA-PEG were smaller, with a size of 68 nm and 111 nm respectively. Intensity-weighted size distributions and corresponding correlation functions of all NPs prepared in this work are presented in FIG. 13 A) - AB). The polydispersity (PI) parameter of the prepared NPs was below 0.4, with NPs obtained from tetramer OLGADMAs having an especially low PI (< 0.2) indicating a homogeneous size distribution. Both OLGADMA- and PLGA-PEG-based NPs exhibited negative ^-potential in deionized water at 25 °C. The ^-potential of dexamethasone-loaded OLGADMA-based NPs was generally less negative than OLGADMA NPs, possibly due to differences in surface chemistries deriving from partial surface adsorption of dexamethasone and/or NP size.

The PEG content of OLGADMA-based NPs was estimated by quantitation of the PEG di-alcohol deriving from basic hydrolysis of the NPs. The procedure used for estimating the PEG content of OLGADMA-based NPs is provided below:

Accurately weighed freeze-dried nanoparticles were dissolved in aq. NaOH (1 M, 1 mL) and left stirring for 3 days at room temperature. The solutions were then freeze-dried and a solution of sodium acetate in deuterium oxide (0.3 mg/mL, 1 mL) was added to the lyophilizates. ¹H NMR spectra of the solutions were recorded with a 30 s delay. The mass of the PEG dialcohol released by basic hydrolysis of the NPs was estimated by integration of the characteristic resonance at 3.55 ppm against sodium acetate as the internal standard. The PEG content of NPs was calculated according to the equation presented below: mass of PEG dialcohol

PEG content (wt. %) = - — - ; - ; - x 100 mass of freeze — dried NPs

Table 8. Estimation of PEG content of nanoparticles

This result has been rationalized in terms of the aqueous solubility of the PEGDA700 co-monomer, which can easily diffuse from the dispersed nanodroplets of the monomer mixture into the water phase during polymerization.

Samples of NP4Aa and DNP4Aa were further analyzed by transmission electron microscopy (TEM) which confirmed the presence of spherical NPs (FIG. 5). TEM micrographs of NP4Aa show spherical NPs presenting a dotted pattern accompanied by a matter-dense core and a less dense periphery. The procedure used for obtaining TEM micrographs is provided below: Samples for TEM were prepared by sonication of NP suspensions for 60 sec followed by syringe filtration through 5.0 pm syringe filters. The resulting suspension (10 pL) was then deposited onto Formvar/Carbon supported copper grids 200 mesh and allowed to adsorb for 3 min before removing the excess sample with filter paper. The grids were left to dry at room temperature for 24 h before analysis. Imaging was performed using TEM at 80 kV with minimum dose exposure system.

This example shows that the nanoparticles of the present invention may be prepared with high control over physical properties such as size, polydispersity and ^-potential.

Example 9 - Drug encapsulation efficiency and drug loading efficiency

This example shows how the drug encapsulation efficiency and drug loading efficiency of nanoparticles comprising a drug may be determined. The drug encapsulation efficiency (EE) of dexamethasone-loaded NPs was calculated via quantitation of the non-encapsulated dexamethasone.

The general procedure for dexamethasone quantification is outlined below:

Analytical curves were constructed measuring the absorption of standard aqueous solutions of dexamethasone (25, 20, 15, 10, 5, 1 , 0.5 and 0 pg/mL) at 240 nm using a quartz cuvette. Limits of detection (LOD) and quantification (LOQ) were calculated as 3.3 o/S and 10 o/S, respectively, where o is the standard deviation of intercept and S is the slope of the calibration plot. The measurements were carried-out in triplicate for the quantitation of dexamethasone in the various experiments. Samples were subjected to dilution prior to measurement, in the event of absorbances larger than 1.

Encapsulation Efficiency and Loading Efficiency Estimation. The encapsulation efficiency of nanoparticles was estimated by quantitation of un-encapsulated dexamethasone and subtraction of this value from the dexamethasone feed according to the following equation: un — encapsulated dexamethasone mass

%EE = - - - — — - X 100 dexamethasone feed mass

Un-encapsulated dexamethasone was quantified spectrophotometrically from methanol/water solutions (1 :1 volume ratio) obtained by combining the filtrates from ultrafiltration step and methanol solutions obtained by washing the reaction vial and filters used for ultrafiltration. The loading efficiency of nanoparticles was determined as the ratio of the concentration of dexamethasone and the mass of the solids obtained after 48 h of freeze-drying of nanoparticle suspensions. mass of dexamethasone in 1 mL of suspension %LE = - mass of F— sol 7Tid3 -s ob ; tai —ned77 f -rom 11 ml of sus -pensi —on X 100

The results are shown below:

Table 9. Estimation of the encapsulation efficiency and loading efficiency of drug-loaded OLGADMA-based nanoparticles

OLGADMA-based NPs had EEs in the range of 39-70% while an EE of 74.5% was achieved with DNP-PLGA-PEG. The highest EE was achieved with DNP4Aa, while DNP8B had the lowest EE. The drug loading efficiency (LE) was estimated from the EE and the mass of solids obtained after 48 h of freeze-drying of dexamethasone-loaded NP suspensions. Dexamethasone-loaded OLGADMA-based NPs had LEs ranging from 23-59% while DNP- PLGA-PEG had an LE of 25.5%.

This example shows that nanoparticle compositions comprising an active agent of the present invention may be prepared with high encapsulation efficiencies and drug loading efficiencies.

Example 10 - Stability of nanoparticles at 37 °C in water

This example shows the superior size stability of the nanoparticle compositions of the present invention compared to PLGA-PEG nanoparticle compositions. This example further investigates the structure of the nanoparticle compositions using FTIR spectroscopy. PLGA- PEG microparticles develop an acidic core and undergo swelling during incubation at or above physiological temperature in aqueous medium, due to hydrolytic polymer degradation. While these processes can affect carrier size, cargo stability and drug release kinetics, they are often poorly understood at the nanoscale. The in vitro stability of empty NPs of Example 2 was tested by incubation of aqueous NP suspensions at the physiological temperature of 37 °C over a period of 5 weeks. OLGADMA/PEGDA700 and PLGA-PEG-COOH nanoparticle suspensions (2 mL) were placed in test tubes, sealed with parafilm, incubated at 37 °C and left stirring at 500 rpm. At determined time points, samples (300 pL) were collected for DLS and pH analysis, then freeze-dried for FTIR analysis. NP size, PI and ^-potential weekly were recorded (FIG. 6). OLGADMA-based suspensions maintained a high degree of colloidal stability throughout the study. Importantly, five OLGADMA-based NPs showcased a marked size-stability, with limited size-oscillations detected throughout the study. Conversely, the NP- PLGA-PEG control of Example 6 displayed a substantial and progressive increase in size over time. The size of NP-PLGA-PEG doubled after two weeks of incubation, reaching a 10-fold increase in size after 5 weeks of incubation. Remarkably, the PI of OLGADMA-based NPs was maintained below 0.4 throughout the study, while the PI of NP-PLGA-PEG gradually increased after 2 weeks of incubation, reaching a value of 0.7 which indicates a substantial broadening of the NP size distribution. Furthermore, the presence of large particles in NP- PLGA-PEG suspensions was detectable at week 4 and 5, which is indicative of NP aggregation. The ^-potential of all NPs was negative throughout the study, with most of the measurements regarding OLGADMA-based NPs showing values below -40 mV. While the

potential of OLGADMA-based NPs was variable during the experiment and showed no regular trend, the ^-potential of NP-PLGA-PEG gradually progressed towards less negative values. To establish an eventual acidification of NP suspensions due to hydrolysis of esters contained within the NPs, we measured the pH of the samples (FIG. 16). The pH of all freshly prepared suspensions was found to be < 5, with the NP-PLGA-PEG suspension being the most acidic and the suspension NP4Aa the least acidic. Suspensions containing OLGADMA-based NPs generally retained a pH above 4 during the study, while the pH of NP-PLGA-PEG suspensions gradually decreased, until reaching a value of 2.4 after 5 weeks of incubation.

NP4Aa, NP4Ab, NP4Ba, and NP4Bb were further analyzed by FTIR spectroscopy, to identify and compare potential changes in NP chemical composition. While the FTIR spectrum of NP4Ab remained identical over the course of the experiment, spectral changes were been detected with NP4Aa and NP4Bb (FIG. 7). An evolution of a broad vibration in the OH stretch region became visible in both spectra and is more pronounced with NP4Aa. Furthermore, changes in the fingerprint region are detectable in NP4Aa, which are particularly visible at week 5. We hypothesize these changes to derive from partial hydrolysis of esters under experimental conditions. The observed changes in the chemical composition were not accompanied by a simultaneous variation of the size of the NPs, as confirmed by DLS.

This example shows that PLGA-PEG nanoparticles (NP-PGLA-PEG) double in size after two weeks of incubation at 37 °C, and increase in size by ten times after 5 weeks of incubation at 37 °C. By contrast, the nanoparticle compositions of the present invention show almost no change in size throughout the study.

Example 11 - Drug release at 37 °C

This example investigates the release of dexamethasone from dexamethasone-loaded NP suspensions at 37 °C (FIG. 8). The release of dexamethasone was monitored using the sample-separate method over a 7-day period. The method consisted of incubation of the suspensions (400 pL) at 37 °C followed by ultrafiltration of the suspensions (MWCO 100 kDa). The samples were then centrifuged (14000 ref for 5 minutes at 37 °C) at determined time points and the retentate collected for dexamethasone quantitation. The content of the filter was then re-suspended by addition of water (400 pL), re-sealed, sonicated in a bath sonicator (2 min) and re-incubated at 37 °C. This operation was performed after each hour of incubation, over the first 5 h (phase 1), followed by 24 h incubation periods (phase 2). The released dexamethasone was quantified from the individual filtrates and cumulative release curves plotted against time.

The general procedure for dexamethasone quantification is outlined below: Analytical curves were constructed measuring the absorption of standard aqueous solutions of dexamethasone (25, 20, 15, 10, 5, 1 , 0.5 and 0 pg/mL) at 240 nm using a quartz cuvette. Limits of detection (LOD) and quantification (LOQ) were calculated as 3.3 o/S and 10 o/S, respectively, where o is the standard deviation of intercept and S is the slope of the calibration plot. The measurements were carried-out in triplicate for the quantitation of dexamethasone in the various experiments. Samples were subjected to dilution prior to measurement, in the event of absorbances larger than 1.

The prepared suspensions released up to 69% of their dexamethasone content during the 7-day period. The collected filtrates displayed a dexamethasone concentration above the limit of quantitation (LOQ), with exception of four filtrates from suspension DNP6B, which are designated with an asterisk (FIG. 8). Compared to phase 2, dexamethasone release rates were higher during phase 1 , possibly driven by frequent dispersant exchange. DNP-PLGA- PEG suspensions released dexamethasone at a faster rate during phase 2, while OLGADMA- suspensions exhibited slower rates of release. In detail, DNP-PLGA-PEG suspensions were found to release between 3 and 6% of their dexamethasone content daily. Suspensions prepared from DNP4Aa, DNP4Ab and DNP4Bb were releasing between 6 to <1% daily, whilst suspensions DNP6A, DNP6B and DNP8B were releasing <1% of their dexamethasone content daily. The highest total amount of dexamethasone was released from suspension DNP4Bb (69%) while the lowest amount was released from suspensions DNP6B (7%). Except for suspension NP4Bb, OLGADMA-based NP suspensions released less dexamethasone than NP-PLGA-PEG suspensions over 7 days.

This example shows that the nanoparticle compositions comprising an active agent of the invention may be fine-tuned so that they have optimum active agent release properties. Example 12 - Stability of drug-loaded nanoparticles in aqueous and biological media

This example investigates the stability of drug-loaded nanoparticles in aqueous and biological media. Many of the synthetic chemistry developed in the past yields NPs which are not stable in biological fluids. Contrary to dispersants such as deionized water, complete cell culture medium is rich in electrolytes and proteins. These two components can alter the colloidal stability of NPs resulting in modifications of their behaviour in vitro and in vivo. For instance, aggregation can influence the dosimetry, cellular uptake and toxicity of NPs in vitro, and affect pharmacokinetics, biodistribution and toxicity in vivo. To assess the colloidal stability in the presence of salts and proteins, the size of DNP4Aa, DNP4Ab and DNP4Bb was measured in (i) deionized water, (ii) DMEM and (iii) FBS-supplemented DMEM after incubation at 37 °C (FIG. 9). Specifically, dexamethasone-containing nanoparticle suspensions (20 pL) were mixed with the dispersant (900 pL of either water, DMEM, and FBS-supplemented DMEM) and left to equilibrate at room temperature for 15 min. The samples were then incubated at 37 °C for 2 hours and analyzed by DLS size and PI. Prior to DLS analysis, the samples containing FBS were centrifuged (15000 ref at room temperature for 20 minutes), the supernatant discarded, and the sediment re-suspended in FBS-free media (900 pL) by simple inversion of the centrifuge tube.

The NPs retained their initial size after 2 h of incubation in deionized water, while the PI values slightly decreased. Incubation in DMEM led to an 80% increase in size on average. The simultaneous increase in PI values is strongly suggestive of particle aggregation. Conversely, incubation in DMEM supplemented with FBS (10%) induced only a minimal increase in size. The detected size increments were roughly in the range of 4 - 35 nm, while the PI values were maintained below the 0.3 value. We hypothesize the tested NPs to naturally rely on electrostatic stabilization, which becomes challenged in an electrolyte-rich medium such as DMEM. This detrimental effect is lessened in the presence of proteins, possibly due to protein adsorption leading to the formation of a stabilizing protein corona.

This example shows that the nanoparticle compositions comprising an active agent of the invention maintain their physical properties, such as particle size and polydispersity, when stored in aqueous and biological media at elevated temperature.

Example 13 - Stability of drug-loaded NPs during storage at room temperature

This example investigates the stability of drug-loaded nanoparticles in aqueous solution at room temperature. The colloidal stability of DNP4Aa, DNP4Ab and DNP4Bb was evaluated during storage at room temperature (16-25 °C), exposure to moderate levels of natural light and in the absence of mechanical stirring. For this purpose, NP stock suspensions (100 pL) were suspended in deionised water (1.5 ml_), placed in transparent vials and stored on the bench over a period of 4 weeks. The suspensions were gently mixed by three inversions of the vial and analyzed by DLS weekly (FIG. 10). Samples were left to equilibrate for 2 h after preparation before the first measurement was taken. DNP4Aa and DNP4Bb maintained excellent size stability over time, while DNP4Ab showed only marginal size-variations (FIG. 10a). The PI of the suspensions was maintained below 0.4 and was most variable for DNP4Ab (FIG. 10b). The ^-potential was most stable for DNP4Bb, while DNP4Aa and DNP4Ab showed a slight evolution towards less negative values (FIG. 17).

This example shows that the nanoparticle compositions comprising an active agent of the invention maintain their physical properties, such as particle size, polydispersity, and

potential when stored in aqueous solution at room temperature.

Example 14 - Cytotoxicity and cellular uptake in vitro

This example investigates cytotoxicity of both empty and drug-loaded NPs and cellular uptake in vitro of empty NPs. The cytotoxicity of both empty and drug-loaded NPs prepared from tetramer OLGADMAs, the viability of HeLa cells upon 24 and 48 h of incubation with aqueous NP suspensions using the Cell Counting Kit-8 (CCK-8) assay was tested (FIG. 11). The assay uses a water-soluble tetrazolium salt which is converted to a yellow formazan dye by action of cellular dehydrogenases. The amount of the developed formazan dye is directly proportional to the number of living cells in the sample. After 24 h of incubation with NP suspensions, the normalized cell viability was above 80% for all tested NPs and NP concentrations. Furthermore, no significant decrease in cell viability could be detected after 48 h of incubation with NP suspensions. HeLa cells were then incubated with fluorescently (fluorescein) labelled NP4Aa and uptake of these NPs into these cells was verified, with highly uniform distribution (FIG. 12).

Cytotoxicity in vitro

HeLa cells were seeded in 96-well plates (5 x 10³ cells per well) in 100 pL of DMEM supplemented with 10% fetal bovine serum (FBS), 1% penicillin and streptomycin, and incubated for 24 h at 37 °C and 5% CO₂. Then, aliquots (10 pL) of 0.5, 0.25, 0.1 , 0.05, 0.01 and 0 mg/mL aqueous nanoparticle suspensions in water were added, and the cells incubated for 24 h and 48 h at 37 °C and 5% CO₂. Cell viability was measured using the Cell counting Kit-8 (CCK-8) assay, assigning 100% viability to cells treated with water.

Fluorescence microscopy

Fluorescein-labelled NP4Aa were prepared according to the standard nanoprecipitation polymerization and purification protocol, with the addition of fluorescein O- methacrylate (1 wt. % of monomers). NPs had a z-average mean diameter = 272 ± 6.6 nm, PI = 0.20 ± 0.06, ^-potential (deionized water, 25 °C) = -27.68 ± 1.2 mV. The cellular uptake of fluorescein-labelled NP4Aa was investigated using HeLa cells, which were seeded into an 8- well chambered coverslip for cell imaging (5 x 10⁴ cells per chamber) in 300 pL of DMEM with 10% FBS and incubated at 37 °C and 5% CO₂. The media was removed after 48 h of incubation and 300 pL of OptiMEM was added to each chamber, followed by the addition of an aqueous suspension of fluorescein labelled NP4Aa to achieve a NP content of 40, 60 and 100 pg/mL per chamber. The cells were then incubated at 37 °C and 5% C0₂ for 6 h after which the media was removed, the cells washed fourfold with sterile PBS and treated with 300 pL of a 4% paraformaldehyde solution per chamber for 15 min. The paraformaldehyde solution was then removed, the cells washed twice with PBS and stained with Hoechst stain for 15 min in the dark. The stain was then removed, the cells washed twice with PBS and stored in sterile PBS for imaging. The cells were imaged at 40x on a Leica SP8 DLS system using the oil immersion technique. This example shows that the nanoparticle compositions of the present invention, and the nanoparticle compositions comprising an active agent of the present invention, are highly biocompatible.

Example 15 - Optimization of dexamethasone encapsulation The optimization of dexamethasone encapsulation was carried-out during nanoprecipitation polymerization of 4Aa following General Procedure C with the modifications shown in Table 9, below. Examples of optimization runs with a varying amount of dexamethasone in the absence and presence of PEGDA700 are listed in Table 9.

Table 9. Nanoprecipitation polymerizations of 4Aa with different concentrations of dexamethasone in the absence and presence of PEGDA700.

The presence of the PEGDA700 monomer in the reaction mixture proved beneficial for drug encapsulation. Particularly, it was observed that a higher concentration of dexamethasone could be tolerated by the reaction system without compromising NP stability, when PEGDA700 was present.

Claims

1 . A nanoparticle composition obtainable from precipitation polymerisation of one or more oligomers of formula (I):

wherein:

L is a direct bond or a linker group selected from (la), and (lb):

R¹ and R² are independently H or -Me;

R³ and R⁴ are independently H or -Me; and wherein R³ R⁴ _;

2. A nanoparticle composition according to Claim 1 , wherein R¹ R².

3. A nanoparticle composition according to Claim 1 or Claim 2, wherein: q is 1 to 9; r is 0; and preferably wherein R¹ = R⁴; and R² = R³.

4. A nanoparticle composition according to Claim 1 or Claim 2, wherein: q is 0 and/or r is 0 to 18; preferably where r is 1 to 10; more preferably wherein r is 1 to 4.

5. A nanoparticle composition according to any one of Claims 1 to 4, wherein i) at least one of R¹ and R² is -Me; ii) q 0 and one of R³ and R⁴ is -Me; and/or iii) r 0 and R³ is -Me.

6. A nanoparticle composition according to Claim 5, wherein when any of R¹ to R⁴ are - Me: a) the resulting chiral centre has an (S) absolute configuration; b) the resulting chiral centre has an (R) absolute configuration; or c) the resulting chiral centre is racemic.

7. A nanoparticle composition according to any one of Claims 1 to 6, wherein: a) p is an integer from 1 to 10; preferably 1 to 5; more preferably 1 to 3; b) s is an integer from 1 to 10; preferably 1 to 5; more preferably 1 to 3; c) q is an integer from 0 to 9; preferably 1 to 3; more preferably 1 to 2; and/or d) r is an integer from 0 to 18; preferably 1 to 4; more preferably 1 to 2.

8. A nanoparticle composition according to any one of Claims 1 to 7, wherein p + 2q + r + s = 2 to 10, preferably wherein p + 2q + r + s = 2 to 8, more preferably wherein p + 2q + r + s = 4 to 6.

9. A nanoparticle composition according to Claim 1 , wherein the nanoparticle is formed from a precipitation copolymerisation of one or more oligomers of formula (IA) and one or more oligomers of formula (IB):

wherein: y is an integer from 2 to 20; z is an integer from 2 to 20; and

R⁵ R⁶, and R⁷ are as defined in Claim 1.

10. A nanoparticle composition according to any one of Claims 1 to 9, wherein: a) R⁵ is independently selected from: H, -(Ci-C₆)alkyl, -(C₆)aryl, halo, and -CN; wherein said -(Ci-C₆)alkyl or -(C₆)aryl group is optionally substituted with one or more group independently selected from: -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, halo, and -OH; b) R⁶ is independently selected from: H, -(Ci-C₆)alkyl, -(C₆)aryl, halo, and -CN; wherein said -(Ci-C₆)alkyl or -(C₆)aryl group is optionally substituted with one or more group independently selected from: -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, halo, and -OH; and/or c) R⁷ is independently selected from: H, -(Ci-C₆)alkyl, -(C₆)aryl, halo, and -CN; wherein said -(Ci-C₆)alkyl or -(C₆)aryl group is optionally substituted with one or more group independently selected from: -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, halo, and -OH; preferably wherein R⁵, R⁶, and/or R⁷ are independently selected from H or -Me; more preferably wherein R⁵, R⁶, and R⁷ are independently selected from H or -Me.

11. A nanoparticle composition according to any one of Claims 1 to 10, wherein at least two of R⁵, R⁶, and R⁷ are H.

12. A nanoparticle composition according to any one of Claims 1 to 11 , wherein the nanoparticle is obtainable from precipitation copolymerisation of: i) one or more oligomers of formula (I), (IA) and (IB); and ii) one or more oligomers of formula (II), (I I A) and (I IB):

wherein:

R⁸ is independently H or -Me;

R⁹ is independently H or -Me;

R¹⁰ is independently H or -Me;

R¹¹ is independently H or -Me

R¹² is H or -Me;

X is independently -Ci-C₃-alkyl-; and m is an integer from 5 to 50.

13. A nanoparticle composition according to any one of Claims 1 to 12, wherein the nanoparticle molecular weight (MW) is < 100 kDa.

14. A nanoparticle composition according to any one of Claims 1 to 13, wherein the z- average mean diameter of the nanoparticles is from 10 to 500 nm, as measured by dynamic light scattering.

15. A nanoparticle composition according to any one of Claims 1 to 13, wherein the composition comprises nanospheres.

16. A nanoparticle composition according to any one of Claims 1 to 15, wherein the composition further comprises an active agent, wherein the active agent is an active pharmaceutical ingredient, a cosmetic, or an agrochemical ingredient, wherein the active agent is stable in aqueous solution at temperatures up to 60 °C, preferably up to 70 °C, more preferably up to 80 °C.

17. A nanoparticle composition according to Claim 16, wherein the active agent is adsorbed and/or encapsulated by the nanoparticles.

18. A nanoparticle composition according to Claim 16 or 17, wherein the active ingredient has a molecular weight (MW) of < 10000 Daltons, preferably < 6000 Daltons, more preferably < 900 Daltons, most preferably < 500 Daltons.

19. A method for preparing a nanoparticle composition by precipitation polymerisation, said method comprising the steps of: i) providing a mixture comprising an oligomer of formula (I) as defined in any one of Claims 1 to 1 1 and a water-miscible organic solvent; ii) contacting an agitated aqueous solution with the mixture of step i) in the presence of a polymerisation initiator; wherein the aqueous solution is at a temperature of 60 to 80 °C, preferably from 65 to 75 °C, when contacted; and iii) obtaining a precipitate comprising a nanoparticle composition.

20. A method according to Claim 19, further comprising the following preceding steps for preparation of the oligomer of formula (I): a) performing an esterification of an acid of formula (IV):

wherein L, R¹, R², p and s are as defined in any one of Claims 1 to 8 and PG is a protecting group, preferably a silyl ether protecting group; with a compound of formula (VI):

wherein R⁵, R⁶ and R⁷ are as defined in any one of Claims 1 to 1 1 ; to yield an oligomer of formula (V):

wherein L, R¹, R², R⁵, R⁶, R⁷, p and s are as defined in any one of Claims

1 to 1 1 and PG is a protecting group, preferably a silyl ether protecting group; and deprotecting the oligomer of formula (V) and performing an esterification with a compound of formula (VII):

wherein R⁵, R⁶ and R⁷ are as defined in any one of Claims 1 to 11 , and wherein LG is a leaving group, preferably selected from -F, -Cl, -Br, -

b) to provide an oligomer of formula (I).

21. A method according to Claim 19 or Claim 20, wherein the oligomer of formula (I) is obtained from the oligomerisation of lactic acid and glycolic acid monomers, or derivatives thereof.

22. A method according to Claim 21 , wherein the ratio of lactic acid monomer units to glycolic acid monomer units, or derivatives thereof, is from 0.5 to 2.0 to 1 .0, preferably from 0.8 to 1.2.

23. A method according to Claims 21 or 22, wherein: a. the lactic acid monomer units are L-lactic acid monomer units; b. the lactic acid monomer units are D-lactic acid monomer units; or c. the lactic acid monomer units are L-lactic acid monomer units and D-lactic acid monomer units in a 1 :1 ratio.

24. A method according to any one of Claims 19 to 23, wherein the method further comprises providing an active agent in the mixture of step i) and obtaining a nanoparticle composition in step iii) comprising encapsulated active agent; wherein the active agent is an active pharmaceutical ingredient, a cosmetic, or an agrochemical igngredient, wherein the active agent is stable in aqueous solution at temperatures up to 60 °C, preferably up to 70 °C, more preferably up to 80 °C.

25. A method according to any one of Claims 19 to 24, wherein the water-miscible organic solvent in step i) comprises tetrahydrofuran (THF), dioxane, or acetonitrile, preferably tetrahydrofuran (THF).

26. A nanoparticle composition comprising an active pharmaceutical ingredient, as defined in any one of Claims 16 to 18, for use in therapy.

27. A nanoparticle composition comprising an active pharmaceutical agent as defined in any one of Claims 16 to 18, wherein the active pharmaceutical ingredient is an anti- inflammatory drug, preferably a synthetic glucocorticoid, such as dexamethasone, betamethasone, or prednisolone, for use in treating nausea in a subject, for example where the nausea is a symptom of chemotherapy and/or radiotherapy.

28. Use of a nanoparticle composition comprising an agrochemical ingredient, as defined in any one of Claims 16 to 18, as a controlled release agrochemical composition.

29. Non-therapeutic use of a nanoparticle composition comprising a cosmetic, as defined in any one of Claims 16 to 18, as a controlled release cosmetic composition.

30. An oligomer of formula (I):

wherein:

L is a direct bond or a linker group selected from (la), and (lb):

R¹ and R² are independently H or -Me;

R³ and R⁴ are independently H or -Me; and wherein R³ R⁴ _;

R⁵ is independently selected from: H, -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃- Cwjcycloalkyl, -(C₆-Cio)aryl, 4- to 10-membered heterocycloalkyl, 5- to 10- membered heteroaryl, halo, and -CN; wherein said -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Cio)cycloalkyl, -(C₆-Cio)aryl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl group is optionally substituted with one or more group independently selected from: -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, halo, -CN, -OH, and - NH₂;

R⁶ is independently selected from: H, -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃- Cwjcycloalkyl, -(C₆-Cio)aryl, 4- to 10-membered heterocycloalkyl, 5- to 10- membered heteroaryl, halo, and -CN; wherein said -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Cio)cycloalkyl, -(C₆-Cio)aryl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl group is optionally substituted with one or more group independently selected from: -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, halo, -CN, -OH, and - NH₂; R⁷ is independently selected from: H, -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃- Cio)cycloalkyl, -(C₆-Cio)aryl, 4- to 10-membered heterocycloalkyl, 5- to 10- membered heteroaryl, halo, and -CN; wherein said -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, -(C₃-Cio)cycloalkyl, -(C₆-Cio)aryl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl group is optionally substituted with one or more group independently selected from: -(Ci-C₆)alkyl, -O(Ci-C₆)alkyl, halo, -CN, -OH, and - NH₂; p is an integer from 1 to 20; s is an integer from 1 to 20; q is an integer from 0 to 9; r is an integer from 0 to 18; p + 2q + r + s = 2 to 20; and wherein when q + r = 0, L is a direct bond.

31. An acid of formula (IV):

wherein:

L is a direct bond or a linker group selected from (la), and (lb):

R¹ and R² are independently H or -Me;

32. An oligomer of formula (V):

wherein:

L is a direct bond or a linker group selected from (la), and (lb):

R¹ and R² are independently H or -Me;

R³ and R⁴ are independently H or -Me; and wherein R³ R⁴ _;

33. The oligomer of Claims 30 or 32, or the acid of Claim 31 , wherein L, R¹, R², R⁵, R⁶, R⁷, p and s are as defined in any one of Claims 2 to 1 1 .

34. A process for preparing an oligomer according to Claim 30 or Claim 33, the process comprising: a) performing an esterification of an acid of formula (IV):

wherein L, R¹ , R², p and s are as defined in any one of Claims 1 to 8 and PG is a protecting group, preferably a silyl ether protecting group: with a compound of formula (VI):

wherein L, R¹, R², R⁵, R⁶, R⁷, p and s are as defined in any one of Claims 1 to 1 1 and PG is a protecting group, preferably a silyl ether protecting group; and b) deprotecting the oligomer of formula (V), and performing an esterification with a compound of formula (VII):

wherein R⁵, R⁶ and R⁷ are as defined in any one of Claims 1 to 1 1 , and wherein LG is a leaving group, preferably selected from -F, -Cl, -Br, -

to provide an oligomer of formula (I).

35. A process for preparing an oligomer according to Claim 32 or Claim 33, the process comprising: a) performing an esterification of an acid of formula (IV):

wherein L, R¹, R², p and s are as defined in any one of Claims 1 to 8 and PG is a protecting group, preferably a silyl ether protecting group: with a compound of formula (VI):