Particle compositions comprising peptide and uses thereof

Abstract

Provided herein are compositions comprising a solid particle or pellet comprising a phosphorylcholine-phagostimulant peptide conjugate, including a salt thereof, and an ester-terminated poly (glycolide-co-lactide) wherein the phosphorylcholine-phagostimulant peptide conjugate is an amorphous solid; characterized by any one of: (i) an average particle size of less than 30 [mu] m as determined by SEM; (ii) the powder XRD lacks a corresponding peak having a net intensity peak height above about 30 counts. In addition, methods of treating an ocular disease or disorder in a subject by administering a therapeutically effective amount of a composition of the invention into the eye of the subject are also provided.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 395,863, filed on August 7, 2022, entitled “GRANULAR COMPOSITIONS COMPRISING APEPTIDE AND USES THEREOF,” the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention relates to solid polymer particles comprising peptides and uses thereof, such as for preventing or treating ocular diseases or disorders and / or conditions associated therewith in a subject. Background Art

[0004] Ocular inflammation - inflammation of any part of the eye, is one of the most common eye diseases. Ocular inflammation refers to various inflammatory diseases of the eye, one of which is uveitis. These diseases are common in all age groups and may be associated with systemic diseases such as Crohn's disease, Behcet's disease, juvenile idiopathic arthritis, etc. Inflammation may also be associated with other common eye symptoms such as dry eyes and dry macular degeneration. Several medications have known side effects of causing uveitis and / or dry eyes. The most common treatment for ocular inflammation is steroids, specifically corticosteroids. However, there are several known side effects of these treatments, which are sometimes serious.

[0005] Dazdotuftide or phosphorylcholine-tuftsin conjugate (PTC) is a bispecific synthetic peptide molecule with immunomodulatory activity. It is composed of tuftsin (Thr-Lys-Pro-Arg), a natural immunomodulatory peptide produced by enzymatic cleavage of the Fc domain of IgG heavy chains in the spleen. Phosphorylcholine (PC) is a zwitterionic small molecule secreted by helminths that allows helminths to survive in the host, induce conditions of immune tolerance, and survive on the surface of certain bacteria and apoptotic cells.

[0006] There is a need for a solid formulation of phosphorylcholine-tuftsin conjugate for direct administration to the eye. Specifically, such a solid formulation should be characterized by adequate storage shelf life and gradual release of the active agent at the site of administration over a predetermined period of time. Summary of the invention

[0007] In one aspect of the present invention, a composition is provided, which comprises a phosphorylcholine-tuftsin conjugate, including a salt thereof, wherein the phosphorylcholine-tuftsin conjugate is represented by the following formula 1:

[0008] The phosphorylcholine-tuftsin conjugate is an amorphous solid; and the phosphorylcholine-tuftsin conjugate is in the form of particulate matter characterized by an average particle size of less than 300 um as determined by SEM; and wherein the composition is characterized by a powder XRD lack of a corresponding peak of the phosphorylcholine-tuftsin conjugate having a net intensity peak height of more than 400 counts.

[0009] In one embodiment, the salt thereof is a pharmaceutically acceptable salt, wherein the water content of the composition is below 20%.

[0010] In one embodiment, the composition is a pharmaceutical composition comprising a pharmaceutically effective amount of the phosphorylcholine-tuftsin conjugate and further comprising a pharmaceutically acceptable carrier.

[0011] In another aspect, a composition is provided, comprising a plurality of particles, wherein each of the plurality of particles is a solid particle comprising a mixture of poly(glycolide-co-lactide) and a phosphorylcholine-tuftsin conjugate, wherein: the plurality of particles is characterized by at least one dimension being greater than 100 um; and the phosphorylcholine-tuftsin conjugate is an amorphous solid as determined by XRD.

[0012] In one embodiment, the weight concentration of the phosphorylcholine-tuftsin conjugate within the plurality of particles is about 1% to about 50%; and wherein the phosphorylcholine-tuftsin conjugate is in the form of particles characterized by an average particle size of less than 300 um as determined by SEM.

[0013] In one embodiment, at least one of the following: (i) 50% to 100% w / w of the polymer chains of the poly(glycolide-co-lactide) are ester terminated; (ii) the weight ratio between polylactide and polyglycolide in the poly(glycolide-co-lactide) is at least 1:1; (iii) the acid value of the poly(glycolide-co-lactide) is below 1 mg(KOH) / g; or any combination of (i)-(iii).

[0014] In one embodiment, the composition is characterized by a powder XRD lack of a net intensity peak height corresponding to the phosphorylcholine-tuftsin conjugate above 400 counts.

[0015] In one embodiment, the phosphorylcholine-tuftsin conjugate is represented by the following formula 1:

[0016]

[0017] In one embodiment, the composition is characterized by a density of 0.3 to 0.4 mg / mm 3 .

[0018] In one embodiment, the plurality of particles is an ocular drug implant (ODI).

[0019] In one embodiment, the ODI is in the form of elongated particles characterized by at least one of: a length dimension of about 1 mm to about 10 mm; a width dimension of about 0.1 mm to about 0.8 mm; optionally, wherein the ODI comprises a therapeutically effective amount of the phosphorylcholine-tuftsin conjugate.

[0020] In another aspect, an ocular drug implant (ODI) is provided, wherein the ODI is a solid material in the form of particulates, the solid material comprising a mixture of poly(glycolide-co-lactide) and a peptide; wherein: the ODI is characterized by at least one dimension being greater than 100 um; and the particulates are characterized by an average particle size of at most about 100 um as determined by SEM.

[0021] In one embodiment, the concentration of the peptide in the ODI is from about 1% to about 50% by weight.

[0022] In one embodiment, at least one of the following: (i) the weight ratio between polylactide and polyglycolide in the poly(glycolide-co-lactide) is at least 50:50; (ii) at least 80% w / w of the polymer chains of the poly(glycolide-co-lactide) are ester-terminated; (iii) the acid value of the poly(glycolide-co-lactide) is below 1 mg(KOH) / g; or a combination of (i)-(iii).

[0023] In one embodiment, the peptide is a hydrophilic peptide characterized by an aqueous solubility of at least 10 g / L; optionally, wherein the peptide is a phosphorylcholine-peptide conjugate.

[0024] In one embodiment, the ODI is substantially in the form of elongated particles, optionally characterized by at least one of the following: a length dimension of about 1 mm to about 10 mm; a width dimension of about 0.1 mm to about 0.8 mm.

[0025] In one embodiment, the ODI is an extrudate.

[0026] In one embodiment, the ODI is characterized by substantial release of the phosphorylcholine-tuftsin conjugate or the peptide in an aqueous medium.

[0027] In one embodiment, the weight ratio between polylactide and polyglycolide in the poly(glycolide-co-lactide) is at least 50:50; wherein at least 80% w / w of the polymer chains of the poly(glycolide-co-lactide) are ester-terminated; and wherein the substantial release comprises a cumulative release of at least 30% of the initial amount of the peptide or the phosphorylcholine-tuftsin conjugate over a period of time ranging from about 2 days to about 30 days.

[0028] In one embodiment, at least 80% by weight of the particulate matter has a particle size of about 5 um to about 100 um as determined by SEM.

[0029] In one embodiment, the average particle size of the particles is about 10 um to about 50 um as determined by SEM.

[0030] In one embodiment, the ODI comprises a therapeutically effective amount of the peptide.

[0031] In another aspect, a method for treating an ocular disease or disorder in a subject is provided, the method comprising administering a therapeutically effective amount of a composition of the invention or an ODI of the invention into the eye of the subject.

[0032] In one embodiment, the therapeutically effective amount comprises a daily dose of 0.01 μg to 100 μg of the phosphorylcholine-tuftsin conjugate or the peptide.

[0033] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the invention belongs. Although methods and materials similar to or equivalent to the methods and materials described herein can be used in the practice or testing of embodiments of the present invention, exemplary methods and / or materials are described below. In the event of a conflict, the patent specification (including definitions) shall prevail. In addition, these materials, methods and examples are merely illustrative and are not intended to be necessarily restrictive. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] The present invention will now be described with respect to certain examples and embodiments with reference to the following illustrative drawings so that it may be more fully understood. In the drawings:

[0035] Figure 1 is the powder XRD of original unmilled PTC pellets (upper panel, black) and ground PTC powder according to the present invention (lower panel, red). "PTC" refers to the compound of Formula 1 disclosed herein.

[0036] Figure 2A-2B are SEM images of original unmilled PTC particles (2A) and PTC particles according to the present invention (2B).

[0037] Figure 3A The SEM images of exemplary rod-shaped solid particles (i.e., ocular drug implants, ODIs) of the present invention obtained by extrusion of Resomer RG 752S with ground PTC powder according to the present invention (9% w / w drug loading). The left image shows a cross section, and the right image shows the surface of the rod-shaped solid particles.

[0038] Figure 3B is a graph showing the % aqueous cumulative release of PTC from ODI consisting of ester-terminated PLGA (Resomer RG 752S).

[0039] Figure 3C is an image of an exemplary rod-shaped solid particle (ODI) of the present invention.

[0040] Figure 3D is a graph showing the aqueous cumulative release of PTC from exemplary rod-shaped solid particles (ODI) of the present invention composed of ester-capped PLGA (Resomer RG 752S) with a drug loading of 9% compared to similar particles composed of uncapped Resomer RG 752H. DETAILED DESCRIPTION

[0041] The present invention, in some embodiments thereof, relates to solid compositions (e.g., ophthalmic compositions) comprising, inter alia, a phosphorylcholine-tuftsin conjugate, and to methods of treating medical conditions by administering the composition to a subject in need thereof. The present invention, in further embodiments thereof, relates to ophthalmic compositions for ocular administration and their use in treating medical conditions in a subject in need thereof.

[0042] The present invention is based on the following surprising discovery in some embodiments thereof: the poly(glycolide-co-lactide) (PLGA)-based solid particles (i.e., ODI) comprising a phosphorylcholine-tuftsin conjugate (PTC) disclosed herein exhibit an improved release profile compared to microspheres composed of similar components. Specifically, the inventors surprisingly found that ester-terminated PLGA (referred to herein as Resomer 752S) exhibits excellent drug loading efficiency and aqueous release profile (showing sustained release, as shown herein) when used in the solid particles of the present invention compared to similar acid-terminated polymers (i.e., uncapped PLGA, referred to herein as Resomer 752H). In addition, the inventors also surprisingly found that by using PTC with an average particle size reduced to less than about 30um, uniform solid particles are produced, and the slow release profile from the solid particles is improved. In contrast, similar solid particles containing unmilled (original) solid PTC with an average particle size of about 30um to about 100um produce a burst release profile.

[0043] As used herein, the term "phosphorylcholine tuftsin conjugate" refers to a phosphorylcholine moiety covalently linked to tuftsin or to a tuftsin derivative, optionally via a spacer. As used herein, the term "phosphorylcholine tuftsin conjugate" also includes any salt (e.g., a pharmaceutically acceptable salt) and any isotope thereof.

[0044] As used herein, the term "tuftsin" refers to a tetrapeptide (threonine-lysine-proline-arginine, TKPR; SEQ ID NO: 1). In some embodiments, the PTC is or includes a tuftsin (i.e., a peptide having an amino acid sequence defined in SEQ ID NO: 1) covalently bound to a phosphorylcholine moiety via a side chain (e.g., a phosphate group is directly bound to the side chain of threonine or to the side chain of lysine). In some embodiments, the PTC is or includes a tuftsin (i.e., a peptide having an amino acid sequence defined in SEQ ID NO: 1) covalently bound to a phosphorylcholine moiety via an amino terminus (e.g., a phosphate group is directly bound to an amino group to generate a phosphoramidate). In some embodiments, the PTC is or includes a tuftsin (i.e., a peptide having an amino acid sequence defined in SEQ ID NO: 1) covalently bound to a phosphorylcholine moiety via an amino terminus (e.g., a phosphate group is directly bound to an amino group to generate a phosphoramidate). In some embodiments, the PTC is or includes a tuftsin (ie, a peptide having an amino acid sequence defined in SEQ ID NO: 1) covalently bound to a phosphorylcholine moiety via the carboxyl terminus (eg, the carboxyl group is directly bound to the phosphate group to form a phosphorylated carboxylate).

[0045] The term "phosphorylcholine moiety" includes phosphorylcholine, i.e. And derivatives of phosphorylcholine. As used herein, the term "derivative of phosphorylcholine" refers to any compound based on phosphorylcholine. In some embodiments, the derivative retains the immunomodulatory effect of phosphorylcholine. In some embodiments, the phosphorylcholine derivative is a derivative including phosphorylcholine.

[0046] In some embodiments, the derivative of phosphorylcholine is selected from: phenylphosphorylcholine, substituted phenylphosphorylcholine (e.g., aminophenylphosphorylcholine, nitrophenylphosphorylcholine, halogenated phenylphosphorylcholine, hydroxyphenylphosphorylcholine, alkylphenylphosphorylcholine) and 12-(3-iodophenyl)dodecylphosphorylcholine, etc. Each possibility is an independent embodiment of the present invention.

[0047] In some embodiments, the derivative of phosphorylcholine is represented by the following Formula 2:

[0048] wherein each R is independently an optionally substituted alkyl (e.g., methyl, or any C1-10, or C2-C10 alkyl); and wherein X is a spacer. In some embodiments, X comprises a small molecule, such as natural and / or unnatural amino acids (one or more), C5-C10 cycloalkylene, optionally substituted C1-C6 alkylene, -C(=O)-C1-C6 alkylene, optionally substituted C6-C10 arylene, aryl (or heteroaryl)-azo, heteroaromatic ring (one or more), carbocyclyl; a bond (e.g., an amide bond, an ester bond, an azo bond, a thioester bond, a disulfide bond, -NC(=O)-, -C(=O)N-, CONR '-, -CNNR'-, -CSNR'-, -NC(=O)O-, -NC(=S)O-, -NC(=S)N-, -SO2-, -SO-, -SR', -C(=O)-, -OC(=O)-, -OC(=O)O-, -OC(=S)O- and -OC(=S)N-; -SC(=O)), formula -(RO)x-diol, wherein R represents a C1-C10 alkyl group; and x is an integer ranging from 1 to 10, or any combination thereof.

[0049] In some embodiments, X is or includes a straight chain or a branched chain. In some embodiments, X includes a main chain including a straight chain or a branched chain. In some embodiments, X includes a cyclic (aromatic or aliphatic) main chain.

[0050] In some embodiments, the derivative of phosphorylcholine is represented by Formula 2, wherein R is methyl.

[0051] In some embodiments, X is

[0052] In some embodiments, the MW of the spacer is less than 500 Da, less than 400 Da, less than 300 Da, less than 200 Da, less than 100 Da, or 30 to 100 Da, 30 to 200 Da, 30 to 300 Da, including any ranges therebetween.

[0053] In some embodiments, the spacer is 1 to 50, 1 to 100, 2 to 100, 2 to 80, 2 to 60, 5 to 50, 10 to 50, 10 to 40, 2 to 30, 2 to 20, 2 to 10, 1 to 5, 5 to 10, 5 to 15, 5 to 25, 5 to 50 single C-C bond lengths, including any range therebetween.

[0054] The term "tuftsin derivative" refers to a tuftsin peptide (TKPR, SEQ ID NO: 1) linked to at least two other independently selected amino acids. Unnatural amino acids, preferably uncharged and non-polar unnatural amino acids, such as β-alanine-6-aminohexanoic acid and 5-aminopentanoic acid, may also be included in the tuftsin derivative. In some embodiments, the tuftsin derivative is TKPR (X1) (X2), wherein X1 is an amino acid selected from Gly, Ala, Val, Thr, Leu, Ile and Met; and wherein X2 is an amino acid selected from Tyr, Trp, Phe, Cys, Ser, Thr, Gly, Ala, Val, Thr, Leu, Ile and Met.

[0055] In some embodiments, the tuftsin derivative is a peptide that contains TKPR and retains the immunomodulatory effects of tuftsin. The derivative is not merely a fragment of the polypeptide, nor is the amino acid substituted or removed (analog), but rather, it may have additional amino acid residues and / or modifications to the polypeptide, such as post-translational modifications.

[0056] In some embodiments, the tuftsin derivative is Threonine-Lysine-Proline-Arginine-Glycine-Tyrosine (TKPRGY, SEQ ID NO: 2).

[0057] In some embodiments, as used herein, the term "portion" refers to a portion of a molecule that lacks one or more atoms compared to a corresponding molecule. As used herein, the term "portion" also refers to a portion of a molecule that may include an entire functional group or a portion of a functional group as a substructure (e.g., an amino group lacking hydrogen, a phosphate group lacking hydrogen or a hydroxyl group, an amino acid residue, etc.). The term "portion" also refers to a portion of a molecule that exhibits a specific set of chemical and / or pharmacological properties similar to a corresponding molecule.

[0058] As used herein, the term "connected" or "attached" refers to a bond between at least two molecules or moieties such that they are a single molecule. In some embodiments, the bond is a chemical bond. In some embodiments, the bond is a covalent bond. According to the principles of the present invention, the natural and non-natural amino acids contained in the tuftsin derivatives are adjacent to each other and attached, and at least one phosphorylcholine derivative is directly attached or indirectly attached to at least one tuftsin derivative via a spacer. In some embodiments, at least one phosphorylcholine or a derivative thereof is connected to the N-terminus of at least one tuftsin or a derivative thereof. In some embodiments, at least one phosphorylcholine or a derivative thereof is connected to the C-terminus of at least one tuftsin or a derivative thereof.

[0059] In some embodiments, the phosphorylcholine-tuftsin conjugate comprises one or more phosphorylcholine moieties attached to the tuftsin derivative. In certain embodiments, the phosphorylcholine moiety (i.e., a derivative of phosphorylcholine represented by Formula 2) is covalently bound to the tuftsin derivative. In some embodiments, the covalent binding is via the side chain of the tuftsin derivative. In some embodiments, the covalent binding is via the side chain of Tyr (e.g., via an azo bond bound to the side chain of Tyr). In some embodiments, the phosphorylcholine-tuftsin conjugate is represented by the following Formula 1.

[0060] In one aspect of the present invention, a composition is provided, comprising a phosphorylcholine-tuftsin conjugate (PTC), including any salt thereof, wherein the PTC is in the form of a particulate matter, the particulate matter being characterized by any of the following: (i) an average particle size of less than 300um or less than 200um as determined by SEM; and (ii) a powder XRD lacking a corresponding peak of the PTC having a net intensity peak height of more than about 400 counts. In some embodiments, the PTC is as disclosed herein.

[0061] In another aspect of the invention, a composition is provided comprising a peptide, including any salt thereof, wherein the peptide is in the form of a particulate material characterized by any of the following: (i) an average particle size of less than 300um or less than 200um as determined by SEM; and (ii) a powder XRD lack of a corresponding peak of the peptide having a net intensity peak height of more than about 400 counts. In some embodiments, the peptide is a peptide-phosphorylcholine conjugate, as disclosed herein for PTC. In some embodiments, the peptide is a peptide-phosphorylcholine conjugate comprising a phosphorylcholine moiety bound to (i) a side chain (e.g., a Lys or Tyr side chain) of the peptide and / or (ii) to the C-terminus or N-terminus of the peptide.

[0062] In some embodiments, the peptide is 3 to 50, 3 to 10, 3 to 20, 3 to 5, 5 to 10 amino acid residues long, including any range therebetween.

[0063] As used herein, the terms "peptide", "polyamino acid", "polypeptide" and "protein" are used interchangeably and refer to polymers of amino acid residues. In some embodiments, the peptide of the present invention is or includes a therapeutic peptide sequence. The term "therapeutic peptide sequence" refers to any peptide sequence configured to induce a therapeutic effect (e.g., treatment, prevention, alleviation of symptoms of a disease, etc.) in a subject. In addition, the term "therapeutic peptide sequence" also includes any polyamino acid sequence that can modify the activity, functionality, survival, health, appearance, structure, development, behavior, or any combination thereof of a cell. In some embodiments, the therapeutic sequence is capable of binding to an intracellular target (e.g., an enzyme) to control (upregulate or downregulate) the activity of the intracellular target.

[0064] As used herein, the terms "peptide", "polyamino acid", "polypeptide" and "protein" include natural peptides, peptide derivatives such as beta peptides, peptide mimetics (generally including non-peptide bonds or other synthetic modifications), and peptide analog mimics and semi-mimics or any combination thereof. In another embodiment, the terms "peptide", "polyamino acid" and "protein" are applicable to amino acid polymers in which at least one amino acid residue is an artificial chemical analog of the corresponding naturally occurring amino acid.

[0065] The term "derivative" or "chemical derivative" includes any chemical derivative of a polypeptide having one or more residues chemically derivatized (or chemically modified) by reaction on a side chain or any functional group of the peptide. Such derivatized molecules include, for example, peptides carrying one or more protecting groups (e.g., side chain protecting group(s) and / or N-terminal protecting group), and / or peptides in which free amino groups have been derivatized to form amine hydrochlorides, p-toluenesulfonyl, benzyloxycarbonyl, tert-butyloxycarbonyl, acetyl or formyl groups. Free carboxyl groups can be derivatized to form amides, salts, methyl and ethyl esters or other types of esters or hydrazides thereof. Free hydroxyl groups can be derivatized to form O-acyl or O-alkyl derivatives. The imidazole nitrogen of histidine can be derivatized to form N-im-benzylhistidine. Also included as chemical derivatives are those peptides containing one or more naturally occurring amino acid derivatives of the twenty standard amino acid residues. For example: 4-hydroxyproline can be substituted for proline; 5-hydroxylysine can be substituted for lysine; 3-methylhistidine can be substituted for histidine; homoserine can be substituted for serine; and Dab, Daa and / or ornithine (O) can be substituted for lysine.

[0066] In addition, the peptide derivatives can be distinguished from the native sequence of the peptides of the present invention by chemical modifications, including but not limited to terminal-NH2 acylation, acetylation or thioglycolic acid amidation, and amidation of terminal and / or side chain carboxyl groups (e.g., with ammonia, methylamine, etc.). The peptides can be linear, cyclic or branched, etc., in any conformation, which can be achieved using methods known in the art.

[0067] As used herein, the term "amino acid" means an organic compound containing both a basic amino group and an acidic carboxyl group. Included within the scope of this term are naturally occurring amino acids, protected amino acids (e.g., containing one or more protecting groups on the carboxyl group, amine and / or side chain of the amino acid), unusual non-naturally occurring amino acids (such as D-amino acids), and amino acids known to exist in biology in free or bound form but not usually found in proteins. Modified, unusual, non-naturally occurring amino acids, and amino acids known to exist in biology in free or bound form but not usually found in proteins. Included within the scope of this term are modified and unusual amino acids, such as those disclosed in, for example, Roberts and Vellaccio (1983) The Peptides. 5: 342-429. Modified, unusual or non-naturally occurring amino acids include, but are not limited to, D-amino acids, hydroxylysine, 4-hydroxyproline, N-Cbz protected aminovaleric acid (Nva), ornithine (O), aminooctanoic acid (Aoc), 2,4-diaminobutyric acid (Abu), homoarginine, norleucine (Nle), N-methylaminobutyric acid (MeB), 2-naphthylalanine (2Np), aminoheptanoic acid (Ahp), phenylglycine, β-phenylproline, tert-leucine, 4-aminocyclohexylalanine (Cha), N-methyl-norleucine, 3,4-dehydroproline, N,N-dimethylaminoglycine, N-methylaminoglycine, 4-aminopiperidine-4-carboxylic acid, 6-aminohexanoic acid, trans-4-(aminomethyl)-cyclohexyl Alkanecarboxylic acids, 2-, 3- and 4-(aminomethyl)-benzoic acids, 1-aminocyclopentanecarboxylic acid, 1-aminocyclopropanecarboxylic acid, cyanopropionic acid, 2-benzyl-5-aminopentanoic acid, norvaline (Nva), 4-O-methyl-threonine (TMe), 5-O-methyl-homoserine (hSM), tert-butylalanine (tBu), cyclopentylalanine (Cpa), 2-amino-isobutyric acid (Aib), N-methyl-glycine (MeG), N-methyl-alanine (MeA), N-methyl-phenylalanine (MeF), 2-thienyl-alanine (2Th), 3-thienyl-alanine (3Th), O-methyl-tyrosine (YMe), 3-benzothienyl-alanine (Bzt) and D-alanine (DA1).

[0068] The term "polyamino acid" also includes random polymers (i.e., lacking a specific amino acid sequence throughout the composition and including a population of random polymers of varying lengths and sequences) and polypeptides with a specific amino acid sequence. The terms "peptide sequence" and "amino acid sequence" are used interchangeably herein. In some embodiments, the peptide sequence is or includes a D-amino acid sequence. In some embodiments, at least 70%, at least 80%, at least 90%, at least 95% of the amino acids in the peptide sequence are in D-configuration. In some embodiments, the amino acids in the peptide sequence are in D-configuration.

[0069] In some embodiments, a composition of the invention (eg, ODI) comprises a peptide in the form of a particulate as disclosed herein.

[0070] In another aspect of the present invention, a composition is provided, which comprises PTC, including a salt thereof, wherein the PTC is represented by the following Formula 1:

[0071]

[0072] The PTC is an amorphous solid; and the PTC is in the form of a particulate matter characterized by any of the following: (i) an average particle size of less than 300um or less than 200um as determined by SEM; and (ii) a powder XRD lack of corresponding peaks with net intensity peak heights above about 400 counts. In some embodiments, the PTC is an amorphous powder.

[0073] In some embodiments, the average particle size of the particles is 10nm to 300um, 10nm to 200um, 10nm to 180um, 10nm to 150um, 10nm to 100um, 20nm to 100um, 10nm to 80um, 10nm to 75um, 10nm to 1um, 10nm to 10um, 100nm to 10um, 100nm to 1um, 100nm to 1um, 100nm to 5um, 100nm to 5um, 10nm to 500um, 100nm to 500um, 300nm to 10um, 300nm to 5um, 300nm to 1um, 300nm to 500um, 300nm to 800um, 500nm to 10um, 500nm to 1um, 10nm to 100nm, 100nm to 500nm, 500nm to 800um, 800nm ​​to 30um, 800nm ​​to 5um, 5um to 30um, 1nm to 30um, 1um to 10um, 1um to 75um, 1um to 150um, 1um to 100um, 1um to 50um, 1um to 60um, 10um to 30um, including any range therebetween, wherein the average particle size is determined by SEM. In some embodiments, the particle size of at least 80% by weight of the particulate matter has a particle size determined by SEM of about 5um to about 100um, about 20um to about 100um, about 20um to about 80um, about 20um to about 60um, about 20um to about 50um, about 20um to about 40um.

[0074] In some embodiments, the particulate matter is an amorphous powder. In some embodiments, the PTC (particulate matter) is characterized by a substantial lack of corresponding peaks in the powder XRD (X-ray diffraction pattern). In some embodiments, the XRD of the PTC is characterized by corresponding peaks significantly lower than corresponding peaks of the original powdered PTC. The term "original" refers to the PTC obtained by freeze-drying a purified (or crude) PTC solution. The inventors observed that the original PTC is substantially characterized by an average particle size of about 200um, and further in the form of irregularly shaped pellets. In addition, the original PTC is also characterized by the presence of corresponding small peaks in the powder XRD (see Figure 1 , the above diffraction pattern), while the PTC of the present invention substantially lacks any obvious corresponding XRD peaks, such as Figure 1 Shown (red diffraction pattern below).

[0075] In some embodiments, the particle size of the particulate material is as described above, wherein the particulate material is amorphous, characterized by a powder XRD of PTC lacking a corresponding peak (i.e., a peak of PTC), with a net intensity of more than 400 counts, more than 300 counts, more than 200 counts, more than 100 counts, about 50 counts, more than about 40 counts, more than about 30 counts, more than about 20 counts, more than about 10 counts, more than about 5 counts, including any ranges therebetween. In some embodiments, the particle size of the particulate material is as described above, wherein the powder XRD of PTC substantially lacks a corresponding peak with a total intensity of more than about 200 counts, more than about 150 counts, more than about 100 counts, more than about 80 counts, more than about 60 counts, more than about 50 counts, more than about 40 counts, more than about 30 counts, more than about 20 counts, more than about 10 counts, including any ranges therebetween. In some embodiments, the corresponding peak of the PTC measured by powder XRD has a peak height (net intensity) of 1 to 200 counts, 1 to 100 counts, 1 to 300 counts, 1 to 50 counts, 1 to 40 counts, 1 to 30 counts, 1 to 20 counts, 1 to 10 counts, including any range therebetween, where the peak height refers to the normalized peak intensity.

[0076] The inventors surprisingly found that the PTC in the form of particulates described herein (e.g., PTC of Formula 1) is highly superior to the original PTC, especially when incorporated into the solid particles (ODI) of the present invention, resulting in ODI with an optimal active agent (PTC) loading and also characterized by a sustained release profile of the active agent.

[0077] In some embodiments, the salt of PTC is a pharmaceutically acceptable salt. Pharmaceutically acceptable salts are well known in the art, and include, in particular, alkali metal salts, alkaline earth metal salts and / or ammonium salts, as well as halides (e.g., chlorides), citrates, acetates, trifluoroacetates, phosphates, borates, lactates and the like salts and mixtures thereof. In some embodiments, the peptides disclosed herein (e.g., PTC) are pharmaceutical grade active agents (e.g., characterized in that the chemical purity is above 97%). In some embodiments, the entire composition of the composition and / or ODI of the present invention is substantially a chemically pure compound.

[0078] In some embodiments, the composition of the present invention is a pharmaceutical composition comprising a pharmaceutically effective amount of PTC and further comprising a pharmaceutically acceptable carrier. In some embodiments, the composition of the present invention is a pharmaceutical composition comprising a pharmaceutically effective amount of a peptide and further comprising a pharmaceutically acceptable carrier.

[0079] In some embodiments, the composition of the present invention is formulated for ocular administration. In some embodiments, the pharmaceutical composition is an ophthalmic composition. In some embodiments, the terms "ophthalmic composition" and "pharmaceutical composition" are used interchangeably herein. In some embodiments, the pharmaceutical composition is formulated for ocular administration. In some embodiments, the composition of the present invention comprises a phosphorylcholine-tuftsin conjugate as the sole pharmaceutically active ingredient. In some embodiments, the composition of the present invention is substantially devoid of any additional pharmaceutically active ingredient. In some embodiments, the composition of the present invention is substantially devoid of any additional peptides. In some embodiments, the composition of the present invention is substantially devoid of any additional anti-inflammatory agents.

[0080] In another aspect, a composition is provided, comprising a plurality of particles, wherein each of the plurality of particles is a solid particle comprising poly(glycolide-co-lactide) (PLGA) and a phosphorylcholine-tuftsin conjugate of the present invention. In some embodiments, the solid particle is ODI. The terms "solid particle" and "ODI" are used interchangeably herein.

[0081] In some embodiments, PLGA and PTC are mixed together in solid particles. In some embodiments, PLGA and PTC are in the form of a mixture in solid particles. In some embodiments, PLGA and PTC are in the form of a uniform mixture in solid particles. In some embodiments, solid particles are composite materials including PLGA and PTC or composite materials mainly composed of PLGA and PTC. In some embodiments, solid particles are a mixture of PLGA and PTC or are mainly composed of a mixture of PLGA and PTC. In some embodiments, "mainly composed of..." includes 80% to 100%, 80% to 99%, 90% to 99%, 90% to 100%, 92% to 99%, 93% to 99%, 95% to 99%, 95% to 97%, 93% to 100%, 95% to 100%, 97% to 99%, 97% to 100% by dry weight of solid particles.

[0082] In some embodiments, PLGA is in the form of a matrix. In some embodiments, the mixture includes PTC particles embedded or incorporated into the PLGA matrix. In some embodiments, the mixture includes PTC particles surrounded by the PLGA matrix.

[0083] As used herein, the term "matrix" refers to one or more layers of polymer chains randomly (and / or with an ordered distribution) distributed therein. In addition to PTC particles, the matrix may also include any material incorporated into these layers and / or inserted between these layers. In some embodiments, the matrix includes randomly oriented polymer chains. In some embodiments, each polymer chain in the matrix is ​​in contact with at least one additional polymer chain. In some embodiments, the polymer chains are randomly distributed in the matrix to obtain a three-dimensional network structure containing void spaces between these chains. In some embodiments, the polymer chains are randomly distributed in the matrix to form an interwoven polymer network optionally having a plurality of pores (or void spaces). In some embodiments, the matrix is ​​an interwoven matrix composed of randomly distributed polymer chains and is characterized by low porosity, as disclosed herein. In some embodiments, the matrix substantially lacks polymer chains arranged or oriented in a particular direction.

[0084] In some embodiments, (i) PLGA is substantially ester-terminated; and / or (ii) the weight ratio between polylactide and polyglycolide in poly(glycolide-co-lactide) is 50:50 to 95:5, including any range therebetween. In some embodiments, ester-terminated PLGA refers to the alkylated terminal carboxyl group of the polymer (e.g., terminal glycolate alkylation). In some embodiments, the terminal carboxyl group is alkylated by a C1-C10 alkyl group to obtain a terminal C1-C10 ester (e.g., methyl ester). In some embodiments, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% w / w, or 60% to 95%, 70% to 95%, 80% to 95%, about 80% to about 90%, about 85% to about 90% of the entire polymer chain of PLGA is ester-terminated by weight.

[0085] In some embodiments, at least 50%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% w / w, or 60% to 95%, 70% to 95%, 50% to 95%, 50% to 99%, 80% to 95%, about 80% to about 90%, about 85% to about 90% of the entire polymer chains of PLGA are ester-terminated.

[0086] In some embodiments, the ester-capped PLGA has an acid value of at most 20%, at most 15%, at most 10% compared to the acid value of the same polymer that is not ester-capped (i.e., the free acid polymer). In some embodiments, the acid value of the ester-capped PLGA is below 1 mg KOH / gr PLGA.

[0087] In some embodiments, the PLGA comprises less than 20%, less than 10%, less than 5%, less than 3%, less than 1% of uncapped PLGA (eg, PLGA having terminal carboxyl groups) based on the total weight of the PLGA.

[0088] In some embodiments, the PLGA is characterized by an average molecular weight (Mw) of 5,000 to 10,000, 10,000 to 20,000, 10,000 to 15,000, 5,000 to 15,000, 7,000 to 20,000 Da, including any ranges therebetween.

[0089] In some embodiments, the solid particles disclosed herein are in a solid state at a temperature below the melting point of PLGA (eg, below 200°C, or below 150°C).

[0090] In another aspect, the ODI of the present invention comprises a biodegradable polymer and a peptide, wherein the peptide is in the form of a particulate, as disclosed herein, and is mixed with the biodegradable polymer throughout the volume of the ODI, and wherein the weight concentration of the peptide within the ODI is as disclosed herein (between 1-50% w / w). In some embodiments, the biodegradable polymer is a polyester. In some embodiments, the polyester is uncapped. In some embodiments, the polyester is ester-capped. In some embodiments, the polyester comprises any one of the following: polycaprolactone, poly-ε-caprolactone (PCL), polyglycolide, polylactide, poly-l-lactide (PLLA), poly-d,l-lactide (PLA), polyglycolide, polylactic acid, polycaprolactone (PCL), polyhydroxyalkanoate, polyhydroxybutyrate, polyethylene adipate, polybutylene succinate, poly(3-hydroxybutyrate-co-3-hydroxyvalerate), polyethylene terephthalate (PET), polybutylene terephthalate, polyethylene naphthalate (PEN), including any copolymer or any combination thereof. In some embodiments, the biodegradable polymer is PLGA, and the peptide is PTC, as disclosed herein.

[0091] In some embodiments, the composition of the invention comprising the solid particles disclosed herein is a pharmaceutical composition. In some embodiments, the composition of the invention consists essentially of pharmaceutical grade components. In some embodiments, the composition of the invention is used to treat an ocular disease or disorder or a condition associated therewith via administration of a pharmaceutically effective amount of the composition into the eye of a subject. In some embodiments, the pharmaceutically effective amount of the composition comprises a pharmaceutically effective amount of PTC.

[0092] In some embodiments, the solid particles (ODI) are melt-granulated unit pharmaceutical dosage forms of the PTC of the present invention. In some embodiments, the solid particles (ODI) contain a therapeutic amount of a peptide (i.e., a therapeutic peptide, such as a PTC disclosed herein) in the following ranges per ODI: 0.01 to 200 μg, 0.01 to 100 μg, 1 to 100 μg, 0.1 to 100 μg, 10 to 100 μg, 100 to 200 μg, 50 to 200 μg, 20 to 100 μg, 20 to 200 μg, including any range or value therebetween.

[0093] ODI refers to intraocular implants well known in the art. ODI is made and implanted in order to regulate the outflow of drugs, thereby prolonging the time when the disease state is controlled. ODI can release high drug concentrations at the expected position by site-specific implantation. In addition, ODI also increases patient compliance, minimizes parenteral treatment pain, and maintains drug concentration in the treatment window by continuous control of the release of loaded drugs. ODI can be applied to a subject by implantation, such as by intravitreal injection, anterior chamber injection, and subconjunctival injection.

[0094] In some embodiments, the solid particles are extruded (or hot melt extruded) particles. In some embodiments, the solid particles are characterized in that at least one size is greater than 50um, greater than 100um, greater than 200um, greater than 300um, greater than 400um, greater than 500um, greater than 0.5mm, greater than 1mm, including any range therebetween. The term "size" refers to any one of the length dimension, width dimension (e.g., cross section or diameter / radius) or both. In some embodiments, the term "size" refers to the average particle size of the composition of the present invention. In some embodiments, the solid particles are substantially lacking microspheres, such as particles (e.g., spherical particles) with an average particle size of 1 to 50um, 1 to 30um, 1 to 20um (including any range therebetween). In some embodiments, the particles are in the form of pellets. In some embodiments, the particles are in the form of solid pellets. In some embodiments, the particles or pellets are substantially uniform in shape. In some embodiments, the particles or pellets are characterized by substantially uniform size distribution, PTC loading or both.

[0095] In some embodiments, the weight concentration of the conjugate within the solid particles (or within the composition) is about 1% to about 50%, about 1% to about 40%, about 1% to about 30%, about 5% to about 50%, about 5% to about 30%, about 1% to about 20%, about 5% to about 20%, about 1% to about 10%, about 10% to about 50%, about 10% to about 40%, about 20% to about 50%, including any range therebetween. The inventors have successfully manufactured exemplary ODIs of the present invention having a PTC loading of up to about 20% w / w (a loading of about 2.5% to about 20%). Currently, the inventors speculate that it is possible to obtain significantly higher PTC loadings of up to at least 40% by weight in ODIs.

[0096] In some embodiments, the composition of the present invention consists essentially of ester-terminated PLGA and PTC of the present invention. In some embodiments, the solid particles of the present invention consist essentially of ester-terminated PLGA and PTC of the present invention.

[0097] In some embodiments, the PTC is in an amorphous state within the solid particles as determined by XRD. In some embodiments, the PTC within the solid particles substantially maintains the particle size of the powdered PTC. In some embodiments, the PTC within the solid particle(s) substantially maintains the amorphous state of the powdered PTC. In some embodiments, the compositions of the present invention (or the plurality of particles disclosed herein) are characterized by substantially the same XRD as the powdered PTC disclosed herein.

[0098] In some embodiments, the PTC is substantially uniformly distributed within the solid particles of the present invention. In some embodiments, the PTC is substantially uniformly distributed within the compositions of the present invention. Uniform distribution can be determined by HPLC, such as by measuring the PTC concentration in 3 or more different probes sampled from the compositions of the present invention. The composition is considered uniform if the standard deviation of the PCT concentration values ​​of the samples is below 10%.

[0099] In some embodiments, the weight ratio between polylactide and polyglycolide in poly(glycolide-co-lactide) is at least 50:50, at least 60:40, at least 70:30, at least 80:20, at least 90:10, 50:50 to 95:5, 50:50 to 90:10, 50:50 to 85:15, 50:50 to 80:20, 60:40 to 95:5, 60:40 to 90:10, 60:40 to 85:15, 60:40 to 80:20, about 70:30 to about 80:20, including any range in between. Without being bound by any particular theory, the inventors (based on experimental data) hypothesize that a weight ratio between polylactide and polyglycolide of above 1:1 (i.e., the weight of polylactide exceeds the weight of polyglycolide), and more particularly PLGA of above 60:40 (such as about 75:25 or about 65:35), results in a solid particle (ODI) of the present invention characterized by a preferred sustained release profile of the active agent (PTC). PLGA having a weight ratio of polylactide to polyglycolide of below 1:1 (e.g., 10:90, 25:75, or 5:95 to 50:50, including any range therebetween) can be used to make ODIs with rapid drug release.

[0100] In some embodiments, the solid particles (ODI) have an elongated shape. In some embodiments, each solid particle of the present invention is characterized by an elongated shape. In some embodiments, the solid particles are basically characterized by rod-shaped, bar-shaped, needle-shaped, cylindrical, elliptical, etc. It will be appreciated by those skilled in the art that the shape of each solid particle may be slightly or greatly different from a specific geometric shape. Therefore, the solid particles may have a rod-like, bar-like, needle-like, cylindrical, or elliptical shape, which means that the actual shape of the particles has a certain deviation (e.g., at least 10%, at least 50% or greater deviation) from the perfect geometric shape. In some embodiments, the solid particles are substantially lacking in hollow particles.

[0101] The solid particles can be in any shape, such as cube, rectangle, prism, cone, etc.

[0102] In some embodiments, the solid particles are uniformly shaped particles, wherein at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 99% of the solid particles have substantially (e.g., size deviation up to 20% or up to 10%, including any range therebetween) the same shape, including any range therebetween. In some embodiments, the solid particles (ODI) are substantially in the form of rod-shaped particles or cylindrical particles (see Figure 3A ).

[0103] In some embodiments, the solid particles are characterized by a length dimension of at least 100 um, at least 500 um, about 0.5 to about 100 mm, about 0.5 to about 50 mm, about 0.5 to about 30 mm, about 0.5 to about 10 mm, about 1 to about 100 mm, about 1 to about 50 mm, about 1 to about 30 mm, about 1 to about 10 mm, about 1 to about 5 mm, including any range therebetween. In some embodiments, the length dimension is greater than 100 mm.

[0104] In some embodiments, the solid particles are characterized by a width dimension of about 0.05 to about 2 mm, about 0.05 to about 1.5 mm, about 0.05 to about 1 mm, about 0.1 to about 2 mm, about 0.1 to about 1 mm, about 0.1 to about 0.6 mm, about 0.2 to about 2 mm, about 0.2 to about 1 mm, about 0.2 to about 0.8 mm, about 0.1 to about 0.8 mm, including any range therebetween. In some embodiments, the width dimension of the solid particles is predetermined by the inner cross-section of the device (e.g., catheter) used to deliver the particles intraocularly to the subject. Those skilled in the art will appreciate that for intraocular delivery, the particles of the present invention must be compatible with the device for intraocular delivery, and therefore, without limitation, the width dimension of the particles must be less than 0.8 mm, preferably less than 0.6 mm.

[0105] As used herein, the terms "length dimension" and "width dimension" each independently refer to an average value (e.g., number average) as determined by SEM or measured by calipers. Methods for determining the average length or average width of solid particles in a given sample are well known in the art. In an exemplary embodiment, the average length or average width of the elongated particles can be determined by SEM or other microscope, using appropriate SEM or other microscope image processing software, or by measuring each particle individually using a caliper. Exemplary elongated solid particles of the present invention are presented in Figure 3C middle.

[0106] In some embodiments, the solid particles are characterized by an aspect ratio of 1, about 2 to about 100, about 2 to about 10, about 2 to about 20, about 2 to about 30, about 2 to about 50, about 5 to about 100, about 5 to about 50, about 5 to about 20, about 5 to about 30, including any ranges therebetween. In some embodiments, the solid particles of the present invention are characterized by a length dimension, a width dimension, and optionally an aspect ratio, as described herein.

[0107] In some embodiments, the solid particles are substantially non-porous, characterized by a porosity of less than 20%, less than 10%, less than 5%, including any range therebetween.

[0108] In some embodiments, the solid particles and / or compositions comprising the solid particles are characterized by a density of 0.2 to 0.6 mg / mm 3 , 0.3 to 0.45 mg / mm 3 , about 0.3 to about 0.4 mg / mm 3 , 0.30 to 0.33 mg / mm 3 , 0.32 to 0.35 mg / mm 3 , 0.35 to 0.40 mg / mm 3 , 0.40 to 0.45 mg / mm 3 , 0.3 to 0.33 mg / mm 3 , including any ranges therebetween.

[0109] In another aspect of the present invention, a composition is provided, comprising a plurality of particles, wherein each of the plurality of particles is a solid particle, the solid particle comprising a mixture of PLGA and a peptide in the form of a particulate; wherein the plurality of particles within the composition are characterized by at least one dimension being greater than 50um, greater than 100um, greater than 200um, greater than 300um, greater than 400um, greater than 500um, greater than 0.5mm, greater than 1mm, 0.1 to 10mm, 0.1 to 3mm, 0.1 to 2mm, including any range therebetween; and wherein the average particle size of the particulate is at most about 300um, at most about 200um, at most about 150um, at most about 70um, or at most about 30um, or 10 to 200um, 10 to 150um, 10 to 100um, 10 to 70um, 10 to 50um, including any range therebetween; wherein the average particle size of the particulate is determined by SEM. In some embodiments, the solid particles are elongated particles characterized by a width dimension greater than 50um, greater than 100um, greater than 200um, greater than 300um, greater than 400um, greater than 500um, greater than 0.5mm, greater than 1mm, 0.1 to 3mm, 0.1 to 2mm, 0.5 to 1mm, 0.5 to 2mm, including any range therebetween. In some embodiments, the solid particles are as described above.

[0110] In some embodiments, any of the particle size of the peptide, the weight concentration of the peptide within the particle / composition, the chemical composition of the PLGA, and other physicochemical parameters of the particle are as described herein for solid particles comprising a PTC.

[0111] In some embodiments, the peptide is a hydrophilic peptide. In some embodiments, the hydrophilic peptide is characterized by an aqueous solubility (i.e., in an aqueous solution in the absence of an organic solvent) of at least 10 g / L, at least 20 g / L, at least 50 g / L, at least 70 g / L, at least 100 g / L, at least 200 g / L, at least 300 g / L, at least 500 g / L (including any ranges therebetween) at a temperature of 20°C to 30°C.

[0112] In some embodiments, the solid particles disclosed herein are hot melt particles. In some embodiments, the solid particles disclosed herein are extruded particles, ie particles obtained via hot melt extrusion.

[0113] In some embodiments, the corresponding peak of the solid particles of the present invention (ODI) is characterized in that the XRD peak height (net intensity) of the peptide is much higher than that of the control, wherein the control is a non-extruded mixture containing the same components. In some embodiments, the corresponding peak of ODI (i.e., the XRD peak of the peptide) is at least 10 times, at least 8 times, at least 5 times, at least 2 times, at least 1.5 times lower than the control, including any range therebetween.

[0114] In some embodiments, the corresponding peak of the composition of the present invention is characterized by an XRD peak height (net intensity) much higher than a control, wherein the control is a non-extruded composition comprising a component as a composite, and wherein the XRD peak refers to the corresponding peak of the peptide. In some embodiments, the composition is characterized in that the corresponding XRD peak of the peptide is reduced by up to 500%, up to 90%, up to 80%, up to 70%, up to 60%, up to 50%, up to 40%, up to 30%, up to 20%, up to 20%, up to 15%, up to 10% and up to 5% when compared to the corresponding peak of the control, including any range therebetween.

[0115] In some embodiments, the solid particles (ODI) disclosed herein are characterized by a large release of peptides (e.g., hydrophilic peptides, such as PTC) therefrom. In some embodiments, the term "release" refers to the release of peptides into an aqueous medium (e.g., at a temperature of 10 to 50° C., and / or the pH of the aqueous medium is about 5 to about 8, including any range therebetween). In some embodiments, the term "large release" refers to the release of at least 10%, at least 30%, at least 50%, at least 70%, at least 90% of the initial peptide load within the solid particles of the invention or within the composition of the invention, including any range therebetween. In some embodiments, the solid particles disclosed herein are characterized by a delayed onset of release after the solid particles are contacted with an aqueous medium, such that a large release occurs after 1 day, after 2 days, after 3 days, after 4 days, or after 5 days, or after a period of time ranging from 2 to 20 days, 2 to 10 days, 5 to 20 days, 5 to 15 days, 5 to 10 days. It is assumed that the release profile obtained in the aqueous medium indicates in vivo release at the site of application in the subject (e.g., intraocular release).

[0116] In some embodiments, the term "substantial release" refers to a cumulative release of at least 10%, at least 30%, at least 50%, at least 70%, at least 90% of the initial peptide load over a period of time ranging from about 1 to about 90 days, about 1 to about 5 days, about 1 to about 10 days, about 2 to about 5 days, about 2 to about 10 days (including any range therebetween). In some embodiments, the cumulative release is measured from the start of release, wherein the start of release is as described herein. In some embodiments, the release profile of the peptide is substantially gradual or sustained and lacks a burst release, wherein release refers to cumulative release, as described herein. Exemplary release profiles are as follows Figure 3B In some embodiments, the release of the peptide can be determined by HPLC.

[0117] In another aspect, provided is a method for treating an ocular disease or disorder in a subject, the method comprising administering to the eye of the subject a therapeutically effective amount of a composition of the invention (eg, an ophthalmic composition comprising the solid particles disclosed herein).

[0118] In some embodiments, the subject's eye suffers from inflammation. In some embodiments, the inflammation is ocular inflammation. In some embodiments, the subject's eye suffers from any of dry eye, dry macular degeneration, diabetic macular edema, and postoperative inflammation. In some embodiments, the ocular inflammation is uveitis.

[0119] In some embodiments, the methods are used to treat or prevent a disease or disorder associated with ocular inflammation.

[0120] As used herein, the term "ocular inflammation" refers to any inflammation of any part of the eye. In some embodiments, the inflammation is inflammation of the middle layer of the eye. In some embodiments, the inflammation is uveitis. In some embodiments, the ocular inflammation comprises dry eye or dry macular degeneration. In some embodiments, the ocular inflammation is associated with other diseases.

[0121] Non-limiting examples of systemic diseases that can lead to ocular inflammation are Crohn's disease, Behcet's disease, and juvenile idiopathic arthritis. In some embodiments, ocular inflammation is associated with an adverse reaction to a drug or environmental trigger. Non-limiting examples of such drugs include rifabutin, quinolones, vaccines, and allergens. In some embodiments, ocular inflammation is associated with postoperative inflammation. Non-limiting examples of this category include post-cataract surgery, post-laser eye surgery, and post-keratoplasty.

[0122] As used herein, the terms "treatment" or "treating" ocular inflammation include alleviating at least one symptom thereof, reducing its severity, or inhibiting its progression. Treatment does not necessarily mean that the disease, disorder, or condition is completely cured. To be an effective treatment method, the useful compositions herein need only reduce the severity of the disease, disorder, or condition, reduce the severity of the symptoms associated therewith, or improve the quality of life of the patient or subject. In some embodiments, treating ocular inflammation includes at least one of preventing the occurrence of ocular inflammation, reducing the progression of ocular inflammation, and inhibiting the progression of ocular inflammation.

[0123] In some embodiments, treatment comprises reducing inflammation. In some embodiments, treatment comprises reducing abnormal inflammation. In some embodiments, treatment comprises reducing inflammation in an eye of a subject.

[0124] In some embodiments, treating comprises reducing secretion of at least one pro-inflammatory cytokine.

[0125] In some embodiments, reduction includes at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or 100% reduction. Each possibility represents a separate embodiment of the present invention. It will be appreciated by those skilled in the art that each cytokine does not need to reduce the same amount. Some cytokines may be reduced more than other cytokines.

[0126] In another aspect of the present invention, a method for increasing the ocular bioavailability of a phosphorylcholine-tuftsin conjugate in a subject is provided, comprising administering an ophthalmic composition of the present invention to an eye of the subject.

[0127] In some embodiments, the ocular bioavailability is increased by at least 10% compared to a control, wherein the control is as disclosed below. In some embodiments, the increase is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%, at least 100%, at least 200%, at least 500%, at least 1000%, at least 5000%, at least 10.000%, at least 100.000%, including any range or value therebetween.

[0128] In some embodiments, the method is used to extend the residence time of the phosphorylcholine-tuftsin conjugate on or in the eye (e.g., cornea and / or aqueous humor and / or vitreous and / or choroid). In some embodiments, the extension is a time period lasting the following range: 1 to 90 days, 1 to 5d, 2 to 10d, 5 to 20d, 2 to 20d, 2 to 30d, 5 to 50d, including any value therebetween, wherein the term "extended" is compared to a control composition consisting of the same components as the composition of the present invention, wherein the PTC is in the form of substantially spherical microparticles (e.g., an average particle size of about 10 to about 100um). In some embodiments, the control composition comprises the same components as the composition of the present invention, wherein the polymer is uncapped PLGA (see Figure 3D ).

[0129] In some embodiments, increasing ocular bioavailability comprises increasing the concentration of the phosphorylcholine-tuftsin conjugate in the aqueous humor and / or vitreous of the eye. In some embodiments, the increase is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%, at least 100%, at least 200%, at least 500%, at least 1000%, at least 5000%, at least 10.000%, at least 100.000%, including any range or value therebetween, as compared to a control composition.

[0130] In some embodiments, the subject is selected from a human subject and an animal subject.

[0131] As used herein, the terms "administering", "administration" and similar terms refer to any method of delivering a composition containing a peptide (i.e., an active agent) to a subject in a manner that provides a therapeutic effect in reasonable medical practice. In some embodiments, administration is ocular or intraocular administration. In some embodiments, administration is administration via a catheter (such as an ocular catheter) or any other means disclosed herein for delivering solid particles to the eye or into the eye. In some embodiments, administration is via intravitreal administration. In some embodiments, the administration step is repeated, for example, 2, 3, 4, 5, or 10 times within 24 hours to 1 year.

[0132] In some embodiments, the amount of the composition to be administered (dosage) will, of course, depend on the subject being treated, the medical condition being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, and the like.

[0133] In some embodiments, the daily dose (i.e., the amount of phosphorylcholine-tuftsin conjugate per day) is 0.01 to 200 μg, 0.01 to 100 μg, 50 to 2000 μg, 200 to 2000 μg, 50 to 100 μg, 100 to 200 μg, 200 to 300 μg, 300 to 400 μg, 400 to 500 μg, 500 to 600 μg, 600 to 700 μg, 700 to 800 μg, 800 to 900 μg, 900 to 1000 μg, 1000 to 1100 μg, 1100 to 1300 μg, 1300 to 1500 μg, 1500 to 1800 μg, 1800 to 2000 μg, including any range or value therebetween.

[0134] In some embodiments, the daily dose (ie, the amount of phosphorylcholine-tuftsin conjugate per day) is 0.01 to 100 μg or 1 to 100 μg.

[0135] According to one embodiment of the present invention, the pharmaceutical composition described above is packaged in a packaging material and a label is printed in or on the packaging material for use in treating the diseases or disorders described herein.

[0136] According to another embodiment of the present invention, the pharmaceutical composition is packaged in a packaging material and a label is printed in or on the packaging material for use in monitoring a disease or disorder as described herein.

[0137] If desired, the products of the present invention may be presented in a package or dispenser device, such as a kit approved by the U.S. Food and Drug Administration (FDA), which may include one or more unit dosage forms containing the disclosed composition. The package may, for example, include metal or plastic foil, such as a blister package. The package or dispenser device may be accompanied by instructions for use. The package or dispenser may also be accompanied by precautions in a form associated with the container and specified by a government agency that regulates the production, use or sale of the drug, which reflects the agency's approval of the form of the composition or human or veterinary use. Such precautions may, for example, be a prescription drug label approved by the FDA or an approved product insert.

[0138] In some embodiments, the kit comprises a single dosage form, wherein the dosage form comprises a daily dose of the disclosed composition. In some embodiments, the kit comprises multiple dosage forms. In some embodiments, the kit comprises multiple dosage forms, wherein the multiple dosage forms are equivalent to a daily dose of the disclosed composition.

[0139] In some embodiments, the method is used to extend the release period of the phosphorylcholine-tuftsin conjugate on or in the eye. In some embodiments, the phosphorylcholine-tuftsin conjugate is slowly released. In some embodiments, the phosphorylcholine-tuftsin conjugate is released in a controlled manner. In some embodiments, the method is used to trigger the delayed release start of PTC, wherein the delay is as described herein. In some embodiments, the method is used to trigger the sustained release of the phosphorylcholine-tuftsin conjugate.

[0140] In this context, the term "controlled manner" indicates that the drug is released substantially constantly. In this context, the term "constantly" may refer to a duration as described above (1 to 90 days).

[0141] It will be appreciated that the compositions of the present invention may be administered in conjunction with other drugs, including other anti-inflammatory drugs.

[0142] In another aspect of the invention, a method for making the solid particles of the invention is provided, the method comprising extruding a powdered composition or kit comprising: a peptide characterized by an average particle size disclosed herein (e.g., a PTC of the invention); and a PLGA disclosed herein, wherein the PLGA is characterized by an average particle size of 10nm to 100um, 10nm to 1um, 10nm to 10um, 100nm to 10um, 100nm to 1um, 100nm to 5um, 10nm to 100um, 100nm to 80um, 100nm to 70um, 100nm to 60um, 100nm to 50um, 100nm to 30um, 100nm to 20um, 100nm to 10um, 10 0nm to 5um, 100nm to 1um, 300nm to 10um, 300nm to 5um, 300nm to 1um, 300nm to 500um, 300nm to 800um, 500nm to 10um, 500nm to 1um, 500nm to 50um, 500nm to 100um, 10nm to 100nm, 100nm to 500nm, 500nm to 80um, 800nm ​​to 30um, 800nm ​​to 5um, 5 to 30um, 1 to 30um, 1 to 10um, 10 to 30um, 10 to 60um, 10 to 80um, 30 to 60um, 30 to 50um, including any range therebetween; wherein extrusion is carried out under suitable conditions. In some embodiments, each of the peptide (e.g., PTC of the present invention) and PLGA is introduced into the extruder separately. In some embodiments, the peptide (e.g., PTC of the present invention) is mixed with PLGA to obtain a composition, which is then introduced into an extruder. In some embodiments, extrusion is performed at a temperature of 60° C. to 80° C., 60° C. to 70° C., 65° C. to 75° C., 70° C. to 80° C. (including any ranges therebetween).

[0143] In some embodiments, the method is used to make particles or pellets (i.e., ODI) of the present invention. In some embodiments, the method is used to obtain an extrudate. In some embodiments, the extrudate is further shaped via a hot molding process selected from extrusion, injection, hot blown film, molding (e.g., casting, compression molding, rotational molding) or any combination thereof. In some embodiments, the extrudate is formable or processable to obtain solid particles of the present invention characterized by a predetermined shape and / or size (one or more).

[0144] In some embodiments, a method is provided for shaping the particles of the present invention, the method comprising extruding an extrudate in an extruder by utilizing an extrusion die characterized by a predetermined shape and / or size.

[0145] In some embodiments, the method includes a preliminary step of milling or grinding any one of the original peptide (e.g., original PTC) and the original PLGA to obtain a powdered composition or kit comprising the peptide and PLGA, characterized by a particle size disclosed herein. In some embodiments, the original PLGA and the original peptide are milled or ground simultaneously or separately. In some embodiments, the milling or grinding is accompanied by a cooling milling or grinding chamber.

[0146] In some embodiments, the components that make up the compositions (and / or extrudates) of the invention can be processed via an extrusion process. In some embodiments, the physical properties of the components that make up the compositions and / or extrudates of the invention (such as particle size, chemical composition, ratio between peptide and PLGA, thermal stability of peptide) are compatible with or suitable for an extrusion process.

[0147] In some embodiments, the solid particles (or pellets) of the present invention are substantially stable under suitable storage conditions (e.g., temperatures as described herein, and exposure to ambient atmosphere). In some embodiments, the solid particles (or pellets) of the present invention are substantially stable at temperatures of 30 to 60° C., -50 to 60° C., 0 to 10° C., 10 to 30° C., 30 to 50° C. (including any ranges therebetween).

[0148] As used herein, the term "stable" refers to the ability of a solid particle (or granule) of the invention to substantially maintain its structure, physical and / or chemical properties. In some embodiments, a solid particle (or granule) of the invention is referred to as being stable when it substantially maintains its structure (e.g., shape and / or size such as thickness, length, etc.), substantially lacks cracks, substantially maintains the initial peptide load, or any combination thereof, wherein substantially as described herein.

[0149] Chemical Definition

[0150] The compounds are described using standard nomenclature. 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.

[0151] In some embodiments, compounds of the invention include any salt, any solvate, any hydrate, any stereoisomer, any isotope (e.g., deuterated compounds), and / or any derivative (e.g., biologically active derivative) of any compound or formula disclosed herein.

[0152] Examples of isotopes that may be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 15 N.17 O. 18 O. 18 F. 31 P 、32 P. 35 S. 36 Cl and 125 I.

[0153] Unless otherwise indicated or otherwise excluded by context, the compounds described herein include enantiomers, mixtures of enantiomers, diastereomers, tautomers, racemates, and other isomers, such as optical isomers, as if each were specifically described. It should be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be in the (R-) or (S-) configuration. The compounds provided herein may be enantiomerically pure, or may be diastereomers or mixtures of enantiomers. It should be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. Therefore, those skilled in the art will recognize that, for compounds that undergo epimerization in vivo, administering the compound in its (R-) form is equivalent to administering the compound in its (S-) form. Unless stated to the contrary, formulae containing chemical bonds represented only by solid lines and not by wedges or dashed lines contemplate every possible isomer, e.g., each enantiomer, diastereomer, and meso compound, as well as mixtures of isomers, such as racemic or scalemic mixtures.

[0154] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -(C=O)NH2 is attached through the carbon of the keto (C=O) group.

[0155] As used herein, the term "substituted" means that any one or more hydrogens on a specified atom or group are replaced by a portion selected from a specified group, provided that the normal valence of the specified atom is not exceeded and the resulting compound is stable. For example, when the substituent is an oxy group (i.e., =O), two hydrogens on the atom are replaced. For example, a pyridyl group substituted by an oxy group is pyridine. This combination is allowed only when the combination of substituents and / or variables produces a stable compound or a useful synthetic intermediate. A stable active compound refers to a compound that can be isolated and formulated into a dosage form with a shelf life of at least one month. A stable production intermediate or precursor of an active compound is stable if it does not degrade within the time required for a reaction or other use. A stable portion or substituent is a portion or substituent that will not degrade, react or decompose within the time required for use. Non-limiting examples of unstable portions are those portions that combine heteroatoms in an unstable arrangement, as generally known and identifiable by those skilled in the art.

[0156] Any suitable group may be present in a "substituted" or "optionally substituted" position that forms a stable molecule and meets the desired objectives of the invention, and includes, but is not limited to, alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxyl, keto, nitro, cyano, azido, oxy, silyl, thio-oxy, sulfonyl, sulfone, sulfoxide, sulfonylamino or thiol. Additional substituents are disclosed herein. In addition, the term "substituted" includes one or more (e.g., 2, 3, 4, 5, 6 or more) substituents, wherein the substituent(s) may be the same or different, and wherein each of the substituents is as described herein.

[0157] The term "substituent" is independently selected from -OH, oxy, carbonyl, halogen, -OR', -NO2, -CN, -CONH2, -CONR'2, -CNNR'2, -CSNR'2, -CONH-OH, -CONH-NH2, -NHCOR', -NHCSR', -NHCNR, -NC(=O)OR', -NC(=O)NR', ​​-NC(=S)OR', -NC(=S)NR', ​​-SO2R', -SOR', -SR', -SO2OR', -SO2 N(R')2, -NHNR'2, -NNR', -NR'R', NR'NR'2, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(C1-C6 alkyl), hydroxy(C1-C6 alkoxy), alkoxy(C1-C6 alkyl), alkoxy(C1-C6 alkoxy), C1-C6 alkyl-OR', C1-C6 alkyl-NR'2 , C1-C6 alkyl-SR', -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -CO2H, -CO2R', -OCOR, -OCOR', -OC(=O)OR', -OC(=O)NR', ​​-OC(=S)OR', -OC(=S)NR', ​​optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl) (C0-C3 alkane alkyl), (3- to 6-membered monocyclic heterocyclic)(C0-C3 alkyl), (6- to 10-membered monocyclic or bicyclic aryl)(C0-C3 alkyl), (5- to 10-membered monocyclic or bicyclic heteroaryl)(C0-C3 alkyl), R'C(O)-O-(C0-C3 alkyl)-, R'C(O)-(R'N)-(C0-C3 alkyl)-, R'S(O)2-O-(C0-C3 alkyl)-, R'S(O)2-(R'N)-(C0-C3 alkyl)-, R'C(O)-, R'S(O)-, and R'S(O)2-;wherein each R' is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C7 cycloalkyl)-(C0-C3 alkyl)-, (4 to 6 membered heterocyclic)-(C0-C3 alkyl)-, (5 to 10 membered monocyclic or bicyclic aryl)-(C0-C3 alkyl)-, (5 to 10 membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, OR', -C ONH2, -CONR'2, -CNNR'2, -CSNR'2, -CONH-OH, -CONH-NH2, -NHCOR', -NHCSR', -NHCNR, -NC(=O)OR', -NC(=O)NR', ​​-NC(=S)OR', -NC(=S)NR', ​​-NR'NR'2 and -NNR', each of which may be optionally substituted as valence permits. ;

[0158] As used herein, the term "alkyl" describes an aliphatic hydrocarbon including straight and branched chain groups. As used herein, the term "alkyl" also includes saturated or unsaturated hydrocarbons, thus this term also includes alkenyl and alkynyl groups.

[0159] The term "alkenyl" describes an unsaturated alkyl group as defined herein having at least two carbon atoms and at least one carbon-carbon double bond. As noted above, an alkenyl group may be unsubstituted or substituted with one or more substituents.

[0160] As defined herein, the term "alkynyl" is an unsaturated alkyl group having at least two carbon atoms and at least one carbon-carbon triple bond. As described above, the alkynyl group may be substituted or unsubstituted with one or more substituents.

[0161] The term "cycloalkyl" describes an all-carbon monocyclic or fused ring (ie, rings that share a pair of adjacent carbon atoms) group in which one or more of the rings does not have a completely conjugated pi electron system. As indicated herein, a cycloalkyl group may be substituted or unsubstituted.

[0162] The term "aryl" describes an all-carbon monocyclic or fused-ring polycyclic (ie, rings that share adjacent pairs of carbon atoms) group having a completely conjugated pi-electron system. As indicated herein, an aryl group may be substituted or unsubstituted.

[0163] The term "alkoxy" describes an O-alkyl group and an -O-cycloalkyl group as defined herein. The term "aryloxy" describes an -O-aryl group as defined herein.

[0164] In this article, each of the alkyl, cycloalkyl and aryl groups in the general formula may be substituted with one or more substituents, whereby each substituent may independently be, for example, a halide, an alkyl, an alkoxy, a cycloalkyl, a nitro, an amino, a hydroxyl, a thiol, a thioalkoxy, a carboxyl, an amide, an aryl and an aryloxy group, depending on the substituted group and its position in the molecule. Other substituents are also contemplated.

[0165] In some embodiments, the term "carbocyclyl" includes aryl, polycyclyl, heteroaryl, cycloalkyl or heterocyclyl, or any combination thereof.

[0166] The term "halide", "halogen" or "halo / halo" describes fluorine, chlorine, bromine or iodine. The term "haloalkyl" describes an alkyl as defined herein further substituted with one or more halides. The term "haloalkoxy" describes an alkoxy as defined herein further substituted with one or more halides. The term "hydroxyl" or "hydroxy" describes an -OH group. The term "mercapto" or "thiol" describes an -SH group. The term "thioalkoxy" describes an -S-alkyl and -S-cycloalkyl as defined herein. The term "thioaryloxy" describes an -S-aryl and -S-heteroaryl as defined herein. The term "amino" describes an -NR'R" group or a salt thereof, wherein R' and R" are as described herein.

[0167] The term "heterocyclyl" describes a monocyclic or fused ring group having one or more atoms such as nitrogen, oxygen and sulfur in the ring(s). These rings may also have one or more double bonds. However, these rings do not have a completely conjugated π electron system. Representative examples are piperidine, piperazine, tetrahydrofuran, tetrahydropyran, morpholino, etc.

[0168] The term "carboxy" describes a -C(O)OR' group or a carboxylate salt thereof, wherein R' is hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl (bonded through a ring carbon), or heterocyclyl (bonded through a ring carbon), or "carboxylate" as defined herein.

[0169] The term "carbonyl" describes a -C(O)R' group, wherein R' is as defined above. The above term also includes the thio derivatives thereof (thiocarboxy and thiocarbonyl).

[0170] The term "thiocarbonyl" describes a -C(S)R' group, where R' is as defined above. A "thiocarboxy" group describes a -C(S)OR' group, where R' is as defined herein. "Sulfinyl" describes a -S(O)R' group, where R' is as defined herein. "Sulfonyl" or "sulfonic acid" describes a -S(O)2R' group, where R' is as defined herein.

[0171] A "carbamoyl" or "carbamate" group describes a -OC(O)NR'R" group, wherein R' is as defined herein and R" is as defined for R'. A "nitro" group refers to a -NO2 group. As used herein, the term "amide" includes C-amides and N-amides. The term "C-amide" describes a -C(O)NR'R" terminal group or a -C(O)NR'- linking group, as defined above for these phrases, wherein R' and R" are as defined herein. The term "N-amide" describes a -NR"C(O)R' terminal group or a -NR'C(O)- linking group, as defined above for these phrases, wherein R' and R" are as defined herein.

[0172] "Cyano" or "nitrile" refers to a -CN group. The term "azo" or "diazo" describes an -N=NR' terminal group or an -N=N- linking group, as defined above for these phrases, wherein R' is as defined above. The term "guanidine" describes an -R'NC(N)NR"R"' terminal group or an -R'NC(N)NR"- linking group, as defined above for these phrases, wherein R', R" and R"' are as defined herein. As used herein, the term "azide" refers to a -N3 group. The term "sulfonamide" refers to a -S(O)2NR'R" group, wherein R' and R" are as defined herein.

[0173] The term "phosphono" or "phosphonate" describes a -OP(O)-(OR')2 group, where R' is as defined above. The term "phosphinyl" describes a -PR'R" group, where R' and R" are as defined above. The term "alkylaryl" describes an alkyl group, as defined herein, substituted with an aryl group, as described herein. An exemplary alkylaryl group is benzyl.

[0174] The term "heteroaryl" describes a monocyclic or fused ring (i.e., a ring that shares a pair of adjacent atoms) group having one or more atoms such as, for example, nitrogen, oxygen, and sulfur in the ring (one or more), and in addition having a completely conjugated π electron system. As used herein, the term "heteroaryl" refers to an aromatic ring in which at least one atom forming the aromatic ring is a heteroatom. The heteroaryl ring may be formed by three, four, five, six, seven, eight, nine, and more than nine atoms. The heteroaryl group may be optionally substituted. Examples of heteroaryl groups include, but are not limited to, aromatic C3-8 heterocyclic groups containing one oxygen or sulfur atom, or two oxygen atoms, or two sulfur atoms or up to four nitrogen atoms, or one oxygen or sulfur atom in combination with up to two nitrogen atoms, and their substituted and benzo-fused and pyrido-fused derivatives - for example, connected by one of the carbon atoms forming the ring. In certain embodiments, the heteroaryl group is selected from Azolyl, iso Azolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl.

[0175] In some embodiments, heteroaryl is selected from pyrrolyl, furanyl (furanyl or furyl), phenylthio (thienyl), imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3- Azolyl ( oxazolyl), 1,2- Azolyl (iso Azolyl), oxadiazolyl, 1,3-thiazolyl (thiazolyl), 1,2-thiazolyl (isothiazolyl), tetrazolyl, pyridyl (pyridyl) pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, indazolyl, indolyl, benzothiophenyl, benzofuranyl, benzothiazolyl, benzimidazolyl, benzodioxolyl, acridinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, thienophenylthio, 1,8-naphthyridinyl, other naphthyridinyl, pteridinyl or phenothiazinyl. When the heteroaryl group includes more than one ring, each additional ring is saturated (perhydro) or partially unsaturated (e.g., dihydro or tetrahydro) or maximally unsaturated (non-aromatic). Thus, the term heteroaryl includes bicyclic radicals in which both rings are aromatic and bicyclic radicals in which only one ring is aromatic. Such examples of heteroaryl groups include 3H-indolyl, 2(1H)-quinolyl, 4-oxo-1,4-dihydroquinolyl, 2H-1-oxoisoquinolyl, 1,2-dihydroquinolyl, (2H)quinolyl N-oxide, 3,4-dihydroquinolyl, 1,2-dihydroisoquinolyl, 3,4-dihydro-isoquinolyl, chromonyl, 3,4-dihydroiso-quinoxalinyl, 4-(3H)quinazolinyl, 4H-chromenyl, 4-chromanone (4-chr omanonyl), oxindolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydro-quinolyl, 1H-2,3-dihydroisoindolyl, 2,3-dihydrobenzo[f]isoindolyl, 1,2,3,4-tetrahydrobenzo-[g]isoquinolyl, 1,2,3,4-tetrahydro-benzo[g]isoquinolyl, chromanyl, isochromanonyl, 2,3-dihydrochromononyl, 1,4-benzo-dihydro alkyl, 1,2,3,3,4-tetrahydro-quinoxalinyl, 5,6-dihydro-quinolyl, 5,6-dihydroiso-quinolyl, 5,6-dihydroquinoxalinyl, 5,6-dihydroquinazolinyl, 4,5-dihydro-1H-benzimidazolyl, 4,5-dihydro-benzo oxazolyl, 1,4-naphthoquinolyl, 5,6,7,8-tetrahydro-quinolyl, 5,6,7,8-tetrahydro-isoquinolyl, 5,6,7,8-tetrahydroquinoxalinyl, 5,6,7,8-tetrahydroquinazolinyl, 4,5,6,7-tetrahydro-1H-benzimidazolyl, 4,5,6,7-tetrahydro-benzo oxazolyl, 1H-4-oxa-1,5-diaza-naphthalen-2-onyl, 1,3-dihydroimidizolo-[4,5]-pyridin-2-one, 2,3-dihydro-1,4-dinaphthoquinone, 2,3-dihydro-1H-pyridine pyrrolo[3,4-b]quinolinyl, 1,2,3,4-tetrahydrobenzo[b]-[1,7]naphthopyridinyl, 1,2,3,4-tetrahydrobenzo[b][1,6]naphthopyridinyl, 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolyl, 1,2,3,4-tetrahydro-9H-pyrido[4,3-b]indolyl, 2,3-dihydro-1H-pyrrolo[3,4-b]indolyl, 1H-2,3,4,5-tetrahydro-azepine [3,4-b]indolyl (1H-2,3,4,5-tetrahydro-azepino[3,4-b]indolyl), 1H-2,3,4,5-tetrahydroazepino[3,4-b]indolyl [4,3-b]indolyl, 1H-2,3,4,5-tetrahydro-aza [4,5-b]indolyl, 5,6,7,8-tetrahydro[1,7]naphthyridinyl, 1,2,3,4-tetrahydro-[2,7]-naphthyridinyl, 2,3-dihydro[1,4] 2,3-dihydro[1,4]dioxino[2,3-b]pyridyl, 2,3-dihydro[1,4]dioxino[2,3-b]pyridyl , 1,2,3,4-tetrahydro[1,5]-naphthyridinyl, 1,2,3,4-tetrahydro[1,6]naphthyridinyl, 1,2,3,4-tetrahydro[1,7]naphthyridinyl, 1,2,3,4-tetrahydro-[1,8]naphthyridinyl or 1,2,3,4-tetrahydro[2,6]naphthyridinyl. In some embodiments, the heteroaryl group is optionally substituted. In one embodiment, one or more substituents are each independently selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, C1-6-alkyl, C1-6-haloalkyl, C1-6-hydroxyalkyl, C1-6-aminoalkyl, C1-6-alkylamino, alkylsulfinyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl or trifluoromethyl.

[0176] Examples of heteroaryl groups include, but are not limited to, furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, Azoles, benzo Azoles, Isopropylamine azole, benzyl isocyanate oxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine, furazan, 1,2,3- oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, pteridine, benzene Phenoxazole, Non-substituted and mono-substituted or di-substituted derivatives of oxadiazole, benzopyrazole, quinolizine, cinnoline, phthalazine, quinazoline and quinoxaline. In some embodiments, the substituent is halo, hydroxyl, cyano, O—C1-6-alkyl, C1-6-alkyl, hydroxy-C1-66-alkyl and amino-C1-6-alkyl.

[0177] As used herein, the terms "halo" and "halide" are used interchangeably herein to describe a halogen atom, ie, fluorine, chlorine, bromine, or iodine, also referred to herein as fluoride, chloride, bromide, and iodide.

[0178] "Pharmaceutically acceptable salts" are derivatives of the disclosed compounds, wherein the parent compound is modified by preparing its inorganic and organic, pharmaceutically acceptable acid or base addition salts. Salts of the current compounds can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (such as sodium hydroxide, calcium hydroxide, magnesium hydroxide or potassium hydroxide, carbonate, bicarbonate or the like), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are generally carried out in water or an organic solvent or a mixture of the two. In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are typical where feasible. Salts of the current compounds also include solvates of these compounds and salts of these compounds. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts include salts acceptable to humans. Lists of pharmaceutically acceptable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA., p. 1418 (1985).

[0179] As used herein, substantially pure means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard analytical methods such as thin layer chromatography (TLC), nuclear magnetic resonance (NMR), gel electrophoresis, high performance liquid chromatography (HPLC) and mass spectrometry (MS), gas chromatography mass spectrometry (GC-MS), and similar methods used by those skilled in the art to assess such purity, or sufficiently pure that further purification will not detectably alter the physical and chemical properties of the substance, such as enzymatic and biological activities. Traditional and modern methods for purifying compounds to produce substantially chemically pure compounds are known to those skilled in the art. However, a substantially chemically pure compound may be a mixture of stereoisomers.

[0180] General considerations

[0181] As used herein, the term "about" refers to ± 10%.

[0182] The terms "comprises," "comprising," "includes," "including," "having" and their conjugates mean "including but not limited to."

[0183] The term "consisting of" means "including and limited to."

[0184] The term "consisting essentially of" means that the composition, method, or structure may include additional ingredients, steps, and / or parts, but only if the additional ingredients, steps, and / or parts do not materially alter the basic and novel characteristics of the claimed composition, method, or structure.

[0185] The word “exemplary” is used herein to mean “serving as an example, instance, or illustration.” Any implementation described as “exemplary” is not necessarily to be construed as preferred or advantageous over other implementations and / or to exclude the incorporation of features from other implementations.

[0186] The word “optionally” is used herein to mean “is provided in some embodiments and not provided in other embodiments.” Any particular embodiment of the present invention may include a number of “optional” features, unless such features are incompatible.

[0187] As used herein, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

[0188] Throughout this application, various embodiments of the present invention may be presented in range format. It should be understood that the description in range format is only for convenience and brevity, and should not be construed as a rigid limitation on the scope of the present invention. Therefore, the description of a range should be considered to have specifically disclosed all possible subranges and individual numerical values ​​within the range. For example, a description such as a range of 1 to 6 should be considered to have specifically disclosed subranges, such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numbers within the range, such as 1, 2, 3, 4, 5, and 6. This applies no matter how wide the range is.

[0189] Whenever a numerical range is indicated herein, it is intended to include any cited numeral (fractional or integer) within the indicated range. The phrases "range between / between a first indicated numeral and a second indicated numeral" and "range from / to a first indicated numeral to / from a second indicated numeral" are used interchangeably herein and are intended to include the first and second indicated numerals and all fractions and integers therebetween.

[0190] As used herein, the term "method" refers to manners, means, techniques and procedures for accomplishing a given task, including but not limited to those manners, means, techniques and procedures known to practitioners in the fields of chemistry, pharmacology, biology, biochemistry and medicine or readily developable from known manners, means, techniques and procedures.

[0191] It should be understood that certain features of the invention described in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of the invention described in the context of a single embodiment for brevity may also be provided individually or in any suitable sub-combination. All combinations of embodiments related to the invention are specifically encompassed by the invention and disclosed herein, just as each combination is individually and explicitly disclosed. In addition, all sub-combinations of various embodiments and elements thereof are also specifically encompassed by the invention and disclosed herein, just as each such sub-combination is individually and explicitly disclosed herein.

[0192] After examining the following examples, other objects, advantages and novel features of the present invention will become apparent to those skilled in the art, and these examples are not intended to be limiting. In addition, as described above and as claimed in the following claims section, each of the various embodiments and aspects of the present invention is experimentally supported in the following examples.

[0193] Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples.

[0194] Example

[0195] Material

[0196] The materials and equipment used in this article are listed in Table 1.

[0197] Table 1. List of materials and equipment used

[0198]

[0199]

[0200] Specifically, the PLGA polymers used herein are detailed in Table 1A below.

[0201] Table 1A:

[0202]

[0203] "Acid-capped" PLGA refers to uncapped PLGA as used herein.

[0204] method

[0205] HPLC-UV method

[0206] For HPLC runs, a standard analytical HPLC method based on an acetonitrile / water gradient was used.

[0207] Each batch was tested for system suitability as described in the following sections.

[0208] For each HPLC experiment, two independent standards (A and B) were prepared with a net peptide concentration of 0.3 mg / mL in water. The required amount of API was accurately weighed into a 50 mL falcon tube, followed by addition of water by weight and then vortexed for 30 seconds to 1 minute until the API was completely dissolved. The solution was transferred to an HPLC vial and prepared for HPLC analysis.

[0209] Determination of physical mixtures by HPLC-UV

[0210] After grinding and sieving, the drug loading and stability of the physical mixtures were determined. 5 mg of sample was weighed into an aluminum weigh boat and transferred to a low binding Eppendorf, followed by the addition of 50 μL ACN. It was vortexed vigorously until the polymer dissolved and the API precipitated. Next, water was added and the mixture was vortexed vigorously again until the API was completely dissolved and the polymer precipitated. For the physical mixture loaded with 18% drug, 2950 μL of water was added, while for the physical mixture loaded with 9% drug, 1450 μL of water was added. Finally, the Eppendorf was centrifuged at 5'000 RPM for 30 seconds.

[0211] Determination of extrudates by HPLC-UV

[0212] The extrudates were analyzed for drug loading and stability by cutting the extrudates to specific weights to give the same final concentration as the standard after adding the diluent (net peptide concentration of 0.3 mg / mL). The cut extrudates were placed in a low binding Eppendorf, followed by the addition of ACN. They were vortexed vigorously until the polymer dissolved and the API precipitated. Next, water was added and the mixture was vortexed vigorously again until the API was completely dissolved and the polymer precipitated. Finally, the Eppendorf was centrifuged and the supernatant analyzed.

[0213] In vitro drug release studies on extrudates

[0214] The extrudate was cut into the desired size and weighed into a 5 mL low binding Eppendorf tube before the addition of phosphate buffered saline (pH 7.4). At designated time points, aliquots were sampled for API quantification by HPLC.

[0215] Modulated Differential Scanning Calorimetry (mDSC)

[0216] mDSC analysis was performed using a Q1000 instrument (TA Instruments, USA) to study the thermal profiles of TRS, polymers, physical mixtures and extrudates. An inert atmosphere in the chamber was maintained by purging nitrogen at a flow rate of 50 mL / min.

[0217] Thermoanalytical curves were determined by following mDSC using heat-cold-heat cycles. Approximately 2-3 mg of sample was weighed into a sealed aluminum pan, balanced at 5°C, and after 5 minutes of isothermal, the sample was heated up to 60°C at 2°C / min, cooled to 5°C at 2°C / min, and heated up to 60°C at 2°C / min again. A modulation period of 60 seconds was applied with an amplitude temperature of ±0.7°C. Data were processed using Universal Analysis 2000 software.

[0218] X-ray powder diffraction (XRPD)

[0219] X-ray powder diffraction (XRPD) analysis of the samples was performed using a Bruker D2 Phaser powder diffractometer equipped with a Lynx Eye detector. The sample (approximately 5 mg) was centered on a silicon sample holder with a 5 mm pocket. During data acquisition, the sample was continuously rotated and scanned in the range of 4.0° to 40° 2θ using a step size of 0.02° 2θ. The DIFFRAC plus The data were processed by EVA software, and the detailed parameters are summarized in Table 2.

[0220] Table 2. Experimental parameters used for XRPD analysis

[0221] parameter condition instrument Bruker D2 Phaser Scan Mode continuous source <![CDATA[Copper, K α > wavelength 1.54060nm 2θ range (start / stop) 4.0-40°2θ Detector Lynx Eye Sample Movement Rotation Generator / voltage 30kV / 10mA 2θ step size 0.02° Time / Pace(Dwell) 0.1 seconds

[0222] Scanning electron microscopy (SEM)

[0223] General Procedure

[0224] The surface morphology of the samples was examined by scanning electron microscopy (SEM). The extrudates were fixed to aluminum stubs using conductive double-sided carbon tape, sputter coated to 10 nm with gold in a Quorum Q150ES sputter coater (Quorum Technologies Ltd, UK), and imaged using a Tescan Vega3 scanning electron microscope (Tescan Bruno, Czech Republic). Magnified details and beam voltage are included in the scanning electron micrographs of this report.

[0225] Exemplary Methods for Making Extruded Solid Particles of the Present Invention .

[0226] Approximately 20% nominal drug loading in Resomer RG 752S, 0.5 mm extrusion die.

[0227] By first using a tube mill 100 ( -Werke) mechanically grinds TRS (batch number BZ8-200816) and Resomer RG 752S separately to prepare a physical mixture. The ground API is then sieved through a 75 μm mesh. After this, the components are weighed in a 50 mL falcon tube and mixed with a Turbula mixer. The mixture is manually fed into the extruder and processed at a constant screw speed above 50°C. The extrudate is cut and divided into 16 different parts according to the extrusion sequence. It is found that the most suitable extrusion temperature is about 60°C to about 80°C. Temperatures significantly below 60°C will result in reduced uniformity of ODI, while temperatures above 80°C may trigger at least partial decomposition of peptides (e.g., PTC).

[0228] As described above, the drug loading and stability of the API in the extrudate were quantified by HPLC-UV. In vitro drug release studies were performed as outlined above - cutting and weighing 3 mm long extrudates, with a target of 200 μg API per implant. In addition, three 3 mm blocks were cut and weighed from each section from 1 to 16 (N=16, n=3) and the uniformity of the entire length of the extrudate was evaluated by measuring (physical mixture by HPLC-UV) in the same manner as outlined above. Finally, the average diameter of the extrudate was measured with a caliper.

[0229] XRPD diffractograms (not shown) confirmed that TRS remained amorphous after extrusion. mDSC results also showed that the extrusion process did not affect the glass transition temperature of the API and polymer blends.

[0230] Error! Reference source not found.SEM image showing an exemplary drug loaded extrudate of the present invention which appears to have a partially smooth and non-porous surface.

[0231] The inventors successfully used Resomer RG 752S to form extrudates with approximately 18% PTC loading. Extrusions containing 18% PTC loading in Resomer RG 752S provided slightly higher yields than the trial using Resomer RG 502 (9.6% and 4.7%, respectively), providing a total of 16 parts after a residence time of 60 minutes. Visually, these extrudates appeared smoother, more uniform and homogeneous, and were also less brittle. SEM images showed that the drug-loaded extrudates had a rougher surface and a cross-section with a certain porosity when compared to the blank extrudate of Resomer RG 752S. The average diameter of the extrudates was 0.59±0.01 mm, compared to the placebo, which had an average diameter of 0.57 mm.

[0232] The determination of the physical mixture and the extrudate showed that the API (PTC) was stable during the grinding and sieving process and after extrusion. The API in the extrudate was chemically stable for at least 3 months after storage at -20°C, 2-8°C and 25°C.

[0233] The uniformity of the exemplary extrudates of the invention was also evaluated, which showed that the exemplary extrudates were substantially uniform, exhibiting an average drug loading of about 17.5 ± 0.3%, equivalent to 198 ± 10 μg. This theoretically represents an implant-to-implant variation of only 0.3 μg API per day at most over 30 days.

[0234] Drug release studies on exemplary extrudates of the invention showed promising release profiles up to 33 days, when >90% of the API had been released (see Figure 3B After a slow release up to 20 days (average release of 3.6±0.4 μg API per day), an acceleration followed, when the degradation of the PLGA matrix reached its autocatalytic acceleration.

[0235] To this end, the inventors hypothesized that the PLGA microparticle approach was insufficient due to its low encapsulation efficiency, low material recovery and rapid drug release. In contrast, exemplary PLGA-based extrudates (ODIs) of the present invention, composed of TRS and Resomer RG 752S, suitable for preclinical studies, were successfully prepared by hot melt extrusion at two drug loadings, namely 9% and 18%. The average diameters of these implants were 0.59 mm and 0.60 mm, and the lengths were approximately 3 mm. The average precision of the nominal doses contained in the extrudates (200 μg and 100 μg, respectively) was 99% and 91%, respectively, with an intra-batch coefficient of variation of approximately 5%. Both drug loadings showed in vitro release profiles that lasted for 33 days.

[0236] When stored under appropriate conditions, two tested exemplary extrudates of the present invention showed no degradation for at least 3 months.

[0237] In addition, the inventors have also successfully prepared ODIs based on TRS and uncapped PLGA (i.e., containing unesterified acid groups at the ends of the polymer chains). In addition, PLGA with a lactic acid: glycolic acid ratio of less than 1:1 (e.g., 25:75) has been successfully used in the production of ODIs. In most cases, these exemplary ODIs are characterized by faster release curves compared to ester-capped PLGA and / or PLGA with a lactic acid: glycolic acid ratio of more than 1:1. However, these fast-release ODIs may be suitable for therapeutic applications requiring relatively fast release of drugs.

[0238] Although the present invention has been described in conjunction with specific embodiments of the present invention, it is apparent that various alternatives, modifications and variations will be apparent to those skilled in the art. Therefore, it is intended to cover all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

[0239] All publications, patents and patent applications mentioned in this specification are incorporated by reference in their entirety into this specification to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference herein. In addition, the citation or identification of any reference in this application should not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting.

Claims

1. A composition comprising a phosphorylcholine-tuftsin conjugate, including a salt thereof, wherein: The phosphorylcholine-tuftsin conjugate is represented by the following formula 1: The phosphorylcholine-tuftsin conjugate is an amorphous solid; and The phosphorylcholine-tuftsin conjugate is in the form of particles characterized by having an average particle size of less than 300 um as determined by SEM; And wherein the composition is characterized by a powder XRD lack of a net intensity peak height of more than 400 counts corresponding to the phosphorylcholine-tuftsin conjugate.

2. The composition according to claim 1, wherein the salt thereof is a pharmaceutically acceptable salt, wherein the water content of the composition is below 20%.

3. The composition according to claim 1 or 2, wherein the composition is a pharmaceutical composition comprising a pharmaceutically effective amount of the phosphorylcholine-tuftsin conjugate and further comprising a pharmaceutically acceptable carrier.

4. A composition comprising a plurality of particles, wherein each of the plurality of particles is a solid particle comprising a mixture of poly(glycolide-co-lactide) and a phosphorylcholine-tuftsin conjugate, wherein: The plurality of particles are characterized by at least one dimension being greater than 100 um; and The phosphorylcholine-tuftsin conjugate was an amorphous solid as determined by XRD.

5. The composition of claim 4, wherein the weight concentration of the phosphorylcholine-tuftsin conjugate within the plurality of particles is from about 1% to about 50%; and wherein the phosphorylcholine-tuftsin conjugate is in the form of particulate matter characterized by an average particle size of less than 300 um as determined by SEM.

6. A composition according to claim 4 or 5, wherein at least one of the following: (i) 50% to 100% w / w of the polymer chains of the poly(glycolide-co-lactide) are ester-terminated; (ii) the weight ratio between polylactide and polyglycolide in the poly(glycolide-co-lactide) is at least 1:1; (iii) the acid value of the poly(glycolide-co-lactide) is below 1 mg(KOH) / g; or any combination of (i)-(iii).

7. The composition of any one of claims 4 to 6, wherein the composition is characterized by a powder XRD lack of a net intensity peak height of more than 400 counts corresponding to the phosphorylcholine-tuftsin conjugate.

8. The composition according to any one of claims 4 to 7, wherein the phosphorylcholine-tuftsin conjugate is represented by the following formula 1:

9. The composition according to any one of claims 4 to 8, characterized in that Density 0.3 to 0.4 mg / mm 3 .

10. The composition of any one of claims 4 to 9, wherein the plurality of particles is an ocular drug implant (ODI).

11. The composition of claim 10, wherein the ODI is in the form of elongated particles characterized by at least one of: a length dimension of about 1 mm to about 10 mm; a width dimension of about 0.1 mm to about 0.8 mm; optionally, wherein the ODI comprises a therapeutically effective amount of the phosphorylcholine-tuftsin conjugate.

12. An ocular drug implant (ODI), wherein the ODI is a solid material in the form of a particulate matter, the solid material comprising a mixture of poly(glycolide-co-lactide) and a peptide; wherein: The ODI is characterized by at least one dimension being greater than 100 um; and The particulate matter is characterized by an average particle size of up to about 100 um as determined by SEM.

13. The ODI of claim 12, wherein the peptide is present in the ODI at a concentration of about 1% to about 50% by weight; and wherein the water content of the ODI is below 20% by weight.

14. The ODI according to claim 11 or 12, wherein at least one of the following: (i) the weight ratio between polylactide and polyglycolide in the poly(glycolide-co-lactide) is at least 50:50; (ii) at least 80% w / w of the polymer chains of the poly(glycolide-co-lactide) are ester terminated; (iii) the acid value of the poly(glycolide-co-lactide) is below 1 mg(KOH) / g; or a combination of (i)-(iii).

15. The ODI according to any one of claims 11 to 14, wherein the peptide is a hydrophilic peptide characterized by an aqueous solubility of at least 10 g / L; optionally, wherein the peptide is a phosphorylcholine-peptide conjugate.

16. The ODI according to any one of claims 11 to 15, wherein the ODI is substantially in the form of elongated particles, optionally characterized by at least one of the following: a length dimension of about 1 mm to about 10 mm; a width dimension of about 0.1 mm to about 0.8 mm.

17. The ODI according to any one of claims 4 to 16, wherein the ODI is an extrudate.

18. The ODI according to any one of claims 4 to 17, wherein the ODI is characterized by a substantial release of the phosphorylcholine-tuftsin conjugate or the peptide in an aqueous medium.

19. The ODI of claim 18, wherein the weight ratio between polylactide and polyglycolide in the poly(glycolide-co-lactide) is at least 50:50; wherein at least 80% w / w of the polymer chains of the poly(glycolide-co-lactide) are ester terminated; and wherein the substantial release comprises cumulative release of at least 30% of the initial amount of the peptide or the phosphorylcholine-tuftsin conjugate over a period of time ranging from about 2 days to about 30 days.

20. The ODI of any one of claims 4 to 19, wherein at least 80% by weight of the particulate matter has a particle size of about 5 um to about 100 um as determined by SEM.

21. The ODI of any one of claims 4 to 20, wherein the average particle size of the particulate matter is from about 10 um to about 50 um as determined by SEM.

22. The ODI according to any one of claims 4 to 21, wherein the ODI comprises a therapeutically effective amount of the peptide.

23. A method for treating an ocular disease or disorder in a subject, the method comprising administering to the subject intraocularly a therapeutically effective amount of the composition of any one of claims 4 to 11 or the ODI of any one of claims 12 to 22.

24. The method of claim 23, wherein the therapeutically effective amount comprises a daily dose of 0.01 μg to 100 μg of the phosphorylcholine-tuftsin conjugate or the peptide.

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