Granular compositions containing peptides and uses thereof

Abstract

[0003] Provided are compositions comprising solid particles or granules comprising a phosphorylcholine-Tuftsin conjugate (including salts thereof) and ester end-capped poly(glycolide-co-lactide), wherein the phosphorylcholine-Tuftsin conjugate is an amorphous solid and characterized by one of: (i) an average particle size of less than 30 μm as determined by SEM; and (ii) a powder XRD that does not have a corresponding peak with a net intensity peak height greater than about 30 counts. Also provided are methods for treating an ocular disease or disorder in a subject by intraocularly administering to the subject a therapeutically effective amount of a composition of the invention.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 395,863, entitled "GRANULAR COMPOSITIONS COMPRISING A PEPTIDE AND USES THEREOF," filed August 7, 2022, the entire disclosure of which is incorporated herein by reference.

[0002] The present invention relates to solid polymer granules comprising peptides and uses thereof, such as for the prevention or treatment of ocular diseases or disorders and / or conditions related thereto in a subject. [Background technology]

[0003] Ocular inflammation, or 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 prevalent in all age groups and may be associated with systemic diseases such as Crohn's disease, Behçet's disease, and juvenile idiopathic arthritis. The inflammation may also be associated with other common eye conditions such as dry eye and dry macular degeneration. Several medications have known side effects of causing uveitis and / or dry eye. The most common treatment for ocular inflammation is steroids, specifically corticosteroids. However, these treatments have several known and sometimes serious side effects.

[0004] Dazdotuftide, or phosphorylcholine-tuftsin conjugate (PTC), is a bispecific synthetic peptide molecule with immunomodulatory activity. It consists of tuftsin (Thr-Lys-Pro-Arg), a naturally occurring immunomodulatory peptide generated by enzymatic cleavage of the Fc domain of the IgG heavy chain in the spleen. Phosphorylcholine (PC) is a small zwitterionic molecule secreted by helminths, which induces a state of immune tolerance in the host, allowing the helminths to survive on the surface of some bacteria and apoptotic cells.

[0005] There is a strong need for solid formulations of phosphorylcholine-tuftsin conjugates for direct administration to the eye, particularly those that should be characterized by a sufficient shelf life and sustained release of the active agent at the site of application within a predetermined period of time. Summary of the Invention

[0006] In one aspect of the invention, there is provided a composition comprising a phosphorylcholine-tuftsin conjugate (including salts thereof), wherein the phosphorylcholine-tuftsin conjugate has the formula 1: [ka] wherein the phosphorylcholine-Tuftsin conjugate is an amorphous solid and the phosphorylcholine-Tuftsin conjugate is in the form of a particulate material characterized by an average particle size of less than 300 μm as determined by SEM, and wherein the composition is characterized in that powder XRD does not have a corresponding peak for the phosphorylcholine-Tuftsin conjugate having a net intensity peak height of more than 400 counts.

[0007] In one embodiment, the salt is a pharmaceutically acceptable salt and the composition has a water content of less than 20%.

[0008] In one embodiment, the composition is a pharmaceutical composition comprising a pharmaceutically effective amount of a phosphorylcholine-tuftsin conjugate and further comprising a pharmaceutically acceptable carrier.

[0009] In another aspect, a composition is provided comprising a plurality of particles, each of the plurality of particles being 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 greater than 100 μm, and the phosphorylcholine-tuftsin conjugate is an amorphous solid as determined by XRD.

[0010] In one embodiment, the weight concentration of the phosphorylcholine-tuftsin conjugate in the plurality of particles is about 1 to about 50%, and the phosphorylcholine-tuftsin conjugate is in the form of a particulate material characterized by an average particle size of less than 300 μm as determined by SEM.

[0011] In one embodiment, the poly(glycolide-co-lactide) is characterized by at least one of: (i) 50% to 100% w / w of the polymer chains of the poly(glycolide-co-lactide) are ester end-capped; (ii) the polylactide:polyglycolide weight ratio in the poly(glycolide-co-lactide) is at least 1:1; (iii) the poly(glycolide-co-lactide) has an acid value of less than 1 mg(KOH) / g; or any combination of (i)-(iii).

[0012] In one embodiment, the composition is characterized by a powder XRD that does not have a peak corresponding to a phosphorylcholine-Tuftsin conjugate having a net intensity peak height of greater than 400 counts.

[0013] In one embodiment, the phosphorylcholine-tuftsin conjugate has Formula 1: [ka] is expressed by

[0014] In one embodiment, the composition has a concentration of 0.3 to 0.4 mg / mm 3 It is characterized by a density of

[0015] In one embodiment, the plurality of particles is an ophthalmic drug implant (ODI).

[0016] In one embodiment, the ODI is in the form of an elongated particle characterized by at least one of a length dimension of about 1 to about 10 mm and a width dimension of about 0.1 to about 0.8 mm, and optionally the ODI comprises a therapeutically effective amount of a phosphorylcholine-tuftsin conjugate.

[0017] In another aspect, an ophthalmic drug implant (ODI) is provided, wherein the ODI is a solid material comprising a mixture of poly(glycolide-co-lactide) and a peptide in the form of particulate matter, the ODI being characterized by at least one dimension greater than 100 um, and the particulate matter being characterized by an average particle size of at most about 100 um as determined by SEM.

[0018] In one embodiment, the weight concentration of the peptide in the ODI is about 1 to about 50%.

[0019] In one embodiment, the poly(glycolide-co-lactide) is characterized by at least one of: (i) a polylactide:polyglycolide weight ratio of at least 50:50 in the poly(glycolide-co-lactide); (ii) at least 80% w / w of the polymer chains of the poly(glycolide-co-lactide) are ester end-capped; (iii) the poly(glycolide-co-lactide) has an acid value of less than 1 mg(KOH) / g; or a combination of (i)-(iii).

[0020] In one embodiment, the peptide is a hydrophilic peptide characterized by a water solubility of at least 10 g / L, and optionally the peptide is a phosphorylcholine-peptide conjugate.

[0021] In one embodiment, the ODI is in the form of substantially elongated particles, optionally characterized by at least one of a length dimension of about 1 to about 10 mm and a width dimension of about 0.1 to about 0.8 mm.

[0022] In one embodiment, the ODI is an extrudate.

[0023] In one embodiment, the ODI is characterized by a substantial release of the phosphorylcholine-tuftsin conjugate or peptide in aqueous media.

[0024] In one embodiment, the poly(glycolide-co-lactide) has a polylactide:polyglycolide weight ratio of at least 50:50, at least 80% w / w of the polymer chains of the poly(glycolide-co-lactide) are ester end-capped, and the substantial release comprises a cumulative release of at least 30% of the initial amount of the peptide or phosphorylcholine-tuftsin conjugate within a period ranging from about 2 to about 30 days.

[0025] In one embodiment, at least 80% by weight of the particulate material has a particle size of about 5 to about 100 um as determined by SEM.

[0026] In one embodiment, the particulate matter has an average particle size of about 10 to about 50 um as determined by SEM.

[0027] In one embodiment, the ODI comprises a therapeutically effective amount of the peptide.

[0028] In another aspect, a method is provided for treating an ocular disease or disorder in a subject, the method comprising intraocularly administering to the subject a therapeutically effective amount of a composition of the invention or an ODI of the invention.

[0029] In one embodiment, the therapeutically effective amount comprises a daily dose of 0.01 to 100 μg of phosphorylcholine-tuftsin conjugate or peptide.

[0030] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those 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 case of conflict, the present patent specification, including definitions, will control. Furthermore, the materials, methods, and examples are merely illustrative and are not necessarily limiting.

[0031] In order that the present invention may be more fully understood, it will now be described with reference to specific examples and embodiments and with reference to the following illustrative drawings. [Brief explanation of the drawings]

[0032] [Figure 1] Powder XRD of pristine uncrushed PTC pellets (top graph, black) and crushed PTC powder according to the present invention (bottom graph, red). "PTC" refers to the compound of Formula 1 as disclosed herein. [Figure 2] 2A-2B are SEM images of pristine, unground PTC particulate material (2A) and PTC particulate material according to the present invention (2B). [Figure 3A] 1 shows SEM images of exemplary rod-shaped solid particles (i.e., ophthalmic drug implants, ODIs) of the present invention obtained by extrusion of Resomer RG 752 S and milled PTC powder (9% w / w drug loading) of the present invention. The image on the left shows a cross section, and the image on the right shows the surface of the rod-shaped solid particle. [Figure 3B] 1 is a graph showing the cumulative release rate (%) of PTC in water from an ODI consisting of ester end-capped PLGA (Resomer RG 752 S). [Figure 3C] 1 is an image of an exemplary rod-shaped solid particle (ODI) of the present invention. [Figure 3D]1 is a graph showing the cumulative release of PTC in water from exemplary rod-shaped solid particles (ODI) of the present invention with a 9% drug loading made of ester end-capped PLGA (Resomer RG 752 S) compared to similar particles made of non-end-capped Resomer RG 752 H. DETAILED DESCRIPTION OF THE INVENTION

[0033] In some embodiments, the present invention relates to solid compositions (e.g., ophthalmic compositions) comprising, inter alia, phosphorylcholine-tuftsin conjugates, as well as methods for treating a medical condition by administering the compositions to a subject in need thereof. In further embodiments, the present invention relates to ophthalmic compositions for ocular administration and their use in treating a medical condition in a subject in need thereof.

[0034] In some embodiments, the present invention is based on the surprising discovery that poly(glycolide-co-lactide) (PLGA)-based solid particles (i.e., ODIs) containing the phosphorylcholine-tuftsin conjugate (PTC) disclosed herein exhibit enhanced release profiles when compared to microspheres composed of similar components. Specifically, the inventors surprisingly discovered that ester-end-capped PLGA (referred to herein as Resomer 752 S) when utilized in the solid particles of the present invention exhibits superior drug loading efficiency and aqueous release profile (demonstrated as sustained release, as demonstrated herein) when compared to similar acid-terminated polymers (i.e., unend-capped PLGA, referred to herein as Resomer 752 H). Furthermore, the inventors surprisingly discovered that utilizing PTC having a small average particle size of less than about 30 μm results in homogeneous solid particles and an enhanced sustained release profile therefrom. In contrast, similar solid particles containing unmilled (pristine) solid PTC having an average particle size of about 30 to about 100 μm resulted in a burst release profile.

[0035] As used herein, the term "phosphorylcholine-tuftsin conjugate" refers to a phosphorylcholine moiety covalently attached to tuftsin or a tuftsin derivative, optionally via a spacer. As used herein, the term "phosphorylcholine-tuftsin conjugate" further encompasses any salts (e.g., pharmaceutically acceptable salts) and any isotopes thereof.

[0036] As used herein, the term "tuftsin" refers to the tetrapeptide (threonine-lysine-proline-arginine, or TKPR; SEQ ID NO: 1). In some embodiments, the PTC is or comprises tuftsin (i.e., a peptide having the amino acid sequence defined in SEQ ID NO: 1) covalently linked to a phosphorylcholine moiety through its side chain (e.g., the phosphate group is directly attached to the side chain of threonine or the side chain of lysine). In some embodiments, the PTC is or comprises tuftsin (i.e., a peptide having the amino acid sequence defined in SEQ ID NO: 1) covalently linked to a phosphorylcholine moiety through its amino terminus (e.g., the phosphate group is directly attached to the amino group, forming a phosphoramidite). In some embodiments, the PTC is or comprises tuftsin (i.e., a peptide having the amino acid sequence defined in SEQ ID NO: 1) covalently linked to a phosphorylcholine moiety through its amino terminus (e.g., the phosphate group is directly attached to the amino group, forming a phosphoramidite). In some embodiments, the PTC is or comprises tuftsin (i.e., a peptide having the amino acid sequence defined in SEQ ID NO: 1) covalently bound via its carboxy terminus to a phosphorylcholine moiety (e.g., the carboxy group is bound directly to a phosphate, generating a phosphorylated carboxy group).

[0037] The term "phosphorylcholine moiety" refers to phosphorylcholine, i.e. [ka] 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 effects of phosphorylcholine. In some embodiments, the phosphorylcholine derivative is a derivative that includes phosphorylcholine.

[0038] In some embodiments, the derivative of phosphorylcholine is selected from phenylphosphorylcholine, substituted phenylphosphorylcholine (e.g., aminophenylphosphorylcholine, nitrophenylphosphorylcholine, halophenylphosphorylcholine, hydroxyphenylphosphorylcholine, alkylphenylphosphorylcholine), and 12-(3-iodophenyl)dodecylphosphocholine, among others. Each possibility is a separate embodiment of the present invention.

[0039] In some embodiments, the derivative of phosphorylcholine has Formula 2: [ka] wherein each R is independently an optionally substituted alkyl (e.g., methyl, or any C1-10 or C2-C10 alkyl), and X is a spacer. In some embodiments, X is a natural and / or unnatural amino acid, a C5-C10 cycloalkylene, an optionally substituted C1-C6 alkylene, —C(═O)—C1-C6 alkylene, an optionally substituted C6-C10 arylene, an aryl (or heteroaryl)-azo, a heteroaromatic ring, a carbocyclyl, a bond (an amide bond, an ester bond, an azo bond, a thioester bond, a disulfide bond, —NC(═O)—, —C(═O)N—, CONR and -OC(=S)N-, -SC(=O), etc.), glycols of the formula -(RO)x- (wherein R represents a C1-C10 alkyl and x is an integer ranging from 1 to 10), or any combination thereof.

[0040] In some embodiments, X is or comprises a straight or branched chain. In some embodiments, X comprises a backbone that comprises a straight or branched chain. In some embodiments, X comprises a cyclic (aromatic or aliphatic) backbone.

[0041] In some embodiments, the derivative of phosphorylcholine is represented by formula 2, where R is methyl.

[0042] In some embodiments, X is [ka] is.

[0043] In some embodiments, the spacer has a MW of less than 500 Da, less than 400 Da, less than 300 Da, less than 200 Da, less than 100 Da, or between 30 and 100 Da, 30 and 200 Da, 30 and 300 Da (including any range therebetween).

[0044] In some embodiments, the spacer is a single CC bond length of 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 (including any range therebetween).

[0045] The term "tuftsin derivative" refers to tuftsin (TKPR, SEQ ID NO: 1) linked to at least two additional 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 tuftsin derivatives. In some embodiments, the tuftsin derivative is TKPR(X1)(X2), where X1 is an amino acid selected from Gly, Ala, Val, Thr, Leu, Ile, and Met, and X2 is an amino acid selected from Tyr, Trp, Phe, Cys, Ser, Thr, Gly, Ala, Val, Thr, Leu, Ile, and Met.

[0046] In some embodiments, a tuftsin derivative is a peptide that contains TKPR and retains the immunomodulatory effects of tuftsin. Derivatives are not simply fragments of the polypeptide, nor do they have substituted or removed amino acids (analogs), but rather may have additional amino acid residues and / or modifications made to the polypeptide, such as post-translational modifications.

[0047] In some embodiments, the tuftsin derivative is threonine-lysine-proline-arginine-glycine-tyrosine (TKPRGY, SEQ ID NO: 2).

[0048] In some embodiments, the term "moiety" as used herein refers to a portion of a molecule that lacks one or more atoms compared to a corresponding molecule. As used herein, the term "moiety" may further refer to a portion of a molecule that can include either an entire functional group or a portion of a functional group as a substructure (e.g., an amino group lacking a hydrogen, a phosphate group lacking a hydrogen or a hydroxyl, an amino acid residue, etc.). The term "moiety" further refers to a portion of a molecule that exhibits a particular set of chemical and / or pharmacological properties similar to the corresponding molecule.

[0049] As used herein, the term "linked" refers to a bond between at least two molecules or moieties such that they become a single molecule. In some embodiments, the bond is a chemical bond. In some embodiments, the bond is a covalent bond. In accordance with the principles of the present invention, natural or unnatural amino acids contained in tuftsin derivatives are adjacent to and linked to one another, and at least one phosphorylcholine derivative is linked to at least one tuftsin derivative directly or indirectly via a spacer. In some embodiments, at least one phosphorylcholine or derivative thereof is linked to the N-terminus of at least one tuftsin or derivative thereof. In some embodiments, at least one phosphorylcholine or derivative thereof is linked to the C-terminus of at least one tuftsin or derivative thereof.

[0050] In some embodiments, the phosphorylcholine-tuftsin conjugate comprises one or more phosphorylcholine moieties attached to a tuftsin derivative. In certain embodiments, the phosphorylcholine moiety (i.e., a derivative of phosphorylcholine represented by Formula 2) is covalently attached to the tuftsin derivative. In some embodiments, it is covalently attached via the side chain of the tuftsin derivative. In some embodiments, it is covalently attached via the side chain of Tyr (e.g., via an azo bond attached to the side chain of Tyr). In some embodiments, the phosphorylcholine-tuftsin conjugate is represented by Formula 1 below:

[0051] In one aspect of the present invention, there is provided a composition comprising a phosphorylcholine-tuftsin conjugate (PTC), optionally including a salt thereof, wherein the PTC is in the form of a particulate material characterized by any one of (i) an average particle size of less than 300 μm or less than 200 μm as determined by SEM, and (ii) a powder XRD that does not have a corresponding peak for the PTC with a net intensity peak height of greater than about 400 counts. In some embodiments, the PTC is as disclosed herein.

[0052] In another aspect of the present invention, there is provided a composition comprising a peptide (optionally including a salt thereof), wherein the peptide is in the form of a particulate material characterized by any one of (i) an average particle size of less than 300 μm or less than 200 μm as determined by SEM, and (ii) a powder XRD showing no corresponding peak for the peptide with a net intensity peak height of more than about 400 counts. In some embodiments, the peptide is a peptide-phosphorylcholine conjugate disclosed herein for PTC. In some embodiments, the peptide is a peptide-phosphorylcholine conjugate comprising (i) a side chain (e.g., a Lys or Tyr side chain) of the peptide and / or (ii) a phosphorylcholine moiety attached to the C-terminus or N-terminus of the peptide.

[0053] In some embodiments, the peptide is between 3 and 50, 3 and 10, 3 and 20, 3 and 5, 5 and 10 amino acid residues in length (including any range therebetween).

[0054] As used herein, the terms "peptide," "polyamino acid," "polypeptide," and "protein" are used interchangeably and refer to a polymer of amino acid residues. In some embodiments, the peptides of the present invention are or comprise therapeutic peptide sequences. The term "therapeutic peptide sequence" refers to any peptide sequence configured to elicit a therapeutic effect in a subject (e.g., treatment, prevention, alleviation of symptoms of a disease, etc.). Furthermore, the term "therapeutic peptide sequence" encompasses any polyamino acid sequence that can alter the activity, functionality, survival, fitness, appearance, structure, growth, behavior, or any combination thereof, of a cell. In some embodiments, a therapeutic sequence can bind to an intracellular target (e.g., an enzyme) to regulate (upregulate or downregulate) the activity of the intracellular target.

[0055] As used herein, the terms "peptide," "polyamino acid," "polypeptide," and "protein" encompass natural peptides, peptide derivatives such as beta-peptides, peptidomimetics (typically containing non-peptide bonds or other synthetic modifications), and peptide analogs peptoids and semipeptoids, or any combination thereof. In another embodiment, the terms "peptide," "polyamino acid," and "protein" apply to amino acid polymers in which at least one amino acid residue is an artificial chemical analog of a corresponding naturally occurring amino acid.

[0056] 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 with a side chain or any functional group within the peptide. Such derivatized molecules include, for example, peptides having one or more protecting groups (e.g., side chain protecting groups and / or N-terminal protecting groups) and / or peptides in which free amino groups have been derivatized to form amine hydrochlorides, p-toluenesulfonyl groups, carbobenzoxy groups, t-butyloxycarbonyl groups, acetyl groups, or formyl groups. Free carboxyl groups may be derivatized to form amides, salts, methyl and ethyl esters or other types of esters, or hydrazides thereof. Free hydroxyl groups may be derivatized to form O-acyl or O-alkyl derivatives. The imidazole nitrogen of histidine may be derivatized to form N-im-benzylhistidine. Chemical derivatives also include peptides containing one or more naturally occurring amino acid derivatives of the 20 standard amino acid residues. For example, 4-hydroxyproline may be used in place of proline, 5-hydroxylysine may be used in place of lysine, 3-methylhistidine may be used in place of histidine, homoserine may be used in place of serine, and Dab, Daa and / or ornithine (O) may be used in place of lysine.

[0057] Furthermore, peptide derivatives may differ from the native sequence of the peptides of the invention by chemical modifications including, but not limited to, acylation, acetylation, or thioglycolic acid amidation of the NH2 terminus and amidation of terminal and / or side chain carboxy groups, for example, with ammonia and methylamine. The peptides may be linear, cyclic, or branched, and have any conformation that can be achieved using methods known in the art.

[0058] As used herein, the term "amino acid" refers to an organic compound containing both a basic amino group and an acidic carboxyl group. The term includes naturally occurring amino acids, protected amino acids (e.g., containing one or more protecting groups on the carboxyl, amine, and / or amino acid side chains), unusual non-naturally occurring amino acids (such as D-amino acids), and amino acids that are known to occur biologically in free or conjugated form but do not normally occur in proteins. The term also includes modified and unusual amino acids, such as those disclosed in 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-methylnorleucine, 3,4-dehydroproline, N,N-dimethylaminoglycine, N-methylaminoglycine, 4-aminopiperidine-4-carboxylic acid, 6-aminocaproic acid, trans 4-(aminomethyl)-cyclohexanecarboxylic acid, 2-, 3-, and 4-(aminomethyl)-benzoic acid, 1-aminocyclopentanecarboxylic acid, 1-aminocyclopropanecarboxylic acid, cyanopropionic acid, 2-benzyl-5-aminopentanoic acid, norvaline (Nva), 4-O-methylthreonine (TMe), 5-O-methylhomoserine (hSM), tert-butylalanine (tBu), cyclopentylalanine (Cpa), 2-aminoisobutyric acid (Aib), N-methylglycine (MeG), N-methylalanine (MeA), N-methylphenylalanine (MeF), 2-thienylalanine (2Th), 3-thienylalanine (3Th), O-methyltyrosine (YMe), 3-benzothienylalanine (Bzt), and D-alanine (DAl).

[0059] The term "polyamino acid" further encompasses random polymers (i.e., lacking a specific amino acid sequence throughout the composition and comprising a random population of polymers of different lengths and different sequences) and polypeptides having a specific amino acid sequence. The terms "peptide sequence" and "amino acid sequence" are used interchangeably herein. In some embodiments, a peptide sequence is or comprises a D-amino acid sequence. In some embodiments, at least 70%, at least 80%, at least 90%, or at least 95% of the amino acids in a peptide sequence are in the D-form. In some embodiments, the amino acids in a peptide sequence are in the D-form.

[0060] In some embodiments, a composition of the invention (eg, an ODI) comprises a peptide disclosed herein in the form of a particulate material.

[0061] In another embodiment of the invention, there is provided a composition comprising a PTC (including salts thereof), wherein the PTC has Formula 1: [ka] wherein the PTC is an amorphous solid, and the PTC is in the form of a particulate material characterized by any one of (i) an average particle size of less than 300 μm or less than 200 μm as determined by SEM, and (ii) a powder XRD that does not have a corresponding peak with a net intensity peak height greater than about 400 counts. In some embodiments, the PTC is an amorphous powder.

[0062] In some embodiments, the average particle size of the particulate matter is 10 nm to 300 um, 10 nm to 200 um, 10 nm to 180 um, 10 nm to 150 um, 10 nm to 100 um, 20 nm to 100 um, 10 nm to 80 um, 10 nm to 75 um, 10 nm to 1 um, 10 nm to 10 um, 100 nm to 10 um, 100 nm to 1 um, 100 nm to 5 um, 10 nm to 500 um, 100 nm to 500 um, 300 nm to 10 um, 300 nm to 5 um, 300 nm to 1 um um, 300 nm to 500 um, 300 nm to 800 um, 500 nm to 10 um, 500 nm to 1 um, 10 nm to 100 um, 100 nm to 500 nm, 500 nm to 800 um, 800 nm to 30 um, 800 nm to 5 um, 5 to 30 um, 1 to 30 um, 1 to 10 um, 1 to 75 um, 1 to 150 um, 1 to 100 um, 1 to 50 um, 1 to 60 um, 10 to 30 um (including any range therebetween), where the average particle size is as determined by SEM. In some embodiments, at least 80 wt% of the particulate material has a particle size of about 5 to about 100 um, about 20 to about 100 um, about 20 to about 80 um, about 20 to about 60 um, about 20 to about 50 um, or about 20 to about 40 um, as determined by SEM.

[0063] In some embodiments, the particulate material is an amorphous powder. In some embodiments, the PTC (particulate material) is characterized by a powder XRD (X-ray diffractogram) that is substantially free of corresponding peaks. In some embodiments, the XRD of the PTC is characterized by corresponding peaks that are significantly lower than those of the pristine powdered PTC. The term "pristine" refers to PTC obtained by freeze-drying a purified (or crude) PTC solution. The inventors have observed that pristine PTC is substantially characterized by an average particle size of about 200 μm and is in the form of irregularly shaped pellets. Furthermore, while pristine PTC is characterized by small corresponding peaks in powder XRD (see Figure 1, top diffractogram), the PTC of the present invention is substantially free of any significant corresponding XRD peaks as visualized by Figure 1 (red bottom diffractogram).

[0064] In some embodiments, the particle size of the particulate material is as described above, and the particulate material is amorphous as characterized by a PTC powder XRD that is free of corresponding peaks (i.e., PTC peaks) with a net intensity of greater than 400 counts, greater than 300 counts, greater than 200 counts, greater than 100 counts, about 50 counts, about 40 counts, about 30 counts, about 20 counts, about 10 counts, or about 5 counts (including any ranges therebetween). In some embodiments, the particle size of the particulate material is as described above, and the PTC powder XRD is substantially free of corresponding peaks with a net intensity of greater than about 200 counts, greater than about 150 counts, greater than about 100 counts, greater than about 80 counts, greater than about 60 counts, greater than about 50 counts, greater than about 40 counts, greater than about 30 counts, greater than about 20 counts, or greater than about 10 counts (including any ranges therebetween). In some embodiments, the corresponding peak of the PTC as 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 peak height refers to normalized peak intensity.

[0065] The inventors have surprisingly discovered that the particulate form of PTC described herein (e.g., PTC of Formula 1) is significantly superior to the original PTC, particularly with regard to its incorporation into the solid particles (ODI) of the present invention, to obtain ODIs having an optimal loading of the active agent (PTC) and further characterized by a sustained release profile of the active agent.

[0066] In some embodiments, the salt of PTC is a pharmaceutically acceptable salt. Pharmaceutically acceptable salts are well known in the art, including 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 similar salts, and mixtures thereof. In some embodiments, the peptides (e.g., PTC) disclosed herein are pharmaceutical-grade active agents (e.g., characterized by chemical purity of greater than 97%). In some embodiments, all components of the compositions and / or ODIs of the present invention are substantially chemically pure compounds.

[0067] In some embodiments, the compositions of the present invention are pharmaceutical compositions comprising a pharmaceutically effective amount of a PTC and further comprising a pharmaceutically acceptable carrier. In some embodiments, the compositions of the present invention are pharmaceutical compositions comprising a pharmaceutically effective amount of a peptide and further comprising a pharmaceutically acceptable carrier.

[0068] In some embodiments, the compositions of the present invention are formulated for ocular administration. In some embodiments, the pharmaceutical compositions are ophthalmic compositions. In some embodiments, the terms "ophthalmic composition" and "pharmaceutical composition" are used interchangeably herein. In some embodiments, the pharmaceutical compositions are formulated for ocular administration. In some embodiments, the compositions of the present invention comprise a phosphorylcholine-tuftsin conjugate as the only pharmaceutically active ingredient. In some embodiments, the compositions of the present invention are substantially free of any additional pharmaceutically active ingredients. In some embodiments, the compositions of the present invention are substantially free of any additional peptides. In some embodiments, the compositions of the present invention are substantially free of any additional anti-inflammatory agents.

[0069] In another aspect, a composition is provided comprising a plurality of particles, each of which is a solid particle comprising poly(glycolide-co-lactide) (PLGA) of the present invention and a phosphorylcholine-tuftsin conjugate. In some embodiments, the solid particle is an ODI. The terms "solid particle" and "ODI" are used interchangeably herein.

[0070] In some embodiments, the PLGA and PTC are mixed together within the solid particles. In some embodiments, the PLGA and PTC are in the form of a mixture within the solid particles. In some embodiments, the PLGA and PTC are in the form of a homogeneous mixture within the solid particles. In some embodiments, the solid particles are composite materials comprising or consisting essentially of PLGA and PTC. In some embodiments, the solid particles are mixtures of or consisting essentially of PLGA and PTC. In some embodiments, "consisting essentially of" includes 80-100%, 80-99%, 90-99%, 90-100%, 92-99%, 93-99%, 95-99%, 95-97%, 93-100%, 95-100%, 97-99%, or 97-100% of the solid particles by dry weight.

[0071] In some embodiments, the PLGA is in the form of a matrix. In some embodiments, the mixture comprises PTC particles embedded or incorporated within the PLGA matrix. In some embodiments, the mixture comprises PTC particles encapsulated in the PLGA matrix.

[0072] As used herein, the term "matrix" refers to one or more layers of polymer chains randomly distributed (and / or having an ordered distribution) therein. In addition to PTC particles, the matrix may further include any material embedded within and / or sandwiched between these layers. In some embodiments, the matrix includes randomly oriented polymer chains. In some embodiments, each polymer chain within the matrix is in contact with at least one additional polymer chain. In some embodiments, the polymer chains are randomly distributed within the matrix to obtain a three-dimensional mesh structure with voids between the chains. In some embodiments, the polymer chains are randomly distributed within the matrix, thus forming an entangled polymer mesh, optionally with a plurality of pores (or voids). In some embodiments, the matrix is an entangled matrix of randomly distributed polymer chains and is characterized by low porosity as disclosed herein. In some embodiments, the matrix is substantially free of polymer chains aligned or oriented in a particular direction.

[0073] In some embodiments, (i) the PLGA is substantially ester end-capped, and / or (ii) the weight ratio of polylactide to polyglycolide in the poly(glycolide-co-lactide) is 50:50 to 95:5 (including any range therebetween). In some embodiments, ester end-capped PLGA refers to alkylated terminal carboxy groups of the polymer (e.g., alkylation of the terminal glycolic acid). In some embodiments, the terminal carboxy groups are alkylated with a C1-C10 alkyl to obtain terminal C1-C10 esters (e.g., methyl esters). 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 60-95%, 70-95%, 80-95%, about 80-90%, or about 85-90% by weight of the total polymer chains of the PLGA are ester end-capped.

[0074] 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 60-95%, 70-95%, 50-95%, 50-99%, 80-95%, about 80 to about 90%, or about 85 to about 90% of the total polymer chains of the PLGA are ester end-capped.

[0075] In some embodiments, the ester end-capped PLGA has an acid value that is at most 20%, at most 15%, or at most 10% lower than the acid value of the same polymer that is not ester end-capped (i.e., the free acid polymer). In some embodiments, the acid value of the ester end-capped PLGA is less than 1 mg(KOH) / gr PLGA.

[0076] In some embodiments, the PLGA comprises less than 20%, less than 10%, less than 5%, less than 3%, or less than 1% by weight of non-end-capped PLGA (e.g., PLGA with terminal carboxy groups) relative to the total weight of PLGA.

[0077] In some embodiments, the PLGA is characterized by an average molecular weight (Mw) of 5,000-10,000, 10,000-20,000, 10,000-15,000, 5,000-15,000, 7,000-20,000 Da (including any range therebetween).

[0078] In some embodiments, the solid particles disclosed herein are in a solid state at temperatures below the melting point of PLGA (eg, below 200° C. or below 150° C.).

[0079] 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 material as disclosed herein and is mixed with the biodegradable polymer throughout the volume of the ODI, and the weight concentration of the peptide in the ODI is as disclosed herein (1-50% w / w). In some embodiments, the biodegradable polymer is a polyester. In some embodiments, the polyester is not end-capped. In some embodiments, the polyester is ester end-capped. In some embodiments, the polyester comprises any one of polycaprolactone, polyε-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 a PTC disclosed herein.

[0080] In some embodiments, the compositions of the present invention comprising the solid particles disclosed herein are pharmaceutical compositions. In some embodiments, the compositions of the present invention consist essentially of pharmaceutical-grade ingredients. In some embodiments, the compositions of the present invention are for use in treating an ocular disease or disorder or a condition associated therewith by intraocular administration of a pharmaceutically effective amount of the composition to a subject. In some embodiments, the pharmaceutically effective amount of the composition comprises a pharmaceutically effective amount of PTC.

[0081] 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) comprise a therapeutic amount of the peptide (i.e., a therapeutic peptide such as a PTC disclosed herein) in the range of 0.01-200 μg, 0.01-100 μg, 1-100 μg, 0.1-100 μg, 10-100 μg, 100-200 μg, 50-200 μg, 20-100 μg, or 20-200 μg (including any range or value therebetween) per ODI.

[0082] ODIs refer to intraocular implants that are well known in the art. ODIs are designed to be implanted to control drug release, thereby extending the time a condition remains under control. ODIs can release high concentrations of drugs at the intended location through site-specific implantation. Furthermore, ODIs increase patient compliance, minimize the pain of parenteral treatment, and maintain drug concentrations within a therapeutic time window through the continuous, controlled release of the loaded drug. ODIs can be administered to a subject by implantation, such as intravitreal injection, intracameral injection, or subconjunctival injection.

[0083] In some embodiments, the solid particles are extruded (or hot-melt extruded) particles. In some embodiments, the solid particles are characterized by at least one dimension greater than 50 um, greater than 100 um, greater than 200 um, greater than 300 um, greater than 400 um, greater than 500 um, greater than 0.5 mm, or greater than 1 mm (including any range therebetween). The term "dimension" refers to any one of the length dimension, width dimension (e.g., cross-section or diameter / radius), or both. In some embodiments, the term "dimension" refers to the average particle size in the composition of the present invention. In some embodiments, the solid particles are substantially free of microspheres, such as particles (e.g., spherical particles) having an average particle size of 1-50 um, 1-30 um, or 1-20 um (including any range therebetween). In some embodiments, the particles are in the form of granules. In some embodiments, the particles are in the form of solid granules. In some embodiments, the particles or granules are substantially uniform in shape. In some embodiments, the particles or granules are characterized by a substantially uniform size distribution, loading, or both of the PTC.

[0084] In some embodiments, the weight concentration of the conjugate in the solid particles (or compositions) 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%, or about 20 to about 50%, including any range therebetween. The inventors have successfully produced exemplary ODIs of the present invention with loadings of PTC of up to about 20% w / w (about 2.5 to about 20% loading). The inventors currently estimate that significantly higher loadings of PTC in ODIs, up to at least 40% by weight, can be obtained.

[0085] In some embodiments, the compositions of the present invention consist essentially of the ester end-capped PLGA and PTC of the present invention. In some embodiments, the solid particles of the present invention consist essentially of the ester end-capped PLGA and PTC of the present invention.

[0086] In some embodiments, the PTC is in an amorphous state in the solid particles as determined by XRD. In some embodiments, the PTC in the solid particles substantially retains the particle size of the powdered PTC. In some embodiments, the PTC in the solid particles substantially retains the amorphous state of the powdered PTC. In some embodiments, the compositions of the present invention (or a plurality of particles disclosed herein) are characterized by substantially the same XRD as the powdered PTC disclosed herein.

[0087] In some embodiments, the PTC is substantially homogeneously distributed in the solid particles of the present invention. In some embodiments, the PTC is substantially homogeneously distributed in the compositions of the present invention. Homogeneous distribution can be determined by HPLC, such as by measuring the PTC concentration in three or more different probes taken from the compositions of the present invention. The composition is considered homogeneous when the standard deviation of the PTC concentration values for the samples is less than 10%.

[0088] In some embodiments, the weight ratio of polylactide:polyglycolide in the 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, between 50:50 and 95:5, between 50:50 and 90:10, between 50:50 and 85:15, between 50:50 and 80:20, between 60:40 and 95:5, between 60:40 and 90:10, between 60:40 and 85:15, between 60:40 and 80:20, or between about 70:30 and about 80:20 (including any range therebetween). Without being limited by any particular theory, the inventors hypothesize (based on experimental data) that PLGA having a polylactide:polyglycolide weight ratio of greater than 1:1, more particularly greater than 60:40, such as about 75:25 or about 65:35 (i.e., a weight excess of polylactide over polyglycolide), can produce solid particles (ODIs) of the present invention characterized by a favorable sustained release profile of the active agent (PTC) therefrom. For the production of ODIs with rapid drug release, PLGAs having a polylactide:polyglycolide weight ratio of less than 1:1 (e.g., 10:90, 25:75, or 5:95 to 50:50 (including any range therebetween) can be utilized.

[0089] In some embodiments, the solid particles (ODI) have an elongated shape. In some embodiments, each of the solid particles of the present invention is characterized by an elongated shape. In some embodiments, the solid particles are characterized as being substantially rod-shaped, rod-shaped, needle-shaped, cylindrical, ellipsoidal, etc. One skilled in the art will appreciate that each shape of the solid particles may vary slightly or substantially from a particular geometric shape. Thus, the solid particles may have a rod-like, rod-like, needle-like, cylindrical, or ellipsoidal shape, meaning that the actual shape of the particle has some deviation (e.g., at least 10%, at least 50%, or more) from the perfect geometric shape. In some embodiments, the solid particles are substantially free of hollow particles.

[0090] The solid particles may be of any shape, such as cubic, rectangular, prismatic, or conical.

[0091] 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% (including any range therebetween) of the solid particles have substantially the same shape (e.g., with a size deviation of up to 20% or up to 10% (including any range therebetween)). In some embodiments, the solid particles (ODI) are in the form of substantially rod-shaped or cylindrical particles (see FIG. 3A).

[0092] In some embodiments, the solid particles are characterized by a length dimension of at least 100 μm, at least 500 μm, 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, or about 1 to about 5 mm (including any range therebetween). In some embodiments, the length dimension is greater than 100 mm.

[0093] 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, or 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 interior cross-section of a means (e.g., a catheter) for intraocular delivery of the particles to a subject. Those skilled in the art will understand that for intraocular delivery, the particles of the present invention must be compatible with the means for intraocular delivery, and therefore, without limitation, the width dimension of the particles should be less than 0.8 mm, preferably less than 0.6 mm.

[0094] 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 with a caliper. Methods for determining the average length or width of the present solid particles in a given sample are well known in the art. In an exemplary embodiment, the average length or width of 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 with a caliper. An exemplary elongated solid particle of the present invention is shown in FIG. 3C.

[0095] 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 range therebetween). In some embodiments, the solid particles of the present invention are characterized by length dimensions, width dimensions, and optionally aspect ratios, as described herein.

[0096] 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).

[0097] In some embodiments, the solid particles and / or compositions comprising the solid particles have a concentration of 0.2 to 0.6 mg / mm 3 , 0.3 to 0.45 mg / mm 3 , about 0.3~about 0.4mg / mm 3 , 0.30-0.33mg / mm 3 , 0.32-0.35mg / mm 3 , 0.35-0.40mg / mm 3 , 0.40-0.45mg / mm 3 , 0.31-0.33mg / mm 3 (including any range therebetween).

[0098] In another aspect of the invention, there is provided a composition comprising a plurality of particles, each of the plurality of particles being a solid particle comprising a mixture of PLGA and a peptide in the form of a particulate material, wherein the plurality of particles in the composition are characterized by at least one dimension of greater than 50 um, greater than 100 um, greater than 200 um, greater than 300 um, greater than 400 um, greater than 500 um, greater than 0.5 mm, greater than 1 mm, 0.1-10 mm, 0.1-3 mm, 0.1-2 mm (including any ranges therebetween), and the particulate material has an average particle size of at most about 300 um, at most about 200 um, at most about 150 um, at most about 70 um, or at most about 30 um, or 10-200 um, 10-150 um, 10-100 um, 10-70 um, 10-50 um (including any ranges therebetween), wherein the average particle size of the particulate material is determined by SEM. In some embodiments, the solid particles are elongated particles characterized by a width dimension of greater than 50 um, greater than 100 um, greater than 200 um, greater than 300 um, greater than 400 um, greater than 500 um, greater than 0.5 mm, greater than 1 mm, 0.1-3 mm, 0.1-2 mm, 0.5-1 mm, 0.5-2 mm (including any range therebetween). In some embodiments, the solid particles are as described herein above.

[0099] In some embodiments, the particle size of the peptide, the weight concentration of the peptide in the particle / composition, the chemical composition of the PLGA, and any one of the other physicochemical parameters of the particle are as described herein for the solid particle comprising PTC.

[0100] 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 without organic solvents) 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, or at least 500 g / L (including any range therebetween) at a temperature of 20-30° C. In some embodiments, the peptide is or comprises a PTC disclosed herein.

[0101] In some embodiments, the solid particles disclosed herein are hot melt particles. In some embodiments, the solid particles disclosed herein are extruded particles, i.e., particles obtained by a hot melt extrusion process.

[0102] In some embodiments, the corresponding peak of the solid particles of the present invention (ODI) is characterized by a substantially higher XRD peak height (net intensity) of the peptide when compared to a control, where the control is a non-extruded mixture containing the same components. In some embodiments, the corresponding peak of the ODI (i.e., the XRD peak of the peptide) is at least 10-fold, at least 8-fold, at least 5-fold, at least 2-fold, or at least 1.5-fold lower than the control (including any range therebetween).

[0103] In some embodiments, the compositions of the invention are characterized by a substantially higher XRD peak height (net intensity) compared to a control, where the control is a non-extruded composition comprising the component as a composite, and the XRD peak refers to the corresponding peak of the peptide. In some embodiments, the compositions are characterized by a corresponding XRD peak of the peptide that is 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% (including any range therebetween) lower than the corresponding peak of the control.

[0104] In some embodiments, the solid particles (ODIs) disclosed herein are characterized by a substantial release of the peptide (e.g., a hydrophilic peptide such as PTC) therefrom. In some embodiments, the term "release" refers to the release of the peptide into an aqueous medium (e.g., an aqueous medium at a temperature of 10-50°C and / or a pH of about 5 to about 8, including any range therebetween). In some embodiments, the term "substantial release" refers to the release of at least 10%, 30%, at least 50%, at least 70%, or at least 90% of the initial peptide load into the solid particles or compositions of the invention, including any range therebetween. In some embodiments, the solid particles disclosed herein are characterized by a delayed onset of release, such that substantial release occurs after 1 day, 2 days, 3, 4, or 5 days, or after a period ranging from 2 to 20 days, 2 to 10 days, 5 to 20 days, 5 to 15 days, or 5 to 10 days, after contacting the solid particles with an aqueous medium. It is assumed that the release profile obtained in aqueous media is indicative of in vivo release at the intended site of application (eg, intraocular release).

[0105] In some embodiments, the term "substantial release" refers to the cumulative release of at least 10%, at least 30%, at least 50%, at least 70%, or at least 90% of the initial load of the peptide within a period 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, or about 2 to about 10 days (including any range therebetween). In some embodiments, the cumulative release is measured from the onset of release, where the onset of release is as described herein. In some embodiments, the release profile of the peptide is substantially gradual or sustained and does not include a burst release, where release refers to a cumulative release as described herein. An exemplary release profile is shown in Figure 3B. In some embodiments, the release of the peptide can be determined by HPLC.

[0106] In another aspect, a method is provided for treating an ocular disease or disorder in a subject, the method comprising intraocularly administering to the subject a therapeutically effective amount of a composition of the invention (e.g., an ophthalmic composition comprising the solid particles disclosed herein).

[0107] In some embodiments, the subject's eye is suffering from inflammation. In some embodiments, the inflammation is ocular inflammation. In some embodiments, the subject's eye is suffering from any one of dry eye, dry macular degeneration, diabetic macular edema, and postoperative inflammation. In some embodiments, the ocular inflammation is uveitis.

[0108] In some embodiments, the method is for treating or preventing a disease or disorder associated with ocular inflammation.

[0109] 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 layers 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 another disease.

[0110] Non-limiting examples of systemic diseases that can cause ocular inflammation include Crohn's disease, Behçet's disease, and juvenile idiopathic arthritis. In some embodiments, the ocular inflammation is associated with an adverse reaction to a drug or environmental factor. Non-limiting examples of such drugs include rifabutin, quinolones, vaccines, and allergens. In some embodiments, the ocular inflammation is associated with postoperative inflammation. Non-limiting examples of such postoperative inflammation include inflammation after cataract surgery, laser eye surgery, and corneal transplantation.

[0111] As used herein, the term "treatment" or "treating" of ocular inflammation includes 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, the compositions useful herein need only reduce the severity of the disease, disorder, or condition, reduce the severity of symptoms associated therewith, or provide an improvement in the quality of life of the patient or subject. In some embodiments, treating ocular inflammation includes at least one of preventing the onset of ocular inflammation, attenuating the progression of ocular inflammation, and inhibiting the progression of ocular inflammation.

[0112] In some embodiments, treating comprises reducing inflammation. In some embodiments, treating comprises reducing abnormal inflammation. In some embodiments, treating comprises reducing inflammation in the eye of the subject.

[0113] In some embodiments, treating comprises reducing secretion of at least one pro-inflammatory cytokine.

[0114] In some embodiments, reducing includes at least a 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 understood by those skilled in the art that it is not necessary to reduce each cytokine by the same amount. Some cytokines may be reduced more than others.

[0115] Another aspect of the present invention provides a method for increasing the ocular bioavailability of a phosphorylcholine-tuftsin conjugate in a subject, the method comprising administering an ophthalmic composition of the present invention to the eye of the subject.

[0116] In some embodiments, the increase in ocular bioavailability is at least 10% compared to a control, where 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).

[0117] In some embodiments, the method is for prolonging the residence time of a phosphorylcholine-tuftsin conjugate on or in the eye (e.g., the cornea and / or aqueous humor and / or vitreous humor and / or choroid). In some embodiments, the prolongation is for a period ranging from 1 to 90 days, 1 to 5 days, 2 to 10 days, 5 to 20 days, 2 to 20 days, 2 to 30 days, or 5 to 50 days (including any value therebetween), where the term "prolongation" is compared to a control composition comprising the same components as the composition of the invention, wherein the PTC is in the form of substantially spherical microparticles (e.g., having an average particle size of about 10 to about 100 μm). In some embodiments, the control composition comprises the same components as the composition of the invention, wherein the polymer is non-end-capped PLGA (see FIG. 3D).

[0118] In some embodiments, increasing ocular bioavailability comprises increasing the concentration of phosphorylcholine-tuftsin conjugate in the aqueous humor and / or vitreous humor of the eye, ie, by 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%, or at least 100,000% (including any ranges or values therebetween) as compared to a control composition.

[0119] In some embodiments, the subject is selected from a human subject and an animal subject.

[0120] As used herein, the terms "administering" and "administration," and similar terms, refer to any method of delivering a composition containing the peptide (i.e., active agent) to a subject in a manner that provides a therapeutic effect in appropriate medical practice. In some embodiments, the administering is ocular or intraocular administration. In some embodiments, the administering is via a catheter, such as an ocular catheter, or any other means for ocular or intraocular delivery of solid particles disclosed herein. In some embodiments, the administering is via intravitreal administration. In some embodiments, the administering step is repeated, for example, 2, 3, 4, 5, or 10 times within 24 hours to 1 year.

[0121] In some embodiments, the amount of composition administered (dosage) will, of course, be dependent on the subject being treated, the condition being treated, the severity of the ailment, the manner of administration, the judgment of the prescribing physician, etc.

[0122] In some embodiments, the daily dose (i.e., the amount of phosphorylcholine-tuftsin conjugate per day) is 0.01-200 μg, 0.01-100 μg, 50-2000 μg, 200-2000 μg, 50-100 μg, 100-200 μg, 200-300 μg, 300-400 μg, 400-500 μg, 500-600 μg, 600-700 μg, 700-800 μg, 800-900 μg, 900-1000 μg, 1000-1100 μg, 1100-1300 μg, 1300-1500 μg, 1500-1800 μg, 1800-2000 μg (including any range or value therebetween).

[0123] In some embodiments, the daily dose (ie, the amount of phosphorylcholine-tuftsin conjugate per day) is 0.01-100 μg or 1-100 μg.

[0124] According to one embodiment of the present invention, the pharmaceutical compositions described hereinabove are packaged in packaging material and are identified in printing in or on the packaging material for use in treating a disease or disorder described herein.

[0125] According to another embodiment of the present invention, the pharmaceutical composition is packaged in packaging material and is identified in printing in or on the packaging material for use in monitoring a disease or disorder as described herein.

[0126] The articles of manufacture of the invention may, if desired, be presented in a pack or dispenser device, such as a U.S. Food and Drug Administration (FDA)-approved kit, which may contain one or more unit dosage forms containing the disclosed compositions. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also bear a notice associated with the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the agency's approval of the composition form or for human or veterinary administration. Such notice may, for example, be labeling approved by the FDA for prescription drugs or an approved product insert.

[0127] In some embodiments, the kit includes a single dosage form, wherein the dosage form comprises a daily dose of the disclosed compositions. In some embodiments, the kit includes multiple dosage forms. In some embodiments, the kit includes multiple dosage forms, wherein the multiple dosage forms correspond to a daily dose of the disclosed compositions.

[0128] In some embodiments, the method is for extending the release period of a phosphorylcholine-tuftsin conjugate on or in the eye. In some embodiments, the phosphorylcholine-tuftsin conjugate is released slowly. In some embodiments, the phosphorylcholine-tuftsin conjugate is released in a controlled manner. In some embodiments, the method is for inducing the onset of delayed release of a PTC, wherein the delay is as described herein. In some embodiments, the method is for inducing the sustained release of a phosphorylcholine-tuftsin conjugate.

[0129] In this context, the term "controlled manner" indicates that the drug is released substantially continuously, where "continuously" may refer to the time periods described herein above (1 to 90 days).

[0130] Of course, the compositions of the present invention may be administered in conjunction with other drugs, including other anti-inflammatory drugs.

[0131] In another aspect of the present invention, there is provided a method for producing solid particles of the present invention, comprising extruding a powdered composition or kit comprising the peptide (e.g., a PTC of the present invention) and PLGA as disclosed herein, characterized by an average particle size as disclosed herein, wherein the PLGA is in the range of 10 nm to 100 um, 10 nm to 1 um, 10 nm to 10 um, 100 nm to 10 um, 100 nm to 1 um, 100 nm to 5 um, 10 nm to 100 um, 100 nm to 80 um, 100 nm to 70 um, 100 nm to 60 um, 100 nm to 50 um, 100 nm to 30 um, 100 nm to 20 um, 100 nm to 10 um, 100 nm to 100 um, The present invention provides a method for extruding a polymeric polysaccharide (PLGA) characterized by an average particle size of 100 to 5 μm, 100 to 1 μm, 300 to 10 μm, 300 to 5 μm, 300 to 1 μm, 300 to 500 μm, 300 to 800 μm, 500 to 10 μm, 500 to 1 μm, 500 to 50 μm, 500 to 100 μm, 10 to 100 μm, 100 to 500 μm, 500 to 80 μm, 800 to 30 μm, 800 to 5 μm, 5 to 30 μm, 1 to 30 μm, 1 to 10 μm, 10 to 30 μm, 10 to 60 μm, 10 to 80 μm, 30 to 60 μm, or 30 to 50 μm (including any range therebetween), under suitable conditions. In some embodiments, the peptide (e.g., the PTC of the present invention) and PLGA are each introduced separately into an extruder. In some embodiments, the peptide (e.g., a PTC of the present invention) and PLGA are mixed together to form a composition, which is then introduced into an extruder. In some embodiments, extrusion is carried out at a temperature of 60-80°C, 60-70°C, 65-75°C, or 70-80°C (including any range therebetween).

[0132] In some embodiments, the method is for producing particles or granules of the present invention (i.e., ODI). In some embodiments, the method is for obtaining an extrudate. In some embodiments, the extrudate is further subjected to shaping by a thermoforming process selected from extrusion, injection, hot blown film, molding (e.g., cast molding, compression molding, rotational molding), or any combination thereof. In some embodiments, the extrudate is shapable or processable to obtain solid particles of the present invention characterized by a predetermined shape and / or dimensions.

[0133] In some embodiments, a method is provided for shaping the particles of the present invention, comprising extruding an extrudate in an extruder by utilizing an extrusion die characterized by a predetermined shape and / or dimensions.

[0134] In some embodiments, the method includes a preliminary step of milling any one of the intact peptide (e.g., intact PTC) and intact PLGA to obtain a powdered composition or kit comprising the peptide and PLGA characterized by a particle size as disclosed herein. In some embodiments, the intact PLGA and intact peptide are milled simultaneously or separately. In some embodiments, the milling is accompanied by cooling of the milling chamber.

[0135] In some embodiments, the components that make up the compositions (and / or extrudates) of the present invention can be processed by an extrusion process. In some embodiments, the physical properties of the components that make up the compositions and / or extrudates of the present invention (peptide particle size, chemical composition, peptide:PLGA ratio, thermal stability, etc.) are compatible with or suitable for extrusion processes.

[0136] In some embodiments, the solid particles (or granules) of the present invention are substantially stable under suitable storage conditions (e.g., temperatures and exposure to ambient atmosphere as described herein), hi some embodiments, the solid particles (or granules) of the present invention are substantially stable at temperatures of 30-60°C, -50-60°C, 0-10°C, 10-30°C, or 30-50°C (including any range therebetween).

[0137] The term "stable," as used herein, refers to the ability of the solid particles (or granules) of the present invention to substantially maintain their structural, physical, and / or chemical properties. In some embodiments, a solid particle (or granule) of the present invention is considered stable if it is characterized by "substantially maintaining its structure (e.g., shape and / or dimensions such as thickness, length, etc.)," "substantially free of cracks," "substantially maintaining its initial peptide loading," or any combination thereof, where "substantially" is as defined herein.

[0138] chemical definition Compounds are described using standard nomenclature. Unless otherwise defined, 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.

[0139] In some embodiments, compounds of the invention include any salt, any solvate, any hydrate, any stereoisomer, any isotope (e.g., deuterated compound), and / or any derivative (e.g., biologically active derivative) of any of the compounds or formulas disclosed herein.

[0140] Examples of isotopes that can be incorporated into compounds of the present disclosure include, but are not limited to, 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 These include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as I.

[0141] The compounds described herein include enantiomers, mixtures of enantiomers, diastereomers, tautomers, racemates, and other isomers, such as rotamers, as if each were specifically described, unless otherwise specified or excluded by context. It is understood that the compounds provided herein may contain chiral centers. Such chiral centers may be in either the (R) or (S) configuration. The compounds provided herein may be enantiomerically pure or may be diastereomeric or enantiomeric mixtures. It is understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. Thus, one skilled in the art will recognize that administration of a compound in its (R) form is equivalent to administration of the compound in its (S) form, in the case of compounds that undergo epimerization in vivo. Unless otherwise stated, formulas having chemical bonds shown only as solid lines, rather than wedges or dashed lines, envision each possible isomer, e.g., each enantiomer, diastereomer, and meso compound, as well as mixtures of isomers, such as racemic or scalemic mixtures.

[0142] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent, e.g., -(C=O)NH2 is attached through the carbon of the keto (C=O) group.

[0143] As used herein, the term "substituted" means that any one or more hydrogens on the specified atom or group are replaced with a moiety selected from the indicated group, provided that the replacement does not exceed the normal valence of the specified atom and the resulting compound is stable. For example, if a substituent is oxo (i.e., =O), two hydrogens on that atom are replaced. For example, a pyridyl group substituted with oxo is a pyridine. Combinations of substituents and / or variables are acceptable only if such combinations result in stable compounds or useful synthetic intermediates. 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 manufacturing intermediate or precursor of an active compound is stable if it does not decompose within the time required for reaction or other use. A stable moiety or substituent is one that does not decompose, react, or dissociate within the time required for use. Non-limiting examples of unstable moieties are those that bond heteroatoms in unstable configurations, typically known and identifiable to those skilled in the art.

[0144] Any suitable group may be present in the "substituted" or "optionally substituted" position that results in the formation of a stable molecule and satisfies the desired objectives of the present invention, including, but not limited to, alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halo, hydroxy, keto, nitro, cyano, azido, oxo, silyl, sulfoxo, sulfonyl, sulfone, sulfoxide, sulfonylamino, or thiol. Additional substituents are disclosed herein. Furthermore, the term "substituted" encompasses more (e.g., 2, 3, 4, 5, 6, or more) substituents, where the substituents may be the same or different, and each of the substituents is as described herein.

[0145] The term "substituents" independently refers to -OH, oxo, 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', -S02R', -SOR', -SR', -S02OR', -SON(R')2, -NHNR'2, -NNR', -NR'R', NR'NR'2, C1-C6 haloalkyl, and 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 heterocyclic alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(C0-C3 alkyl), (3-6 membered monocyclic heterocycle)(C0-C3 alkyl), (6-10 membered monocyclic or bicyclic aryl)(C0-C3 alkyl), (5-10 membered monocyclic or bicyclic heteroaryl)(C0-C3 R' is independently selected from hydrogen, C-C alkyl, C-C haloalkyl, C-C alkenyl, C-C alkynyl, (C-C cycloalkyl)-(C-C alkyl)-, (4-6 membered heterocycle)-(C-C alkyl)-, R'C(O)-O-(C-C alkyl)-, R'C(O)-(R'N)-(C-C alkyl)-, R'S(O)-O-(C-C alkyl)-, R'S(O)-(R'N)-(C-C alkyl)-, R'C(O)-, R'S(O)-, and R'S(O)-, wherein each R' is independently selected from hydrogen, C-C alkyl, C-C haloalkyl, C-C alkenyl, C-C alkynyl, (C-C cycloalkyl)-(C-C alkyl)-, (4-6 membered heterocycle)-(C-C alkyl)-,is selected from (5-10 membered monocyclic or bicyclic aryl)-(C0-C3 alkyl)-, (5-10 membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, OR', -CONH, -CONR', -CNNR', -CSNR', -CONH-OH, -CONH-NH, -NHCOR', -NHCSR', -NHCNR, -NC(=O)OR', -NC(=O)NR', -NC(=S)OR', -NC(=S)NR', -NR'NR' and -NNR', each of which may be optionally substituted where allowed by valence.

[0146] The term "alkyl" as used herein refers to an aliphatic hydrocarbon, including straight-chain and branched-chain groups. The term "alkyl" as used herein also encompasses saturated or unsaturated hydrocarbons, and thus the term further encompasses alkenyl and alkynyl.

[0147] The term "alkenyl" refers to an unsaturated alkyl, as defined herein, having at least two carbon atoms and at least one carbon-carbon double bond. The alkenyl may be unsubstituted or substituted with one or more substituents described herein above.

[0148] The term "alkynyl," as defined herein, is an unsaturated alkyl having at least two carbon atoms and at least one carbon-carbon triple bond. The alkynyl may be unsubstituted or substituted by one or more substituents as described herein above.

[0149] The term "cycloalkyl" refers to an all-carbon monocyclic or fused ring (i.e., rings that share adjacent pairs of carbon atoms) group in which one or more of the rings do not have a completely conjugated pi-electron system. Cycloalkyl groups can be substituted or unsubstituted as indicated herein.

[0150] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a completely conjugated π-electron system. Aryl groups can be substituted or unsubstituted as indicated herein.

[0151] The term "alkoxy" refers to both -O-alkyl and -O-cycloalkyl groups as defined herein. The term "aryloxy" refers to -O-aryl as defined herein.

[0152] The alkyl, cycloalkyl, and aryl groups in the general formulae herein may each be substituted with one or more substituents, where each substituent may independently be, for example, halide, alkyl, alkoxy, cycloalkyl, nitro, amino, hydroxyl, thiol, thioalkoxy, carboxy, amido, aryl, and aryloxy, depending on the substituted group and its position in the molecule. Additional substituents are also contemplated.

[0153] In some embodiments, the term "carbocyclyl" includes aryl, polycyclyl, heteroaryl, cycloalkyl, or heterocyclyl, or any combination thereof.

[0154] The terms "halide," "halogen," or "halo" refer to fluorine, chlorine, bromine, or iodine. The term "haloalkyl" refers to an alkyl group, as defined herein, further substituted with one or more halides. The term "haloalkoxy" refers to an alkoxy group, as defined herein, further substituted with one or more halides. The terms "hydroxyl" or "hydroxy" refer to an -OH group. The terms "mercapto" or "thiol" refer to an -SH group. The term "thioalkoxy" refers to both an -S-alkyl group and an -S-cycloalkyl group, as defined herein. The term "thioaryloxy" refers to both an -S-aryl and an -S-heteroaryl group, as defined herein. The term "amino" refers to an -NR'R'' group or a salt thereof, where R' and R'' are as defined herein.

[0155] The term "heterocyclyl" refers to a monocyclic or fused ring group containing one or more atoms such as nitrogen, oxygen, and sulfur in the ring, which may also contain one or more double bonds. However, the ring does not have a completely conjugated π-electron system. Representative examples include piperidine, piperazine, tetrahydrofuran, tetrahydropyran, and morpholino.

[0156] The term "carboxy" refers to the group -C(O)OR' or a carboxylate thereof, where R' is hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl (attached through a ring carbon), or heterocyclyl (attached through a ring carbon) as defined herein, or a "carboxylate."

[0157] The term "carbonyl" refers to the group -C(O)R', where R' is as defined hereinabove. The term also includes its thio derivatives (thiocarboxy and thiocarbonyl).

[0158] The term "thiocarbonyl" refers to a -C(S)R' group, where R' is as defined herein above. A "thiocarboxy" group refers to a -C(S)OR' group, where R' is as defined herein. A "sulfinyl" group refers to a -S(O)R' group, where R' is as defined herein. A "sulfonyl" or "sulfonate" group refers to a -S(O)R' group, where R' is as defined herein.

[0159] A "carbamyl" or "carbamate" group refers to the -OC(O)NR'R" group, where R' is as defined herein and R" is as defined for R'. A "nitro" group refers to the -NO2 group. As used herein, the term "amido" encompasses C-amido and N-amido. The term "C-amido" refers to a -C(O)NR'R" terminal group or a -C(O)NR'- linked group, as these terms are defined herein above, where R' and R" are as defined herein. The term "N-amido" refers to a -NR"C(O)R' terminal group or a -NR'C(O)- linked group, as these terms are defined herein above, where R' and R" are as defined herein.

[0160] The term "cyano" or "nitrile" refers to a -CN group. The term "azo" or "diazo" refers to an -N=NR' terminal group or an -N=N- linked group, as these terms are defined herein above, where R' is as defined herein above. The term "guanidine" refers to an -R'NC(N)NR''R''' terminal group or an -R'NC(N)NR''- linked group, as these terms are defined herein above, where R', R'' and R''' are as defined herein. The term "azide" as used herein refers to an -N3 group. The term "sulfonamide" refers to a -S(O)2NR'R'' group, where R' and R'' are as defined herein above.

[0161] The term "phosphonyl" or "phosphonate" refers to the group -OP(O)-(OR')2, where R' is as defined herein above. The term "phosphinyl" refers to the group -PR'R'' where R' and R'' are as defined herein. The term "alkylaryl" refers to an alkyl, as defined herein, substituted with an aryl, as described herein. An exemplary alkylaryl is benzyl.

[0162] The term "heteroaryl" refers to a monocyclic or fused ring (i.e., rings sharing adjacent pairs of atoms) group containing one or more atoms, such as nitrogen, oxygen, and sulfur, in the ring and further 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. Heteroaryl rings may be formed by 3, 4, 5, 6, 7, 8, 9, or 10 or more atoms. Heteroaryl groups 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 a combination of one oxygen or sulfur atom and up to two nitrogen atoms, and substituted versions thereof, as well as benzo- and pyrido-fused derivatives, for example, bonded through one of the ring-forming carbon atoms. In certain embodiments, heteroaryl is selected from among oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinal, pyrazinyl, indolyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl.

[0163] In some embodiments, the heteroaryl group is selected from the group consisting of pyrrolyl, furanyl (furyl), thiophenyl (thienyl), imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3-oxazolyl (oxazolyl), 1,2-oxazolyl (isoxazolyl), oxadiazolyl, 1,3-thiazolyl (thiazolyl), 1,2-thiazolyl (isothiazolyl), tetrazolyl, pyridinyl (pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, 1, Heteroaryl groups are selected from 2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, indazolyl, indolyl, benzothiophenyl, benzofuranyl, benzothiazolyl, benzimidazolyl, benzodioxolyl, acridinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, thienothiophenyl, 1,8-naphthyridinyl, other naphthyridinyl, pteridinyl, or phenothiazinyl. When a heteroaryl group contains two or more rings, 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 two rings are aromatic and bicyclic radicals in which only one ring is aromatic. Examples of such heteroaryls include 3H-indolinyl, 2(1H)-quinolinonyl, 4-oxo-1,4-dihydroquinolinyl, 2H-1-oxoisoquinolyl, 1,2-dihydroquinolinyl, (2H)quinolinyl N-oxide, 3,4-dihydroquinolinyl, 1,2-dihydroisoquinolinyl, 3,4-dihydroisoquinolinyl, chromonyl, 3,4-dihydroisoquinoxalinyl, 4-(3H)quinazolinonyl, 4H-chromenyl, 4-chlorphen ... Rhomanoyl, oxindolyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 1H-2,3-dihydroisoindolyl, 2,3-dihydrobenzo[f]isoindolyl, 1,2,3,4-tetrahydrobenzo-[g]isoquinolinyl, 1,2,3,4-tetrahydrobenzo[g]isoquinolinyl, chromanyl, isochromanonyl, 2,3-dihydrochromonyl, 1,4-benzodioxanyl, 1,2,3,4-Tetrahydroquinoxalinyl, 5,6-dihydroquinolyl, 5,6-dihydroisoquinolyl, 5,6-dihydroquinoxalinyl, 5,6-dihydroquinazolinyl, 4,5-dihydro-1H-benzimidazolyl, 4,5-dihydrobenzoxazolyl, 1,4-naphthoquinolyl, 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolyl, 5,6,7,8-tetrahydroquinoxalinyl, 5,6,7,8-tetrahydroquinazolyl, 4,5,6,7-tetrahydro-1H-benzimidazolyl, 4,5,6, 7-Tetrahydrobenzoxazolyl, 1H-4-oxa-1,5-diazanaphthalen-2-onyl, 1,3-dihydroimidizolo-[4,5]-pyridin-2-onyl, 2,3-dihydro-1,4-dinaphtho-quinolyl, 2,3-dihydro-1H-pyrrole[3,4-b]quinolinyl, 1,2,3,4-tetrahydrobenzo[b]-[1,7]naphthyridinyl, 1,2,3,4-tetrahydrobenz[b][1,6]-naphthyridinyl, 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolyl, 1,2,3,4-tetrahydro 1H-9H-pyrido[4,3-b]indolyl, 2,3-dihydro-1H-pyrrolo-[3,4-b]indolyl, 1H-2,3,4,5-tetrahydroazepino[3,4-b]indolyl, 1H-2,3,4,5-tetrahydroazepino-[4,3-b]indolyl, 1H-2,3,4,5-tetrahydroazepino[4,5-b]indolyl, 5,6,7,8-tetrahydro[1,7]naphthyridinyl, 1,2,3,4-tetrahydro-[2,7]naphthyridyl, 2,3-dihydro[1,4]dioxino[2,3-b]pyridyl, 2,3-dihydro[1,4]dioxino[2,3-b]pyridyl, dro[1,4]-dioxino[2,3-b]pyridyl, 3,4-dihydro-2H-1-oxa[4,6]diazanaphthalenyl, 4,5,6,7-tetrahydro-3H-imidazo-[4,5-c]pyridyl, 6,7-dihydro[5,8]diazanaphthalenyl, 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, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, and trifluoromethyl.

[0164] Examples of heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine, pyrazine, furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine, cinnoline, phthalazine, quinazoline, and quinoxaline. In some embodiments, the substituents are halo, hydroxy, cyano, O-Ci-6 alkyl, Ci-6 alkyl, hydroxy-Ci-6 alkyl, and amino-Ci-6 alkyl.

[0165] As used herein, the terms "halo" and "halide" are referred to interchangeably herein and refer to an atom of the halogen, which is fluorine, chlorine, bromine, or iodine, also referred to herein as fluoride, chloride, bromide, and iodide.

[0166] "Pharmaceutically acceptable salts" are derivatives of the disclosed compounds in which the parent compound has been modified by preparing its inorganic and organic pharmaceutically acceptable acid or base addition salts. Salts of the present compounds can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of an appropriate base (such as a hydroxide, carbonate, or bicarbonate of Na, Ca, Mg, or K), or by reacting the free base form of these compounds with a stoichiometric amount of an appropriate acid. Such reactions are typically carried out in water or an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where feasible. Salts of the present compounds further include solvates of the present compounds and salts of the present compounds. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines and alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include salts acceptable for human consumption. Lists of pharmaceutically acceptable salts are found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA., p. 1418 (1985).

[0167] As used herein, "substantially pure" means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard analytical methods used by those skilled in the art to assess such purity, such as thin layer chromatography (TLC), nuclear magnetic resonance (NMR), gel electrophoresis, high performance liquid chromatography (HPLC) plus mass spectrometry (MS), and gas chromatography-mass spectrometry (GC-MS), or of a state of sufficient purity that further purification does not detectably alter the physical and chemical properties, such as enzymatic and biological activity, of the substance. Both 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.

[0168] general definition As used herein, the term "about" refers to ±10%.

[0169] The terms "comprises," "comprising," "includes," "including," and "having," and their conjugations, mean "including, but not limited to."

[0170] The term "consisting of" means "including and limited to."

[0171] The term "consisting essentially of" means that the composition, method, or structure may include additional ingredients, steps, and / or moieties, but only if the additional ingredients, steps, and / or moieties do not materially alter the basic and novel characteristics of the claimed formulation, method, or structure.

[0172] The word "exemplary" is used herein to mean "serving as an example, instance, or illustration." Any embodiment described as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments and / or excludes the incorporation of features from other embodiments.

[0173] The word "optionally" is used herein to mean "provided in some embodiments and not provided in other embodiments." Any particular embodiment of the present invention may include multiple "optional" features unless such features are inconsistent.

[0174] As used herein, the singular forms "a," "an," and "the" include plural referents 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.

[0175] Throughout this application, various embodiments of the invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be construed to include all the possible subranges specifically disclosed as well as individual numerical values within that range. For example, the description of a range such as 1 to 6 should be construed to include 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 that range, e.g., 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0176] Whenever a range of numbers is given herein, it is intended to include any recited number (fractional or integer) within the given range. The phrases "ranging between a first indicated number and a second indicated number" and "ranging from a first indicated number to a second indicated number" are used interchangeably herein and are intended to include the first and second indicated numbers and all fractional and integer numbers therebetween.

[0177] The term "method" as used herein refers to any manner, means, technique or procedure for accomplishing a given task, including but not limited to any manner, means, technique or procedure known to or readily developed by practitioners in the arts of chemistry, pharmacology, biology, biochemistry and medicine from known manners, means, techniques and procedures.

[0178] It is understood that certain features of the invention that are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the invention that are described in the context of a single embodiment may also be provided separately or in any suitable subcombination. All combinations of embodiments relating to the present invention are expressly embraced by the present invention and are disclosed herein as if each and every combination were individually and explicitly disclosed. Furthermore, all subcombinations of the various embodiments and elements thereof are also specifically embraced by the present invention and are disclosed herein as if each and every such subcombination were individually and explicitly disclosed.

[0179] Additional objects, advantages, and novel features of the present invention will become apparent to those skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each of the various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below finds experimental support in the following examples.

[0180] Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below are found experimentally supported in the following examples. [Example]

[0181] material The materials and equipment used herein are listed in Table 1.

[0182] [Table 1] TIFF2025526636000009.tif207159

[0183] In particular, the PLGA polymers used herein are specified in Table 1A below.

[0184] [Table 2]

[0185] method HPLC-UV method

[0186] For the HPLC run, a standard analytical HPLC method in an acetonitrile / water gradient system was used.

[0187] A system suitability test was performed on each batch as described below.

[0188] For each HPLC experiment, two independent standard solutions (A and B) were prepared in water at a net peptide concentration of 0.3 mg / mL. The required amount of API was accurately weighed into a 50 mL Falcon tube, and water was added by weight. The solution was then vortexed for 30 seconds to 1 minute until the API was completely dissolved. These solutions were transferred to HPLC vials in preparation for HPLC analysis.

[0189] Assay of physical mixtures by HPLC-UV

[0190] The physical mixtures were assayed for drug loading and stability after grinding and sieving. A 5 mg sample was weighed into an aluminum weighing dish and transferred to a low-binding Eppendorf tube, followed by the addition of 50 μL of ACN. This was vortexed vigorously until the polymer dissolved and the API precipitated. Water was then added, and the mixture was vortexed again vigorously until the API was completely dissolved and the polymer precipitated. 2950 μL of water was added for the 18% drug-loaded physical mixture, and 1450 μL of water was added for the 9% drug-loaded physical mixture. Finally, the Eppendorf tubes were centrifuged at 5,000 RPM for 30 seconds.

[0191] Assay of extrudates by HPLC-UV

[0192] The extrudates were assayed for drug loading and stability by cutting them into specific weights to obtain the same final concentration as the standard (0.3 mg / mL net peptide concentration) after the addition of diluents. The cut extrudates were placed in a low-absorption Eppendorf and then ACN was added. This was vortexed vigorously until the polymer was dissolved and the API precipitated. Water was then 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 was analyzed.

[0193] In vitro drug release studies of extrudates

[0194] The extrudate was cut to the desired size and weighed into a 5 mL low-binding Eppendorf tube, after which phosphate-buffered saline (pH 7.4) was added. At designated time points, aliquots were taken for API quantification by HPLC.

[0195] Modulated temperature differential scanning calorimetry (mDSC)

[0196] mDSC analysis was performed to investigate the thermal profiles of TRS, polymer, physical mixtures, and extrudates using a Q1000 instrument (TA Instruments, USA). An inert atmosphere was maintained in the chamber by purging with nitrogen at a flow rate of 50 mL / min.

[0197] Thermal analysis profiles were determined using a heat-cool-heat cycle in the mDSC described below. Approximately 2-3 mg of the sample was weighed into an airtight aluminum pan and equilibrated at 5°C. After 5 minutes of isothermal time, the sample was heated to 60°C at 2°C / min, cooled to 5°C at 2°C / min, and heated again to 60°C at 2°C / min. A modulation period of 60 seconds was applied with a temperature swing of ±0.7°C. The data was processed using Universal Analysis 2000 software.

[0198] X-ray powder diffraction (XRPD)

[0199] X-ray powder diffraction (XRPD) analysis of the sample was performed using a Bruker D2 Phaser powder diffractometer equipped with a Lynx Eye detector. The sample (approximately 5 mg) was placed at the center of a silicon sample holder with a 5 mm pocket. The sample was continuously rotated during data collection and scanned from 4.0° to 40° two-theta (2θ) using a 0.02° 2θ step size. This data was analyzed using DIFFRAC. plus The EVA software was used for processing, and the detailed parameters are summarized in Table 2.

[0200] [Table 3]

[0201] Scanning Electron Microscopy (SEM)

[0202] General Procedure

[0203] The surface topography of the samples was examined by scanning electron microscopy (SEM). Extrudates were mounted on aluminum stubs using conductive double-sided carbon adhesive tape that had been sputter-coated with 10 nm of gold in a Quorum Q150ES sputter coater (Quorum Technologies, UK) and imaged using a Tescan Vega3 scanning electron microscope (Tescan Bruno, Czech Republic). Details of magnification and beam voltages are included with the scanning electron micrographs in this report.

[0204] Exemplary Methods for Producing Extruded Solid Particles of the Present Invention Approximately 20% nominal drug loading in Resomer RG 752 S, 0.5 mm extrusion die.

[0205] A physical mixture was prepared by first mechanically grinding TRS (batch number: BZ8-200816) and Resomer RG 752 S separately using a Tube-Mill 100 (IKA®-Werke). The ground API was then sieved through a 75 μm mesh. After this, the components were weighed into 50 mL Falcon tubes and mixed in a Turbula mixer. This mixture was manually fed into an extruder and processed at a constant screw rotation speed above 50°C. The extrudate was cut and divided into 16 different portions in the order of extrusion. The most suitable extrusion temperature was found to be about 60 to about 80°C. Temperatures significantly lower than 60°C resulted in ODIs with reduced homogeneity, while temperatures above 80°C may result in at least partial degradation of the peptide (e.g., PTC).

[0206] The drug loading and stability of the API in the extrudates were quantified by HPLC-UV as described above. In vitro drug release studies were performed as outlined above, with extrudates cut into 3 mm lengths and weighed to target 200 μg of API per implant. Furthermore, homogeneity throughout the length of the extrudate was assessed by cutting three 3 mm pieces from each portion (N = 16, n = 3) and weighing them. Assaying the physical mixture by HPLC-UV was performed using the same method outlined above. Finally, the average diameter of the extrudates was measured using a vernier caliper.

[0207] XRPD diffractograms (not shown) confirmed that the TRS remained amorphous after extrusion. mDSC results also showed that the extrusion process did not affect the glass transition temperatures of the API and polymer blends.

[0208] "Error! Reference Source Not Found" shows an SEM image of an exemplary drug-loaded extrudate of the present invention, which appeared to have a partially smooth and non-porous surface.

[0209] We successfully utilized Resomer RG 752 S to form extrudates with a PTC loading of approximately 18%. The extrudates with 18% PTC loading in Resomer RG 752 S produced slightly higher yields than the Resomer RG 502 trial (9.6% and 4.7%, respectively), yielding a total of 16 parts after a 60-minute residence time. Visually, these extrudates appeared smoother, more uniform, and homogeneous, and were less brittle. SEM images show that the drug-loaded extrudates have a rougher surface and slightly more porous cross-section compared to the blank Resomer RG 752 S extrudates. The average diameter of these extrudates was 0.59 ± 0.01 mm, compared to the placebo, which had an average diameter of 0.57 mm.

[0210] Assays of the physical mixture and extrudates showed that the API (PTC) was stable after the milling and sieving process and extrusion. The API in the extrudates was chemically stable for at least 3 months after storage at -20, 2-8, and 25°C.

[0211] The homogeneity of the exemplary extrudates of the present invention was also evaluated and found to be substantially homogeneous, exhibiting an average drug loading of about 17.5±0.3%, corresponding to 198±10 μg, which theoretically represents a difference of only 0.3 μg of API / day between implants over a period of up to 30 days.

[0212] Drug release studies of exemplary extrudates of the invention showed promising release profiles over a period of up to 33 days, at which point greater than 90% of the API had been released (see Figure 3B). After up to 20 days of sustained release (averaging 3.6 ± 0.4 μg of API released per day), the acceleration was followed as the degradation of the PLGA matrix reached its autocatalytic acceleration onset point.

[0213] To achieve this goal, we hypothesized that the PLGA microparticle method would be unsuitable due to low encapsulation efficiency, low material recovery, and rapid drug release. In contrast, exemplary PLGA-based extrudates (ODIs) of the present invention, consisting of TRS and Resomer RG 752 S, suitable for preclinical studies, were successfully prepared by hot-melt extrusion at two drug loadings: 9% and 18%. These implants had average diameters of 0.59 mm and 0.60 mm and lengths of approximately 3 mm. These extrudates contained an average nominal dose accuracy of 99% and 91%, respectively (200 μg and 100 μg), and an intra-batch coefficient of variation of approximately 5%. Both drug loadings exhibited prolonged in vitro release profiles over a 33-day period.

[0214] Two tested exemplary extrudates of the present invention showed no degradation for at least three months when stored under appropriate conditions.

[0215] Furthermore, the present inventors have successfully prepared ODIs based on TRS and uncapped PLGA (i.e., containing non-esterified acid groups at the end of the polymer chain). Furthermore, PLGA with a lactic acid:glycolic acid ratio of less than 1:1 (e.g., 25:75) has been successfully utilized for the manufacture of ODIs. In most cases, these exemplary ODIs were characterized by a more rapid release profile compared to ester-capped PLGA and / or PLGA with a lactic acid:glycolic acid ratio of greater than 1:1. However, these rapid-release ODIs may be suitable for therapeutic applications requiring relatively rapid drug release.

[0216] While the present invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications, and variations that fall within the spirit and broad scope of the appended claims.

[0217] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference. Furthermore, citation or identification of any reference herein should not be construed as an admission that such reference is available as prior art to the present invention. To the extent section headings are used, they should not be construed as necessarily limiting.

Claims

1. 1. A composition comprising a phosphorylcholine-tuftsin conjugate (including salts thereof), The phosphorylcholine-tuftsin conjugate has the formula 1: 【Chemical Formula 1】 is represented by the phosphorylcholine-tuftsin conjugate is an amorphous solid; and the phosphorylcholine-tuftsin conjugate is in the form of a particulate material characterized by an average particle size of less than 300 um as determined by SEM; and the composition is characterized by a powder XRD that does not have a corresponding peak of the phosphorylcholine-tuftsin conjugate having a net intensity peak height of greater than 400 counts; composition.

2. 10. The composition of claim 1, wherein the salt is a pharmaceutically acceptable salt and the composition has a water content of less than 20%.

3. 3. The composition of claim 1, 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. 1. A composition comprising a plurality of particles, each of the plurality of particles is a solid particle comprising a mixture of poly(glycolide-co-lactide) and phosphorylcholine-tuftsin conjugate; the plurality of particles are characterized by at least one dimension greater than 100 um; and The phosphorylcholine-tuftsin conjugate is an amorphous solid as determined by XRD. composition.

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

6. 6. The composition of claim 4 or 5, characterized by at least one of: (i) 50% to 100% w / w of the polymer chains of the poly(glycolide-co-lactide) are ester end-capped; (ii) the poly(glycolide-co-lactide) has a polylactide:polyglycolide weight ratio of at least 1:1; (iii) the poly(glycolide-co-lactide) has an acid value of less than 1 mg(KOH) / g; or any combination of (i)-(iii).

7. 7. The composition of any one of claims 4 to 6, wherein the composition is characterized by a powder XRD that does not have a peak corresponding to the phosphorylcholine-tuftsin conjugate having a net intensity peak height of greater than 400 counts.

8. The phosphorylcholine-tuftsin conjugate has the formula 1: 【Chemistry 2】 The composition according to any one of claims 4 to 7, wherein the composition is represented by:

9. 0.3-0.4mg / mm ３ The composition according to any one of claims 4 to 8, characterized by a density of

10. The composition of any one of claims 4 to 9, wherein the plurality of particles is an ophthalmic 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 to about 10 mm and a width dimension of about 0.1 to about 0.8 mm, and optionally the ODI comprises a therapeutically effective amount of the phosphorylcholine-tuftsin conjugate.

12. an ophthalmic drug implant (ODI), said ODI being a solid material comprising a mixture of poly(glycolide-co-lactide) and a peptide in the form of particulate matter; the ODI is characterized by at least one dimension 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. Ophthalmic Drug Implants (ODIs).

13. The ODI of claim 12, wherein the weight concentration of the peptide in the ODI is about 1 to about 50%, and the water content of the ODI is less than 20% by weight.

14. 13. The ODI of claim 11 or 12, characterized by at least one of: (i) the poly(glycolide-co-lactide) has a polylactide:polyglycolide weight ratio of at least 50:50; (ii) at least 80% w / w of the polymer chains of the poly(glycolide-co-lactide) are ester end-capped; (iii) the poly(glycolide-co-lactide) has an acid value of less than 1 mg(KOH) / g; or a combination of (i)-(iii).

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

16. 16. The ODI of any one of claims 11 to 15, wherein the ODI is in the form of a substantially elongated particle, optionally characterized by at least one of a length dimension of about 1 to about 10 mm and a width dimension of about 0.1 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 of any one of claims 4 to 17, characterized by a substantial release of the phosphorylcholine-tuftsin conjugate or peptide in an aqueous medium.

19. 19. The ODI of claim 18, wherein the poly(glycolide-co-lactide) has a polylactide:polyglycolide weight ratio of at least 50:50, at least 80% w / w of the polymer chains of the poly(glycolide-co-lactide) are ester end-capped, and 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 ranging from about 2 to about 30 days.

20. 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 to about 100 um as determined by SEM.

21. 21. The ODI of any one of claims 4 to 20, wherein the particulate matter has an average particle size of about 10 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, comprising intraocularly administering to the subject a therapeutically effective amount of a composition described in any one of claims 4 to 11 or an ODI described in any one of claims 12 to 22.

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

Images