Poly(amino acid)-saccharide-lipid conjugates

Abstract

This present disclosure provides various diamine centered poly(amino acid)-saccharide-lipid conjugates. In various embodiments, the conjugates can safely be used as water solubility or bioavailability enhancers. In one aspect, the present disclosure provides a conjugate having the structural formula wherein B is a residue of a compound having three or four available binding positions, e.g., an alkylene diamine; S is a saccharide, for example, a residue of a mono-, di- or trisaccharide group, in which each saccharide unit is a sugar, a sugar alcohol, an amino sugar or a sugar acid; L is a lipophilic carrier residue selected from fatty acid residues (for example, residues of lauric acid, myristic acid, linoleic acid, palmitic acid, oleic acid and elaidic acid), steroid acid and sterol residues, and residues of retinoids carotenoids, tocopherols, and tocotrienols; Q is a residue of ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, pentaethylene glycol or hexaethylene glycol; P is a residue of a polyaminoacid homopolymer; R2 is a terminal group selected from H, methyl, ethyl and maleimide; D is a secondary group that is as defined above for L or is a methyl-capped poly(ethylene glycol) residue; and d is 0, or d is 1.

Description

[0001] POLY(AMINO ACID)-SACCHARIDE-LIPID CONJUGATES

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003]

[0001] This patent application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 705,342, filed on 9 October 2024, the disclosure of which is hereby incorporated herein by reference in its entirety.

[0004] BACKGROUND OF THE DISCLOSURE

[0005] 1. Field of the Disclosure

[0006]

[0002] The present disclosure relates to novel saccharide-lipid conjugates, as well as their use in various compositions such as pharmaceutical (including nutraceutical) compositions, as well as in therapeutic methods.

[0007] 2, Technical Background

[0008]

[0003] A significant problem during product development for new pharmaceuticals is that many promising substances are insoluble in water. In many cases, a promising drug candidate may be discontinued due to insufficient water solubility. Alternatively, different carriers can be used, for example in the form of polymers or oil derivatives. These carriers may often give rise to adverse effects that can be severe.

[0009]

[0004] There remains a continued need for the development of new carriers for lipophilic pharmaceuticals.

[0010] SUMMARY OF THE DISCLOSURE

[0011]

[0005] In one aspect, the present disclosure provides a PAA-saccharide-lipid conjugate having the structural formula

[0012] Dd ZQ-P-R2B S' L wherein

[0013] B is a residue of a compound having three or four available binding positions selected from the group consisting of diamines, triamines, tetraamines, diaminoalcohols, aminoalcohols, aminodiols, aminotriols, amino acids, triols (such as glycerol), tetraols, triacids, tetracids, and carboxyl-containing diols and polyamines;

[0014] S is a saccharide, for example, a residue of a mono-, di- or trisaccharide group, in which each saccharide unit is a sugar, a sugar alcohol, an amino sugar or a sugar acid; L is a lipophilic carrier residue selected from fatty acid residues (for example, residues of lauric acid, myristic acid, linoleic acid, palmitic acid, oleic acid and elaidic acid), steroid acid and sterol residues, and residues of retinoids (e.g., residues of retinoic acids), carotenoids, tocopherols, and tocotrienols;

[0015] Q is a residue of ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, pentaethylene glycol or hexaethylene glycol;

[0016] P is a residue of a polyaminoacid homopolymer selected from poly(serine), poly(alanine), poly(glutamine), poly(glutamic acid) poly(aspartic acid), poly(lysine), poly(arginine), poly(proline), poly(glycine), and N-methyl analogs thereof, having a degree of polymerization n;

[0017] R2is a terminal group selected from H, methyl, ethyl and maleimide;

[0018] D is a secondary group that is as defined above for L or is a methyl-capped poly(ethylene glycol) residue; and d is 0, or d is 1.

[0019]

[0006] In another aspect, the disclosure provides a process for making a conjugate as described herein, the process comprising coupling a poly(amino acid), a saccharide and a lipophilic group to a center backbone.

[0020]

[0007] In another aspect, the disclosure provides a conjugate as described herein for use as a pharmaceutical excipient, or for use in a medicament.

[0021]

[0008] In another aspect, the disclosure provides a therapeutic composition comprising a conjugate as described herein and a therapeutic agent.

[0022]

[0009] In another aspect, the disclosure provides a composition for use in the treatment of a subject having a condition, the composition comprising a conjugate as described herein and a therapeutic agent suitable for treating the condition.

[0023]

[0010] In another aspect, the disclosure provides a method for treating a subject having a condition, the method comprising administering to the subject with a composition as described herein.

[0024] [OH] In another aspect, the disclosure provides a use of a conjugate as described herein for increasing bioavailability of a therapeutic agent.

[0025]

[0012] In another aspect, the disclosure provides a use of a conjugate as described herein for increasing solubility of a therapeutic agent in an aqueous system.

[0026]

[0013] Additional aspects of the disclosure will be apparent in view of the disclosure and claims below. BRIEF DESCRIPTION OF THE DRAWING

[0027]

[0014] The accompanying drawing (“FIG ”) provides liquid chromatography-mass spectrometry data for an example of a conjugate according to the disclosure.

[0028] DETAILED DESCRIPTION

[0029]

[0015] The present inventor has demonstrated that poly(amino acid)-saccharide-lipid conjugates have the capacity to improve the solubility of lipophilic drugs in aqueous systems. The materials of the disclosure can thus be used, for example, to replace currently marketed compounds like PEG-lipid conjugates, e.g., polysorbates and Cremophor. The present inventor noted that poly(amino acids) (PAAs) could be a potential replacement for polyethylene glycol (PEG) because they are a more biocompatible and tailored solution. Certain PAAs have several advantages over PEG, including low immunogenicity; certain PAAs are less likely to stimulate the immune system than PEG and can be customized to control the size, surface charge, and the properties that mimic proteins, making them suitable for drug delivery and nucleic acid delivery.

[0030]

[0016] A poly(amino acid) is a polymer having of amino acids as monomeric units. Structural and functional proteins, polypeptides, peptides and polyaminoacids are all derived from amino acids. Poly(amino acid)s are soluble in water, biodegradable, not significantly immunogenic, and have multiple functional groups that can be chemically modified. The use of poly(amino acid)s as structural materials is still limited and challenging, due to a lack of understanding of the structure-function relationship of poly(amino acid)-based materials, hence for practical reasons, a simple homopolymeric poly(amino acid) having only a single type of monomeric unit is desirable for use in drug delivery as compared to hybrid poly(amino acid)s or peptides.

[0031]

[0017] While poly(amino acid)s are polyamides, not all polyamides are poly(amino acid)s. Unlike conventional polyamides like nylons, which are often water-insoluble, these modified polymers can offer superior performance in biological systems. Thus, the present disclosure provides water-soluble and biocompatible polyamides having versatile properties for a wide range of biomedical applications.

[0032]

[0018] The present inventor has noted that certain poly(amino acids) can be highly water- soluble. Highly water soluble poly(amino acids) include poly(arginine), poly(lysine), poly(proline), poly(serine), poly(alanine), poly(glycine), poly(glutamine), poly(asparagine), poly(glutamic acid) and poly(aspartic acid), as well as N-methyl analogs thereof (especially N-glycine). While the solubility of a poly(amino acid) having a charged side chain can be significantly influenced by the conditions of its local environment, e.g., pH, the solubility of a poly(amino acid) having a neutral side chain is generally not.

[0033]

[0019] Specifically disclosed herein are the structure and preparation of PA A- saccharidelipid conjugates having a suitable diamine central backbone with at least three binding positions. PAA, carbohydrate and lipid groups are covalently conjugated to the central backbone. Notably, the novel PAA-saccharide-lipid conjugates disclosed herein can be made in high purity, and can be useful for therapeutic drug delivery, cosmetics and other compound delivery purposes.

[0034]

[0020] The present inventor has noted that the chain length of the PAA can be desirably provided in a highly monodisperse form. Accordingly, in various embodiments of the disclosure, the purity and precision of the average molecular weight of these polymers can be specified to help ensure both safety and solubility. High-performance liquid chromatography (HPLC) can be implemented for ongoing quality control.

[0035]

[0021] Embodiments of the present disclosure are described herein in the context of PAA- saccharide-lipid conjugates for improved safety and enhanced delivery of poorly-water soluble agents. Those of ordinary skill in the art will realize that the following detailed description of the present disclosure is illustrative only and is not intended to be in any way limiting. Other embodiments of the present disclosure will readily suggest themselves to such skilled persons having the benefit of this disclosure.

[0036]

[0022] In the interest of clarity, not all of the routine features of the implementations described herein are shown and described. Moreover, it will be appreciated that a development effort might be complex and time-consuming, but would nevertheless be a routine undertaking of engineering and development for those of ordinary skill in the art having the benefit of the present disclosure.

[0037]

[0023] The present inventor has surprisingly determined that a significant increase in safety and biocompatibility can be provided by the use of particular diamine central backbones in the PAA-saccharide-lipid conjugates. Moreover, use of relatively short diamine central backbones can provide a conjugate with a safety profile that is suitable even for parenteral administration. Without intending to be bound by theory, the present inventor surmises that a longer length between the two amino bonding sites may provide stronger interaction between the polymers and cell surfaces, or may destabilize or cause red blood cells to break down.

[0038]

[0024] While a bulky ring structure or longer alkyl chains or more lipophilic carrier groups can in some cases cause higher hemolytic activity, the present inventor has determined that fatty acid groups 18 carbons or shorter can reduce hemolytic activity. Accordingly, in various desirable embodiments of the disclosure, the lipid group is a fatty acyl group having a number-average length of 18 carbons or shorter. However, longer acyl groups or steroid, retinoid, carotenoid, tocopherol or tocotrienol residues may be desirable in certain situations, especially in oral administration or low-level injectable concentrations.

[0039]

[0025] There is a clear difference between fatty acid-based and cholesterol or cholesterol- like based conjugates. The former can exhibit considerably less hemolytic potential, due to a combination of low critical micelle concentrations and presumably low degrees of partitioning of the fatty acid based conjugates into the cell membranes. Cholesterol based conjugates can exhibit a higher hemolytic potential regardless of the center backbones. Hence, linear lipid acyl groups may have less hemolytic potential, making them more suitable for parenteral drug delivery.

[0040]

[0026] Accordingly, another aspect of various embodiments of the present disclosure relates to the observation that selected PAA-saccharide-fatty acid conjugates are often suitable for parenteral application and PAA-saccharide-cholesterol conjugates may in many cases only be suitable for certain oral administrations or injectable only at low concentration levels.

[0041]

[0027] Polyoxyethylene-derived polymers have been widely used as pharmaceutical delivery vehicles for many decades, although their tendency to form peroxides is well known and their deleterious effects on various drugs have been proven. Like other surface-active compounds, polyoxyethylene-lipid based polymers can cause hemolysis when they come in contact with red blood cells. Despite the adverse effects caused by polysorbates and polyethoxylated castor oil (sold under the trade-name “Cremophor”), these two leading regulatory approved intravenous excipients have been accepted in cancer treatment since the drugs are effective and the alternative would otherwise be that the patient is not treated. The conjugates of the disclosure can in many cases have reduced potential side effects, e.g., immune response and the production of anti-PEG antibodies which can cause the rapid clearance of PEGylated agents from circulation, which decreases their efficacy.

[0042]

[0028] The present disclosure provides convenient and economic synthesis methods for preparing PAA-saccharide-lipid conjugates and various linear linkage groups may be used for coupling each carrier groups to the central backbone, e.g., diamine backbone. There are several advantages provided by the methods of the present disclosure such as simplified synthesis, high production yield and low cost for starting materials, which, of course is desirable for a commercial product. Hence the presently-described synthetic methods are desirable for preparing a wide range of the conjugates of the disclosure.

[0043]

[0029] One aspect of the disclosure provides a PAA-saccharide-lipid conjugate having a structure according to the General Formula (I):

[0044] DdQ-P— R2

[0045] B

[0046] S L

[0047] General Formula I wherein

[0048] B is a residue of a compound having three or four available binding positions selected from the group consisting of diamines, triamines, tetraamines, diaminoalcohols, aminoalcohols, aminodiols, aminotriols, amino acids, triols (such as glycerol), tetraols, triacids, tetracids, and carboxyl-containing diols and polyamines;

[0049] S is a saccharide, for example, a residue of a mono-, di- or trisaccharide group, in which each saccharide unit is a sugar, a sugar alcohol, an amino sugar or a sugar acid;

[0050] L is a lipophilic carrier residue selected from fatty acid residues (for example, residues of lauric acid, myristic acid, linoleic acid, palmitic acid, oleic acid and elaidic acid), steroid acid and sterol residues, and residues of retinoids (e.g., residues of retinoic acids), carotenoids, tocopherols, and tocotrienols;

[0051] Q is a residue of ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, pentaethylene glycol or hexaethylene glycol;

[0052] P is a residue of a polyaminoacid homopolymer selected from poly(serine), poly(alanine), poly(glutamine), poly(glutamic acid), poly(aspartic acid), poly(asparagine), poly(lysine), poly(arginine), poly(proline), poly(glycine), and N-methyl analogs thereof (e.g., N-methylglycine), having a degree of polymerization n;

[0053] R is a terminal group selected from H, methyl, ethyl and maleimide;

[0054] D is a secondary group that is as defined above for L or is a methyl-capped poly(ethylene glycol) residue); and d is 0, or d is 1.

[0055]

[0030] The person of ordinary skill in the art will appreciate that a real-world sample of the conjugates of the disclosure will often have a range of PAA chain lengths, a type of poly(amino acid), and a range of peptides, and hybrid PAA-PEG systems as such various individual molecules within a sample may have different polymers combining PAA and PEG. However, as described above, it can in many circumstances be desirable to control the variation, especially of the value of a polymer size. Thus, the definition of General Formula (I) contemplates that the materials can be in the form of mixtures of individual compounds each with their own particular definitions of S, L, P, Q, R and D. General Formula (I) thus defines various substituents. But the disclosure also specifically contemplates various individual identities for various substituents, e.g., a polymer with uniform or hybrid subunits, e.g., different amino acids or a combination of PEG and PAA.

[0056]

[0031] As described above, B is a residue of a compound having three or four available binding positions selected from the group consisting of diamines, triamines, tetraamines, diaminoalcohols, aminoalcohols, aminodiols, aminotriols, amino acids, triols (such as glycerol), tetraols, triacids, tetracids, and carboxyl-containing diols and polyamines. As used herein, a “residue” is a portion of a molecule remaining when the indicated compound is coupled with other parts of the conjugate. Moreover, “residues” can come from many different compounds. For example, an -O-CH2-CH(NH-)-CH2-CH2-O- moiety is an aminodiol residue, regardless of whether the feed used to make it is an aminodiol or a halogen-containing diol, and an -O-CH2-CH2-N< moiety is an aminoalcohol residue, whether the feed used to make it is an aminoalcohol or a halogenated amine.

[0057]

[0032] In various embodiments, B is a residue of a diamine having the structural formula H2N(CH2)mNH2 wherein m is in the range of 2-10.

[0058]

[0033] The present inventor has determined that a diamine backbone can in many cases be preferable to a triamine backbone. A relatively short diamine backbone, can be desirable in some embodiments. Accordingly, in some embodiments as described herein, m has a number-average value in the range of 2-8. For example, in some embodiments, m has a number-average value in the range of 2-6, or 2-5, or 2-4. In some embodiments, m has a number-average value of 3. In some embodiments, m has a number-average value of 2, or a number average value of 4. The present inventor has noted that values of m in the range of 2- 4 are especially suitable for parenteral administration, while values across the 2-10 range can be suitable for oral administration.

[0059]

[0034] However, in other embodiments, a longer diamine backbone can be suitable. For example, in some embodiments as described herein, m has a number-average value in the range of 5-10. For example, in some embodiments, m has a number-average value in the range of 5-8 or 8-10. Without intending to be bound by theory, the present inventor suggests a longer diamine has a larger “space” or less steric hindrance for the synthesis, especially with longer PAA chains or bulkier lipids, and as such can offers a relative higher yield of the conjugate due to fewer steric effects.

[0035] The person of ordinary skill in the art can select a value of “m” based on the present disclosure, especially the showing that lower values of “m” can provide improved hemolytic stability and thus an improved safety profile.

[0060]

[0036] When such a diamine residue is selected as B, the conjugate can, in some embodiments, have the formula:

[0061] The S group can be attached, for example, through a sugar acyl group. The L group can be attached, for example, through an acyl group. The P group can be attached to the oxygen of the ethylene glycol-based linker Q, for example, via esterification with the C-terminus of the poly(amino acid).

[0062]

[0037] In various embodiments, B is a residue of a triamine or a tetraamine.

[0063]

[0038] In various embodiments, B is a residue of a diaminoalcohol, an aminoalcohol, an aminodiol, or an aminotri ol.

[0064]

[0039] In various embodiments, B is a residue of a triol (such as glycerol) or a tetraol.

[0065]

[0040] In various embodiments, B is a residue of an amino acid, a triacid, a tetracid, or carboxyl-containing diol or polyamine.

[0066]

[0041] S can be a variety of saccharide residues, such as residues of mono-saccharides, disaccharides and trisaccharides. Each saccharide unit can be, e.g., a sugar, a sugar alcohol, a sugar acid, or an amino sugar.

[0067]

[0042] In various embodiments as described herein, S is selected from a disaccharide, monosaccharide, or a trisaccharide group. For example, in some embodiments, S is a disaccharide group. In some embodiments, S is a monosaccharide group. In some embodiments, S is a trisaccharide group. The number of saccharide units can impact the HLB (Hydrophilic-lipophilic balance) value of the conjugate, and the person of ordinary skill in the art can, based on the disclosure herein, determine a particular saccharide group, along with particular “P” and “L” groups, to provide an overall desirable HLB value.

[0068]

[0043] A variety of individual monosaccharide units can be present in the S groups, for example, sugars, sugar alcohols, amino sugars and sugar acids. In various embodiments, the saccharide units of S are individually selected from hexoses and pentoses and sugar alcohol, sugar acid and amino sugar analogs thereof. In various embodiments, saccharide units of S are individually selected from hexoses and sugar alcohol, sugar acid and amino sugar analogs thereof. Individual saccharide units of S can be interconnected by glycosidic bonds, as would be familiar to the person of ordinary skill in the art.

[0069]

[0044] Notably, it can be desirable for saccharide unit of S that is directly bound to the nitrogen of the diamine central backbone to be derived from a sugar acid and to be bound to the nitrogen of the diamine as an amide. The present inventors have noted that linkage as an amide can provide especially stable compounds. In various such embodiments, any saccharide unit of S that is not directly bound to the nitrogen of the diamine is a sugar. However, other linkages are possible. For example, the linkage between the diamine central backbone and the saccharide can be in the form of an amine, for example, through amination of a sugar alcohol, or reaction of a aldehyde or ketone form of a saccharide unit with an amine to form an imine followed by Amadori rearrangement thereof:

[0070]

[0045] In some embodiments as described herein, the structural formula of S is as follows: in which -(CxiH2xiOxi-i)-CO- is a sugar acyl residue derived from a sugar acid in which xl is 4 or 5, and (CX2H2X2-IOX2-I)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof. In various such embodiments, xl is 5 and x2 is 6.

[0071]

[0046] In various embodiments, S has the following structure: or is an open-chain version thereof.

[0072]

[0047] In various embodiments, S is lactobionyl or gluconyl or a combination thereof (e.g., in a molar ratio of at least 9: 1 lactobionykgluconyl). In various embodiments, S is lactobionyl. In other embodiments, S is a residue from gluconolactone or neuraminic acid.

[0073] In other embodiments, S is a residue from another disaccharide or trisaccharide, which can be modified (e.g., by oxidation). Examples include sucrose, lactose, maltose, trehalose , turanose, cellobiose raffinose, melezitose and maltotriose.

[0074]

[0048] In various embodiments, L includes (or is) a fatty acyl group based on a saturated or unsaturated fatty acid (i.e., including all combinations thereof). Accordingly, in various embodiments, L is -C(O)-R1, wherein R1is an alkanyl or alkenyl group having a numberaverage number of carbons in the range of 6-22. The person of ordinary skill in the art will appreciate that in most real-world samples of fatty acids, the fatty group has a range of carbon chain lengths and degrees of unsaturation, and so the conjugates of the disclosure will likewise often have a range of carbon chain lengths and degrees of unsaturation in the fatty acyl component, especially those derived from natural sources.

[0075]

[0049] In various such embodiments, R1has a number-average number of carbons in the range of 6-20, or 6-18. In various such embodiments, R1has a number-average number of carbons in the range of 10-22, e.g., 10-20 or 10-18. In various such embodiments, R1has a number-average number of carbons in the range of 12-22, e.g., 12-20 or 12-18. In various such embodiments, R1has a number-average number of carbons in the range of 14-22, e.g., 14-20 or 14-18. In various desirable embodiments as described above, R1has a numberaverage number of carbons that is no more than 18.

[0076]

[0050] Both saturated and unsaturated R1groups can be suitable for use. In various embodiments as otherwise described herein, R1has a number-average number of unsaturation in the range of 0-3, e.g., 0-2. Of course, many real world samples will include R1 groups having more than one number of unsaturations. For example, some samples may have a distribution of stearoyl, oleoyl and linoleoyl residues. Others may include a combination of oleoyl and linoleoyl residues, for example, in a ratio of about 10: 1.

[0077]

[0051] In various desirable embodiments, R1is a linear alkanyl or alkenyl group.

[0078]

[0052] In various embodiments as described herein, R1is derived from one or more of caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, alpha-linoleic acid, arachidonic acid and erucic acid. Various desirable fatty acids from which RJ-C(O)- can be derived are further described in Table 1 and Table 2; mixtures of such fatty acids (e.g., as are present in various fatty acid materials derived from natural sources such as Tall tree oil and Sunflower oil) are specifically contemplated.

[0079] Table 1 Saturated fatty acids

[0080] Table 2 Unsaturated fatty acids

[0081]

[0053] However, in many embodiments, it can be desirable for the -C(O)-R1group of a conjugate sample to largely have the same chemical identity, e.g., largely cis- CH3(CH2)?CH=CH(CH2)7-C(O)-, as would be the case for an R1-C(O)- Lipid group derived from oleic acid. In various embodiments as otherwise described herein, -C(O)-R1is at least 80 mol% of a single chemical identity, e.g., at least 85 mol%. In various embodiments as otherwise described herein, -C(O)-R1is at least 90 mol% of a single chemical identity, e.g., at least 95 mol%. In various embodiments as described herein, the single chemical identity is selected from n-hexanoyl, n-octanoyl, n-decanoyl, n-dodecanoyl, n-tetradecanoyl, n- hexadecanoyl, n-octadecanoyl, n-eicosanoyl and n-docosanoyl. In various embodiments as described herein, the single chemical identity is selected from: cis-CH3(CH2)5CH=CH(CH2)7C(O)-, cis,cisCH3CH2CH=CHCH2CH=CHCH2CH=CH(CH2)7C(O)-, cis,cis,cis-CH3(CH2)4CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)3C(O)-, and cis-CH3(CH2)7CH=CH(CH2)iiC(O)-.

[0082]

[0054] For example, in various embodiments, that single chemical identity is cis-CH3- (CH2)7CH=CH(CH2)7C(O)-. In various embodiments, that single chemical identity cis,cis- CH3(CH2)4CH=CHCH2CH=CH(CH2)7C(O)-. In various embodiments, that single chemical identity is cis-CH3(CH2)3CH=CH(CH2)7C(O)-. In other embodiments, that single chemical identity is any one of the other residues mentioned in Tables 1 and 2.

[0083]

[0055] In other embodiments, L includes (or is) a sterol or steroid acyl group, such as cholesterol or a bile acid or a similar group. In various embodiments, the steroid acyl group is an acyl group derived from cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, chenodeoxycholic acid, or lithocholic acid. In other embodiments, the steroid acyl group is an acyl group derived from cholesterol .

[0084]

[0056] Steroid acyl groups can be coupled to the backbone B via acylation. Sterols can be coupled using ethylene glycol linkers as described herein for the linker for the poly(amino acid); similar use of mesylate leaving group chemistry can be used to make the necessary etherification to the linker and the necessary reaction with the backbone. Mesylation can also be used to make a direct bond between a sterol group and a backbone.

[0085]

[0057] In other embodiments, L is a lipophilic vitamin residue, such as vitamin A ((retinal, retinoic acid or retinoids) and vitamin E (tocopherols or tocotri enols). Reaction chemistry described above with respect to steroid acids and sterols can be used for these residues.

[0086]

[0058] Q is a group that links the backbone B to the poly(amino acid) P. As described above, Q is selected from residues of ethylene glycol, diethylene glycol, triethylene glycol or tetraethylene glycol. For example, in various embodiments, Q is a residue of di ethylene glycol. In various embodiments, Q is a residue of ethylene glycol. In various embodiments, Q is a residue of triethylene glycol, tetraethylene glycol, pentaethylene glycol or hexaethylene glycol. The person of ordinary skill in the art will appreciate that an ethylene glycol substituent can conveniently form an ester with the C-terminus or with an carboxylic acid side chain of the poly(amino acid); however, other couplings to the poly(amino acid) are possible. An ethylene glycol subunit can be mesylated with methanesulfonyl chloride, then reacted with an amine or hydroxyl of a backbone to make an amine or an ether linkage.

[0059] As described above, P is poly(amino acid). The person of ordinary skill in the art, based on the description herein, can select a variety of poly(amino acids) from use in the conjugates of the disclosure.

[0087]

[0060] For example, in various embodiments, P is a residue of poly(N-methylglycine) (also known as poly (sarcosine). In various such embodiments, P has a number-average molecular weight in the range of 1000-4000 g / mol.

[0088]

[0061] In various embodiments, P is a residue of poly(glutamic acid). In various such embodiments, P has a number-average molecular weight in the range of 750-7,500 g / mol, e.g., in the range of 1,500-3,000 g / mol.

[0089]

[0062] In various embodiments, P is a residue of poly(lysine). In various such embodiments, P has a number-average molecular weight in the range of 1,000-10,000 g / mol, e.g., in the range of 2,100-6,300 g / mol, or 2.100-4,300 g / mol.

[0090]

[0063] In various embodiments, P is a residue of poly (arginine). In various such embodiments, P has a number-average molecular weight in the range of 900-9,600 g / mol, e.g., in the range of 1,900-5,800 g / mol, or 1,900-3,850 g / mol.

[0091]

[0064] In various embodiments, P is a residue of poly(aspartic acid). In various such embodiments, P has a number-average molecular weight in the range of 700-6,850 g / mol.

[0092]

[0065] In various embodiments, P is a residue of poly(proline). In various such embodiments, P has a number-average molecular weight in the range of 1000-10000 g / mol.

[0093]

[0066] In various embodiments, P is a residue of poly (asparagine). In various such embodiments, P has a number-average molecular weight in the range of 1000-10000 g / mol.

[0094]

[0067] In various embodiments, P is a residue of poly(serine). In various such embodiments, P has a number-average molecular weight in the range of 1000-10000 g / mol.

[0095]

[0068] In various embodiments, P is a residue of poly (glutamine). In various such embodiments, P has a number-average molecular weight in the range of 1000-10000 g / mol.

[0096]

[0069] In various embodiments, P is a residue of poly(alanine). In various such embodiments, P has a number-average molecular weight in the range of 1000-10000 g / mol.

[0097]

[0070] In various embodiments, n, the degree of polymerization of the poly(amino acid) P, has a number-average value in the range of 5-50 (e.g., 8-45), or 9.5-52.5. In various embodiments, n has a number-average value in the range of 5-45, e.g., 5-40, or 5-30, or 5-20, or 5-15, or 5-10. In various embodiments, n has a number-average value in the range of 8-50, e.g., 8-45, or 8-40, or 8-30, or 8-20, or 8-15, or 8-12, or 8-10, or 9-23, or 9.8-22.2. In various embodiments, n has a number-average value in the range of 10-50, e.g., 10-45, or 10-40, or 10-30, or 10-20, or 10-15. In various embodiments, n has a number-average value in the range of 9-14, e.g., 9-13, or 10-14, or 10.5-13.5, or 11-13, or 11.5-12.5, or 11.8-12.2, or 10.2- 13.8, or 10.8-13.2, or 11.4-12.6. In various embodiments, n has a number-average value in the range of 18-28, e.g., 20-26, or 22-24, or 22.5-23.5, or 22.8-23.2. In various embodiments, n has a number-average value in the range of 25-40. In various embodiments, n has a number-average value in the range of 40-50, e.g., 42-48, or 44-46, or 44.5-45.5, or 44.8-45.2.

[0098]

[0071] The poly(amino acid) is terminated with R2, which can be H (e.g., to provide an amine at the N-terminus of the poly(amino acid) or a carboxylic acid at the C-terminus of the poly(amino acid)) or an methyl or ethyl group (i.e., to form a methyl or ethyl ester at the C- terminus of the poly(amino acid) or a methyl or ethyl amine at the N-terminus of the poly(amino acid)). In various embodiments, R2has a number-average number of carbons of at least 0.95, e.g., at least 0.99 or at least 1 (e.g., free of hydroxyl or amine). In various embodiments, R2has a number-average number of carbons in the range of 0.9-1.1, or 0.95- 1.05, or 0.98-1.02. In various embodiments, R has a number average number of carbons in the range 0-3, e.g., 0-2. In various embodiments, R2has a number-average number of carbons in the range of 0-0.94, e.g., 0-0.75, or 0-0.5, or 0-0.1, or 0-0.05; in such embodiments, there is a substantial amount of R that is hydrogen.

[0099]

[0072] In various embodiments, R2is maleimide, i.e., with the N-terminus nitrogen of the poly(amino acid) as the nitrogen of the maleimide.

[0100]

[0073] In various embodiments, the poly(amino acid) has a low degree of poly dispersity, which can be especially important for those conjugates used in parenteral administrations. The present inventor has found that use of a poly(amino acid) that has low poly dispersity can provide improved results, especially with respect to providing good dispersion of waterinsoluble materials in aqueous systems. Poly dispersity Index (PDI) is defined by the equation below:

[0101] PDI = — Mnwhere Mwis the weight average molecular weight and Mnis the number average molecular weight. For example, in various embodiments, the “P” group has a PDI (poly dispersity index) of no more than 1.2, e.g., no more than 1.1. In various embodiments, the “PAA” group has a PDI of no more than 1.1, or no more than 1.08. The poly dispersity index of the “P” group is understood to be the same as the poly dispersity index of the poly(amino acid) used to make the conjugate. Molecular weights can be determined by liquid chromatography / mass spectrometry, either of the conjugates or of the poly(amino acid) compound used to make the conjugates.

[0102]

[0074] Commercial scale synthesis of poly(amino acid)s relies on two main methods: ringopening polymerization (ROP) of N-carboxyanhydrides (NCAs) and microbial fermentation. NCA-based ROP is the predominant technique for laboratory and industrial synthesis of a wide range of poly(amino acids), while fermentation is primarily used for natural polymers, e.g., s-poly(L-lysine). In the ROP reaction, polymer molecular weight can be controlled by the initial concentration of monomer ([M]o), e.g., A-carboxy anhydride and an initiator ([I]o), e.g., primary amine such aniline). Theoretically with a fixed monomer concentration, a molar ratio of [M]o / [I]o = 50 / 1 produces a poly(N-methylglycine) ranging from 2,500 to 3,500 g / mol in number-average molecular weight and a narrow polydispersity is achievable with addition of a carboxylic acid catalyst ([C]o). For example, when using benzoic acid at a ratio of 50 / 1 / 5 / M]o / [I]o / [C]o), the PDI can be well below 1.2.

[0103]

[0075] In various embodiments, and in many of the particular embodiments as described herein, d is 0, i.e., D is absent.

[0104]

[0076] However, in other embodiments, d is 1, i.e., D is present.

[0105]

[0077] In some embodiments, D is as described for L in any embodiment above.

[0106]

[0078] In other embodiments, D is a methylated polyethylene glycol) residue having g ethylene glycol units. In various such embodiments, g has a number-average value in the range of 5-50, e.g., 5-40, or 5-30, or 5-20, or 5-15, or 5-10. In various embodiments, g has a number-average value in the range of 8-50, e.g., 8-45, or 8-40, or 8-30, or 8-20, or 8-15, or 8- 12, or 8-10. In various embodiments, g has a number-average value in the range of 10-50, e.g., 10-45, or 10-40, or 10-30, or 10-20, or 10-15. In various embodiments, g has a numberaverage value in the range of 9-14, e.g., or 9-13, or 10-14, or 10.5-13.5, or 11-13, or 11.5- 12.5, or 11.8-12.2, or 10.2-13.8, or 10.8-13.2, or 11.4-12.6. In various embodiments, g has a number-average value in the range of 18-28, e.g., 19-22, or 22-24, or 22.5-23.5, or 22.8-23.2. In various embodiments, g has a number-average value in the range of 25-35, e.g., 30-36, or 32-34, or 32.5-33.5, or 32.8-33.2. In various embodiments, g has a number-average value in the range of 40-50, e.g., 42-48, or 44-46, or 44.5-45.5, or 44.8-45.2.

[0107]

[0079] In various embodiments as described herein, m is 3; S has the structural formula as below: in which -(CxiH2xiOxi-i)-CO- is a sugar acyl residue derived from a sugar acid in which xl is 4 or 5, and (CX2H2X2-IOX2-I)- is a sugar residue-derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof; -C(O)-R1is at least 80 mol% of cis- CH3(CH2)7CH=CH(CH2)?C(O)-, e.g., at least 85 mol%; R2is methyl; and P has a poly dispersity index of no more than 1.1, e.g., no more than 1.07. For example, in some embodiments, xl is 5 and x2 is 6. In some embodiments, S has the structure or is an open-chain version thereof. In some embodiments, S is lactobionyl. In some embodiments, -C(O)-R1is at least 90 mol% of cis-CH3(CH2)7CH=CH(CH2)?C(O)-, e.g., at least 95 mol%. In some embodiments, P has a polydispersity index of no more than 1.06, e.g., no more than 1.05.

[0108]

[0080] In various embodiments as described herein, m is 3; S has the structural formula in which -(CXIH2XIOXI-I)-CO- is a sugar acyl residue derived from a sugar acid in which xl is 4 or 5, and (CX2H2X2-IOX2-I)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof; -C(O)-R1is at least 80 mol% of cis- CH3(CH2)7CH=CH(CH2)7C(O)-, e.g., at least 85 mol%; and the P group is a PAA residue having a number-average molecular weight in the range of 500 to 5000 g / mol and having a poly dispersity index of no more than 1.1, e.g., no more than 1.08. In some embodiments, S has the following structure: or is an open-chain version thereof. In various embodiments as otherwise described herein, the conjugate has the structural formula of Chemical Structure 1:

[0109] Chemical Structure 1 where -C(O)-L* is as described for L in any embodiment as described herein.

[0110]

[0081] In various such embodiments of Chemical Structure 1, the fatty acyl residue of Chemical Structure 1 is derived from one or more of lauric acid, myristic acid, palmitic acid, linoleic acid, oleic acid and stearic acid. The PAA ranges from 5 to 50 of repeated subunits.

[0111]

[0082] In various embodiments, the conjugate is Oleoyldiaminopropane-ethylene-

[0112] Poly sarcosine -lactobionate (ODPS), which can be represented by the Chemical Structure 2:

[0113] Chemical Structure 2 (ODPS)

[0114]

[0083] The “oleyl” group is understood to represent a -C(O)R1group that is at least 80 mol% derived from oleic acid. In Chemical Structure 2, m(PAA)nis a poly(sarcosine) residue, and n is any desirable value as described above. In some embodiments, the numberaverage value of n is 10 or 20 in the range of 9.2-23.8, e.g., 9.6 - 10.2, 10.3-13.2, or 19.4-

[0115] 23.6.

[0116]

[0084] In various embodiments, the conjugate is Stearylpropanediamine polyglutamic acid- triethylene-glycol-ether-lactobionate (STQS), which can be represented by Chemical Structure 3a:

[0117] Chemical Structure 3a (STQS), or Stearylpropanediamine polyglutamic acid-diethylene-glycol-ether-lactobionate (SDQS), which can be represented by Chemical Structure 3b:

[0118] Chemical Structure 3b (SDQS).

[0119] The “stearyl” group is understood to represent an R1group that is at least 80 mol% derived from stearic acid. The number-average value of n is in the range of 5-50.

[0120]

[0085] In various embodiments, the conjugate is represented by Chemical Structure 4:

[0121] Chemical Structure 4

[0122] L, P and R2are as described in any embodiment or combination thereof herein, and m is in the range of 2-6, e.g., is 3.

[0123]

[0086] In various embodiments, the conjugate is Cholesterylethyldiamino-PAA - lactobionate (CDPAS), which can be represented by Chemical Structure 5:

[0124]

[0087] The “cholesteryl” group is understood to represent an R1group that is at least 65 mol% derived from choloic acid. In Chemical Structure 5, n is any desirable value as described above.

[0125]

[0088] In various embodiments as described herein, the conjugate has one of the following structures: wherein m ranges from 2-10, e.g.., is 3.

[0126]

[0089] Any of the L groups in these example compounds can be used in any other embodiment as described herein.

[0127]

[0090] Any of the Q groups in these example compounds can be used in any other embodiment as described herein.

[0128]

[0091] Any of the S groups in these example compounds can be used in any other embodiment as described herein.

[0129]

[0092] The present inventor has determined that improved performance can be provided when one or more of various analytical targets are achieved for the conjugates of the disclosure.

[0130]

[0093] In various embodiments of the conjugates as otherwise described herein, PAA is Polysarcosine that has a number-average molecular weight in the range of 700 and 3,500 g / mol corresponding to a degree of polymerization 10 to 50 as below:

[0131]

[0094] In various embodiments of the conjugate is oleoyldiaminopropanedi ethyleneether(DE)-poly sarcosine (n=10) -lactobionate, shown in

[0132] Chemical Structure 6:

[0133] C67H120N12O24

[0134] Mol. Wt.: 1477.74

[0135] Chemical Structure 6 (ODDEPS)

[0136]

[0095] In various embodiments of the conjugates as otherwise described herein, the conjugate has a purity of at least 85 wt%. Such materials can be especially desirable for use in oral applications. In various embodiments, the single chemical identity is oleoyl, myristyl, palmitoyl, stearoyl or linoleoyl.

[0137]

[0096] In some embodiments as described herein, the conjugate has a hydrophilic lipophilic balance (i.e. Griffin HLB) value in the range of 13-18, e.g., in the range of 13-15, e.g., the Griffin HLB of oleoyldiaminopropanedi ethylene-ether-poly sarcosine (n=10) -lactobionate is 14.9.

[0138]

[0097] Another aspect of the disclosure provides a polyaminoacid-saccharide-lipid conjugate useful, for example, as a solubility or bioavailability enhancer for safely delivering hydrophobic or lipophilic compound or compounds, represented by General formula I above, in which L is selected from a group consisting of resdiues fatty acids including lauric acid, myristic acid, linoleic acid, palmitic acid, oleic acid, elaidic acid and residues of sterols and steroid acids; P is a polymeric amino acids including but not limited to poly(serine), poly(alanine), poly(glutamine), poly(aspartic acid), poly(lysine), poly-(arginine), poly(proline) and poly(N-methylated glycine), in which the degree of polymerization n ranges from 5 to 50 of subunits; and B is an alpha, omega-diamino-n-alkane having 1-6 CH2 units, e.g., 3 CH2 units or 2 CH2 units. The particular selections of B, L, P and Q can be as described in any not-inconsi stent embodiment herein, d is desirably 0.

[0098] In various embodiments as described herein, the synthesis method for preparing the polymeric conjugate as described herein comprises the steps of:

[0139] (1) synthesizing a short-chain of (tetra-, tri-, di-) ethylene glycol linked polyaminoacid;

[0140] (2) coupling activated polyamino-glycol ether to the unprotected amino group of the center backbone;

[0141] (3) conjugating a lipid or disaccharide to the backbone, thereby forming a PAA- saccharide-lipid conjugate having a high purity of conjugates in the range of 85% to 115% by HPLC assay. wherein the coupling steps are trough etherification or esterification or amidation or a combination thereof.

[0142]

[0099] In other embodiments as described herein, the synthesis method for preparing the polymeric conjugate as described herein comprises the steps of:

[0143] (1) extending the PAA chain by repeating the short ethylene glycol chain reaction or linked a desirable length of PAA to the PAA chain

[0144] (2) conjugating a lipid or disaccharide to the backbone, thereby forming a PAA- saccharide-lipid conjugate having a hybrid PAA-PAA chain. wherein the sequence or order of coupling steps or sites is interchangeable and includes etherification or esterification or amidation or a combination thereof.

[0145]

[0100] In some embodiments of the polymeric conjugate as described herein, m* in the backbone is 0 or 1 thereby forming a PAA-saccharide-lipid conjugate with no or less hemolytic potential suitable for clinical parenteral administrations as well as oral applications having the following structure(s): wherein: m is 3 (i.e., the backbone is propane), m is 2, the backbone is ethylene;

[0146] -C(O)-L* is a fatty acyl residue, e.g., lauric acid, myristic acid, linoleic acid, palmitic acid, linoleic acid, oleic acid or stearic acids; and the poly(amino acid) P has a degree of polymerization n ranging from 5 to 50.

[0147]

[0101] In some embodiments of the polymeric conjugate as described herein, the distance between the 2 terminal amines is less than 4 carbons; such conjugates are especially useful for parenteral administrations. However, they can also be useful for oral administration or other applications.

[0148]

[0102] In some embodiments of the polymeric conjugate as described herein, the m in the backbone is at least 4; such conjugates can be suitable for oral administration or other applications.

[0149]

[0103] In some embodiments of the polymeric conjugate as described herein, the weight ratio of the PAA- saccharide conjugate to an oncology compound is between about 300 and about 1 for the drug delivery. In some embodiments of the polymeric conjugate as described herein, the weight ratio of the PAA-saccharide-lipid conjugate to a non-oncology compound is between about 200 and about 1 for the compound delivery.

[0150]

[0104] In various embodiments of the polymer as described herein, the PAA-saccharide- lipid conjugate is selected from the following structures:

[0151] wherein n ranges from 5 to 50.

[0152]

[0105] Any of the L groups in these example compounds can be used in any other embodiment as described herein.

[0153]

[0106] Any of the Q groups in these example compounds can be used in any other embodiment as described herein.

[0154]

[0107] Any of the S groups in these example compounds can be used in any other embodiment as described herein.

[0155]

[0108] Various poly(amino acid)s are commercially available, although typically for long chain PAAs, e.g., n > 20. Ring-opening polymerization (ROP) is the chemical process used to turn N-carboxyanhydride (NCA) monomers into poly(amino acid)s. Over last six decades, NCA polymerizations have been the most common technique, especially for homopolymers which is suitable for the PAA used in the present disclosure as showed in the Reaction Scheme 1.

[0156] Reaction Scheme 1 NCA polymerizations of PAA

[0157] Reaction Scheme 1 is the most common and versatile method for preparing PAAs with controlled molecular weights and narrow polydispersity. The process generally follows three steps: 1. Ring-opening polymerization (ROP) of A-carboxyanhydrides (NCAs). This is the most common and versatile method for preparing PAAs with controlled molecular weights and narrow polydispersity. The process generally follows three steps:

[0158] 1. Monomer synthesis: NCAs are prepared from the corresponding amino acids. This often involves with reacting an amino acid with phosgene or a phosgene equivalent, though more benign, phosgene-free methods exist. For amino acids with reactive side chains, orthogonal protecting groups are necessary before NCA formation.

[0159] 2. Polymerization: An initiator, often a primary amine, initiates the ROP of the NCA monomer, often in conjunction with a carboxylic acid catalyst . The polymerization proceeds via the release of carbon dioxide as the ring opens and the polymer chain grows.

[0160] 3. Deprotection (if needed): After polymerization, protecting groups on the side chains are removed to yield the final functional PAA

[0161]

[0109] NCAs are prepared from the corresponding amino acids. This starts from reacting an amino acid with phosgene or a phosgene equivalent, though more benign, phosgene-free methods exist. For amino acids with reactive side chains, orthogonal protecting groups are necessary before NCA formation ([M]o). For amino acids with reactive side chains, orthogonal protecting groups are necessary before NCA formation. Polymerization is typically controlled by a ratio of [M]o / [I]o : An initiator ([I]o), typically a primary amine, e.g., aniline, a tertiary amine, or a transition metal complex, catalyzes the ROP of the NCA monomer. The polymerization proceeds via the release of carbon dioxide as the ring opens and the polymer chain grows. Additionally a carboxylic acid ([C]o), e.g., benzoic acid, helps to speed up the reaction. A typical ratio = [M]o / [I]o / [C]o = 5 to 10,000 / 1 / 0 to 5, respectively.

[0162] [HO] The person of ordinary skill in the art will appreciate that a variety of methods for making poly(amino acids) are available. See, e.g., J. Cheng et al., “Synthesis of Polypeptides by Ring-Opening Polymerization of alpha-Amino Acid N-Carboxyanhydrides,” Top. Curr. Chem., Vol. 310, “Peptide Based Materials” (2011); A. Birke et al., “Polysarcosine- containing copolymers: Synthesis, characterization, self-assembly, and applications,” Progress in Polymer Science, 81, 163-208 (2018); S. Wang et al., “Precision Synthesis of Poly sarcosine via Controlled Ring-Opening Polymerization of N-Carboxyanhydride: Fast Kinetics, Ultrahigh Molecular Weight, and Mechanistic Insights,” J. Am. Chem. Soc., 146(8), 5678-92 (2024); X. Tao, “PEG-Amine-Initiated Polymerization of Sarcosine N- Thiocarboxyanhydrides Toward Novel Double-Hydrophilic PEG-b-Poly sarcosine Diblock Copolymers,” Macromol. Rapid Commun., 35(9), 875-81 (2014). The person of ordinary skill in the art can adapt methodologies in these references and in the many other reports of poly(amino acid) synthesis for use in the methods described herein.

[0163] [Hl] In some embodiments, the coupling of the poly(amino acid) can be performed before the coupling of the center backbone, especially in the case of a diamine center backbone. When the poly(amino acid) of the conjugate is to be carboxyl or aminoterminated, it can be desirable to have the ethylene glycol (or oligo-ethylene glycol)linked at the time of the coupling of the center diamine backbone.

[0164]

[0112] In various embodiments, the coupling of the ethylene glycol to the carboxyl or amino group of the polyaminoacid can be performed in a stepwise fashion, e.g., by first coupling a single triethylene glycol to polyaminoacid, e.g., by performing esterification, then to the central backbone by forming a C-N bond through mesylation. An example of this is shown in Reaction Scheme 2, below.

[0165] Reaction Scheme 2 DCC Mediated coupling of triethylene glycol and PAA

[0166]

[0113] Dicyclohexyl carbodiimide (DCC) is a strong condensing agent that activates carboxyl groups by forming unstable O-acyl urea with N-protected amino acid and facilitates the attack of nucleophilic molecule. Thus it brings about condensation reaction by quenching water molecule and forming dicyclohexyl urea. The activation of carboxyl groups in amino acid hydrochloride by DCC and the reaction between carboxyl groups of amino acid and hydroxyl groups of the diethylene glycol (DEG). Unlike amino group, hydroxyl groups of DEG cannot abstract proton from hydrochloride. Therefore the hydrochloride salt was expected to act as amino protecting group in the condensation reaction. In case if extra protection is required, a so-called “Boc” protecting group is used to protect the free amine of PAA. The person of ordinary skill in the art will appreciate that Boc is a useful group for protecting the free amine in other methods of the disclosure. The person of ordinary skill in the art will appreciate that other protecting groups can also be used to protect the free amine.

[0167]

[0114] Similarly benzyl (Bn) groups may be used for protecting the hydroxyl group of DEG. Removal of benzyl groups to free the hydroxyl group of the DEG-reagent can be achieved by any suitable reagents. For example, the benzyl group can be removed by hydrogenation in presence of palladium catalyst and the DEG can be used without protection in slight excessive amount (by molar ratio) than PAA. While a benzyl group is used in the example of Reaction Scheme 2, the person of ordinary skill in the art will identify other suitable alcohol protecting groups.

[0168]

[0115] And while the extension of the poly(amino acid) is shown in Scheme 1 as being performed before the coupling with the center diamine group, in other embodiments the acylation can be performed with hydroxyl protecting group or amine tert-Butyloxycarbonyl (Boc) protecting group still in place, and the alcohol or amine deprotection can be performed after acylation.

[0169]

[0116] Following the reaction in Reaction Scheme 2, prior to removing the protecting group on the terminal amine of the backbone, the second amine group can be coupled with the PAA-ethylene first, then acylated with a R1-C(O)- acyl group. One example of this is shown in Reaction Scheme 3. This can be done, for example, by reaction of an appropriate acid chloride. For example, in various embodiments as described herein, the coupling of the R1-C(O)- acyl group to the second amine group is performed using an R1-C(O)-halide. The person of ordinary skill in the art can determine suitable reaction conditions, e.g., in N- methyl-2-pyrrolidinone (NMP) at 20 to 30 °C. The acid chloride can be prepared separately by dissolving the corresponding acid in tetrahydrofuran (THF), adding excess triethylamine (TEA) as base and then adding isobutyl chloroformate (IBCF). Treatment with oxalyl chloride is another way to make acid chlorides suitable for the acylation.

[0170] Reaction Scheme 3 Synthesis of A3- fatty acid propanediamino-diethylene glycol PAA

[0171]

[0117] With the PAA and the acyl group coupled to the second amine, the first amine can be deprotected using a suitable deprotection. Accordingly, in various embodiments, the coupling of the saccharide to the first amine group comprises deprotecting the first amine group and coupling the saccharide in the form of a sugar acid or a lactone version thereof. An example of the deprotection of Boc-protected amino groups can be found in Example 2 of the following sections. The carbohydrate can then be coupled to the central backbone via the first amine. An example of this is represented in the Reaction Scheme 4. In this method, any suitable saccharide, such as lactobionolactone can reacted with A3- fatty acid propanediamino-PAA-12 in di chloromethane to produce the final product of A3- fatty acid propanediamino-PAA- 12-W-lactobionate.

[0172] Reaction Scheme 4 Synthesis of TV3-fatty acid propanediamino-PAA-A'-lactobionate

[0118] In various embodiments of the present disclosure, the synthetic methods described herein, e.g., those represented in various above reaction schemes, can be modified in any suitable manner. For example, the “backbone” 1,3-diaminopropane (propane-1, 3-diamine) can be substituted by variety of agents, including but not limited to ethylenediamine, putrescine (butane- 1,4-diamine), cadaverine (pentane-l,5-diamine), hexamethylenediamine (hexane- 1,6-diamine) and the like.

[0173]

[0119] A non-limiting feature or aspect of various embodiments of the present disclosure, preferred fatty acids range from carbon chain lengths of about C8 to about C22, preferably between about CIO and about Cl 8, consisting of capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, myristoleic acid palmitoleic acid, sapienic acid oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoelaidic acid and a-linolenic acid.

[0174]

[0120] Another non-limiting feature or aspect of various embodiments of the present disclosure, when oleic acid as the lipid group, the purity of oleic acid should be in the range from 65% to 88% as defined in the current European Pharmacopoeia (EP). Further refining may be necessary when a purer oleic acid is desired.

[0175]

[0121] Further non-limiting feature or aspect of various embodiments of the present disclosure, when no commercial source is available or particular polyaminoacid is desirable, a polymerization of N-carboxyanhydride (NCA) is commonly utilized for the polyaminoacid preparation. NCAs, also called also called Leuchs' anhydrides, are typically prepared by phosgenation of amino acids, wherein R = amino acid chain includes but not limited to serine, alanine, glutamine, aspartic acid, lysine, arginine, proline, glycine and / or N-methylated-glycine. NCA monomers are convert to polyaminoacid, through ring-opening polymerization as described above. Alternatively N-thiocarboxyanhydrides may be used via a similar Ring-opening polymerization (ROP).

[0176]

[0122] The solvent for the PAA-lipid conjugation reaction in the disclosed methods can be selected by the person of ordinary skill in the art. Polar solvents, e.g., polar aprotic solvents can be suitable in many embodiments. In some embodiments, the solvent is one or more of A A-di methyl form am ide (DMF), dimethylsulfoxide (DMSO), pyridine, tetrahydrofuran (THF), di chloromethane (DCM), chloroform, 1,2-dichloroethane, ethyl acetate, isopropanol, methanol and the like.

[0177]

[0123] The disclosed methods can be used to prepare a variety of novel PAA-saccharide- lipid conjugates. For example, the methods can be used to prepare A’-lipid propanediamino- P A A-Afl-lactobi onate in highly pure PAA form containing any lipophilic carrier groups.

[0178]

[0124] Thus, substitution of polysorbates and Cremophor by PAA-saccharide-lipid conjugates of the disclosure can offer significant improvements in reduced immunogenicity, and improved safety, and can meet a significant unmet need in the field of chemotherapeutics and biocompatible formulations

[0179]

[0125] In various embodiments, formulations of the disclosure can be provided in the absence of ethanol (e.g., no more than 0.1 wt% ethanol). This is especially useful in PAA- saccharide-lipid conjugate-based parenteral formulations. Lack of alcohol can further prevent potential alcohol intoxication and the amounts of excipients are significantly reduced as compared to Cr-EL or PS80 based parenteral formulations.

[0180]

[0126] The person of ordinary skill in the art can provide suitable parenteral formulations that include the conjugates of the disclosure. For example, in a 5 wt% PAA-saccharide-lipid conjugate aqueous solution, in some embodiments the concentration of the above drug substance can in some embodiments be up to 1 wt%. Formulations for parenteral administration can be, e.g., formulated with an appropriate amount of sodium chloride (e.g., 9 wt%) in purified water. pH adjustment can be provided as necessary, e.g., using sodium hydroxide and / or hydrochloric acid, or an appropriate buffer.

[0181]

[0127] The conjugates of the disclosure can also be used in solid dosage forms. For example, in one example of a preparation, PAA-saccharide-lipid conjugate is added to a stainless steel vessel equipped with propeller type mixing blades and appropriate volumes of ethanol are added to the vessel with mixing. The drug substance is charged into the vessel with constant mixing at a temperature to 40-50 °C. Mixing is continued until the drug is visually dispersed fully and a homogenous solution was achieved. Ethanol is removed by vacuum at a temperature to 35° - 45 °C. The material can proceed to encapsulation or tableting. One example of a general composition is described below:

[0128] Another aspect of the disclosure is a conjugate as described herein, for use as a pharmaceutical excipient, or for use as in a medicament.

[0182]

[0129] Another aspect of the disclosure is a therapeutic composition comprising a conjugate as described herein and a therapeutic agent.

[0183]

[0130] Another aspect of the disclosure is a composition for use in the treatment of a subject having a condition, the composition comprising a conjugate as described herein and a therapeutic agent.

[0184]

[0131] Another aspect of the disclosure is a method for treating a subject having a condition, the method comprising administering to the subject a composition of the disclosure. In some embodiments as described herein, the therapeutic agent is suitable for treating the condition.

[0185]

[0132] Another aspect of the disclosure provides a composition comprising a conjugate as described herein and a therapeutic agent for use as a medicament.

[0186]

[0133] Another aspect of the disclosure is a use of a conjugate as described herein for increasing bioavailability of a therapeutic agent.

[0187]

[0134] Another aspect of the disclosure is a use of a conjugate as described herein for increasing solubility of a therapeutic agent in an aqueous system.

[0188]

[0135] Another aspect of the disclosure is use of a conjugate as described herein as a pharmaceutical excipient, or as a therapeutic.

[0189]

[0136] A variety of therapeutic agents are suitable for use in the compositions, methods and uses of the present disclosure. But the person of ordinary skill in the art will appreciate from the present disclosure that the compositions, methods and uses of the present disclosure are especially advantageous with respect to therapeutic agents that are poorly water-soluble or water-insoluble. For example, in various embodiments, the therapeutic agent has a water solubility in deionized water of no more than 5 mg / mL, e.g., no more than 2 mg / mL at 37 °C. In various embodiments, the therapeutic agent has a water solubility in deionized water of no more than 1 mg / mL at 37 °C, e.g., no more than 0.5 mg / mL, or no more than 0.2 mg / mL. In various embodiments, the therapeutic agent has a water solubility in deionized water of no more than 0.1 mg / mL at 37 °C, e.g., no more than 0.05 mg / mL, or no more than 0.02 mg / mL. In various embodiments, the therapeutic agent has a water solubility in pH 7.4 phosphate- buffered saline of no more than 5 mg / mL, e.g., no more than 2 mg / mL at 37 °C. In various embodiments, the therapeutic agent has a water solubility in pH 7.4 phosphate-buffered saline of no more than 1 mg / mL at 37 °C, e.g., no more than 0.5 mg / mL, or no more than 0.2 mg / mL. In various embodiments, the therapeutic agent has a water solubility in pH 7.4 phosphate-buffered saline of no more than 0.1 mg / mL at 37 °C, e.g., no more than 0.05 mg / mL, or no more than 0.02 mg / mL.

[0190]

[0137] Similarly, the compositions, methods and uses of the present disclosure are especially advantageous with respect to therapeutic agents that are lipophilic. For example, in various embodiments of the compositions, methods and uses of the disclosure, the therapeutic agent has a log D7.4 value of at least 2, e.g., at least 2.25, at least 2.5 or at least 2.75. In various embodiments, the therapeutic agent has a log D7.4 value of at least 3, e.g., at least 3.25, at least 3.5 or at least 3.75. In various embodiments, the therapeutic agent has a log D7.4 value of at least 4, e.g., at least 4.25, at least 4.5 or at least 4.75. The log D7.4 value is determined using the shake-flask method described below: Two solutions are prepared: n- Octanol saturated with water, and pH 7.4 phosphate-buffered saline (PBS) saturated with n- octanol. 490 pL of pH 7.4 PBS (n-octanol saturated) is placed into a well of a 96-well plate.

[0191] 20 pL of a 50 pM test compound stock (in a suitable n-octanol- and / or water-miscible organic solvent) is added to the well. 490 pL of n-octanol (water saturated) is added the well. The plate is capped shaken for 24 hours at 37 °C. HPLC is used to determine the relative amounts of the test compound in the n-octanol phase and in the aqueous phase. The logD7.4 value is determined as log D7.4 = log((OR / AR)), in which (OR / AR) is the ratio of relative amounts of compound in the octanol phase and in the aqueous phase (which can be taken from appropriate HPLC detector responses without calculating absolute amounts). The partitioning of the test compound stock solvent is ignored in this analysis. In other embodiments, the therapeutic agent has a log P value of any value described above, determined as described above using deionized water instead of the PBS.

[0192]

[0138] While LogP = Log D regardless the pH range for non-ionized solutes, Log D is pH- independent, it changes with pH as its calculations account for all forms of a compound at a specific pH, including ionized, partially ionized, and unionized species. Hereby a ratio of a selected conjugate to therapeutic agent has to be optimized, ideally the solubility can be achieved in a pH range of 3 to 9. e.g., 4 to 8, 5 to 7. Typically a buffered solution or pH adjustment is required.

[0193]

[0139] In various embodiments, the therapeutic agent is a therapeutic agent selected from Apixaban, Atorvastatin, Cabazitaxel, Celecoxib, Docetaxel, Dolutegravir, Edaravone, Etomidate, Everolimus. Midazolam. Paclitaxel, (oral) Propofol, Rivaroxaban, Tacrolimus, Tenofovir Alafenamide and Ticagrelor.

[0140] The amounts of the conjugate of the disclosure and the therapeutic agent will vary depending on the particular dosage form and the particular dosage desired. The person of ordinary skill can select particular amounts based on the present disclosure and based on the identification of a desired therapeutic agent.

[0194]

[0141] In various embodiments, the conjugate of the disclosure is present in an amount above its critical micelle concentration. For example, in some embodiments, the conjugate is present in aqueous solution in an amount above its critical micelle concentration or less than 0.1 mmol. Without intending to be bound by theory, it is believed that the conjugates of the disclosure work in part by forming micelles with the therapeutic agent.

[0195]

[0142] In various embodiments, a weight ratio of the conjugate of the disclosure to the therapeutic agent is in the range 500:1 - 1:2, e.g., 200: 1 - 1 :2, or 100: 1 - 1 :2, or 50: 1 - 1 :2, or 20: 1 - 1 :2. In various embodiments, a weight ratio of the conjugate of the disclosure to the therapeutic agent is in the range of 500: 1 - 1 : 1, e.g., 200: 1 - 1 :1, or 100:1 - 1 : 1, or 50: 1 to 1 : 1, or 20: 1 - 1 :1, or 10:1 - 1 : 1, or 5: 1 - 1 : 1. In various embodiments, a weight ratio of the conjugate of the disclosure to the therapeutic agent is in the range of 500: 1 - 2: 1, e.g., 200: 1 - 2: 1, or 100: 1 - 2:1, or 50:1 - 2: 1, or 20: 1 - 2: 1, or 10: 1 - 2: 1, or 5: 1 - 2: 1. In various embodiments, a weight ratio of the conjugate of the disclosure to the therapeutic agent is in the range of 500: 1 - 4: 1, e.g., 200: 1 - 4: 1, or 100: 1 - 4: 1, or 50: 1 - 4:1, or 20: 1 - 4: 1, or 10: 1 to 4: 1.

[0196]

[0143] The therapeutic agent can be present in the composition in a variety of amounts, depending on the therapeutic agent and depending on the particular form of the composition. For example, in various embodiments, the therapeutic agent is present in the composition in an amount of at least 0.1 wt%, e.g., at least 0.2 wt%. In various embodiments, the therapeutic agent is present in the composition in an amount of at least 0.5 wt%, e.g., 1 wt%. In various embodiments, the therapeutic agent is present in the composition in an amount of at least 2 wt%, e.g., at least 5 wt%. In various embodiments, the therapeutic agent is present in the composition in an amount of at least 10 wt%, e.g., at least 20 wt%.

[0197]

[0144] In various embodiments, the therapeutic agent is present in the composition in an amount in the range of 0.1-10 wt%, e.g., 0.2-10 wt%, or 0.1-5 wt%, or 0.2-5 wt%, or 0.1-2 wt%, or 0.2-2 wt%. In various embodiments, the therapeutic agent is present in the composition in an amount in the range of 0.5-20 wt%, e.g., 1-20 wt%, or 0.5-10 wt%, or 0.5- 10 wt%, or 0.5-5 wt%, or 1-5 wt%. In various embodiments, the therapeutic agent is present in the composition in an amount in the range of 2-30 wt%, e.g., 5-30 wt%, or 2-20 wt%, or 5- 20 wt%, or 2-10 wt%, or 5-15 wt%. In various embodiments, the therapeutic agent is present in the composition in an amount in the range of 10-50 wt%, e.g., 20-50 wt%, or 10-30 wt%, or 20-40 wt%, or 10-20 wt%, or 20-30 wt%.

[0198]

[0145] The conjugate of the disclosure can be in the composition in a variety of amounts. In various embodiments, the conjugate of the disclosure is present in an amount of at least 1 wt%, e.g., at least 2 wt%. In various embodiments, the conjugate of the disclosure is present in an amount of at least 5 wt%, e.g., at least 10 wt%. In various embodiments, the conjugate of the disclosure is present in an amount of at least 15 wt%, e.g., at least 20 wt%. In various embodiments, the conjugate of the disclosure is present in an amount of at least 25 wt%, e.g., at least 30 wt%.

[0199]

[0146] In various embodiments, the conjugate of the disclosure is present in the composition in an amount in the range of 1-25 wt%, e.g., 2-25 wt%, or 1-15 wt%, or 2-15 wt%, or 1-10 wt%, or 2-10 wt%, or 1-5 wt%, or 2-5 wt%. In various embodiments, the conjugate of the disclosure is present in the composition in an amount in the range of 5-35 wt%, e.g., 10-35 wt%, or 5-25 wt%, or 10-25 wt%, or 5-15 wt%, or 10-20 wt%. In various embodiments, the conjugate of the disclosure is present in the composition in an amount in the range of 15-50 wt%, e.g., 20-50 wt%, or 15-40 wt%, or 20-40 wt%, or 15-30 wt%, or 20- 35 wt%. In various embodiments, the conjugate of the disclosure is present in the composition in an amount in the range of 20-60 wt%, e.g., 25-60 wt%, or 20-50 wt%, or 25- 50 wt%, or 20-40 wt%, or 25-45 wt%.

[0200]

[0147] Of course, the person of ordinary skill in the art can use the relative mass ratios described above to determine various suitable amounts of conjugate for a particular amount of therapeutic agent.

[0201]

[0148] The compositions described herein can be provided in a variety of types of dosage forms. For example, in various embodiments the compositions of the disclosure are in the form of aqueous solutions or suspensions. Such solutions or suspensions can be provided, e.g., for oral or topical or intranasal or parenteral administration. In other embodiments, the composition of the disclosure is in the form of a concentrate for dilution into an aqueous solution or suspension. In other embodiments, the composition of the disclosure are in the form of a cream or gel, e.g., for topical administration or ophthalmic applications. In other embodiments, the compositions of the disclosure are in the form of a solid formulation, for example, in the form of a tablet or granule. Such solid formulations can be useful for oral or buccal administration. A variety of other types of dosage forms are generally familiar to the person of ordinary skill in the art

[0149] The following examples are further illustrating the disclosures and should not be constructed as in any way limiting its scope.

[0202] EXAMPLES

[0203]

[0150] Chemicals and Reagents: lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, lactobionic acid, bile acids, glucuronic acid, amino acids, e.g., N-methylglycine and other chemicals or reagents were obtained from Sigma-Aldrich (St. Louis, MO, USA) or Alfa Aesar (Ward Hill, MA, USA) or Thermo Fisher Scientific (Rockford, IL) and other commercial sources. All PAA-saccharide-lipid conjugates used in the studies were made inhouse by LipoSeuticals Inc. (Monmouth Junction, NJ, USA).

[0204]

[0151] Example 1. Preparation of tert-Butyl Carbamates (Boc)-Protected Amino Groups

[0205]

[0152] A high yield and effective catalyst-free and room temperature synthetic method was reported previously (Weiszhar Z., et al (2012). Eur J P harm Set. 45(4):492-8) and used with slight modification. To a solution of starting compound in MeOH, di - / -butyl dicarbonate was added in a one to one molar ratio. The resulting mixture was stirred overnight at room temperature. When the reaction was complete, solvent was removed under vacuum; the residue was dissolved into EtOAc and washed with saturated NH4CI aqueous solution once, then dried over Na2SC>4 and condensed to yield the expected product (> 90%). Example of this reaction is demonstrated in Reaction Scheme 5, where R is a main structure of the central backbone. This method gives N- / -Boc derivatives chemoselectively without substantial amounts of side products (such as isocyanate, urea). Reaction Scheme 5

[0206]

[0153] Example 2. Deprotection of Boc-Protected Amino Groups

[0207]

[0154] Effective reagents for the deprotection of tert-butyl carbamates or tert-butyl esters include phosphoric acid and trifluoroacetic acid. The reactions give high yields and are very convenient. Equal volumes of trifluoroacetic acid were added to a solution of Boc-carbamate (10% of crude product) in CH2Q2. The resulting solution was stirred at room temperature for overnight and the solvent was evaporated and the residue was re-dissolved into CH2Q2, then washed with saturated NaHCCh and dried over MgSC Solvent was evaporated and was used in next step without further purification.

[0208]

[0155] Example s Boc protected pSar-10-OH

[0209]

[0156] Synthesis of PAAs is a mutual methodology over the last 6 decades, various processes can be found in literature. In general, polymerizations are carried out in a suitable solvent, e.g., dimethylformamide (DMF), dichloromethane (DCM) , acetonitrile or tetrahydrofuran (THF) with a desirable ratio of initial concentration of monomer (M)o to initiator (I)o, e.g., the monomer to initiator ratio ([M]o / [I]o) of 10, 20, or 50 is corresponding to a degree of polymerization 10, 20, or 50 and molar masses depending on the subunit weight, e.g., 700-1000 g / mol, 1400-2000 g / mol, and 3500-5000 g / mol, respectively. For example, a pSarlO-OH (C29H50N10O11) has a molar mass 715 g / mol. While various sizes or types of pSar, e.g., 10 to 40, are commercially available and Fmoc-pSarlO-OH was used for the experiment. The fluorenylmethoxycarbonyl protecting group (Fmoc) is a base-labile amine protecting group and can be readily removed [Gregg B. Fields, “Methods for Removing the Fmoc Group.” in Peptide Synthesis Protocols. (1994) Humana Press Inc , Totowa, NJ], Approximately 100g of Fmoc-pSar-OH 10 was treated by using 250 mL of a Fmoc-deblocking solution, the Fmoc-removal solution was comprised with 2% DBU (1,8- diazabicyclo[5.4.0]undec-7-ene) / 5% piperazine / NMP (N-methyl-2-pyrrolidone), the first treatment was at 25 °C for 15 min. The resin was filtered, and another 250 mL of the Fmoc- deblocking solution was charged to the resin. The reaction solutions were combined and an equal volume of CHCI3 was added, the mixture was stirred by using a mechanical propeller at 25 °C for 30 min. The organic layer was evaporated and followed by recrystallization from methanol gave a while solid (50- 60%).

[0210]

[0157] The free pSar-10 was further modified by following Example 1 to protect the secondary amine at the N-terminus with a tert-butyloxycarbonyl (Boc) group, the amine is reacted with di-tert-butyl dicarbonate (Boc)2O) in the presence of a base (e.g., triethylamine) in THF at room temperature or with mild heating.

[0211]

[0158] This method is also suitable for the preparation of other Boc-protected poly(amino acid)s.

[0212]

[0159] Example 4. Preparation of Boc- 1-animohexamethyleneamine

[0213]

[0160] Hexamethylenediamine (20 mol) is transferred to a 30-liter round-bottomed flask equipped with a mechanic stirrer. A solvent mixture of 15 L containing methylene chloride / methanol (4 / 1, v / v, total 10 L) is charged into the flask and the reaction flask is placed in an ice-water bath to maintain solution temperature 0-10 °C. BOC2O (5 mol) in methylene chloride (1.0L) was slowly added. After the addition is completed, the reaction mixture is allowed to continue 2 more hours under vigorous stirring. The consumption of BOC2O is monitored by TLC method. The unreacted hexamethylenediamine is removed by washing with sodium bicarbonate solution (10% NaHCCh in water). The organic layer is collected and dried over sodium sulfate for 1-2 hours. Sodium sulfate is removed by filtration and the solvent is removed under reduced pressure by rotary evaporator. The crude product obtained is refrigerated (4-8 °C) (85-105% yield). The resulting compound (Chemical Structure 6) is stable for at least 1 week in the refrigerator.

[0214] Chemical Structure 6

[0215]

[0161] Example 5. Preparation of cholic chloride

[0216]

[0162] Cholic acid (150 g) was transferred into a 5-liter round-bottomed flask and dissolved in methylene chloride (500 mL). The reaction flask was placed in an ice-water bath to maintain a temperature between 0-10 °C. Oxalyl chloride (55g) was added slowly into the reaction flask via a funnel. The reaction was continued for 2 hours under constant stirring.

[0217] The solvent was removed in vacuo and unreacted oxalyl chloride was further removed by coevaporation with hexanes (500 mL) in vacuo to yield a yellowish solid (Chemical structure 7, 150-165g, 85-100% yield), the resulting product is used for the next step without further purifications.

[0218] Chemical structure 7

[0219]

[0163] Example 6 Preparation of Boc-protected 1,3-propanediamines

[0220]

[0164] Following the same steps in Example 4 and the crude product obtained with a yield of 85-105% (Chemical structure 8)

[0221] Chemical structure 8

[0165] Example 7. Preparation of Poly sarcosine-di ethylene glycol ester

[0222]

[0166] The synthesis of polyaminoacid diethylene glycol ester is shown in Scheme 6. A series of poly(amino acid)s was transformed to corresponding poly( amino acid) ethylene glycol ester s in good to excellent yields. Polysarcosineio (83 g, 0.1 mol) was taken in a round bottom flask. Freshly distilled chlorotrimethylsilane (“TMSC1,” 21.73g or 25.5 mL, 0.2 mol) was added slowly and stirred with a magnetic stirrer. Then diethylene glycol (15 mL, 0.115 mol) was added and the resulting solution or suspension was stirred at room temperature for 24 hrs. After the completion of reaction (as monitored by TLC), the reaction mixture was the solution was concentrated on a rotary evaporator to a syrupy substance, give the product amino acid ester hydrochloride. The crude product was dissolved in 200 ml of Dichloromethane (DCM), washed with 3x200mL water. The organic layer was dried over sodium sulfate (0.010 kg, 0.35 mol) for 1 hour. The salt is removed by filtration and the solvent was removed in vacuo to yield a solid (90-110%).

[0223] + HCI Reaction Scheme 6

[0224]

[0167] Example 8. Preparation of Mesylated Polysarcosine-diethylene glycol ester

[0225]

[0168] Polysarcosine-diethylene glycol ester (Boc-pSar-TE) (~ 93 g) was transferred into a 5-liter round-bottomed flask equipped with a mechanic stirrer and placed in ice -bath. 500 mL THF and tri ethylamine (24 g) were added. The reaction mixture was cooled to 0-10 °C and mesyl chloride (24 g) was added through a funnel and the mixture was kept at 0-10 °C. The reaction was continued under constant stirring and kept at 0-10 °C for 1 hour. The mixture was washed with 300 mL of 0.5AHC1 twice. The organic layers were collected and dried over sodium sulfate (60 g) for 1 hour. The salt was removed by filtration and the solvent was removed in vacuo to yield a yellowish liquid (Chemical Structure 9: 145-160 g, 90-110% yield).

[0226] Chemical Structure 9

[0169] Example 9. Preparation of 1,3-propanediamine-lactobionate

[0227]

[0170] The Boc-protected 1,3-propanediamines from Example 6 (20g, ~ 0.11 mol) was dissolved in 200 mL of CH2C12 (DCM) and transferred to a IL round-bottomed flask equipped with a mechanical stirrer. Tri ethylamine (10 g) was added to the flask and the mixture was cooled down to 0 and 10 °C in ice-water bath under constant stirring. Predried lactobionic acid (41 g, ~ 0.12 mol) was added. The reaction was completed in 2 hours under constant stirring at ambient room temperature. The ending reaction was monitored by checking the peak profile using HPLC. The final product was washed with diluted HC1

[0228] (0. IN) or NaOH (0. IN) to yield a neutral pH (7), then extracted with methylene chloride (DCM), repeated the steps of water wash and DCM extraction steps until the desired purity was achieved in the HPLC chromatogram. The DCM layer was collected and dried over sodium sulfate (100 g) for approximately 2 hours. The salt was removed by filtration and the solution was removed under vacuum (Chemical Structure 10: 90-220% yields).

[0229] Chemical Structure 10

[0230]

[0171] Example 10. Preparation of Preparation of 1,3-propanediamine-lactobionate-DE- PSarlO

[0231]

[0172] The steps of Example 2 were followed to remove the protection group from the Boc-l,3-propanediamine-lactobionate of Example 9 to free the NH2 end group. Formation of the C-N bond was by the N-alkylation of amine of the center backbone with the mesyl activated hydroxyl of the PSar-DE from Example 8. In a 1 -liter round-bottomed flask equipped with a mechanic stirrer and a heating mantle, 1,3-propanediamine-lactobionate from Example 9 (73 g, 0.175 mol) was mixed with the mesylated Boc-pSar-DE from Example 8 (165 g, 0.17 mol) in 200 ml of a mixture of THF and water (1 / 1, v / v). The reaction was continually stirred for 2-4 hours under reflux and nitrogen purging protection. The solvent was removed in vacuo and 500mL of CH2Q2 was added to the residue. The solution was washed with 50 mL each of water and 27VNaOH. The Organic layer was collected and dried over Na2SO4, solvent removed to afford Boc-aminopropaneamine-PSar-DE-Lactobionate (Chemical Structure 11), the crude product was transferred to the next step without further purification.

[0232] Chemical Structure 11

[0233]

[0173] Example 11. Preparation of Preparation of 1,3-propanediamine-lactobionate-DE- PSarlO - Oleate (ODDEPS)

[0234]

[0174] The crude product (~ 81 g, 0.12 mol) from Example 10 was dissolved in 800 mL of methylene chloride (DCM) in a round bottom flask (2 L) equipped with a mechanical stirrer. In a separate container, oleoyl chloride (40g, 0.13 mol) was dissolved in methylene chloride (200 mL) and slowly added to the 1,3-propanediamine-lactobionate-DE-PSario via a funnel. After the addition was completed, the reaction was continued for 2 hours under constant stirring at ambient room temperature. The completion of reaction was determined by the complete disappearance of oleoyl chloride on TLC. The reaction mixture was washed with 300 mL of 0.5 N NaOH, 3 times and the methylene chloride layer was collected and dried over sodium sulfate (100 g) for approximately 2 hours. The salt was removed by filtration and the solution and the steps of Example 2 were followed to remove the protection group to free the NH end group of pSar-DE and solvent was removed under vacuum to yield a yellowish wax (Chemical Structure 12, 65-75% yields).

[0235]

[0175] Using the intermediate from the Example 5 and following the steps in Examples 7 through 11, Choloylpropanediamino-PSar-lactobionate conjugate (Chemical Structure 7) was prepared.

[0236]

[0176] Examples 3 to 12 are suitable for making a PAA-saccharide-lipid conjugate with all kinds of available lipids including but not limited to fatty acids such lauric acid, myristic acid, palmitic acid, stearic acid, myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, bile acid or its analogues including but limited to cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, chenodeoxycholic acid, lithocholic acid or cholesterol, retinol, tocopherols or tocotrienols. As described above, in various desirable embodiments the PAA group has in the range of 5 to 50 subunits.

[0237]

[0177] Examples 3 to 12 are suitable for making a PAA-saccharide-lipid conjugate with all kinds of polyaminoacid including but not limited to poly(serine), polyalanine, polyglutamine, polyaspartic acid, poly(lysine), poly-(arginine), poly(proline), poly(n-methylated-glycine).

[0238]

[0178] While homopolyaminoacid is commonly used, hybrid polymer is practically suitable for target delivery or improved therapeutically applications. Such hybrid polymers include mixed 2 or more types of amino acids, lysine-glycine or alanine-glycine ethyl ester, tyrosine -glutamic acid, lysine -leucine -valine.

[0239]

[0179] Further hybrid polymer includes a mixed PAA and PEG chains, in which the molecule or chain length of PAA is general larger than PEG, the range of the molar ratio of PAA to PEG is 10 to 1, e.g., 8 to 1, 5 to 1 or 3 to 1.

[0240]

[0180] Example 13 MS Profile of 1,3-propanediamine-lactobionate-DE-PSario - Oleate The MS profile of 1,3-propanediamine-lactobionate-DE-PSario - Oleate (ODDEPS) was identified by a LC-MS. The method parameters are summarized as follows:

[0241] Chromatography Conditions

[0242] Parameter Setting

[0243] Column Inertsil C8-3, 3pm, 3x 100 mm (GL Sciences)

[0244] Mobile phase 0.1% formic acid / acetonitrile = 6 / 4

[0245] Injection volume 0.5 pL (1 mg / mL)

[0246] Flow rate 0.4 mL / min

[0247] Mass Spectrometry Conditions

[0248] Parameter Setting

[0249] Ion source Electronic Spray Ion (ESI+)

[0250] Scan time 10 min (avoiding first 2 min elution)

[0251] Interface temperature 350 °C

[0252] DL temperature 250 °C

[0253] Heater temperature 400 °C

[0254] Nebulizer gas flow 2.50 L / min

[0255] Heater gas flow 10.00 L / min

[0256] Dry gas flow 10.0 L / min

[0257] QI scan: 400-2200 m / z

[0258]

[0181] Mass spectrometric identification is as follows:

[0259] As shown in Figure 1, ODDEPS was positively identified with a mean value of 1477 g / mol which closely matched to the theoretical value.

[0260]

[0182] One feature or aspect of an embodiment is demonstrated at the time of the filing of this patent application to possibly reside broadly in a method of making a polymer including but not limited to the following said PAA-saccharide-lipid conjugates described herein.

[0261]

[0183] In various embodiments as otherwise described herein, the PAA-saccharide-lipid conjugates centered with a shorter diamine (e.g., 2-4 carbons) and a fatty acid can generally be safer for parenteral applications based the results from both in vitro and in vivo tests herein. In addition, the same polymers demonstrated a very low bioavailability which is preferable for oral applications.

[0184] In various embodiments as otherwise described herein, individual lipid-related impurities and monosugar impurities (e.g., glucuronic acid) is desirably less than 5 wt%; most desirable is less than 2%. Higher amounts of lipid-related impurities may form selfemulsifying systems which can result in a reduced solubility of the solute. Higher monosugar content can decrease the surface area which can also lower the solubility of the solute or cause shorter solution stability.

[0262]

[0185] In various embodiments as otherwise described herein, the concentration of the PAA-saccharide-lipid conjugate in an aqueous system (e.g., a parenteral formulation or other liquid formulation, a cream or a gel) is at least the critical micelle concentration (CMC). In some embodiments, the CMC is the range of 0.01 to 0.1 mM, e.g., 0.01 to 0.015 mM, or 0.02-0.05 mM.

[0263]

[0186] The present disclosure, in various embodiments, provides a novel PAA-saccharide- lipid conjugate system. Appropriate polymer structure and molecular purity can have direct impact on the safety and biocompatibility for use in drug or other molecule delivery. A therapeutic agent may be solubilized or encapsulated in such conjugates to form a solid or semisolid or solution or micro-suspension.

[0264]

[0187] Generally, in various embodiments the disclosure provides conjugates comprising a diamine backbone with a polymer (PAA) chain, lactobionic acid (a saccharide) and a lipid or alike group bonded to the backbone. In some embodiments, spacer or linker groups including amino acids may be included between the backbone and the PAA chains, carbohydrates or lipophilic groups. Furthermore, the terminal end of PAA chain may be a charged or polar moiety.

[0265]

[0188] The said polymers of the present invention are effective to formulate compositions of active agents, such as oncology drugs, whereby side effects and toxicities associated with therapeutic treatments may be reduced. The permeation enhancement properties of PAA- saccharide-conjugates may increase the in vivo targeted delivery of drugs and improve oral bioavailability of various drugs.

[0266]

[0189] One embodiment of the disclosure is a chemical compound or a method of making a compound represented by the formula:

[0267]

[0190] In order to reduce possible immunogenicity, a shorter diamine backbone (m < 4) is preferable; however ethylenediamine may not be highly desirable for a bulky L group such as those based on steroids, where the yield of the synthesis was low. The order of conjugating positions on the backbone for each carrier is not restricted; hence they are interchangeable as long as chemically feasible.

[0268]

[0191] Another embodiment of the disclosure is a method of making a compound wherein a conjugate as described herein is made by a method comprising the (interchangeable) steps of: a. selecting a central backbone with at least three available sites for the conjugations between the three carriers and the central backbone; b. selecting a lipid as the first carrier; c. selecting a PAA as the second career; d. selecting a saccharide as the third carrier; and e. selecting a linker or linkers for coupling reactions of alkylation including A-alkylation or (9-alkylation or esterification or etherification or amidation between carriers and center backbones.

[0269]

[0192] In various embodiments, making extended PAA with a glycol may be required in order to coupling to the center diamine backbone, especially for those PAAs with carboxyl as the terminal group. A glycol includes but not limited to ethylene glycol, diethylene glycol, tri ethylene glycol, tetraethylene glycol.

[0270]

[0193] In various embodiments, the order of each conjugation step is not restricted and may further comprise the steps of alkylation, etherification, esterification or amidation: f. protecting the hydroxyl or amino groups; g. bonding the first carrier to the central backbone; h. removing the hydroxyl or amino protecting group of the center backbone i. bonding the second carrier to the central backbone; j. ; and k. bonding the third carrier to the central protecting group. l. Removing the protection group of PAA if any

[0194] In various embodiments, only shorter diamines centered polymers with a lipid group of fatty acids are suitable for parenteral applications due to a low hemolytic potential.

[0271]

[0195] In various the PAA component of the conjugate is a PAA having between 5 and 50 subunits. The PAA chain may, for example, consist of between about 6 and 45 subunits. More preferably the PAA chain consists of between about 8 and 20 subunits.

[0272]

[0196] In various embodiments, the PAA is a branched PAA having 2 or more subchains each chain having PAA subunits between 5 and 23.

[0273]

[0197] In various embodiments, the conjugate is a compound represented by the formulas of the Chemical Structure 1 through 11.

[0274]

[0198] In various embodiments, the polymer chain is a hybrid polymer having 2 or more type of polymers, e.g., PAA / PEG ranges from 10 to 1 in the molar ratio, preferably a large PAA overs a smaller PEG.

[0275]

[0199] In various embodiments, the lipid group is selected from residues of steroid acids including cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, tauroch enodeoxy cholic acid, glycochenodeoxy cholic acid, chenodeoxy cholic acid, and lithocholic acid.

[0276]

[0200] In various embodiments, the saccharide component is selected from monosaccharides and disaccharides and their analogues or derivatives, including but not limited to ascorbic acid, sugar acids, amino sugars including but not limited to ascorbic acid, gluconic acid, glucaric acid, glucuronic acid, galacturonic acid, steviol glycoside, sucralose, lactitol, maltitol, isomalt, maltotriitol, maltotetraitol, mogrosides, glycyrrhizin, inulin and osladin.

[0277]

[0201] In various embodiments, the PAA chain is substantially monodisperse, especially for intravenous administration of pharmaceutical agent. The substantially monodisperse PAA chain may contain a few numbers of oligomers of different chain lengths (e.g., different chains having n = 10 but also n=9, n=12, etc.). The preferable number of oligomers is 1 to 10, although in many embodiments the number of oligomers is 3 to 10.

[0278]

[0202] In various embodiments, the PAA chain has a narrow molecular weight distribution resulting a PAA-saccharide-lipid conjugates with a purity from 85% to 115% based on the HPLC assay of by the HPLC peak area normalization.

[0279]

[0203] While preferred embodiments of the present invention have been described, those skilled in the art will recognize that other and further changes and modifications may be made without departing from the spirit of the invention, and all such changes and modifications should be understood to fall within the scope of this invention.

[0280]

[0204] Various aspects and embodiments of the disclosure are provided by the following claims, which may be combined in any number and in any combination that is not logically or technically inconsistent.

[0281] Embodiment 1. A lipid / PAA / saccharide conjugate having the structural formula

[0282] DdQ-P— R2Bs

[0283] S L wherein

[0284] B is a residue of a compound having three or four available binding positions selected from the group consisting of diamines, triamines, tetraamines, diaminoalcohols, aminoalcohols, aminodiols, aminotriols, amino acids, triols (such as glycerol), tetraols, triacids, tetracids, and carboxyl-containing diols and polyamines; and

[0285] S is a saccharide, for example, a residue of a mono-, di- or trisaccharide group, in which each saccharide unit is a sugar, a sugar alcohol, an amino sugar or a sugar acid;

[0286] L is a lipophilic carrier residue selected from fatty acid residues (for example, residues of lauric acid, myristic acid, linoleic acid, palmitic acid, oleic acid and elaidic acid), steroid acid and sterol residues, and residues of retinoids (e.g., residues of retinoic acids), carotenoids, tocopherols, and tocotrienols;

[0287] Q is a residue of ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, pentaethylene glycol or hexaethylene glycol;

[0288] P is a residue of a polyaminoacid homopolymer selected from poly(serine), poly(alanine), poly(glutamine), poly(glutamic acid) poly(aspartic acid), poly(asparagine), poly(lysine), poly(arginine), poly(proline), poly(glycine), and N-m ethyl analogs thereof (e.g., N-methylglycine), having a degree of polymerization n;

[0289] R is a terminal group selected from H, methyl, ethyl and maleimide;

[0290] D is a secondary group that is as defined above for L or is a methyl-capped poly(ethylene glycol) residue; and d is 0, or d is 1. Embodiment 2. The conjugate of embodiment, 1, wherein B is a residue of a diamine having the structural formula EENCEE CEEjmNEE wherein m is in the range of 2-10.

[0291] Embodiment 3. The conjugate of embodiment 2, having the structural formula

[0292] Embodiment 4. The conjugate of embodiment 2 or embodiment 3, wherein m has a number-average value in the range of 2-8, e.g., in the range of 2-6, or 2-5, or 2-4.

[0293] Embodiment 5. The conjugate of embodiment 2 or embodiment 3, wherein m has a number-average value of 3.

[0294] Embodiment 6. The conjugate of embodiment 2 or embodiment 3, wherein m has a number-average value of 2, or m has a number-average value of 4.

[0295] Embodiment 7. The conjugate of embodiment 2 or embodiment 3, wherein m has a number-average value in the range of 5-10, e.g., 5-8 or 8-10.

[0296] Embodiment 8. The conjugate of embodiment 1, wherein B is a residue of a triamine or a tetraamine.

[0297] Embodiment 9. The conjugate of embodiment 1 wherein B is a residue of a diaminoalcohol, an aminoalcohol, an aminodiol, or an aminotriol.

[0298] Embodiment 10. The conjugate of embodiment 1, wherein B is a residue of a triol (such as glycerol) or a tetraol.

[0299] Embodiment 11. The conjugate of embodiment 1, wherein B is a residue of an amino acid, a triacid, a tetracid, or carboxyl-containing diol or polyamine.

[0300] Embodiment 12. The conjugate of any of embodiments 1-11, wherein S is a residue of a di saccharide group.

[0301] Embodiment 13. The conjugate of any of embodiments 1-11, wherein S is a residue of a monosaccharide group.

[0302] Embodiment 14. The conjugate of any of embodiments 1-11, wherein S is a residue of a trisaccharide group. Embodiment 15. The conjugate of any of embodiments 1-14, wherein saccharide units of S are individually selected from hexoses and pentoses and sugar alcohol, sugar acid and amino sugar analogs thereof.

[0303] Embodiment 16. The conjugate of any of embodiments 1-14 wherein saccharide units of S are individually selected from hexoses and sugar alcohol, sugar acid and amino sugar analogs thereof.

[0304] Embodiment 17. The conjugate of any of embodiments 1-16, wherein the saccharide unit of S that is directly bound to the nitrogen of the diamine central backbone is derived from a sugar acid and is bound as an amide.

[0305] Embodiment 18. The conjugate of embodiment 17, wherein any saccharide unit of S that is not directly bound to the nitrogen of the diamine is a sugar.

[0306] Embodiment 19. The conjugate of any of embodiments 1-18, wherein S has the structural formula in which -(CxiEExiOxi-ij-CO- is a sugar acyl residue derived from a sugar acid in which xl is 4 or 5, and (CX2H2X2-IOX2-I)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof.

[0307] Embodiment 20. The conjugate of embodiment 19, wherein xl is 5 and x2 is 6.

[0308] Embodiment 21. The conjugate of any of embodiments 1-20, wherein S has the structure

[0309] Embodiment 22. The conjugate of any of embodiments 1-21, wherein S is lactobionyl or gluconyl.

[0310] Embodiment 23. The conjugate of any of embodiments 1-21, wherein S is lactobionyl. Embodiment 24. The conjugate of any of embodiments 1-23, wherein L is -C(O)-R1, wherein R1is an alkanyl and / or alkenyl group having a number-average number of carbons in the range of 6-22.

[0311] Embodiment 25. The conjugate of any of embodiments 1-24, wherein R1has a numberaverage number of carbons in the range of 6-20, or 6-18.

[0312] Embodiment 26. The conjugate of any of embodiments 1-24, wherein R1has a numberaverage number of carbons in the range of 10-22, e.g., 10-20 or 10-18.

[0313] Embodiment 27. The conjugate of any of embodiments 1-24, wherein R1has a numberaverage number of carbons in the range of 12-22, e.g., 12-20 or 12-18.

[0314] Embodiment 28. The conjugate of any of embodiments 1-24, wherein R1has a numberaverage number of carbons in the range of 14-22, e.g., 14-20 or 14-18.

[0315] Embodiment 29. The conjugate of any of embodiments 1-28, wherein R1has a numberaverage number of carbons that is no more than 18.

[0316] Embodiment 30. The conjugate of any of embodiments 1-29, wherein R1has a numberaverage number of unsaturations in the range of 0-3, e.g., 0-2.

[0317] Embodiment 31. The conjugate of any of embodiments 1-29, wherein R1is a linear alkyl or alkenyl group.

[0318] Embodiment 32. The conjugate of any of embodiments 1-26 wherein R1is derived from one or more of caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, alpha-linoleic acid, arachidonic acid and erucic acid.

[0319] Embodiment 33. The conjugate of any of embodiments 1-32, wherein L is -C(O)-R1, and wherein -C(O)-R1is at least 80 mol% of a single chemical identity, e.g., at least 85 mol%.

[0320] Embodiment 34. The conjugate of any of embodiments 1-32, wherein L is -C(O)-R1, and wherein -C(O)-R1is at least 90 mol% of a single chemical identity, e.g., at least 95 mol%. Embodiment 35. The conjugate of embodiment 33 or embodiment 34, wherein the single chemical identity is cis-CH3(CH2)7CH=CH(CH2)?C(O)-.

[0321] Embodiment 36. The conjugate of embodiment 33 or embodiment 34, wherein the single chemical identity is cis,cis-CH3(CH2)4CH=CHCH2CH=CH(CH2)7C(O)-.

[0322] Embodiment 37. The conjugate of embodiment 33 or embodiment 34, wherein the single chemical identity is cis-CH3(CH2)3CH=CH(CH2)7C(O)-.

[0323] Embodiment 38. The conjugate of embodiment 33 or embodiment 34, wherein the single chemical identity is selected from n-hexanoyl, n-octanoyl, n-decanoyl, n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl, n-octadecanoyl, n-eicosanoyl and n-docosanoyl.

[0324] Embodiment 39. The conjugate of embodiment 33 or embodiment 34, wherein the single chemical identity is selected from cis-CH3(CH2)5CH=CH(CH2)7C(O)-, cis,cis-CH3CH2CH=CHCH2CH=CHCH2CH=CH(CH2)7C(O)-, cis,cis,cis-CH3(CH2)4CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)3C(O)- and cis-CH3(CH2)7CH=CH(CH2)nC(O)-.

[0325] Embodiment 40. The conjugate of any of embodiments 1-39, wherein L includes (or is) a steroid acyl group (e.g., a bile acyl group).

[0326] Embodiment 41. The conjugate of embodiment 40, wherein the steroid acyl group is an acyl group derived from cholic acid, deoxycholic acid, glycocholic acid taurocholic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, chenodeoxycholic acid, or lithocholic acid.

[0327] Embodiment 42. The conjugate of embodiment 40, wherein the steroid acyl group is an acyl group derived from cholesterol.

[0328] Embodiment 43. The conjugate of any of embodiments 1-42, wherein L includes (or is) a lipophilic vitamin such as vitamin A or vitamin E.

[0329] Embodiment 44. The conjugate of any of embodiments 1-43, wherein Q is a residue of di ethylene glycol.

[0330] Embodiment 45. The conjugate of any of embodiments 1-43, wherein Q is a residue of ethylene glycol. Embodiment 46. The conjugate of any of embodiments 1-43, wherein Q is a residue of tri ethylene glycol, tetraethylene glycol, pentaethylene glycol or hexaethylene glycol.

[0331] Embodiment 47. The conjugate of any of embodiments 1-46, wherein P is a residue of poly(N-methylglycine).

[0332] Embodiment 48. The conjugate of Embodiment 47, wherein P has a number-average molecular weight in the range of 1000-4000 g / mol.

[0333] Embodiment 49. The conjugate of any of embodiments 1-46, wherein P is a residue of poly(glutamic acid).

[0334] Embodiment 50. The conjugate of embodiment 49, wherein P has a number-average molecular weight in the range of 750-7,500 g / mol, e.g., in the range of 1,500-3,000 g / mol.

[0335] Embodiment 51. The conjugate of any of embodiments 1-46, wherein P is a residue of poly(lysine).

[0336] Embodiment 52. The conjugate of embodiment 51, wherein P has a number-average molecular weight in the range of 1,000-10,000 g / mol, e.g., in the range of 2,100-6,300 g / mol, or 2.100-4,300 g / mol.

[0337] Embodiment 53. The conjugate of any of embodiments 1-49, wherein P is a residue of poly (arginine).

[0338] Embodiment 54. The conjugate of embodiment 53, wherein P has a number-average molecular weight in the range of 900-9,600 g / mol, e.g., in the range of 1,900-5,800 g / mol, or 1,900-3,850 g / mol.

[0339] Embodiment 55. The conjugate of any of embodiments 1-46, wherein P is a residue of poly(aspartic acid).

[0340] Embodiment 56. The conjugate of embodiment 55, wherein P has a number-average molecular weight in the range of 700-6,850 g / mol.

[0341] Embodiment 57. The conjugate of any of embodiments 1-46, wherein P is a residue of poly (proline).

[0342] Embodiment 58. The conjugate of embodiment 57, wherein P has a number-average molecular weight in the range of 1000-10000 g / mol. Embodiment 59. The conjugate of any of embodiments 1-46, wherein P is a residue of poly (asparagine).

[0343] Embodiment 60. The conjugate of embodiment 58, wherein P has a number-average molecular weight in the range of 1000-10000 g / mol.

[0344] Embodiment 61. The conjugate of any of embodiments 1-46, wherein P is a residue of poly (serine).

[0345] Embodiment 62. The conjugate of embodiment 59, wherein P has a number-average molecular weight in the range of 1000-10000 g / mol.

[0346] Embodiment 65. The conjugate of any of embodiments 1-46, wherein P is a residue of poly (glutamine).

[0347] Embodiment 64. The conjugate of embodiment 61, wherein P has a number-average molecular weight in the range of 1000-10000 g / mol.

[0348] Embodiment 65. The conjugate of any of embodiments 1-46, wherein P is a residue of poly(alanine).

[0349] Embodiment 66. The conjugate of embodiment 63, wherein P has a number-average molecular weight in the range of 1000-10000 g / mol.

[0350] Embodiment 67. The conjugate of any of embodiments 1-64, wherein n has a numberaverage value in the range of 5-50, e.g., 5-40, or 5-30, or 5-20, or 5-15, or 5-10, or has a number-average value in the range of 9.5-52.5.

[0351] Embodiment 68. The conjugate of any of embodiments 1-64, wherein n has a numberaverage value in the range of 8-50, e.g., 8-45, or 8-40, or 8-30, or 8-20, or 8-15, or 8-12, or 8- 10, or 9-23, or 9.8-22.2.

[0352] Embodiment 69. The conjugate of any of embodiments 1-64, wherein n has a numberaverage value in the range of 10-50, e.g., 10-45, or 10-40, or 10-30, or 10-20, or 10-15.

[0353] Embodiment 70. The conjugate of any of embodiments 1-64, wherein n has a numberaverage value in the range of 9-14, e.g., or 9-13, or 10-14, or 10.5-13.5, or 11-13, or 11.5- 12.5, or 11.8-12.2, or 10.2-13.8, or 10.8-13.2, or 11.4-12.6. Embodiment 71. The conjugate of any of embodiments 1-64, wherein n has a numberaverage value in the range of 18-28, e.g., 19-22, or 22-24, or 22.5-23.5, or 22.8-23.2.

[0354] Embodiment 72. The conjugate of any of embodiments 1-64, wherein n has a numberaverage value in the range of 25-35, e.g., 30-36, or 32-34, or 32.5-33.5, or 32.8-33.2.

[0355] Embodiment 73. The conjugate of any of embodiments 1-64, wherein n has a numberaverage value in the range of 40-50, e.g., 42-48, or 44-46, or 44.5-45.5, or 44.8-45.2.

[0356] Embodiment 74. The conjugate of any of embodiments 1-73, wherein P has a poly dispersity index of no more than 1.20, e.g., no more than 1.15.

[0357] Embodiment 75. The conjugate of any of embodiments 1-73, wherein P has a poly dispersity index of no more than 1.10, e.g., no more than 1.07.

[0358] Embodiment 76. The conjugate of any of embodiments 1-75, wherein R is H.

[0359] Embodiment 77. The conjugate of any of embodiments 1-75, wherein R is methyl.

[0360] Embodiment 78. The conjugate of any of embodiments 1-75, wherein R is ethyl.

[0361] Embodiment 79. The conjugate of any of embodiments 1-78, wherein R has a numberaverage number of carbons of at least 0.95, e.g., at least 0.99 or at least 1.

[0362] Embodiment 80. The conjugate of any of embodiments 1-78, wherein R has a numberaverage number of carbons in the range of 0.9-1.1, or 0.95-1.05, or 0.98-1.02.

[0363] Embodiment 81. The conjugate of any of embodiments 1-78, wherein R has a number average number of carbons in the range of 0-2.

[0364] Embodiment 82. The conjugate of any of embodiments 1-78, wherein R has a numberaverage number of carbons in the range of 0-0.94, e.g., 0-0.75, or 0-0.5, or 0-0.1, or 0-0.05.

[0365] Embodiment 83. The conjugate of any of embodiments 1-82, wherein R is mal eimide.

[0366] Embodiment 84. The conjugate of any of embodiments 1-83, wherein d is 0.

[0367] Embodiment 85. The conjugate of any of embodiments 1-83, wherein d is 1.

[0368] Embodiment 86. The conjugate of embodiment 76, wherein D is as described for L in any embodiment above. Embodiment 87. The conjugate of embodiment 86, wherein D is a methylated poly(ethylene glycol) residue having g ethylene glycol units.

[0369] Embodiment 88. The conjugate of any of embodiments 1-87, wherein g has a numberaverage value in the range of 5-50, e.g., 5-40, or 5-30, or 5-20, or 5-15, or 5-10.

[0370] Embodiment 89. The conjugate of any of embodiments 1-87, wherein g has a numberaverage value in the range of 8-50, e.g., 8-45, or 8-40, or 8-30, or 8-20, or 8-15, or 8-12, or 8- 10, or 9-23.

[0371] Embodiment 90. The conjugate of any of embodiments 1-87, wherein g has a numberaverage value in the range of 10-50, e.g., 10-45, or 10-40, or 10-30, or 10-20, or 10-15.

[0372] Embodiment 91. The conjugate of any of embodiments 1-87, wherein g has a numberaverage value in the range of 9-14, e.g., or 9-13, or 10-14, or 10.5-13.5, or 11-13, or 11.5- 12.5, or 11.8-12.2, or 10.2-13.8, or 10.8-13.2, or 11.4-12.6.

[0373] Embodiment 92. The conjugate of any of embodiments 1-87, wherein g has a numberaverage value in the range of 18-28, e.g., 19-22, or 22-24, or 22.5-23.5, or 22.8-23.2.

[0374] Embodiment 93. The conjugate of any of embodiments 1-87, wherein g has a numberaverage value in the range of 25-35, e.g., 30-36, or 32-34, or 32.5-33.5, or 32.8-33.2.

[0375] Embodiment 94. The conjugate of any of embodiments 1-66, wherein g has a numberaverage value in the range of 40-50, e.g., 42-48, or 44-46, or 44.5-45.5, or 44.8-45.2.

[0376] Embodiment 95. The conjugate of any not inconsistent embodiment above, wherein m is 3;

[0377] S has the structural formula as below: in which -(CxiEExiOxi- -CO- is a sugar acyl residue derived from a sugar acid in which xl is 4 or 5, and (CX2H2X2-IOX2-I)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof;

[0378] -C Oj-R1is at least 80 mol% of cis-CH3(CH2)7CH=CH(CH2)7C(O)-, e.g., at least 85 mol%; R is H;

[0379] P has a poly dispersity index of no more than 1.20, e.g., no more than 1.15. Embodiment 96. The conjugate of any not inconsistent embodiment above, wherein m is 3;

[0380] S has the structural formula in which -(CxiEExiOxi- -CO- is a sugar acyl residue derived from a sugar acid in which xl is 4 or 5, and (CX2H2X2-IOX2-I)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof;

[0381] - Oj-R1is at least 80 mol% of cis-CH3(CH2)7CH=CH(CH2)?C(O)-, e.g., at least 85 mol%; and the -P group is a PAA homopolymer having a number-average molecular weight in the range of 800-10,000 g / mol and having a poly dispersity index of no more than 1.2, e.g., no more than 1.1.

[0382] Embodiment 97. The conjugate of embodiment 95 or embodiment 96, wherein xl is 5 and x2 is 6.

[0383] Embodiment 98. The conjugate of any of embodiments 95-97, wherein S has the structure or is an open-chain version thereof.

[0384] Embodiment 99. The conjugate of any of embodiments 95-97, wherein S is lactobionyl.

[0385] Embodiment 100. The conjugate of any of embodiments 95-99, wherein -C(O)-R1is at least 90 mol% of cis-CH3(CH2)7CH=CH(CH2)?C(O)-, e.g., at least 95 mol%.

[0386] Embodiment 101. The conjugate of any of embodiments 95-100, wherein P has a poly dispersity index of no more than 1.2, e.g., no more than 1.1.

[0387] Embodiment 102. The conjugate of any not inconsistent embodiment above, wherein the conjugate has the structural formula of Chemical Structure 1 :

[0388] Embodiment 103. The conjugate of embodiment 102, wherein the fatty acyl residue - Oj-R1is derived from one or more of Lauric acid, Myristic acid, Palmitic acid, Linoleic acid, Oleic acid and Stearic acid.

[0389] Embodiment 104. The conjugate of any not inconsistent embodiment above, wherein the conjugate is oleoyldiaminopropane-ethylene-Polysarcosine-lactobionate (ODPS), which can be represented by the Chemical Structure 2:

[0390] Chemical Structure 2 (ODPS) wherein n is any desirable value as described above, e.g., in the range of 5 to 50.

[0391] Embodiment 105. The conjugate of any not inconsistent embodiment above, wherein the conjugate is Stearylpropanediamine polyglutamine-triethylene-glycol-ether-lactobionate (STQS), which can be represented by Chemical Structure 3a:

[0392] Chemical Structure 3a (STQS), or Stearylpropanediamine polyglutamic acid-diethylene-glycol-ether-lactobionate (SDQS), which can be represented by Chemical Structure 3b:

[0393] Chemical Structure 3b (SDQS). wherein n is any desirable value as described above, e.g., in the range of 5-50.

[0394] Embodiment 106. The conjugate of any not inconsistent embodiment described above, wherein the conjugate is represented by Chemical Structure 4:

[0395] Chemical Structure 4 wherein n is any desirable value as described above, and m is in the range of 2-6, e.g., is 3.

[0396] Embodiment 107. The conjugate of any not inconsistent embodiment described above, wherein the conjugate is Cholesterylethyldiamino-PAA-lactobionate (CDPAS), which can be represented by Chemical Structure 5: wherein n is any desirable value as described above.

[0397] Embodiment 108. The conjugate of any of embodiments 105-107, wherein the numberaverage value of n is in the range of 7.9-41.8, e.g., 8.2-13.2, or 18-23, or 29.4-33.6, or 37.5- 42.5, or 47.8-52.2.

[0398] Embodiment 109. The conjugate of any not-inconsi stent embodiment above, having one of the following structures:

[0399]

[0400] Embodiment 110. The conjugate of any of embodiments 1-109, wherein the conjugate has a purity of at least 80 wt% as measured by HPLC.

[0401] Embodiment 111. The conjugate of any of embodiments 1-109, wherein the conjugate has a purity of at least 85 wt% as measured by HPLC.

[0402] Embodiment 112. The conjugate of any of embodiments 1-72, having a Griffin HLB value in the range of 13-18, e.g., in the range of 13-15.

[0403] Embodiment 113. A process for making a conjugate of any of embodiments 1-112, the process comprising coupling a homopolyaminoacid, a saccharide and an RLC(O)- acyl group to a diamine backbone.

[0404] Embodiment 114. The process of embodiment 113, wherein the method includes providing a monoprotected diamine having a protected first amine group and an unprotected second amine group; coupling a polyaminoacid and an RLC(O)- acyl group to the second amine group, and then deprotecting the protected first amine group and coupling a saccharide to the newly- unprotected first amine group.

[0405] Embodiment 115. The process of embodiment 113 or embodiment 114, performed in the substantial absence of free-radical initiators.

[0406] Embodiment 116. The process of any of embodiments 113-115, wherein the coupling of the poly(amino acid) can be performed before the coupling of the R1-C(O)- acyl group. Embodiment 117. The process of any of embodiments 113-116, wherein the coupling of the poly(amino acid) to the second amine group can be performed in a stepwise fashion, e.g., by first coupling a shorter chain of ethylene glycol to the central backbone or to PAA, then by performing etherification or esterification to achieve the conjugation between polyaminoacid and center diamine backbone.

[0407] Embodiment 118. The process of any of embodiments 113-117, wherein the coupling of the RJ-C(O)- acyl group to the second amine group is performed using an R1-C(O)-halide.

[0408] Embodiment 119. The process of any of embodiments 113-117, wherein the coupling of the saccharide to the first amine group comprises deprotecting the first amine group and coupling the saccharide in the form of a sugar acid or a lactone version thereof.

[0409] Embodiment 120. A conjugate according to any of embodiments 1-112 for use as a pharmaceutical excipient, or for use as in a medicament.

[0410] Embodiment 121. A therapeutic composition comprising a conjugate of any of embodiments 1-112 and a therapeutic agent.

[0411] Embodiment 122. A composition for use in the treatment of a subject having a condition, the composition comprising a conjugate of any of embodiments 1-112 and a therapeutic agent suitable for treating the condition.

[0412] Embodiment 123. A method for treating a subject having a condition, the method comprising administering to the subject a composition of embodiment 112, for example, wherein the administration is oral, intranasal, topical or parenteral.

[0413] Embodiment 124. A composition comprising a conjugate according to any of embodiments

[0414] 1-112 and a therapeutic agent for use as a medicament.

[0415] Embodiment 125. Use of a conjugate according to any of embodiments 1-112 for increasing bioavailability of a therapeutic agent.

[0416] Embodiment 126. Use of a conjugate according to any of embodiments 1-112 for increasing solubility of a therapeutic agent in an aqueous system.

[0417] Embodiment 127. Use of a conjugate according to any of embodiments 1-112 as a pharmaceutical excipient, or as a therapeutic. Embodiment 128. The composition, method or use of any of embodiments 120-127, wherein the therapeutic agent has a water solubility in deionized water of no more than 5 mg / mL, e.g., no more than 2 mg / mL at 37 °C.

[0418] Embodiment 129. The composition, method or use of any of embodiments 120-127, wherein the therapeutic agent has a water solubility in deionized water of no more than 1 mg / mL at 37 °C, e.g., no more than 0.5 mg / mL, or no more than 0.2 mg / mL.

[0419] Embodiment 130. The composition, method or use of any of embodiments 120-127, wherein the therapeutic agent has a water solubility in deionized water of no more than 0.1 mg / mL at 37 °C, e.g., no more than 0.05 mg / mL, or no more than 0.02 mg / mL.

[0420] Embodiment 131. The composition, method or use of any of embodiments 120-127, wherein the therapeutic agent has a water solubility in pH 7.4 phosphate-buffered saline of no more than 5 mg / mL, e.g., no more than 2 mg / mL at 37 °C.

[0421] Embodiment 132. The composition, method or use of any of embodiments 120-127, wherein the therapeutic agent has a water solubility in pH 7.4 phosphate-buffered saline of no more than 1 mg / mL at 37 °C, e.g., no more than 0.5 mg / mL, or no more than 0.2 mg / mL.

[0422] Embodiment 133. The composition, method or use of any of embodiments 120-127, wherein the therapeutic agent has a water solubility in pH 7.4 phosphate-buffered saline of no more than 0.1 mg / mL at 37 °C, e.g., no more than 0.05 mg / mL, or no more than 0.02 mg / mL.

[0423] Embodiment 134. The composition, method or use of any of embodiments 120-133, wherein the therapeutic agent is lipophilic.

[0424] Embodiment 135. The composition, method or use of any of embodiments 120-133, wherein the therapeutic agent has a log D7.4 value (or a log P value) of at least 2, e.g., at least

[0425] 2.25, at least 2.5 or at least 2.75.

[0426] Embodiment 136. The composition, method or use of any of embodiments 120-133, wherein the therapeutic agent has a log D7.4 value (or a log P value) of at least 3, e.g., at least

[0427] 3.25, at least 3.5 or at least 3.75.

[0428] Embodiment 137. The composition, method or use of any of embodiments 120-133, wherein the therapeutic agent has a log D7.4 value (or a log P value) of at least 4, e.g., at least

[0429] 4.25, at least 4.5 or at least 4.75. Embodiment 138. The composition, method or use of any of embodiments 120-137, wherein the therapeutic agent is selected from Apixaban, Atorvastatin, Cabazitaxel, Celecoxib, Docetaxel, Dolutegravir, Edaravone, Etomidate. Everolimus. Midazolam. Paclitaxel. Propofol. Rivaroxaban, Tacrolimus, Tenofovir Alafenamide and Ticagrelor.

[0430] Embodiment 139. The composition, method or use of any of embodiments 120-138, wherein the conjugate is present in an amount above its critical micelle concentration.

[0431] Embodiment 140. The composition, method or use of embodiments 120-138, wherein the conjugate is present in aqueous solution in an amount above its critical micelle concentration or less than 0.1 mmol.

[0432] Embodiment 141. The composition, method or use of any of embodiments 120-140, wherein a weight ratio of the conjugate of the disclosure to the therapeutic agent is in the range 500:1 - 1:2, e.g., 200:1 - 1:2, or 100:1 - 1:2, or 50:1 - 1:2, or 20:1 - 1:2.

[0433] Embodiment 142. The composition, method or use of any of embodiments 120-140, wherein a weight ratio of the conjugate of the disclosure to the therapeutic agent is in the range of 500:1 - 1:1, e.g., 200:1 - 1:1, or 100:1 - 1:1, or 50:1 to 1:1, or 20:1 - 1:1, or 10:1 - 1:1, or 5:1 - 1:1.

[0434] Embodiment 143. The composition, method or use of any of embodiments 120-140, wherein a weight ratio of the conjugate of the disclosure to the therapeutic agent is in the range of 500:1 -2:1, e.g., 200:1 -2:1, or 100:1 -2:1, or 50:1 -2:1, or 20:1 -2:1, or 10:1 -2:1, or 5:1 -2:1.

[0435] Embodiment 144. The composition, method or use of any of embodiments 120-140, wherein a weight ratio of the conjugate of the disclosure to the therapeutic agent is in the range of 500:1 -4:1, e.g., 200:1 -4:1, or 100:1 -4:1, or 50:1 -4:1, or 20:1 -4:1, or 10:1 to 4:1.

[0436] Embodiment 145. The composition, method or use of any of embodiments 120-144, wherein the therapeutic agent is present in the composition in an amount of at least 0.1 wt%, e.g., at least 0.2 wt%.

[0437] Embodiment 146. The composition, method or use of any of embodiments 120-144, wherein the therapeutic agent is present in the composition in an amount of at least 0.5 wt%, e.g., 1 wt%. Embodiment 147. The composition, method or use of any of embodiments 120-144, wherein the therapeutic agent is present in the composition in an amount of at least 2 wt%, e.g., at least 5 wt%.

[0438] Embodiment 148. The composition, method or use of any of embodiments 120-144, wherein the therapeutic agent is present in the composition in an amount of at least 10 wt%, e.g., at least 20 wt%.

[0439] Embodiment 149. The composition, method or use of any of embodiments 120-144, wherein the therapeutic agent is present in the composition in an amount in the range of 0.1-10 wt%, e.g., 0.2-10 wt%, or 0.1-5 wt%, or 0.2-5 wt%, or 0.1-2 wt%, or 0.2-2 wt%.

[0440] Embodiment 150. The composition, method or use of any of embodiments 120-144, wherein the therapeutic agent is present in the composition in an amount in the range of 0.5-20 wt%, e.g., 1-20 wt%, or 0.5-10 wt%, or 0.5-10 wt%, or 0.5-5 wt%, or 1-5 wt%.

[0441] Embodiment 151. The composition, method or use of any of embodiments 120-144, wherein the therapeutic agent is present in the composition in an amount in the range of 2-30 wt%, e.g., 5-30 wt%, or 2-20 wt%, or 5-20 wt%, or 2-10 wt%, or 5-15 wt%.

[0442] Embodiment 152. The composition, method or use of any of embodiments 120-144, wherein the therapeutic agent is present in the composition in an amount in the range of 10-50 wt%, e.g., 20-50 wt%, or 10-30 wt%, or 20-40 wt%, or 10-20 wt%, or 20-30 wt%.

[0443] Embodiment 153. The composition, method or use of any of embodiments 120-152, wherein the conjugate is present in an amount of at least 1 wt%, e.g., at least 2 wt%.

[0444] Embodiment 156. The composition, method or use of any of embodiments 120-152, wherein the conjugate is present in an amount of at least 5 wt%, e.g., at least 10 wt%.

[0445] Embodiment 157. The composition, method or use of any of embodiments 120-152, wherein the conjugate is present in an amount of at least 15 wt%, e.g., at least 20 wt%. In various embodiments, the conjugate of the disclosure is present in an amount of at least 25 wt%, e.g., at least 30 wt%.

[0446] Embodiment 158. The composition, method or use of any of embodiments 120-152, wherein the conjugate is present in the composition in an amount in the range of 1-25 wt%, e.g., 2-25 wt%, or 1-15 wt%, or 2-15 wt%, or 1-10 wt%, or 2-10 wt%, or 1-5 wt%, or 2-5 wt%. Embodiment 159. The composition, method or use of any of embodiments 120-152, wherein the conjugate is present in the composition in an amount in the range of 5-35 wt%, e.g., 10-35 wt%, or 5-25 wt%, or 10-25 wt%, or 5-15 wt%, or 10-20 wt%.

[0447] Embodiment 160. The composition, method or use of any of embodiments 120-152, wherein the conjugate is present in the composition in an amount in the range of 15-50 wt%, e.g., 20-50 wt%, or 15-40 wt%, or 20-40 wt%, or 15-30 wt%, or 20-35 wt%.

[0448] Embodiment 161. The composition, method or use of any of embodiments 120-152, wherein the conjugate is present in the composition in an amount in the range of 20-60 wt%, e.g., 25-60 wt%, or 20-50 wt%, or 25-50 wt%, or 20-40 wt%, or 25-45 wt%.

[0449] Embodiment 162. The composition, method or use of any of embodiments 120-161, wherein the composition is in the form of aqueous solutions or suspensions.

[0450] Embodiment 163. The composition, method or use of any of embodiments 120-161, wherein the composition is in the form of a concentrate for dilution into an aqueous solution or suspension.

[0451] Embodiment 164. The composition, method or use of any of embodiments 120-161, wherein the composition is in the form of a cream or gel, e.g., for topical administration.

[0452] Embodiment 165. The composition, method or use of any of embodiments 120-161, wherein the composition is in the form of a solid formulation, for example, in the form of a tablet.

Claims

1. CLAIMSWhat is claimed is:

1. A conjugate having the structural formulaDdQ-P— R2BS L whereinB is a residue of a compound having three or four available binding positions selected from the group consisting of diamines, triamines, tetraamines, diaminoalcohols, aminoalcohols, aminodiols, aminotriols, amino acids, triols (such as glycerol), tetraols, triacids, tetracids, and carboxyl-containing diols and polyamines; and,S is a saccharide, for example, a residue of a mono-, di- or trisaccharide group, in which each saccharide unit is a sugar, a sugar alcohol, an amino sugar or a sugar acid;L is a lipophilic carrier residue selected from fatty acid residues (for example, residues of lauric acid, myristic acid, linoleic acid, palmitic acid, oleic acid and elaidic acid), steroid acid and sterol residues, and residues of retinoids (e.g., residues of retinoic acids), carotenoids, tocopherols, and tocotrienols;Q is a residue of ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, pentaethylene glycol or hexaethylene glycol;P is a residue of a polyaminoacid homopolymer selected from poly(serine), poly(alanine), poly(glutamine), poly(glutamic acid) poly(aspartic acid), poly(asparagine), poly(lysine), poly(arginine), poly(proline), poly(glycine), and N-m ethyl analogs thereof (e.g., N-methylglycine), having a degree of polymerization n;R is a terminal group selected from H, methyl, ethyl and maleimide;D is a secondary group that is as defined above for L or is a methyl-capped poly(ethylene glycol) residue; and d is 0, or d is 1.Nl JmN \ '1-6H i2. The conjugate of claim 1 , having the structural formulaLwherein m is in the range of 2-10.

3. The conjugate of claim 2, wherein m has a number-average value in the range of 2-4.

4. The conjugate of claim 2, wherein m has a number-average value of 3.

5. The conjugate of claim 1, wherein S is a disaccharide group.

6. The conjugate of claim 1, wherein the saccharide unit of S that is directly bound to the nitrogen of the diamine central backbone is derived from a sugar acid and is bound as an amide.7 The conjugate of claim 1, wherein S has the structural formulain which -(CxiH2xiOxi-i)-CO- is a sugar acyl residue derived from a sugar acid in which xl is 4 or 5, and (CX2H2X2-IOX2-I)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof.

8. The conjugate of claim 1, wherein S has the structure9. The conjugate of claim 1, wherein S is lactobionyl or gluconyl.

10. The conjugate of claim 1, wherein L is -C(O)-R1, and R1has a number-average number of carbons in the range of 6-20.

11. The conjugate of claim 1, wherein L is -C(O)-R1, and R1has a number-average number of carbons in the range of 12-18.

12. The conjugate of claim 1, wherein L is -C(O)-R1, and R1is a linear alkyl or alkenyl group.

13. The conjugate of claim 1, wherein L is -C(O)-R1, and wherein -C(O)-R1is at least 85 mol% of a single chemical identity.

14. The conjugate of claim 1, wherein L includes (or is) a steroid acyl group (e.g., a bile acyl group), or a residue of a sterol (e.g., cholesterol) or a lipophilic vitamin (e.g., retinol, tocopherols, tocotri enols).

15. The conjugate of claim 1, wherein n has a number-average value in the range of 5-50.

16. The conjugate of claim 1, wherein n has a number-average value in the range of 9- 23.

17. The conjugate of claim 1, wherein R2is H.

18. The conjugate of claim 1, wherein P has a polydispersity index of no more than 1.2.

19. The conjugate of claim 1, wherein m is 3;S has the structural formula as below:in which -(CxiH2xi0xi-i)-C0- is a sugar acyl residue derived from a sugar acid in which xl is 4 or 5, and (CX2H2X2-IOX2-I)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof;L is at least 80 mol% of cis-CH3(CH2)7CH=CH(CH2)?C(O)-, e.g., at least 85 mol%; n has a weight-average value in the range of 9.5-52.5, e.g., 9.8-22.2; andP has a poly dispersity index of no more than 1.2, e.g., no more than 1.1.

20. The conjugate of claim 1, wherein the conjugate is oleoyldiaminopropane-ethylene- Poly sarcosine -lactobionate (ODPS), represented by Chemical Structure 2:Chemical Structure 2 (ODPS) wherein n is in the range of 5-40.

21. The conjugate of claim 1, wherein the conjugate is Stearylpropanediamine polyglutamine-triethylene-glycol-ether-lactobionate (STQS), which can be represented by Chemical Structure 3a:Chemical Structure 3a (STQS), or Stearylpropanediamine polyglutamic acid-diethylene-glycol-ether-lactobionate (SDQS), which can be represented by Chemical Structure 3b:Chemical Structure 3b (SDQS). wherein n is any desirable value as described above, e.g., in the range of 5-50.

22. The conjugate of claim 1, having one of the following structures:wherein m ranges from 2-10, e.g., is 3, and wherein n is in the range of 5-50.

23. A process for making a conjugate of any of claims 1-22, the process comprising coupling a poly(amino acid), a saccharide and an RJ-C(O)- acyl group to a diamine backbone.

24. The process of claim 23, wherein the method provides a direct esterification of glycols (e.g., mono-, di-, tri-, tetra-, ethylene glycol) with poly(amino acid).

25. The process of claim 23, wherein the method includes providing a monoprotected diamine having a protected first amine group and an unprotected second amine group; coupling a poly (amino acid) and an R1-C(O)- acyl group to the second amine group, and then deprotecting the protected first amine group and coupling a saccharide to the newly- unprotected first amine group.

26. A conjugate according to any of claims 1-22 for use as a pharmaceutical excipient, or for use as in a medicament.

27. A therapeutic composition comprising a conjugate according to any of claims 1-22 and a therapeutic agent.

28. A composition for use in the treatment of a subject having a condition, the composition comprising a conjugate according to any of claims 1-22 and a therapeutic agent suitable for treating the condition.

29. A method for preparing a composition of claim 28, comprising providing a liquid comprising the therapeutic agent and the conjugate in a solvent (e.g., water or an organic solvent), and lyophilizing or spray drying the liquid to provide a solid material comprising the therapeutic agent and the conjugate.

30. A method for treating a subject having a condition, the method comprising administering to the subject a composition of claim 28, for example, wherein the administration is oral, intranasal, topical or parenteral.

31. A composition comprising a conjugate according to any of claims 1-22 and a therapeutic agent for use as a medicament.

32. Use of a conjugate according to any of claims 1-22 for increasing bioavailability of a therapeutic agent.

33. Use of a conjugate according to any of claims 1-22 for increasing solubility of a therapeutic agent in an aqueous system.

34. Use of a conjugate according to any of claims 1-21 as a pharmaceutical excipient, or as a therapeutic.

35. The composition of claim 27, wherein the therapeutic agent has a water solubility in a buffer having a pH of 7.4 of no more than 0.2 mg / mL at 37 °C.

36. The composition of claim 27, wherein the therapeutic agent has a water solubility in a buffer having a pH in the range of 3-9 of no more than 0.2 mg / mL at 37 °C.

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