WO2025029758A1

WO2025029758A1 - Polyethylene glycol-saccharide-lipid conjugates

Info

Publication number: WO2025029758A1
Application number: PCT/US2024/040087
Authority: WO
Inventors: Nian WU
Original assignee: Individual
Current assignee: Individual
Priority date: 2023-07-28
Filing date: 2024-07-29
Publication date: 2025-02-06
Anticipated expiration: 2026-01-28
Also published as: WO2025029760A1

Abstract

This present disclosure provides various diamine centered PEG-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 PEG-saccharide- lipid conjugate having the structural formula (I) wherein m has a number-average value in the range of 2-10; S is 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 -C(O)-R¹ in which R¹ is an alkanyl or alkenyl group having a number-average number of carbons in the range of 6-22, and/or is a steroid acyl group; P is -(CH₂-CH₂-O)nR² in which "n" has a number-average value in the range of 5-50 (e.g., 8-45) and R² is hydrogen and/or alkanyl and has a number average number of carbons in the range 0-4.

Description

POLYETHYLENE GLYCOL-SACCHARIDE-LIPID CONJUGATES

CROSS-REFERENCE TO RELATED APPLICATIONS

[001] This patent application claims the benefit of priority of each of U.S. Provisional Patent Applications Nos.: 63/516,214, filed on July 28, 2023; 63/518,178, filed on August 8, 2023; 63/578,425, filed on August 24, 2023; 63/578,817, filed on August 25, 2023;

63/567,267, filed on March 19, 2024, and 63/567,281, filed on March 19, 2024, the disclosures of each of which is hereby incorporated herein by reference in its entirety.

BACKGROUND OF THE DISCLOSURE

1. Field of the Disclosure

[002] The present disclosure relates to novel polyethylene glycol (PEG)-saccharide -lipid conjugates, analogues and variants thereof, as well as their use in various compositions such as pharmaceutical (including nutraceutical) compositions, as well as in therapeutic methods.

2, Technical Background

[003] 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.

[004] Hence there remains a need for improved pharmaceutical carriers for water insoluble drugs.

SUMMARY OF THE DISCLOSURE

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

wherein m has a number-average value in the range of 2-10;

S is 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 -C(O)-R¹ in which R¹ is an alkanyl or alkenyl group having a number-average number of carbons in the range of 6-22, and/or is a steroid acyl group; P is -(CH₂-CH₂-O)_nR² in which “n” has a number-average value in the range of 5-50 (e.g., 8-45) and R² is hydrogen and/or alkanyl and has a number average number of carbons in the range 0-4.

[006] In another aspect, the disclosure provides a process for making a conjugate as described herein, the process comprising coupling a poly(ethylene)glycol, a saccharide and an RhC(O)- acyl group to a diamine backbone.

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

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

[009] 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.

[010] 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.

[OH] In another aspect, the disclosure provides a use of a conjugate as described herein as a pharmaceutical excipient.

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

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

[014] 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. Various aspects of the disclosure are described herein using the following chemical nomenclature: mPEG(l l): monomethoxypolyethylene glycols ether 500 (i.e., nominal numberaverage degree of polymerization = 11, nominal number-average molecular weight 500 g/mol). mPEG(12): monomethoxypolyethylene glycols ether 550. mPEG(17): monomethoxypolyethylene glycols ether 750. mPEG(23): monomethoxypolyethylene glycols ether 1,000. mPEG(45): monomethoxypolyethylene glycols ether 2,000. CDPS-12: Choloylpropanediamino-mPEG(12)-lactobionate.

DCPS-12: Cholesteryl(oxyethoxy)acetyldiaminopropane-mPEG(12)-lactobionate.

DEPS-12: Elaidoylpropanediamino-mPEG(12)-lactobionate.

DMPS- 11 : Myristoylpropanediamino-mPEG(l l)-lactobionate.

DMPS- 12 : Myristoylpropanediamino-mPEG(12)-lactobionate.

D0PS-B12 Oleoylbutanediamino-mPEG(12) -lactobionate.

DOP S-E 12: Oleoyl ethyl enedi amino-mPEG( 12)-l actobi onate .

DOP S- 12 : Oleoylpropanedi amino-mPEG( 12)-lactobionate.

DOPS-11 : Oleoylpropanediamino-mPEG(l l)-lactobionate.

DOPS-23 : Oleoylpropanediamino-mPEG(23)-lactobionate.

DOPS-45 : Oleoylpropanediamino-mPEG(45)-lactobionate.

DOP S-Gl 2 : Oleoylpropanedi amino-mPEG( 12)-gluconate.

DOP S-H 12 : Oleoylhexanedi amino-mPEG( 12)-lactobionate

DOPS-P17: Oleoylpropanediamino-mPEG(17)-lactobionate

DOPS-P24: Oleoylpropanediamino-mPEG(24)-lactobionate

DOPS-P45 : Oleoylpropanediamino-mPEG(45)-lactobionate

DLP S - 12 : Linoleoy Ipropanedi amino-mPEG( 12)-l actobi onate

DSPS-12: Stearoylpropanediamino-mPEG(12) -lactobionate

TOP S- 12 : Oleoylbi s(3 -aminopropyl)amine-mPEG( 12)-lactobionate

[015] Additional aspects of the disclosure will be apparent in view of the disclosure and claims below.

BRIEF DESCRIPTION OF THE DRAWINGS

[016] The accompanying drawings (“FIG”), which are incorporated into and constitute a part of this specification, illustrate one or more embodiments of the present disclosure and, together with the detailed description, serve to explain various principles and implementations of the disclosure.

[017] FIG.l depicts HPLC chromatograms of fatty acid based conjugates: Peak 1 = lauroyl-propanediamino-mPEG(12)-lactobionate (DLOPS-12); Peak 2 = myristoylpropane- diamino-mPEG(12)-lactobionate (DMPS-12); Peak 3 = palmitoleoylpropanediamino- mPEG(12)-lactobionate (DPOPS-12); Peak 4 = linoleoyl-propanediamino-mPEG(12)- lactobionate (DLOPS-12); Peak 5 = palmitoylpropanediamino-mPEG(12)-lactobionate (DPPS-12); Peak 6 = oleoylpropanediamino-mPEG(12)-lactobionate (DOPS-12); Peak 7 = oleoypropaneldiamino-mPEG(12)-gluconate; Peak 8 = stearoylpropanediamino-mPEG(12)- lactobionate (DSPS-12). The concentrations injected onto the column were approximately 4 to 6 mg/mL each.

[018] FIG. 2 depicts an HPLC chromatogram of a sample of DOPS-12 made with USP grade mPEG (550) and the purity is > 95%. the concentration injected was approximately 5 mg/mL DEPS-12 = elaidoylpropanediamino-mPEG(12)-lactobionate.

[019] FIG. 3 depicts a HPLC chromatogram of linoleoylpropanediamino-mPEG- lactobionate (DLPS-12 and its isomer iso-DLPS-12) made with the USP grade of mPEG (550) and the purity is > 95%, the concentration injected was approximately 5 mg/mL.

[020] FIGS. 4A and 4B depict spectra of hemolytic potential (4A) DOPS-12 and (4B) TOPS-12.

[021] FIG. 5 depicts a long-term stability of a sample of DOPS-12 stored under 25 °C and 65% relative humidity up to 36 months.

[022] FIG. 6 depicts a LC-MS/MS chromatogram of a sample of DOPS-12 at 50 ng/mL.

[023] FIG. 7 depicts a Toxicokinetic profile of DOPS-12 for 90 min intravenous infusion of 200 mg/kg body weight in female and male Yucatan minipigs following the last dose (Day 28): Male = filled symbols and Female - opened symbols.

[024] FIGS. 8A and 8B depict the body weight profile of DOPS-12 for oral dosing up to 90 days in juvenile Beagle dogs (8A) female and (8B) male.

[025] FIGS. 9A and 9B depict Toxicokinetic profile of DOPS-12 for oral dosing in female (8A) and male (8B) juvenile Beagle dogs after Day-90.

[026] FIG. 10 depicts Pharmacokinetic profile of DOPS-12 from intravenous injection in female and male Beagle dogs.

[027] FIG. 11 depicts a finished conjugate product (DOPS-12).

[028] FIG. 12 depicts the curve fitting plot of the Critical Micelle Concentration test results of DOPS-12 in deionized (DI) water.

[029] FIG 13 depicts the PEG distribution profile in a sample of DOPS-12 as determined by LC-MS

DETAILED DESCRIPTION

[030] The present inventor has determined that polyethylene glycol (PEG)-saccharide- lipid conjugates have the capacity to improve the pharmacology profile and solubility of lipophilic drugs in aqueous systems. They can also provide other advantages, such as minimizing the side effects associated with therapeutic treatment, and providing a variety of new options for formulations of active agents. The present disclosure describes, for the first time, various unique safety features and quality characteristics of certain PEG-saccharide- lipid conjugates. As described in the examples below, up to 200 mg/kg (body weight) of a representative polymer of the disclosure was repeatedly administrated to minipigs in four- week intravenous toxicity studies. Comparable toxicology performance from PEG-lipid based polymer such as polysorbates (Tween™) or polyoxyethylated triglycerides (i.e., Cremophor®) has not been reported to the knowledge of the present inventor. In various embodiments, the materials described herein can help to minimize anaphylactic episodes. In various embodiments, the materials of the disclosure can help to avoid progressive protein degradation and reduce immunogenicity. The materials of the disclosure can thus be used, for example, to replace the currently marketed compounds like polysorbates and Cremophor. The materials of the disclosure can help to meet a critical need while providing a substantial differentiating clinical benefit for all concerned, that is, patients and physicians.

[031] Specifically disclosed herein are the structure and preparation of PEG-sacchari delipid conjugates having a suitable diamine central backbone with at least three binding positions or sites available. PEG, carbohydrate and lipid groups are thus covalently conjugated to the central backbone. Notably, the novel PEG-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. The detailed results from in vitro and in vivo studies in animals disclosed herein demonstrate the safety and quality profiles of such conjugates

[032] The present inventor has noted that the chain length of the PEG 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.

[033] Embodiments of the present disclosure are described herein in the context of PEG- saccharide-lipid conjugates for improved safety and enhanced delivery of poor 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. References will now be made in detail to implementations of the present disclosure as illustrated in the accompanying drawings. The same reference indicators will be used throughout the drawings and the following detailed description to refer to the same or like parts.

[034] 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 for those of ordinary skill in the art having the benefit of the present disclosure.

[035] 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 PEG-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.

[036] Thus, the present disclosure provides diamine-centered PEG-saccharide-lipid conjugates that can exhibit improved safety profiles, such as reduced immunogenicity/antigenicity, in combination with good solubility enhancement properties. Results from in vitro studies and in vivo studies in animals are disclosed herein for the first time. Furthermore the relationship between said polymer structures and the hemolytic potential is also disclosed for the first time. As demonstrated here, the seemingly small structural difference between the diamine central backbones described here and the triamine central backbones of the earlier conjugates can have a significant impact on safety, as demonstrated in the Examples of the present disclosure.

[037] Amide bonds are the most prevalent structures in peptides and proteins. Despite their tremendous therapeutic potential, so far only a limited number of peptides has been commercialized as drugs because of their toxicity (hemolytic activity). For example, a lipopeptides formed from peptide LL-37, a 37-amino acid residue with Leu-Leu at the N- terminus, coupled to fatty acid (FA) chains with 7-10 carbon atoms has been shown to cause about 10% hemolysis at a micromolar level. Increasing the length of the fatty acid chain to 15 carbon atoms increased the hemolysis to 40%.

[038] 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 is a fatty acyl group having a number-average length of 18 carbons or shorter. However, longer acyl groups or steroid acyl groups may be desirable in certain situations, especially in oral administration.

[039] 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.

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

[041] 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 hemolytic activity, and as such can provide further improvements over these currently available vehicles.

[042] The present inventor has noted that most systemic toxicology studies of polymers such as polysorbates or Cremophors in previous work were conducted with rodent species. Accordingly, potential immunogenicity issues of PEG-lipid polymers appear to have been overlooked. In comparison, several intravenous studies in large animals (minipigs) for the PEG-saccharide-lipid conjugates of the disclosure were successfully completed. Reduced or no immunogenic reaction was observed with the tested polymer, especially for oleoylpropylenediamino-mPEG-lactobionate (“DOPS-12,” also referred to as “DOPS-F02” in accordance with the synthetic steps used). No allergic reaction was found at intravenous doses up to 200 mg/kg (body weight) in either Gottingen minipigs or Yucatan minipigs in these internal studies.

[043] Anaphylaxis is a severe, systemic hypersensitivity reaction that is rapid in onset and characterized by life-threatening problems. Further studies in animal models of passive systemic cutaneous anaphylaxis and active systemic anaphylaxis demonstrate a low immunogenicity for various embodiments of the PEG-saccharide-lipid polymers of the present disclosure.

[044] In various embodiments, the present disclosure provides PEG-saccharide-lipid conjugates, many with improved safety, and methods for the synthesis of PEG-saccharide- lipid conjugates. In various embodiments, the conjugates may be based on a PEG oligomer or the USP grade mPEGs ranging from 5 to 50 (e.g., 8-45) subunits of ethylene glycol. The present disclosure also provides different methods for the preparation of PEG-saccharide- lipid conjugates having varying saturated or unsaturated fatty acid or alkyl chain lengths. Such PEG-saccharide-lipid conjugates can be used for drug delivery, in various especial embodiments for intravenous administration of poorly-water soluble or lipophilic agents.

[045] The present disclosure provides convenient and economic synthesis methods for preparing PEG-saccharide-lipid conjugates and various linear linkage groups may be used for coupling each carrier groups to the central 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.

[046] The present disclosure also describes the stability profile of a PEG-saccharide-lipid conjugate that was prepared by the synthesis methods described herein. In various embodiments, the PEG-saccharide-lipid conjugate exhibits long-term stability in both liquid and solid states under room temperature conditions for at least 36 months. Stability of a conjugate can be critically important to ensure safety in clinical applications.

[047] The PEG-saccharide-lipid conjugates can be incorporated into a lyophilized powder or aqueous solution or solid dosage form for drug delivery. While the solubility enhancement of PEG-saccharide-lipid conjugates can be achieved by forming simple micelles in aqueous media, it can in many cases be differentiated from those of so called “self-emulsifying drug delivery systems” (SEDDS) since a self-emulsifying drug delivery system is isotropic mixtures of drug, lipids and surfactants, usually with 2 or more hydrophilic co-solvents or co- emulsifiers . Typically a SEDDS mixture requires relatively higher amounts of solubilizers in compared to the same drug solution made with the novel PEG-saccharide-lipid conjugates. The resulting reduction in the size of dosage forms is also beneficial for patients.

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

General Formula I wherein: m has a number-average value in the range of 2- 10, which represents a distance between the terminal moieties of the center backbone;

S is a saccharide such as 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 -C(O)-R¹ in which R¹ is an alkanyl or alkenyl group having a number-average number of carbons in the range of 6-22, and/or is a steroid acyl group, for example, those derived from cholesterol, cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, chenodeoxy cholic acid, and lithocholic acid (for example, those derived from cholic acid, deoxycholic acid, glycocholic acid);

P is -(CH₂-CH₂-O)_nR² in which n has a number-average value in the range of 5-50 (e.g., 8-45) and R² is hydrogen and/or alkanyl and has a number average number of carbons in the range 0-4.

[049] 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 R¹ chain lengths, a range of R² chain lengths, and a range of n values, and as such various individual molecules within a sample may have different identifies of R¹, R² and n. However, as described above, it can in many circumstances be desirable to control the variation, especially of the value of n. 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 and m. General Formula I thus defines various substituents with number-average values of various substituents. But the disclosure also specifically contemplates various individual compounds with integral values for various substituents. [050] The present inventor has determined that maintaining a relatively small value of m, to provide 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.

[051] 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 PEG chains or bulkier lipids, and as such can offers a relative higher yield of the conjugate due to fewer steric effects.

[052] 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.

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

[054] 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.

[055] 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.

[056] 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:

[057] In some embodiments as described herein, the structural formula of “S” is as follows:

in which -(C_XIH2_XIO_XI-I)-CO- is a sugar acyl residue derived from a sugar acid in which xl is 4 or 5, and (C_X2H2_X2-IO_X2-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.

[058] In various embodiments, “S” has the following structure:

or is an open-chain version thereof.

[059] 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. In other embodiments, “S” is a residue from another disaccharide or tri saccharide, which can be modified (e.g., by oxidation). Examples include sucrose, lactose, maltose, trehalose, turanose, cellobiose raffinose, melezitose and maltotriose. [060] 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)-R', wherein R¹ is 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.

[061] In various such embodiments, R¹ has a number-average number of carbons in the range of 6-20, or 6-18. In various such embodiments, R¹ has a number-average number of carbons in the range of 10-22, e g., 10-20 or 10-18. In various such embodiments, R¹ has a number-average number of carbons in the range of 12-22, e.g., 12-20 or 12-18. In various such embodiments, R¹ has 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, R¹ has a numberaverage number of carbons that is no more than 18.

[062] Both saturated and unsaturated R¹ groups can be suitable for use. In various embodiments as otherwise described herein, R¹ has 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.

[063] In various desirable embodiments, R¹ is a linear alkanyl or alkenyl group.

[064] In various embodiments as described herein, R¹ is 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 R'-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. Table 1 Saturated fatty acids

Table 2 Unsaturated fatty acids

[065] However, in many embodiments, it can be desirable for the -C(O)-R' group 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 RLC(O)- Lipid group derived from oleic acid. In various embodiments as otherwise described herein, -C(O)-R' is at least 80 mol% of a single chemical identity, e.g., at least 85 mol%. In various embodiments as otherwise described herein, -C(O)-R¹ is 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)i iC(O)-

[066] 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.

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

[068] As described above, “P” is -(CH₂-CH₂-O)_nR² in which “n” has a number-average value in the range of 5-50 (e.g., 8-45) and R² is hydrogen and/or alkanyl and has a number average number of carbons in the range 0-4. In various embodiments, n has a numberaverage 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. 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. [069] The poly(ethylene glycol) is terminated with R², which can be H (i.e., to provide a hydroxy) or an alkanyl group (i.e., to provide an ether). In various embodiments, R² has 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). In various embodiments, R² has 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, R² is C1-C4 alkanyl, e.g., methyl or ethyl. In various embodiments, R² is methyl. In various embodiments, R² has a number average number of carbons in the range 0-3, e.g., 0-2. In various embodiments, R² has 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 R² that is hydrogen.

[070] When the -P group is a methylated PEG residue (i.e., R² is methyl), in various embodiments it has a number-average molecular weight in the range of 300-2200 g/mol. For example, in various embodiments, the -P group is a methylated PEG residue having a number-average molecular weight in the range of 300-1200 g/mol, e.g., 300-600 g/mol. In various embodiments, the -P group is a methylated PEG residue having a number-average molecular weight in the range of 500-2200 g/mol, e.g., 500-1200 g/mol, or 500-900 g/mol. In various embodiments, the -P group is a methylated PEG residue having a number-average molecular weight in the range of 700-2200 g/mol, e.g., 700-1200 g/mol, or 700-1100 g/mol. In various embodiments, the -P group is a methylated PEG residue having a number-average molecular weight in the range of 475-575 g/mol. In various embodiments, the -P group is a methylated PEG residue having a number-average molecular weight in the range of 475-525 g/mol or 525-575 g/mol. In various embodiments, the -P group is a methylated PEG residue having a number-average molecular weight in the range of 710-790 g/mol. In various embodiments, the -P group is a methylated PEG residue having a number-average molecular weight in the range of 900-1100 g/mol, e.g., 950-1050 g/mol. In various embodiments, the -P group is a methylated PEG residue having a number-average molecular weight in the range of 1800-2200 g/mol, e.g., 1900-2100 g/mol. Methylated PEG residues and methylated PEGs are described variously in this disclosure as mPEG, as well as mPEGn and m(PEG)n, in which the n indicates a number-average number of ethylene glycol residues. The person of ordinary skill will understand from context whether a methylated PEG or a methylated PEG residue is being discussed.

[071] In various embodiments, the PEG 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 PEG that has low poly dispersity can provide improved results, especially with respect to providing good dispersion of water-insoluble materials in aqueous systems. Poly dispersity Index (PDI) is defined by the equation below:

where M_w is the weight average molecular weight and M_n is the number average molecular weight. For example, in various embodiments, the “P” group has a PDI (poly dispersity index) of no more than 1.1, e.g., no more than 1.07. In various embodiments, the “P” group has a PDI of no more than 1.06, or no more than 1.05. The poly dispersity index of the “P” group is understood to be the same as the poly dispersity index of the PEG used to make the conjugate. Molecular weights can be determined by liquid chromatography/mass spectrometry, either of the conjugates or of the P-H compound used to make the conjugates.

[072] Commercial USP or EP grades of mPEG may be used in various embodiments. mPEG oligomers can also be made by a total synthesis.

[073] In various desirable embodiments, the P group is a long chain, linear or branched synthetic polymer composed of ethylene oxide units, CH3OCH2CH2(OCH2CH2)_nO-, in which n is typically between about 4 and about 45 or otherwise can vary to provide a narrow or mono-distributed polymer with molecular weights from 200-2000 Daltons.

[074] In various embodiments as described herein, m is 3; S has the structural formula as below:

in which -(CxiFExiOxi-ij-CO- is a sugar acyl residue derived from a sugar acid in which xl is 4 or 5, and (C_X2H2x2-iO_X2-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)-R¹ is at least 80 mol% of cis-CH3(CH2)7- CH=CH(CH2)?C(O)-, e.g., at least 85 mol%; R² is methyl; n has a weight-average value in the range of 11.5-12.5, e g., 11.8-12.2; 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)-R¹ is 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.

[075] In various embodiments as described herein, m is 3; S has the structural formula

in which -(C_xiH2xiO_xi-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)-R¹ is 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 methylated PEG residue having a number-average molecular weight in the range of 525-575 g/mol and having 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 following structure:

or is an open-chain version thereof In some embodiments, S is lactobionyl. In some embodiments, -C(O)-R¹ is 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.

[076] In various embodiments as otherwise described herein, the conjugate has the structural formula of Chemical Structure 1 :

Chemical Structure 1 wherein m(PEG)n is a methylated PEG residue. [077] In various such embodiments of Chemical Structure 1, the fatty acyl residue -C(O)- R¹ is derived from one or more of lauric acid, myristic acid, palmitic acid, linoleic acid, Oleic acid and stearic acid. The m(PEG)_n is a methylated PEG residue and “n” is any desirable value as described above.

[078] In various embodiments, the conjugate is Oleoyldiaminopropane-monomethoxy- polyethylene-glycol-ether-lactobionate (DOPS), which can be represented by the Chemical Structure 2:

Chemical Structure 2 (DOPS)

[079] The “oleyl” group is understood to represent a -C(O)R¹ group that is at least 80 mol% derived from oleic acid. In Chemical Structure 2, m(PEG)_nis methylated PEG residue, and “n” is any desirable value as described above. In some embodiments, the numberaverage value of “n” is in the range of 9.2-13.8, e.g., 10.2-13.2, or 11.4-13.6 (mPEG 550 (n = 12) or C58H112N2O24).

[080] In various embodiments, the conjugate is Stearylpropanediaminomonomethoxy- polyethylene-glycol-ether-lactobionate, which can be represented by Chemical Structure 3 :

Chemical Structure 3 (DSPS)

[081] The “stearyl” group is understood to represent an R¹ group that is at least 80 mol% derived from stearic acid. In Chemical Structure 3, m(PEG)n is methylated PEG, and n is any desirable value as described above. In some embodiments, the number-average value of n is in the range of 9.2-13.8, e.g., 10.2-13.2, or 11.4-13.6 (mPEG 550 (n = 12), C58H114N2O24).

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

Chemical Structure 4 wherein m(PEG)_n is methylated PEG (e.g., average number of carbons of R² in the range of 0.95-1.05, or 0.98-1.02), “n” is any desirable value as described above, and m is in the range of 2-6, e.g., is 3.

[083] In various embodiments, the conjugate is choloylpropanediamino-mPEG- lactobionate (CDPS), which can be represented by Chemical Structure 5:

Chemical Structure 5 (CDPS)

[084] The “choloyl” group is understood to represent an R¹ group that is at least 65 mol% derived from choloic acid. In Chemical Structure 4, m(PEG)_n is methylated PEG (e.g., average number of carbons of R² in the range of 0.95-1.05, or 0.98-1.02), and “n” is any desirable value as described above. In some embodiments, the number-average value of “n” is in the range of 9.2-13.8, e.g., 10.8-13.2, or 11.4-12.6 (mPEG 550 (n = 12) or C64H118N2O27). In various embodiments of Chemical Structures 3, 4, or 5, the numberaverage value of n is in the range of 11-13, e g., 11.5-12.5, or 11.8-12.2.

[085] In various embodiments as described herein, the conjugate has one of the following structures:

[086] 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.

[087] In various embodiments of the conjugates as otherwise described herein, -P is provided from a P-H polyethylene glycol) source (e.g., an mPEG) that has a number-average molecular weight in the range of 95.0-105.0% of the labeled nominal value if the labeled nominal value is below 1000 g/mol, or in the range of 90.0-110.0% of the labeled nominal value if the labeled nominal value is in the range of 1000 and 2000 g/mol.

[088] In various embodiments of the conjugates as otherwise described herein, the conjugate has a purity of at least 85 wt% as measured by HPLC. Such materials can be especially desirable for use in oral applications.

[089] In various embodiments of the conjugates as otherwise described herein, the conjugate has a purity of at least 90 wt% as measured by HPLC. Such materials can be especially desirable for use in parenteral applications.

[090] In various embodiments of the conjugates as otherwise described herein, when the R¹-C(O)- group is a fatty acyl group, it is at least 65 mol% of a single chemical identity, e.g., at least 80 mol%, or at least 85 mol%, or at least 90%, or at least 95 mol%. In various embodiments, the single chemical identity is oleoyl, myristyl, palmitoyl, stearyl or linoleyl.

[091] In various embodiments as otherwise described herein, the conjugate includes less than 5 mol% of fatty acid-related analogues (i .e., those having other than the primary R¹- C(O)- identity, e.g., oleoyl).

[092] In various embodiments of the conjugates as otherwise described herein, R¹-C(O) is a fatty acyl and the conjugate of DOPS-12 (oleoylpropanediaminomonomethoxy - polyethylene-glycol-ether-lactobionate) when assayed by HPLC, resembles the peak profile of Figure 1, 2 or 3 and the following relative retention time (RRT), with particular analogs defined as how they differ from DOPS-12 (e.g., in the fatty acyl group, or in the saccharide as for gluconic acid):

¹ in the range of RRT ± 0.2 to ± 0.5

² RRT of oleic acid is set as 1.00

[093] In various embodiments, the conjugates of the present disclosure can be provided at relatively high levels of purity. For example, in various embodiments, the purity of the PEG- sacchari de-lipid conjugates of the disclosure is greater than 80% by HPLC. In various embodiments, purity of the PEG-saccharide-lipid conjugates of the disclosure is greater than 90% by HPLC. In various embodiments, the purity of the PEG-saccharide-lipid conjugates of the disclosure is greater than 95% by HPLC. FIG. 1 depicts HPLC chromatograms of fatty acid based conjugates: Peak 1 = lauroyl-propanediaminomPEG(12)-lactobionate (DLOPS- 12); Peak 2 = myristoylpropanediaminomPEG(12)-lactobionate (DMPS-12); Peak 3 = palmitoleoylpropanediaminomPEG(12)-lactobionate (DPOPS-12); Peak 4 = linoleoyl- propanediaminomPEG(12)-lactobionate (DLOPS-12); Peak 5 = palmitoylpropane- diaminomPEG(12)-lactobionate (DPPS-12), Peak 6 = oleoylpropanediaminomPEG(12)- lactobionate (DOPS-12); Peak 7 = oleoypropaneldiaminomPEG(12)-gluconate; Peak 8 = stearoylpropanediaminomPEG(12)-lactobionate (DSPS-12). The concentrations injected onto the column were approximately 4 to 6 mg/mL each. FIG. 2 depicts a HPLC chromatogram of DOPS-12 made with the USP grade of mPEG (550) and the purity is > 95%. The concentration injected was approximately 5 mg/mL. DEPS-12 = elaidoylpropanediamino- mPEG(12)-lactobionate. FIG. 3 depicts a HPLC chromatogram of linoleoylpropane- diaminomPEG-lactobionate (DLPS-12 and its isomer iso-DLPS-12) made with the USP grade of mPEG (550) and the purity is > 95%, the concentration injected was approximately 5 mg/mL. In various embodiments, the HPLC peak profile of a conjugate of the disclosure resembles the peak profiles in the HPLC chromatograms of Figures 1, 2 and 3.

[094] Notably, a superior solubility enhancement for poorly-soluble drugs can be provided by materials of the disclosure without co-solvents or co-emulsifiers. For example, in the case of a cyclosporine (0.09%) ophthalmic formulation, the particle size of cyclosporine in the marketed product (CEQUA®) is in the range of 12 to 20 nm, based on a SEDDS-like suspension using a mixture of polyoxyl 40 hydrogenated castor oil and polyalkoxylated alcohol. In the comparison, a true solution of 0.1% cyclosporine was obtained with approximately 1% of DOPS-12; the solution was stable for more than 4 years under room temperature. Without intending to be bound by theory, the present inventor believes that a higher purity and lower poly dispersity of the said material contribute to the especially good performance.

[095] In some embodiments as described herein, the conjugate has a hydrophilic- lipophilic balance (i.e. HLB) value in the range of 13-18, e.g., in the range of 13-15.

[096] Another aspect of the disclosure provides a polyethylene glycol-saccharide-lipid conjugate useful, for example, as a solubility or bioavailability enhancer for safely delivering hydrophobic or lipophilic compound or compounds, represented by the formula:

wherein:

Lipid is selected from a group consisting of fatty acids including lauric acid, myristic acid, linoleic acid, palmitic acid, oleic acid, elaidic acid and steroid acids; m(PEG)n is a polymeric polyethylene glycols (i.e., which makes the conjugate polymeric in nature); n ranges from 8 to 45 of ethylene glycol subunits; and m* = 1 to 6 of CH2.

[097] In some embodiments as described herein, the polymer has described herein has one or more of the following properties or specifications: a. the mPEG ranges between 95.0% and 105.0% of the labeled nominal value if the labeled nominal value is below 1000 or between 90.0% and 110.0% of the labeled nominal value if the labeled nominal value is between 1000 and 2000. b. Purity of the said polymeric conjugate is between 85% and 115.0 by HPLC assay if used for oral applications; c. Purity of the said polymeric conjugate is between 90% and 110.0% by HPLC assay if used for parenteral application; d. Purity of oleic acid if utilized is not less than 65% e. Individual related analogue or impurity is less than 5%; and f. Fatty acid based said polymers, resemble of the peak profile of Figures 1, 2 or 3 and the following relative retention time (RRT):

¹ in the range of RRT ± 0.2 to ± 0.5

² whereby RRT of oleic acid is set as 1.00

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

(1) coupling activated monomethoxypolyethylene glycol ether to the unprotected amino group of the center backbone;

(2) conjugating a lipid or disaccharide to the backbone, thereby forming a PEG-saccharide- lipid conjugate having a high purity of conjugates in the range of 85% to 115% by HPLC assay.

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

(1) synthesizing a short-chain of ethylene glycol protected hydroxyl groups on the ethylene glycol and amino group of the center backbone;

(2) extending the PEG chain by repeating the short ethylene glycol chain reaction.

(3) conjugating a lipid or disaccharide to the backbone, thereby forming a PEG- saccharidelipid conjugate having a high purity of PEG oligomer. wherein the sequence or order of coupling steps or sites is interchangeable.

[100] In some embodiments of the polymeric conjugate as described herein, m* in the backbone is 0 or 1 thereby forming a PEG-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: when m* is 1, the backbone is propane; or when m* is zero, the backbone is ethylene;

FA is a fatty acid which is selected from a group including but not limited to lauric acid, myristic acid, linoleic acid, palmitic acid, linoleic acid, oleic acid or stearic acids; and n is ranging from 8 to 45.

[101] In some embodiments of the polymeric conjugate as described herein, the distance between the 2 terminal amines is less than 4 carbons if use for parenteral administrations.

[102] In some embodiments of the polymeric conjugate as described herein, the m in the backbone is greater than 1 thereby forming a PEG-saccharide-lipid that is more suitable for oral administration of other applications.

[103] In some embodiments of the polymeric conjugate as described herein, said PEG- saccharide-lipid conjugates are solid (low-water) or semisolid (higher moisturized) and stable for at least 36 months under room temperature storage conditions.

[104] In some embodiments of the polymeric conjugate as described herein, the monomethoxypolyethylene glycol ether has an average molecular weight between 95.0% and 105.0% of the labeled nominal value if the labeled nominal value is below 1000 or between 90.0% and 110.0% of the labeled nominal value if the labeled nominal value is between 1000 and 2000.

[105] In some embodiments of the polymeric conjugate as described herein, a monosaccharide-related impurity in said polymer is less than 5%. In some embodiments of the polymeric conjugate, the total fatty acid related impurities in said polymeric conjugate are less than 10% and individual fatty acid related impurity is less than 5%. For example, in various embodiments of the polymer as described herein, the purity of said polymeric conjugate is not least than (>) 90% to be used for parenteral compositions. The polymeric conjugate as otherwise described herein can be purified by any means known in the art. For example, in some embodiments as described herein, the polymeric conjugate is purified or dried by lyophilization. In some embodiments of the polymeric conjugate as described herein, the polymeric conjugate is purified or dried by lyophilization if the polymer will be used for parenteral administration. In some embodiments of the polymeric conjugate as described herein, the purity of said polymeric conjugate is not less than (>) 85% to be used for pharmaceutical oral compositions.

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

[107] In various embodiments of the polymer as described herein, the PEG- saccharidelipid conjugate is selected from the following structures:

wherein n ranges from 8 to 45, or is as otherwise described herein.

[108] Another aspect of the disclosure is a method for making a conjugate as described herein. Such a method includes coupling a poly(ethylene)glycol, a saccharide and an R¹- C(O)- acyl group to a diamine backbone. For example, in various embodiments, the method includes providing a monoprotected diamine having a protected first amine group and an unprotected second amine group; coupling a poly(ethylene glycol) and an R'-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. Notably, in various embodiments, the various process steps can be performed in the substantial absence of free- radical initiators.

[109] In some embodiments, the coupling of the poly(ethylene glycol) can be performed before the coupling of the R¹-C(O)- acyl group. When the polyethylene glycol) of the conjugate is to be hydroxy-terminated (i.e., R² in individual molecules being H), it can be desirable to have the hydroxy in a protected form (e.g., as a benzyl ether) at the time of the coupling of the R'- O)- acyl group.

[HO] In various embodiments, the coupling of the poly(ethylene glycol) to the second amine group can be performed in a stepwise fashion, e.g., by first coupling a shorter chain of PEG (or even a single ethylene glycol unit) to the central backbone, then by performing etherification to achieve a longer PEG chain. An example of this is shown in Reaction Scheme 1, below.

Reaction Scheme 1 Synthesis of propanediaminomonomethoxydodecaethylene glycol [HI] Here, a so-called “Boc” protecting group is used to protect the first amine of the diamine. The person of ordinary skill in the art will appreciate that Boc is a useful group for protecting the first 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 first amine.

[112] Similarly benzyl (Bn) groups may be used for protecting the hydroxyl group. Removal of benzyl groups to free the hydroxyl group of the PEG-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 PEG chain can be extended by repeating the same etherification process. While a benzyl group is used in the example of Reaction Scheme 1, the person of ordinary skill in the art will identify other suitable alcohol protecting groups.

[H3] And while the extension of the poly(ethylene glycol) is shown in Scheme 1 as being performed before the coupling with the R^ O)- acyl group, in other embodiments the acylation can be performed with hydroxyl protecting group still in place, and the alcohol deprotection and extension can be performed after acylation.

[114] Following the reaction in Reaction Scheme 1, prior to removing the protecting group on the terminal amine of the backbone, the second amine group can be acylated with a R¹-C(O)- acyl group. One example of this is shown in Reaction Scheme 2. 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 A-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.

Reaction Scheme 2 Synthesis of N³- fatty acid propanediamino-mPEG-12

Reaction Scheme 3 Preparing of Myristoyl Chloride

[115] With the PEG 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 below. 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 N³- fatty acid propanediamino-mPEG- 12 in di chloromethane to produce the final product of N³- fatty acid propanediamino-mPEG- H-Ad-lactobionate.

Reaction Scheme 4 Synthesis of N³ -fatty acid propanedi amino-mPEG- 12-/ ' dactobionate

[H6] 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.

[117] In various embodiments, fatty acid residues range from carbon chain lengths of about C8 to about C22, for example about CIO and about Cl 8, In various embodiments, the fatty acid residue is selected from the group 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.

[118] In various embodiments, when oleic acid is 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.

[119] The solvent for the PEG-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'-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. [120] The disclosed methods can be used to prepare a variety of novel PEG-saccharide- lipid conjugates. For example, the methods can be used to prepare TV ipid propanedi amino- mPEG-12- V¹ -lactob ion ate in highly pure PEG form containing any lipophilic carrier groups.

[121] While a monodisperse PEG is greatly useful for polymer characterization and profiling, the USP (US Pharmacopoeia) grade of polyethyleneglycols with a PDI no more than 1.1 is often used for the scale-up and commercial productions for the economic reasons since the process for the preparation of a pure oligomer PEG is both time and labor consuming. The USP grade materials are generally of sufficiently low poly dispersity that they exhibit many of the same advantageous properties as materials made from monodisperse PEG products. Weight-average and number-average molecular weights of polyethylene glycols can be determined using mass spectrometry, and can be used in determining polydispersity.

[122] The hemolytic activity of polyoxyethylene polymers may be ascribed to their tendency to form peroxides due to the synthetic processes of radical reactions. It should, however, be emphasized that hemolysis is only one form of cytotoxicity of polyoxyethylene polymers.

]123] Notably, the synthetic methods described herein can provide the polymeric conjugates of the disclosure with a minimized degree of peroxide formation. Formation of peroxides can be largely minimized if a total synthesis is used for the polymer productions or the conjugation between the PEG and lipid is stepwise covalent bonding instead of “one-pot” randomized polymerization using free-radical-mediated processes.

[124] The present disclosure provides synthetic methods for preparing PEG-saccharide- lipid conjugates that can provide several advantages such as simplified synthesis, high product yield and low cost of starting materials. In addition, the presently-described synthesitic methods can be adapted to prepare a wide range of PEG-saccharide-lipid conjugates.

[125] Often free radical polymerization, the molecular weight distributions are difficult to be narrowly controlled, typically within 50% of the targeted PEG molecular weight. Narrowdistribution may be achieved with size exclusion chromatograph, typically with 10% of the targeted PEG molecular weight. However it is extremely difficult to achieve a monodistribution of purified PEGs for smaller PEG chains, i.e., the PEG molecular weights are 2000 or less. [126] Unlike free radical polymerization used for the production of polysorbates or Cremophors, in the present disclosure, the composition or structures of PEG-saccharide-lipid conjugates can be well defined and may include all the various functional linker groups described herein. Whenever is suitable, the USP grade polyethylene glycols or their monomethyl ethers with a narrower range of molecular weight distributions, i.e., a few oligomer or ranging ±10% of the mean PEG number-average molecular weight can be used. The synthetic methods described herein can be used to ensure a well-defined conjugate structure. The impurities in a well-defined mPEG product can be minimized, especially for the level of peroxides. Desirably, the level of hydroperoxide in a conjugate of the disclosure as measured by the FOX2 assay (see Wasylaschuk WR, et al (2007). “Evaluation of hydroperoxides in common pharmaceutical excipients. J Pharm Sci. 96(1): 106-16, which is hereby incorporated herein by reference in its entirety) is no more than 100 nmol/g, e.g., no more than 50 nmol/g, or no more than 30 nmol/g.

[127] For the purpose of clarity, the molecular weight (MW) range of oligomers in commercially available polyethylene glycols is largely dependent on the quality or sources, for instance, the number-average molecular weight of the USP grade of Polyethylene Glycol Monomethyl Ether is between 95.0% and 105.0% of the labeled nominal value if the labeled nominal value is below 1000 g/mol (e.g., 750 ±); and it is between 90.0% and 110.0% of the labeled nominal value if the labeled nominal value is below 2000 g/mol. In the Examples of the present disclosure, only the USP grade of monomethyl polyethylene glycols was used for the synthesis of PEG-saccharide-lipid conjugates, in which the mPEG distribution range was within the USP specifications or the targeted number-average molecular weight (Mw) ± 5% (Mw < 1000) to ±10% (up to 2000). Overall, a PDI of mPEG is desirably be less than 1.1.

[128] The significance of purity in the PEG-saccharide-lipid conjugates disclosed in the present invention transcends mere quality control which is a fundamental assurance of patients’ safety. Reactive impurities in marketed pharmaceutical polymeric excipients could cause drug product instability, leading to decreased product performance, loss in potency, and/or formation of potentially toxic degradants, e.g., commercially available Polysorbates are chemically diverse mixtures, the expected structure for polyoxyethylene (20) sorbitan monolaurate and polyoxyethylene (80) sorbitan monooleate, only accounts for about 20% of the total polysorbate from some commercial sources. The composition of polysorbate may also vary between vendors with lot-to-lot variability likely resulting from different (radical) synthesis routes and raw materials used. Polysorbates 80 (PS80) and Cremophor (Cr-EL) are the leading PEG-lipid polymers approved for clinical use. The “maximum daily exposure” in intravenous products is 27,668 mg for Cr-EL and 4,739 mg for PS80 from the FDA database of “Ingredient Search for Approved Drug Products,” which corresponds to approximately 395 mg/kg of Cr-EL or 68 mg/kg of PS80 for a standard human of 70 kg. Often ethanol is used as a co-solvent with PS80 or Cr-EL (Descriptions of the compositions for “Paclitaxel” and “Taxotere” can be found at rxlist.com).

[129] However, a single dose of 3% Cr-EL (in 5 % glucose, 6.3 mL/kg) or 3% PS80 (in 5% glucose, 6.3 mL/kg) with a 30 min infusion in minipigs was reported to cause transient erythema of skin or itching and anxiety. Other published studies also demonstrated the pseudoallergic sensitivity of the two excipients. These pseudoallergic reactions could be largely attributed from high levels of contaminants in the mixtures of Cr-El and PS80 which are impossible to be completely eliminated, and which are believed to result from radical synthesis.

[130] Unlike Cr-EL or PS80 which are a complex mixtures of amphiphilic lipid molecules; the lot-to-lot variation of the PEG-saccharide-lipid conjugates disclosed here can be readily controlled. For instance, in various embodiments of the PEG-saccharide-lipid conjugates of the disclosure, the fatty acid-related impurities can be limited to 5 wt% or less. In contrast, the limits of the fatty acid-related impurities are up to 40% for PS80 and up to 25% for Cr-EL as defined in the polymer monographs of European Pharmacopoeia or US Pharmacopoeia.

[131] Described below are toxicological and pharmacological safety evaluations of selected PEG-saccharide-lipid conjugates of the disclosure. For example, there was no pseudoallergic reaction observed from doses up to 200 mg/kg intravenously in minipig studies and up to 2000 mg/kg orally in dog studies.

[132] The chemical stability of polysorbates versus the PEG-saccharide-lipid conjugates described herein is a major area of differentiation between the two polymeric materials. The ester bond in a pure oleic acid (i.e., 98%)-made polysorbate 80 (PS 80) is still more sensitive or degradable when compared to the amide bond in various PEG-saccharide-lipid conjugates of the disclosure, which can make PS80 more sensitive to degradation. For example, a study showed that the concentration of PS80 rapidly declined to levels <0.05% (v/v) of the plasma volume within 15 min after a bolus injection in mice and the recovery was only 66% of the initial concentration of PS 80. In direct comparison, the recovery of (intact) DOPS-12 was ~ 98% in mouse plasma, While the cause of pseudoallergy is unclear, it could be largely attributed to either high levels of contaminants in the mixtures of PS80 which are impossible to completely eliminate or polysorbate 80 undergoing intrinsic self-oxidation yielding reactive hydro- and alkyl-peroxides.

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

[134] 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 PEG- 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.

[135] 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% PEG-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.

[136] The conjugates of the disclosure can also be used in solid dosage forms. For example, in one example of a preparation, PEG-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 wax-like mixture can solidify when cooled. The material can proceed to encapsulation or tableting. One example of a formulation is described below:

[137] Another aspect of the disclosure is a conjugate as described herein, for use as a pharmaceutical excipient, or for use as in a medicament. [138] Another aspect of the disclosure is a therapeutic composition comprising a conjugate as described herein and a therapeutic agent.

[139] 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.

[140] 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.

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

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

[143] 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.

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

[145] 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.

[146] 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. 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 = lo ((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.

[147] While for many non-ionizable therapeutic agents log P (i.e., as measured using water as the aqueous phase) is about the same as log D7.4 or a log D at any other pH value (i.e., using a buffer as the aqueous phase), this may not the case for many other therapheutic agents, especially for ionizable therapheutic agents. The log D value for such therapheutic agents will change with pH, depending, e.g., on the various ionization states of the therapheutic agent at a specific pH, including ionized, partially ionized, and nonionized species. Various pharmaceutical compositions of the disclosure can have varying pH values, e.g., in the range of 3-9. Accordingly, it can be desirable to ensure solubility at a desired pH of a desired formulation. Moreover, the use of the conjugates of the disclosure are nonionic, and can be suitable for use at a variety of pH values. The person of ordinary skill in the art can provide pharmaceutical compositions of the disclosure having a variety of pH values, e.g., in the range of 3-4.5, or 4-5.5, or 5-6.5, or 6-7.5, or 7-8.5, or 8-9. The person of ordinary skill in the art will use suitable buffers and pH adjustments as necessary.

[148] Moreover, the conjugates of the disclosure can be desirable for use with therapeutic agents that, even if reasonably water soluble at some pH values, are not highly water soluble at other pH values. For example, in various embodiments of the compositions, methods and uses of the disclosure, the therapeutic agent has a log Dx 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 Dx 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 Dx value of at least 4, e g., at least 4.25, at least 4.5 or at least 4.75. In various embodiments, the D_x value is a Ds value, a D&s value, or a D9 value. Log Dx values are determined using the shake-flask method described above. Similarly, in various embodiments, the therapeutic agent has a water solubility in a buffer of pH X 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 a buffer of pH X 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 a buffer of pH X 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 such embodiments, X is 3, or 3.5, or 4, or 4.5. In various such embodiments, X is 5, or 5.5, or 6, or 6.5, or 7. In various such embodiments, X is 8, or 8.5, or 9. Solubilities and log Dx values are determined using 0.1 M citric acid/sodium citrate-buffered saline for pH up to 5.8; 0.1 M phosphate-buffered saline for pH 5.8-8.0, and bicine buffered saline above pH 8.0.

[149] 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.

[150] 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.

[151] 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. [152] 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:l - 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:I.

[153] 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%.

[154] 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%.

[155] 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%. [156] 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%.

[157] 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.

[158] 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, a capsule or granules. 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

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

EXAMPLES

[160] 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, methoxypolyethylene glycols or polyethylene glycol (PEG) 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 PEG-saccharide-lipid conjugates used in the studies were made in-house by LipoSeuticals Inc. (Monmouth Junction, NJ, USA).

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

[162] A high yield and effective catalyst-free and room temperature synthetic method was reported previously (Weiszhar Z., et al (2012). Eur J Pharm Sci. 45(4):492-8) and used with slight modification. To a solution of starting compound in MeOH, di -/-butyl di carbonate 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 Na2SO4 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

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

[164] 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 CH2CI2. The resulting solution was stirred at room temperature for overnight and the solvent was evaporated and the residue was re-dissolved into CH2CI2, then washed with saturated NaHCCh and dried over M SO4. Solvent was evaporated and was used in next step without further purification.

[165] Example 3. Preparation of Boc-l-animohexamethyleneamine

[166] 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, totally 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.

Chemical Structure 6

[167] Example 4. Preparation of cholic chloride

[168] 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. 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.

[169] Example 5 Preparation of Boc-protected 1,3 -propanediamines

[170] Following the same steps in Example 3 and the crude product obtained with a yield of 85-105% (Chemical structure 8)

Chemical structure 8

[171] Example 6. Preparation of mesylated polyethylene glycol monomethoxyl ether [172] Polyethylene glycol monomethoxyl ether (mPEG)-550 (100 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 0.5N HC1 twice. The organic layers were collected and dried over sodium sulfate (10 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: 100-110 g, 90-110% yield).

Chemical Structure 9

[173] Example 7. Preparation of Boc-aminopropylamine-mPEG

[174] Formation of the C-N bond was by the N-alkylation of amine of the center backbone with the activated hydroxyl of the PEG. In a 1 -liter round-bottomed flask equipped with a mechanic stirrer and a heating mantle, Boc-aminopropyleneamine from Example 5 (135 g) was mixed with the mesylated mPEG from Example 6 (114 g) 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 CH2CI2 was added to the residue. The solution was washed with 50 mL each of water and 2/VNaOH. The Organic layer was collected and dried over Na2SO4, solvent removed to afford Boc- aminopropaneamine-mPEG (Chemical Structure 10), the crude product was transferred to the next step without further purification.

Chemical Structure 10

[175] Example 8. Preparation of Preparation of Boc-aminopropaneamine-mPEG-Oleate

[176] The crude product (90 g) from Example 7 was dissolved in methylene chloride (800 mL) in a round bottom flask (2 L) equipped with a mechanical stirrer. In a separate container, oleoyl chloride (100g) was dissolved in methylene chloride (200 mL) and slowly added to the Boc-aminopropaneamino-mPEG 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 was removed under vacuum (Chemical Structure 11 70-75% yields).

Chemical Structure 11

[177] Example 10. Preparation of Preparation of 1,3-propanediamine-lactobionate-mPEG Oleate (DOPS-12)

[178] The steps of Example 2 were followed to remove the protection group from the Boc-aminopropaneamine-mPEG-oleate product of Example 8 to free the hP-amino group. The resulting product (200g) was dissolved in 400 mL of CH2CI2 (DCM) and transferred to a IL round-bottomed flask equipped with a mechanical stirrer. Triethylamine (24 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 (81 g) 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 (0.1N) or NaOH (0.1N) 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. The product was further lyophilized to a yellowish wax (Chemical Structure 2: 70-80% yields).

[179] Using the intermediate from the Example 5 and following the steps in Examples 7, 8 and 9, Choloypropanediamino-mPEG-lactobionate conjugate (Chemical Structure 5) was prepared: [180] Examples 3 to 10 are suitable for making a PEG-sacchari de-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, taurochenodeoxy cholic acid, glycochenodeoxy cholic acid, chenodeoxy cholic acid, and lithocholic acid. As described above, in various desirable embodiments the mPEG group has in the range of 8 to 45 subunits.

[181] 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 PEG-saccharide-lipid conjugate comprising the following structures:

where n is as descried in any embodiment above

[182] Example 11 Chromatography Profile of PEG-saccharide-lipid Conjugates

[183] Individual fatty acid based FA-propanediamino-mPEG(12)-lactobionate conjugates were made according the synthesis described in the present disclosure. The analytical procedure for assay and related compounds of PEG-saccharide-lipid conjugates was a reversed-phase, isocratic HPLC method. The chromatographic conditions are presented in Table 3:

Table 3

[184] The purity and related analogues among these fatty acids may be monitored by the same method, concentrations of approximately 5 mg/mL each of the said polymers were prepared in pure methanol and injected 10 pL each onto the column. Figure 1 shows the resulting chromatogram. A chromatograph of a large-scale batch of DOPS-12 (DOPS-F02) prepared according to Example 10 is provided in Figure 2 and similarly linoleoylpropanediamino-mPEG-lactobionate conjugate and its isoform prepared as the same manner as for DOPS-12 is provided in Figure 3. [185] The relative retention times (RRT) of individual peaks to DOPS-12 (as the RT reference) of each of the fatty acid based PEG-saccharide-lipid conjugates is calculated with the following equation:

Retention time o f individual FA RRT - - ^J- -

Retention time of DOPS— 12 in which the RRT of DOPS-12 = 1.00; the retention time of individual fatty acid is in minutes, the comparison should be in the same chromatogram or same sequence run. Representative RRT is listed in Table 4, with particular analogs defined as how they differ from DOPS-12 (e.g., in the fatty acyl group, or in the saccharide as for gluconic acid):

Table 4

¹ in the range of RRT ± 0.2 to ± 0.5

² positional isomer of Linoleic acid (a different double bond location)

[186] In some embodiments, the HPLC profile of the PEG-saccharide-lipid conjugates made by the present disclosure can exhibit the relative retention time to match the same in Table 4 using the assay procedure described in Example 11 .

[187] Example 12 Screening Test of Hemolytic Potential

[188] Test articles were prepared in triplicate in PBS (phosphate buffered saline) /2.5% glucose buffer at pH 7.4 at 100, 10 and 1 g/L corresponding to 10, 1.0 and 0.1%. 2% RBC (red-blood-cell) from two human donors was suspended. 2 mb aliquots of this cell suspension were supplemented with various concentrations of substances to be tested and the incubation was continued with shaking (on a benchtop tube shaker) for approximately 60 minutes at 20

± 2 °C. The lysis of erythrocytes was followed by measurement of the hemoglobin released into the solution after removal of the intact cells by centrifugation. The degree of hemolysis was calculated according to the formula: % of hemolysis = 100 x EH/EK in which EH represents the optical density measured at 540 nm of the supernatant of the test article-cell reaction mixture and EK represents the optical density at the same wavelength of a supernatant of completely hemolysed erythrocytes (a 10% Saponin as the positive control). Results (n =3) as unit % hemolysis are summarized in Table 5.

Table 5

[189] In Table 5, Solutol HS15 = Polyethylene glycol 12-hydroxy stearate (the FDA approved intravenous excipient); TPGS = d-a-Tocopherol polyethylene glycol 1000 succinate (the FDA approved oral excipient). CDPS-12 = choloylpropanediamino-mPEG(12)- lactobionate; DOPS-12 = oleoylpropanediamino-mPEG(12)-lactobionate; DOPS-H12 = oleoyl-hexanediamino-mPEG(12)-lactobionate; OPS-12 = oleoylputrescinediamino- mPEG(12)-lactobionate; DSPS-12 = stearoylpropanediaminomPEG(12)-lactobionate; DCPS- 12 = cholesteryl(oxyethoxy)acetyldiaminopropane-mPEG(12)-lactobionate; DMPS-12 = myristoylpropanediaminomPEG-(12)-lactobionate; TOPS-12 = oleoylbis(3-aminopropyl)- amine-mPEG( 12)-lactobionate

[190] In general, a value greater than 2% is considered as hemolysis for samples at pM level. While the concentrations of the test articles at 10% tested were relatively higher for such experiment, the results should indicate a relative high hemolytic potential if hemolysis is greater than 5% for the demonstration purpose. [191] The results demonstrated that DOPS-12 (Figure 4A), DMPS-12 and DSPS-12 are the safest excipient as compared to others including Polysorbate 80 and Solutol Hl 5 of the two regulatory approved parenteral excipients (polysorbate 80 and Solutol Hl 5) at a high concentration of 10% level.

[192] For the same lipid group, the triamine (TOPS-12) or di aminohexane (DOPS-H12) centered polymers were not suitable for the parenteral application due to the high level hemolytic potential (Figure 4B). For the same center backbone, increase in hydrophobic or steric size of the lipid groups such as cholesterol (DCPS-12) may also attribute a higher hemolytic potential.

[193] One feature or aspect of an embodiment of the present disclosure, these PEG- saccharide-fatty acid conjugates centered with shorter distance (no more than 4 carbons) between the two terminal diamines are suitable for parenteral application and a longer chain (more than 4 carbons) PEG-saccharide-lipid conjugates may be suitable for oral administrations. Furthermore, a bulkier lipid group such as cholesterol may not be suitable for intravenous administration even if a short chain diamine was utilized.

[194] Example 13 Long-term Storage Stability

[195] Product stability is another key for clinical applications. Bulk samples from a pilot batch of DOPS-12 were evaluated in a formal stability study. 500-600 grams samples of DOPS-12 were packaged in a package configuration that is representative of a commercial package at a ratio (weight to volume) of 0.6 to 1.1 (kg/L). The materials of construction for the polyethylene containers are representative of commercial packaging. Three sets of DOPS-12 were packaged in this manner and tested by the HPLC procedure described in Example 11. No significant change was observed in related analogs or impurities and physical description after 6 months at 40°C/75% RH (relative humidity) and 36 months at 25°C/60% RH (Figure 5).

[196] Example 14 Toxicokinetics (TK) profile of DOPS-12 in Yucatan Minipigs

[197] Due to the tendency of polymer accumulation in body, intravenous dosing study in large animals was a great challenge since no prior knowledge or published reference available. The TK study was part of a 28-day Toxicity study performed by repeated intravenous dosing in Yucatan minipigs under a GLP study protocol approved by the institutional Animal Care and Use Committees (IACUCS). DOPS-12 (also known as DOPS- 12) solutions were administered to both male and female Yucatan minipigs having an age at 7 to 8 months and a weight between 27 and 33 kg (S&S Farms, Ramona, California) with a fixed dose of 2 mL/kg for a targeted dose of 200 mg/kg for up to 28 days. The actual dosing strength ranged from 193 mg/kg to 207 mg/kg (n=6) by 90 minutes infusion. The TK up to 36 hrs post the last dose on Day 28 is used as the Example herein.

[198] As presented in Figure 6, a liquid chromatography with tandem mass spectrometry (LC-MS-MS) was used for the TK plasma samples assay and the TK data were analyzed using a WinNonlin program (ver. 5.3, Pharsight, Mountain View, CA) non-compartmental pharmacokinetic method under the assumption of linear PK (NCA model 202 for constant infusion). Parameters analyzed included the maximal plasma concentration (C_max) and time to maximal plasma concentration (T_max), area under the plasma concentration curve from time zero to 36 hours (AUCo-36hr), area under the plasma concentration curve to infinity from time zero to infinity (AUCo-inf), half-life (h/₂) and systemic clearance (CL). The concentrations at the last TK timepoint were also included to determine the remaining DOPS-12 after 36 hours. The mean C_max values after the last intravenous dose were 2842.6 ± 332.7 pg/mL and 2768.0 ± 257.3 pg/mL for male and female dosed, respectively. For the male dosed animals, the mean ti/2 was 33.6 hr ranging from 29.9 to 36 hours and the mean ti/2 was 38.7 hr ranging from 31.4 to 51.9 hours with the mean CL 0.0017 mL/hr kg after the last dosing. For the female dosed animals, the mean ti/2 was 32.7 hr ranging from 31 to 34.2 hours with the mean CL of 0.005 mL/hr kg. The mean AUC o-36hr) was 62050.5 ± 4670.4 hr-pg/mL for the male dosed animals; the mean AUC<o-36 hr) was 56909.4 ± 3495.4 hr-pg/mL post last dose for the female dosed animals, respectively. Toxicokinetic Parameters of DOPS-12 in the minipigs from a 90 min infusion of 200 mg/kg following last iv administration are summarized in Table 6 and Figure 7. A slow elimination indicated a longer half-life (ti/2) due to a slow rate of clearance. Even though with a polymer accumulation due to a slow clearance, DOPS-12 was well -tolerated by minipigs. This demonstrates suitability for parenteral applications.

Table 6

F = female; M = male; ti/2 = half-life; T_max = time to maximal plasma concentration

[199] Example 15 DOPS-12 Oral Toxicity in Juvenile Beagle Dogs

[200] The study was under a GLP study protocol approved by the institutional Animal Care and Use Committees (IACUCS). The animals were aged at 11 to 13 weeks and randomly assigned to 4 groups, with 3 to 5 dogs/sex each dose groups. The dose levels were selected after initially dosing at 2000 mg/kg and 1000 mg/kg. While both dose strengths were well tolerated, 1000 mg/kg was chosen for the continued study due to the sample availability. They were orally administered with control article (sterile water for injection) or DOPS-12 (or DOPS-F-2) dose formulations (DOPS-12 in sterile water) at 600, 800 and 1000 mg/kg once daily for 90 consecutive days, using a dose volume of 5, 3, 4 and 5 mL/kg, respectively. [201] Body weights in the dosed female and male dogs exhibited no abnormalities in body weight or food consumption during the dosing phase and the recovery phase (Figures 8A and 8B). All of the dogs were grown at a normal pace during the study period and no remarkable adverse reaction was found in the juvenile dogs in the study.

[202] Example 16 DOPS-12 Oral TK in Juvenile Beagle Dogs

[203] Following the general procedure of Example 14, blood samples of animals in DOPS-12 groups were collected at predose and 0.5 h, 2 h, 4 h, 12 h, 24 h and 36 h (selectively on the last dose on the Day 90) post-dose. The actual body exposure to DOPS-12 between female and male groups was similar based on the mean AUC values (Figures 9A and 9B), the dose exposure was 10,500 10,600 and 18,400 h-ng/mL in females and 12,100, 12,900 and 12,700 h-ng/mL in males corresponding to 600, 800 and 1,000 mg/kg on Day 1; the dose exposure was 19,600, 19,700 and 23,900 h-ng/mL in females and 17,700, 22,000 and 23,200 h-ng/mL in males corresponding to 600, 800 and 1,000 mg/kg on Day 90, respectively. Therefore, the difference in DOPS-12 exposure was considered to be insignificant between the female and male groups. A dose accumulation was observed and the mean AUC value was increased with a narrow AUC range. The dose exposure was slightly increased from 600 mg/kg to 800 or 1000 mg/kg on Day 90; this may be largely attributable to the dose accumulative effects.

[204] DOPS-12 exhibited no remarkable adverse signs during the 90-day repeated dosing study. In contrast, mild and transient clinical signs of hypersensitivity reaction including erythema, edema, and scratching were observed from approximately 20 to 60 min post-dose in 1/3 animals at 10 mg/kg oral doses of Polysorbate 80.

[205] Using nonrodent animal models for the safety evaluations on new molecules is always preferable since the concordance rates between animal and human toxicity have been shown to be about 71% when all species are considered, with nonrodents alone predictive for 63% and rodents for 43% of the events. Notably, the data for the animal models presented here is much more probative than rodent data, and as such cannot be directly compared with rodent data in prior studies.

[206] Example 17 DOPS-12 Oral Bioavailability in Juvenile Beagle Dogs

[207] The study was under a study protocol approved by the institutional Animal Care and Use Committees (JACUCs). The animals were administered with DOPS-12-saline solution intravenously by a short infusion at a dosing level of 3 mg/kg or a dosing volume of 0.2 mL/kg. Blood samples were collected at predose, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h and 24 h postdose. A LC-MS/MS method was used to determine the concentration of DOPS-12 in the dog plasma. Related PK parameters were calculated with a non-compartment analysis model using Phoenix WinNonlin 8.2 (Certara, Princeton, New Jersey). Following a single intravenous dose of DOPS-12 at 3 mg/kg level (Figure 10), AUCo-24of plasma DOPS- 12 was 90600 and AUCo- / was 91200 for the female dog; AUCo-24was 133000 h-ng/mL and AUCO-QO was 135000 h-ng/mL for the male dog, respectively. Cmax was 27200 ng/mL, CL was 32.9 mL/h/kg for the female dog; Cmax was 43300 ng/mL, CL was 22.3 mL/h/kg for the male dog, respectively. The half-life (ti/2) was very similar; 3.72 h for the female and 3.97 h for the male respectively. The absolute oral availability (F_abs) can be estimated using the following equation:

AUC_oraixDose_iv abs = 100 %

AUC_iv x Dose_oral

Based on the dose exposures (Example 15), the bioavailability of DOPS-12 is 0.03% on Day 1 and 0.05% on Day 90 for male dogs; the bioavailability of DOPS-12 is 0.06% on Day 1 and 0.05% on Day 90 for female dogs, respectively. A low bioavailability of the polymer as a solubility enhancer is especially beneficial for clinical applications.

[208] Example 18 Experiments on Solubility Enhancement

[209] To establish the solubility enhancement, a determination of the amounts of a polymer required to solubilize a hydrophobic solute was made. Direct comparisons made with the solubility of 1% propofol in variable concentrations or polymers and the results from different polymers and concentrations presented in the Table 7 below and judged by whether a clear solution was achieved.

Table 7

[210] In some embodiments, conjugates of the disclosure have one or both of the following features:

• Oligomer purity of a PEG-saccharide-lipid conjugate is greater than 85% or a labeled nominal value of the polymer is between 85.0% and 115.0%; and

• Individual related analogue or impurity is less than 5%.

[211] Example 19 Toxicity Estimation on Polymer Structures

[212] The hemolytic potencies of surfactants have been studied regarding surfactant physico-chemical parameters and descriptors such as the critical micellar concentration (CMC), the hydrophile-lipophile balance (HLB) and the surfactant partition (oil/water) coefficient (LogP, or log D7.4). Studies indicated that an increase in the hydrophobic chain length promotes the membrane and surfactant binding with a partition coefficient rise. This leads to destabilize the membrane and minimum surfactants concentrations will be able to destroy the membrane. In another hand, the increase of hydrophilic group volume due to its length or flexibility enhancement promotes a conical geometry of the monomer and the membrane curvature generated by the surfactant. Consequently, the surfactant has a higher destabilizing effect, enhancing its hemolysis property. In the case of certain polyoxyethylene ethers, the hemolytic activity increases with the hydrophilic chain length. However there is no valid method(s) to make a prediction and due to the complexity of nature of polymers. Results showed that LogP or HLB is not valid or reliable method for estimation or prediction since there was no a correlation found between the hemolytic teats and the HLB or LogP values (Table 8) in compared to the laboratory results, whereby a suitable PEG-saccharide- lipid conjugate for clinical applications has to come from the experimental testing or studies, not by a prediction or presumption.

Table 8

¹ Partition coefficient calculated using MarvinSketch (Chemaxon, Budapest, Hungary)

² Hydrophilic-lipophilic balance calculated by MarvinSketch based on Griffin method

[213] In various embodiments, the Example conjugates prepared from mPEG(12 subunits) have an HLB values in the range of 13-15 as calculated using the well-known Griffin method. The HLB value will be increased with longer PEG chains, e.g., HLB = ~ 17.3 with 45 ethylene glycol subunits. Herein it is preferable to have an HLB value in the range of 13-18., e.g., 14.5 - 15.5 or 15 - 17.5, as determined by the Griffin method.

[214] Every PEG-saccharide-lipid conjugate has its unique characteristics affecting safety and solubility enhancement, surprisingly certain short diamine as the center backbones exhibited less biological activity than others, even if the difference is only by a few methylene groups between the two terminal amines for the same configuration and carriers, e.g., DOPS-12 (1,3-Diaminopropane centered) versus DOPS-H12 (Hexamethylenediamine centered). The polymer structures based on the shorter diamines exhibit a lower hemolytic potential in comparison with materials based on triamine (TOPS-12) or longer-chain diamines (DOPS-H12) or bulkier lipid moiety (DCPS-12). [215] Example 20 Purification of PEG-saccharide-lipid Conjugates

[216] After most impurities removed by “work-up” at end of the synthesis, solvent residual is often a safety concern. Since the polymers are highly soluble in both organic solvent and water, hence a cleanup process was developed for removing any hazardous residual solvents for the polymers. First the polymer was re-dissolved in pure USP grade ethanol at a weight to weight ratio of 1 to 1, and then removed under vacuum at 35 - 40 °C. The alcohol rinsed polymer was then re-dissolved in pure water (USP grade or better) at a weight to weight ratio of 1 to 3. The polymer solution was transferred into suitable drying trays and placed into a - 45°C freezer overnight.

[217] Cooled the shelves of the Lyophilizer to approximately - 50 °C and loaded the trays which were kept below - 45 °C for a minimum of 8 hours. Set the vacuum to between 50 and 100 millitorr, the shelves to between -30 and -35 °C and maintained at - 32 ±3°C for at least 55-65 hours. When the system pressure reached - 50 mtorr or lower, reduced the chamber pressure and heated the shelves to between 22 and 25°C. Maintained at 22 ±3°C until the product temperature was above 20°C for at least 6 hours, then vented the chamber to partial vacuum Brought the chamber to atmospheric pressure, and unloaded the trays. Figure 11 showed a sample freezing dried polymer (DOPS-12) with a solid and pleasant appearance, only trace amounts of alcohol (< 0.5%) was detected and all other solvents were almost completely removed; either no detectable (USP class II residual solvents) or < 0.5% (USP class III solvents).

[218] Alternatively the polymer can be dried using a spray drying process, e.g., a 10% to 20% of DOPS-12 concentrate in ethanol was flowed into a dryer which was set with following parameters:

Spray dryer: 5L/hr

Air Blower: 40Hz

Inlet Temperature: 79 °C (76 to 82°C)

Outlet Temperature: 30°C (25°C - 35°C)

Flow Rate: 10 to 15 gm/min (or 600g to 900g/hr)

De-Block piston setting: 300

Spray Pressure: 0.2Mpa

Needle Pressure: 0.3Mpa

Cooling water setting: 10°C

Nitrogen generator setting: As needed. [219] In various embodiments, a drying process can be used in the compounding process, for example, using a lyophilizer or a spray dryer. Active pharmaceutical ingredient (API) is co-dissolved with the conjugate in a solvent such as water, alcohol or acetone, and then dried as appropriate using a lyophilizer (when water is used as the solvent) or a spray dryer.

[220] In various embodiments of the disclosure it can be desirable to control the starting materials with specified qualities. One of the three main components in PEG-saccharide-lipid conjugates is fatty acid such as oleic acid which is from a natural source. Even though the manufacturers certified that content of oleic acid is in in upper 80% range, a refining process may be desirable to remove other saturated and unsaturated fatty acids. The second component is a saccharide acid such as lactobionic acid, an oxidative product of lactose which is also from a natural source, therefore certain monosaccharides such as galactose or glucose may be co-existed in lactose, which produces a small quantity of other sugar acids, e.g., galacturonic acid or glucuronic acid, upon oxidation. In addition, monomethoxypolyethylene glycol ether is a mixture of polyethylene chains which is typically ranging from 5 to 10% of the targeted molecular weight per the USP limits. Hence a set of specifications is desirable to control the polymer quality, e.g., the purity assay by the HPLC as demonstrated in Example 11.

[221] Example 21 Active Systemic Anaphylaxis Study in Mice

[222] The study was for the determination of any potential of PEG-saccharide-lipid conjugate to induce or prevent anaphylactic reaction by intravenous administrations. The mouse models of systemic anaphylaxis are important tools for the elucidation of the pathomechanisms of anaphylaxis, and for identifying and characterizing potential therapies for anaphylaxis. Hypothermia serves as the primary quantifiable indicator of anaphylaxis in these models.

[223] This study was under a study protocol approved by the institutional Animal Care and Use Committees (IACUCS). Groups (G#) of 6 animals received single sensitizing injections ofNormal saline (Gl), Positive Control-Ovalbumin [OVA]- 100 pg/animal (G2), test article, 350 mg DOPS-12/kg (G3) to 500 mg/kg body weight (G4) by the intraperitoneal route. Adjuvants-pertussis toxin and aluminum potassium sulfate were used for sensitization of Gl, G2 and G3 groups. After a rest period of 21 days, the animals were challenged with 500 pg OVA/animal (Gl and G2 group), 350 mg/kg test article (G3 and G4 group), by the intravenous route. Clinical signs and mortality were observed twice daily on sensitization day and once a day on other days. On the day of challenge, rectal temperature was measured at pre-treatment and 5, 15 and 30 minutes or until death and observed for clinical signs at 5, 10, 15, 20, 25 and 30 minutes or until death, post challenge.

[224] Ataxia, recumbency, slight tremors, slight lacrimation (clear discharge), dyspnea, slight piloerection was observed in G2 (positive control) animals at 5 to 25 minutes. All animals died at 10 to 25 minutes, post challenge. All mice of G2 group developed anaphylactic symptoms and experienced a steep decrease in body temperature. There were no clinical signs or mortality, change in the rectal temperature in Gl, G3 and G4 groups, post challenge. There was no effect on body weight gain and no abnormalities on gross necropsy. The experiment validity was confirmed via a positive response using positive control Ovalbumin, which elicited signs of anaphylaxis, hypothermia resulting in mortality. No response was observed in the vehicle and test article treated groups. These results concluded that test article DOPS-12 did not demonstrate the potential to produce IgE (reagenic) antibody in the mouse active systemic anaphylaxis model under the testing conditions employed.

[225] Example 22 Passive Systemic Cutaneous Anaphylaxis Study in Rats

[226] The study was under a study protocol approved by the institutional Animal Care and Use Committees (IACUCS). This study of passive systemic anaphylaxis (PSA) was to assess the presence of IgE (reagenic) antibody as the primary quantifiable indicator of anaphylaxis for identifying and characterizing potential clinical applications of PEG-sacchari de-lipid conjugates.

[227] Groups of 4 animals received three sensitizing injections of Vehicle control- Normal saline (Gl), Positive Control- Ovalbumin (OVA) +Aluminum potassium sulfate dodecahydrate (ALH) [OVA+ALH]- 100 mg of OVA + 12 mg ALH/rat (G2), test article, DOPS-12 - 10 mg/rat [200 uL/rat of 50 mg/mL test article formulation] (G3). On days 1, 3 and 5, the respective groups were administered with vehicle control and positive control through intraperitoneal route and test article by intravenous route. On day 10, all the sensitized animals were euthanized using Isoflurane anesthesia, blood collected, serum separated, pooled and stored under 2 to 8 °C for 4 days, for use to challenge. Five naive animal s/group- Gia, G2a and G3a were passively sensitized by intradermal injection (0.1 mL/site at two sites) of sera [1 :2 (50%) and 1 :4 (25%) dilutions of serum with normal saline and undiluted serum] from the donor animal s-Gl, G2 and G3, respectively. Approximately, 24 hours later the intradermal sensitized animals were injected with 0.6 mL of vehicle control or positive control (10 mg/mL OVA) or test item (50 mg/mL) + 0.4 mL of Evan’s blue (1% w/v in normal saline) together by intravenous route. Approximately 30 minutes postdose, the animals were euthanized using Isoflurane anesthetic, the skin excised, inverted and the diameter of blue spots were measured, recorded and photographed.

[228] There were no clinical signs of toxicity or mortality, no effect on body weight gain and no abnormalities on gross necropsy in any DOPS-12 treated animals. The Passive Cutaneous Anaphylaxis response [PCA] (Mean ± SD) as measured by the blue spot diameter (mm) listed in Table 9:

Table 9

[229] The experimental validity was confirmed via a positive response using positive control Ovalbumin, which elicited positive PCA response of 1.68 mm, 7.35 mm and 12.18 mm blue spot diameter corresponding to 25% serum, 50% serum and undiluted serum, in comparison to vehicle-treated group. No response was observed in the test article treated group. Based on these results it is concluded that test article DOPS-12 did not demonstrate the potential to produce IgE (reagenic) antibody in the rat passive cutaneous anaphylaxis model under the testing conditions employed.

[230] Example 23 Solubility enhancement of DOPS-12

[231] PEG-saccharide-lipid conjugates based water soluble dosages are useful in the areas of oncology and non-oncology medicines and bioavailability (BA) enhancements for those medicines with a low BA, especially caused by gastrointestinal metabolism. For orally disintegrating tablets or sublingual tablets or buccal tablets, the size of a tablet is limited and typically less than 500 mg which is possible with the said polymers such as DOPS-12. In order to form a stable solution after dissolved in water, a typical weight ratio of a said polymer to active pharmaceutical ingredient (API) is summarized in Table 10. Table 10

¹ For a standard human of 60 kg.

[232] Only partial examples given in Table 10, wherein the weight ratio of the PEG- saccharide conjugates to an oncology compound is between about 200 (e.g., about 50) and about 1 for the drug delivery and similarly, the weight ratio of the PEG-saccharide-lipid conjugates to a non-oncology compound is between about 200 and about 1 for the compound delivery.

[233] Example 24 Determination of Critical Micelle Concentration of DOPS-12

[234] The testing instrument used for performing the critical micelle concentration (CMC) tests was a Surface Tensiometer model DY-700 (Kyowa Interface Science Co., Ltd., Tokyo, Japan). DI water (50 m ) was placed in a testing container, and the corresponding DOPS-12 solution was placed in the Auto Buret to control the addition volume. The DOPS-12 solution (0.6 mg/mL) was then added by controlled volumetric additions to the testing solution. After each addition, the testing solution was stirred for 30 seconds and allowed to rest for 60 seconds before measuring the surface tension. This process was repeated until the end of the titration.

[235] The results of the CMC tests are shown in numerically and graphically in Figure 12. To calculate the CMC, two lines were fit to plots and the intersection of the two lines was determined (Figure 3). The lines were fit such that the R2 values of the fits were > 0.999. The data points used for the fitting and the actual fitted lines are indicated in the Figure. The CMC was determined to be 12.67 mg/L or approximately 0.01 mmol. For optimal solubility enhancements, the conjugate present in aqueous solution in an amount above its critical micelle concentration is preferably less than 0.1 mmol, e g., 0.005- 0.01 or 0.02 - 0.05.

[236] Example 25 PEG distribution in DOPS-12

[237] A LC-MS was used for the determination of the PEG distribution profile inDOPS- 12. The method parameters are summarized as follows:

Chromatography Conditions

Parameter Setting

Column ACQUITY UPLC BEH C₈, 1.7pm, 2.1 50 mm, Waters

Mobile phase 0.1% formic acid/acetonitrile = 6/4

Injection volume 0.5 L (1 mg/mL)

Flow rate 0.4 mL/min

Mass Spectrometry Conditions

Parameter Setting

Ion source Electronic Spray Ion (ESF)

Scan time 3.5 min

Interface temperature 300 °C

DL temperature 250 °C

Heater temperature 400 °C

Nebulizer gas flow 2.50 L/min

Heater gas flow 10.00 L/min

Dry gas flow 10.00 L/min

QI scan: 300-1500 m/z

[238] As shown in Figure 13, the PEG distribution was in a narrow range as described throughout the disclosure, e.g., ± 5% of the targeted molar mass (mean = 1221 g/mol).

[239] The examples demonstrate the toxicology and pharmacology profiles of the fatty acid based PEG-saccharide conjugates centered with a short diamine which may appropriately enable development of novel therapies and robust pharmaceutical products, parenteral administrations in particular.

[240] In various embodiments as otherwise described herein, the PEG-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.

[241] 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.

[242] In various embodiments as otherwise described herein, the concentration of the PEG-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.

[243] In various embodiments, the present disclosure relates to methods for preparing and safely using a chemical compound as a water solubility enhancer or compound carrier, the compound having a molecular structure below:

in which Lipid is selected from the group consisting of fatty acid of Ce-Cis alkyl, bile acids of cholic acid and its analogues. m(PEG)n is polyethylene glycol monomethoxy ether ranging from 6 to 45 ethylene glycol units (i.e., n units).

[244] The present disclosure, in various embodiments, provides a novel PEG-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.

[245] Generally, in various embodiments the disclosure provides conjugates comprising a diamine backbone with a polymer (PEG) 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 PEG chains, carbohydrates or lipophilic groups. Furthermore, the terminal end of PEG chain may be a charged or polar moiety.

[246] 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 PEG- saccharide-conjugates may increase the in vivo targeted delivery of drugs and improve oral bioavailability of various drugs.

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

[248] In order to reduce possible immunogenicity, a shorter diamine backbone (m* < 2) is preferable; however ethylenediamine may not be highly desirable for a bulk carrier such as steroid acid, 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.

[249] 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 PEG as the first career; c. selecting a lipid as the second carrier; d. selecting a saccharide as the third carrier; and e. selecting a linker or linkers for coupling reactions of alkylation including JV-alkylation or (9-alkylation or esterification or etherification or amidation between carriers and center backbones.

[250] 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 group; g. bonding the first carrier to the central backbone; h. bonding the second carrier to the central backbone; i. removing the hydroxyl or amino protecting group; and j . bonding the third carrier to the central protecting group.

[251] 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.

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

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

[254] In various embodiments, the conjugate is a compound represented by the formulas of the General Structure 1 through 12.

[255] In various embodiments, the lipid group is selected from steroid acid including cholesterol, cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, chenodeoxycholic acid, and lithocholic acid.

[256] 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.

[257] In various embodiments, the PEG chain is substantially monodisperse, especially for intravenous administration of pharmaceutical agent. The substantially monodisperse PEG chain may contain a few numbers of oligomers of different chain lengths (e.g., different chains having n=12 but also n=l 1, n=13, etc.). The preferable number of oligomers is 1 to 10, although in many embodiments the number of oligomers is 3 to 10.

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

[259] In various embodiments, the PEG chain is a monomethoxypolyethylene glycol ether having an average molecular weight between 95.0% and 105.0% of the labeled nominal value if the labeled nominal value is below 1000 or between 90.0% and 110.0% of the labeled nominal value if the labeled nominal value is between 1000 and 2000.

[260] 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.

[261] 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.

Embodiment 1. A lipid/PEG/saccharide conjugate having the structural formula

wherein m has a number-average value in the range of 2-10;

L is -C(O)-R¹ in which R¹ is an alkanyl or alkenyl group having a number-average number of carbons in the range of 6-22, and/or is a steroid acyl group;

Embodiment 2. The conjugate of embodiment 1, 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. Embodiment 3. The conjugate of embodiment 1, wherein m has a number-average value of 3.

Embodiment 4. The conjugate of embodiment 1, wherein m has a number-average value of 2, or m has a number-average value of 4.

Embodiment 5. The conjugate of embodiment 1, wherein m has a number-average value in the range of 5-10, e.g., 5-8 or 8-10.

Embodiment 6. The conjugate of any of embodiments 1-5, wherein S is a disaccharide group.

Embodiment 7. The conjugate of any of embodiments 1-5, wherein S is a monosaccharide group.

Embodiment 8. The conjugate of any of embodiments 1-5, wherein S is a trisaccharide group.

Embodiment 9. The conjugate of any of embodiments 1-8, wherein saccharide units of S are individually selected from hexoses and pentoses and sugar alcohol, sugar acid and amino sugar analogs thereof.

Embodiment 10. The conjugate of any of embodiments 1-9 wherein saccharide units of S are individually selected from hexoses and sugar alcohol, sugar acid and amino sugar analogs thereof.

Embodiment 11. The conjugate of any of embodiments 1-10, 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.

Embodiment 12. The conjugate of embodiment 11, wherein any saccharide unit of S that is not directly bound to the nitrogen of the diamine is a sugar.

Embodiment 13. The conjugate of any of embodiments 1-12, wherein S has the structural formula

in which -(C_xiH2xiO_xi-i)-CO- is a sugar acyl residue derived from a sugar acid in which xl is 4 or 5, and (C_X2H2_X2-iO_X2-i)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof.

Embodiment 14. The conjugate of embodiment 13, wherein xl is 5 and x2 is 6.

Embodiment 15. The conjugate of any of embodiments 1-14, wherein S has the structure

Embodiment 16. The conjugate of any of embodiments 1-15, wherein S is lactobionyl or gluconyl, for example, lactobionyl.

Embodiment 17. The conjugate of any of embodiments 1-15, wherein S is a residue from gluconolactone or neuraminic acid, or 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.

Embodiment 18. The conjugate of any of embodiments 1-17, wherein L includes (or is) - C(O)-R', wherein R¹ is an alkanyl and/or alkenyl group having a number-average number of carbons in the range of 6-22.

Embodiment 19. The conjugate of any of embodiments 1-18, wherein R¹ has a numberaverage number of carbons in the range of 6-20, or 6-18.

Embodiment 20. The conjugate of any of embodiments 1-18, wherein R¹ has a numberaverage number of carbons in the range of 10-22, e.g., 10-20 or 10-18.

Embodiment 21. The conjugate of any of embodiments 1-18, wherein R¹ has a numberaverage number of carbons in the range of 12-22, e.g., 12-20 or 12-18.

Embodiment 22. The conjugate of any of embodiments 1-18, wherein R¹ has a numberaverage number of carbons in the range of 14-22, e.g., 14-20 or 14-18.

Embodiment 23. The conjugate of any of embodiments 1-22, wherein R¹ has a numberaverage number of carbons that is no more than 18. Embodiment 24. The conjugate of any of embodiments 1-23, wherein R¹ has a numberaverage number of unsaturations in the range of 0-3, e.g., 0-2.

Embodiment 25. The conjugate of any of embodiments 1-24, wherein R¹ is a linear alkyl or alkenyl group.

Embodiment 26. The conjugate of any of embodiments 1-25 wherein R¹ is 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.

Embodiment 27. The conjugate of any of embodiments 1-26, wherein L is -C Oj-R¹, and wherein -C^j-R¹ is at least 80 mol% of a single chemical identity, e g., at least 85 mol%.

Embodiment 28. The conjugate of any of embodiments 1-26, wherein L is -C Oj-R¹, and wherein -C Oj-R¹ is at least 90 mol% of a single chemical identity, e.g., at least 95 mol%.

Embodiment 29. The conjugate of embodiment 27 or embodiment 28, wherein the single chemical identity is cis-CH3(CH2)7CH=CH(CH2)?C(O)-.

Embodiment 30. The conjugate of embodiment 27 or embodiment 28, wherein the single chemical identity is cis,cis-CH3(CH₂)4CH=CHCH₂CH=CH(CH₂)7C(O)-.

Embodiment 31. The conjugate of embodiment 27 or embodiment 28, wherein the single chemical identity is cis-CH3(CH2)3CH=CH(CH2)7C(O)-.

Embodiment 32. The conjugate of embodiment 27 or embodiment 28, 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.

Embodiment 33. The conjugate of embodiment 27 or embodiment 28, 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)-.

Embodiment 34. The conjugate of any of embodiments 1-26, wherein L includes (or is) a steroid acyl group (e.g., a bile acyl group). Embodiment 35. The conjugate of any of embodiments 1-26 and 34, wherein the steroid acyl group is an acyl group derived from cholesterol, cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, chenodeoxycholic acid, and lithocholic acid (e.g., cholic acid, deoxycholic acid, or glycocholic acid).

Embodiment 36. The conjugate of any of embodiments 1-35, wherein “n” has a numberaverage value in the range of 5-45, e.g., 5-40, or 5-30, or 5-20, or 5-15, or 5-10.

Embodiment 37. The conjugate of any of embodiments 1-35, 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.

Embodiment 38. The conjugate of any of embodiments 1-35, 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.

Embodiment 39. The conjugate of any of embodiments 1-35, 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 40. The conjugate of any of embodiments 1-35, wherein n has a numberaverage value in the range of 18-28, e.g., 20-26, or 22-24, or 22.5-23.5, or 22.8-23.2.

Embodiment 41. The conjugate of any of embodiments 1-35, wherein n has a numberaverage value in the range of 25-40.

Embodiment 42. The conjugate of any of embodiments 1-35, 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.

Embodiment 43. The conjugate of any of embodiments 1-42, wherein R² has a numberaverage number of carbons of at least 0.95, e.g., at least 0.99 or at least 1.

Embodiment 44. The conjugate of any of embodiments 1-42, wherein R² has a numberaverage number of carbons in the range of 0.9-1.1, or 0.95-1.05, or 0.98-1.02.

Embodiment 45. The conjugate of any of embodiments 1-42, wherein R² is C1-C4 alkanyl, e.g., methyl or ethyl.

Embodiment 46. The conjugate of any of embodiments 1-42, wherein R² is methyl. Embodiment 47. The conjugate of any of embodiments 1-42, wherein R² has a number average number of carbons in the range 0-3, e.g., 0-2.

Embodiment 48. The conjugate of any of embodiments 1-42, wherein R² 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

Embodiment 49. The conjugate of any of embodiments 1-35, wherein the -P group is a methylated PEG residue having a number-average molecular weight in the range of 300-2200 g/mol.

Embodiment 50. The conjugate of any of embodiments 1-35, wherein the -P group is a methylated PEG residue having a number-average molecular weight in the range of 300-1200 g/mol, e.g., 300-600 g/mol.

Embodiment 51. The conjugate of any of embodiments 1-35, wherein the -P group is a methylated PEG residue having a number-average molecular weight in the range of 500-2200 g/mol, e.g., 500-1200 g/mol, or 500-900 g/mol.

Embodiment 52. The conjugate of any of embodiments 1-35, wherein the -P group is a methylated PEG residue having a number-average molecular weight in the range of 700-2200 g/mol, e.g., 700-1200 g/mol, or 700-1100 g/mol.

Embodiment 53. The conjugate of any of embodiments 1-35, wherein the -P group is a methylated PEG residue having a number-average molecular weight in the range of 475-525 g/mol.

Embodiment 54. The conjugate of any of embodiments 1-35, wherein the -P group is a methylated PEG residue having a number-average molecular weight in the range of 525-575 g/mol.

Embodiment 55. The conjugate of any of embodiments 1-35, wherein the -P group is a methylated PEG residue having a number-average molecular weight in the range of 710-790 g/mol.

Embodiment 56. The conjugate of any of embodiments 1-35, wherein the -P group is a methylated PEG residue having a number-average molecular weight in the range of 900-1100 g/mol, e.g., 950-1050 g/mol. Embodiment 57. The conjugate of any of embodiments 1-35, wherein the -P group is a methylated PEG residue having a number-average molecular weight in the range of 1800-2200 g/mol, e.g., 1900-2100 g/mol.

Embodiment 58. The conjugate of any of embodiments 1-57, wherein P has a poly dispersity index of no more than 1.1, e.g., no more than 1.07.

Embodiment 59. The conjugate of any of embodiments 1-57, wherein P has a poly dispersity index of no more than 1.06, e.g., no more than 1.05.

Embodiment 60. The conjugate of any not inconsistent embodiment above, wherein m is 3;

S has the structural formula as below:

in which -(C_XIH2_XIO_XI-I)-CO- is a sugar acyl residue derived from a sugar acid in which xl is 4 or 5, and (C_X2H2_X2-IO_X2-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)-R¹ is at least 80 mol% of cis-CH3(CH2)7CH=CH(CH2)7C(O)-, e g., at least 85 mol%;

R² is methyl; n has a weight-average value in the range of 11.5-12.5, e.g., 11.8-12.2; and

P has a polydispersity index of no more than 1.1, e.g., no more than 1.07.

Embodiment 61. The conjugate of any not inconsistent embodiment above, wherein m is 3;

S has the structural formula in which -(C_XIH2_XIO_XI-I)-CO- is a sugar acyl residue derived from a sugar acid in which xl is 4 or 5, and (C_X2H2_X2-IO_X2-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)-R¹ is 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 methylated PEG residue having a number-average molecular weight in the range of 525-575 g/mol and having a poly dispersity index of no more than 1.1, e.g., no more than 1.07. Embodiment 62. The conjugate of embodiment 60 or embodiment 61 , wherein xl is 5 and x2 is 6.

Embodiment 63. The conjugate of any of embodiments 60-62, wherein S has the structure

or is an open-chain version thereof.

Embodiment 64. The conjugate of any of embodiments 60-63, wherein S is lactobionyl.

Embodiment 65. The conjugate of any of embodiments 60-64, wherein -C(O)-R¹ is at least 90 mol% of cis-CH3(CH2)7CH=CH(CH2)7C(O)-, e.g., at least 95 mol%.

Embodiment 66. The conjugate of any of embodiments 60-65, wherein P has a poly dispersity index of no more than 1.06, e.g., no more than 1.05.

Embodiment 67. The conjugate of any not inconsistent embodiment above, wherein the conjugate has the structural formula of Chemical Structure 1 :

Chemical Structure 1 wherein m(PEG)_n is a methylated PEG residue.

Embodiment 68. The conjugate of embodiment 67, wherein the fatty acyl residue -C(O)- R¹ is derived from one or more of Lauric acid, Myristic acid, Palmitic acid, Linoleic acid, Oleic acid and Stearic acid.

Embodiment 69. The conjugate of any not inconsistent embodiment above, wherein the conjugate is Oleoyldiaminopropane-monomethoxypoly ethyl ene-glycol-ether-lactobionate (DOPS), which can be represented by the Chemical Structure 2:

Chemical Structure 2 (DOPS) wherein m(PEG)_n is a methylated PEG residue, and n is any desirable value as described above.

Embodiment 70. The conjugate of any not inconsistent embodiment above, wherein the conjugate is Stearylpropanediamino-monomethoxypolyethylene-glycol-ether-lactobionate, which can be represented by Chemical Structure 3 :

Chemical Structure 3 (DSPS) wherein m(PEG)n is methylated PEG residue, and n is any desirable value as described above.

Embodiment 71. The conjugate of any not inconsistent embodiment described above, wherein the conjugate is represented by Chemical Structure 4:

Chemical Structure 4 wherein m(PEG)_n is methylated PEG residue and n is any desirable value as described above, and m is in the range of 2-6, e g., is 3. Embodiment 72. The conjugate of any not inconsistent embodiment described above, wherein the conjugate is Choloylpropanediamino-mPEG-lactobionate (CDPS), which can be represented by Chemical Structure 5:

Chemical Structure 5 (CDPS) wherein m(PEG)n is methylated PEG residue, and n is any desirable value as described above.

Embodiment 73. The conjugate of any of embodiments 70-72, wherein the numberaverage value of n is in the range of 9.2-13.8, e.g., 10.2-13.2, or 11-13, or 11.4-13.6, or 11.5- 12.5, or 11.8-12.2.

Embodiment 74. The conjugate of any not-inconsistent embodiment above, having one of the following structures:

Embodiment 75. The conjugate of any of embodiments 1-74, wherein -P is provided from a P-H poly(ethylene glycol) source (e.g., an mPEG) that has a number-average molecular weight in the range of 95.0-105.0% of the labeled nominal value if the labeled nominal value is below 1000 g/mol, or in the range of 90.0-110.0% of the labeled nominal value if the labeled nominal value is in the range of 1000 and 2000 g/mol.

Embodiment 76. The conjugate of any of embodiments 1-75, wherein the conjugate has a purity of at least 85 wt% as measured by HPLC.

Embodiment 77. The conjugate of any of embodiments 1-76, wherein the conjugate has a purity of at least 90 wt% as measured by HPLC.

Embodiment 78. The conjugate of embodiment 76, wherein the conjugate is used in an oral application.

Embodiment 79. The conjugate of embodiment 77, wherein the conjugate is used in a parenteral application. Embodiment 80. The conjugate of any of embodiments 1-79, wherein the R’-C O)- group is a fatty acyl group having at least 65 mol% of a single chemical identity, e.g., at least 80 mol%, or at least 85 mol%, or at least 90%, or at least 95 mol%.

Embodiment 81. The conjugate of embodiment 80, wherein the single chemical identity is oleoyl, myristoyl, palmitoyl, stearoyl or linoleoyl.

Embodiment 82. The conjugate of any of embodiments 1-81, wherein R¹-C(O) is fatty acyl and the conjugate when assayed by HPLC, resembles the peak profile of Figure 1, 2 or 3 and the following relative retention time (RRT):

¹ in the range of RRT ± 0.2 to ± 0.5

² RRT of oleic acid is set as 1.00

Embodiment 83. The conjugate of any of embodiments 1-82, having an HLB value in the range of 13-18, e.g., in the range of 13-15.

Embodiment 84. A polyethylene glycol-saccharide-lipid conjugate useful as a solubility or bioavailability enhancer for safely delivering hydrophobic or lipophilic compound or compounds, represented by the formula:

wherein:

Lipid is selected from a group consisting of fatty acids including lauric acid, myristic acid, linoleic acid, palmitic acid, oleic acid, elaidic acid and steroid acids; m(PEG)n is a polymer of polyethylene glycols; n ranges from 8 to 45 of ethylene glycol subunits; and m* = 1 to 6 of CH2.

Embodiment 85. The polymer of embodiment 84 or any of the above not-inconsi stent embodiments, having one or more of the following properties or specifications: a. the mPEG ranges between 95.0% and 105.0% of the labeled nominal value if the labeled nominal value is below 1000 or between 90.0% and 110.0% of the labeled nominal value if the labeled nominal value is between 1000 and 2000. b. Purity of the said polymeric conjugate is between 85% and 115.0 by HPLC assay if used for oral applications, c. Purity of the said polymeric conjugate is between 90% and 110.0% by HPLC assay if used for parenteral application; d. Purity of oleic acid if utilized is not less than 65% e. Individual related analogue or impurity is less than 5%; and f. Fatty acid based said polymers, resemble of the peak profile of Figures 1, 2 or 3 and the following relative retention time (RRT):

¹ in the range of RRT ± 0.2 to ± 0.5

² whereby RRT of oleic acid is set as 1.00

Embodiment 86. The said polymeric conjugate of embodiment 84 or embodiment 85 or any of the above not-inconsistent embodiments, wherein the synthesis method for preparing a said polymer comprises the steps of:

(1) coupling activated monomethoxypolyethylene glycol ether to the unprotected amino group of the center backbone; (2) conjugating a lipid or disaccharide to the backbone, thereby forming a PEG- saccharide-lipid conjugate having a high purity of conjugates in the range of 85% to 115% by HPLC assay.

Embodiment 87. The said polymeric conjugate of embodiment 84 or embodiment 85, or any of the above not-inconsi stent embodiments, wherein the synthesis method for preparing a said polymer comprises the steps of:

(3) conjugating a lipid or disaccharide to the backbone, thereby forming a PEG- sacchari de-lipid having a high purity of PEG oligomer. wherein the sequence or order of coupling steps or sites is interchangeable.

Embodiment 88. The said polymeric conjugate of any of embodiments 84-87 or any of the above not-inconsi stent embodiments, wherein the m* in the backbone is 0 or 1 thereby forming a PEG-saccharide-lipid conjugate with no or less hemolytic potential suitable for parenteral administrations as well as oral applications having the following structure(s):

wherein when m* is 1, the backbone is propane; or when m* is zero, the backbone is ethylene;

FA is a fatty acid which is select for a group consisting but not limited to lauric acid, myristic acid, linoleic acid, palmitic acid, linoleic acid, oleic acid or stearic acids; and n is ranging from 8 to 45

Embodiment 89. The said polymeric conjugate of any of embodiments 84-88 or any of the above not-inconsistent embodiments, wherein the distance between the 2 terminal amines is less than 4 carbons if use for parenteral administrations. Embodiment 90. The said polymeric conjugate of any of embodiments 84-88 or any of the above not-inconsi stent embodiments, wherein the m* in the backbone is greater than 1 thereby forming a PEG-saccharide-lipid conjugate that is more suitable for oral administration or other applications

Embodiment 91. The said polymeric conjugate of any of embodiments 84-90 or any of the above not-inconsistent embodiments, wherein said PEG-saccharide-lipid conjugates are solid (low-water) or semisolid (higher moisturized) and stable for at least 36 months under room temperature storage conditions.

Embodiment 92. The said polymeric conjugate of any of embodiments 84-91 or any of the above not-inconsistent embodiments, wherein the monomethoxypolyethylene glycol ether having an average molecular weight between 95.0% and 105.0% of the labeled nominal value if the labeled nominal value is below 1000 or between 90.0% and 110.0% of the labeled nominal value if the labeled nominal value is between 1000 and 2000.

Embodiment 93. The said polymeric conjugate of any of embodiments 84-92 or any of the above not-inconsistent embodiments, wherein a monosaccharide-related impurity in said polymer is less than 5%.

Embodiment 94. The said polymeric conjugate of any of embodiments 84-93 or any of the above not-inconsistent embodiments, wherein the total fatty acid related impurities in said polymer are less than 10% and individual fatty acid related impurity is less than 5%.

Embodiment 95. The said polymeric conjugate of any of embodiments 84-89 and 92-94 or any of the above not-inconsistent embodiments, wherein the purity of said polymer is not least than (>) 90% to be used for parenteral compositions.

Embodiment 96. The said polymer of any of embodiments 84-89 and 92-94 or any of the above not-inconsistent embodiments, wherein said polymer is purified or dried by lyophilization if use for parenteral administrations.

Embodiment 97. The said polymeric conjugate of any of embodiments 84-89 and 90-94 or any of the above not-inconsistent embodiments, wherein the purity of said polymer is not less than (>) 85% to be used for pharmaceutical oral compositions. Embodiment 98. The said polymeric conjugate of any of embodiments 84-97 or any of the above not-inconsi stent embodiments, wherein the weight ratio of the PEG-saccharide conjugate to an oncology compound is between about 200 and about 1 for the drug delivery.

Embodiment 99. The said polymeric conjugate of any of embodiments 84-97 or any of the above not-inconsi stent embodiments, wherein the weight ratio of the PEG-saccharide-lipid conjugates to a non-oncology compound is between about 200 and about 1 for the compound delivery.

Embodiment 100. The said polymeric conjugate of polymer of any of embodiments 84-99 or any of the above not-inconsi stent embodiments, wherein said PEG-saccharide-lipid conjugate has a structure selected from the below:

wherein n ranges from 8 to 45.

Embodiment 101. A process for making a conjugate of any of embodiments 1-100, the process comprising coupling a poly(ethylene)glycol, a saccharide and an R¹-C(O)- acyl group to a diamine backbone. Embodiment 102. The process of embodiment 101, wherein the method includes providing a monoprotected diamine having a protected first amine group and an unprotected second amine group; coupling a poly(ethylene glycol) 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.

Embodiment 103. The process of embodiment 101 or embodiment 102, performed in the substantial absence of free-radical initiators.

Embodiment 104. The process of any of embodiments 101-103, wherein the coupling of the poly(ethylene glycol) can be performed before the coupling of the R¹-C(O)- acyl group.

Embodiment 105. The process of any of embodiments 101-104, wherein the coupling of the polyethylene glycol) to the second amine group can be performed in a stepwise fashion, e.g., by first coupling a shorter chain of PEG to the central backbone, then by performing etherification to achieve a longer PEG chain.

Embodiment 106. The process of any of embodiments 101-105, wherein the coupling of the R'-C O)- acyl group to the second amine group is performed using an R¹-C(O)-halide.

Embodiment 107. The process of any of embodiments 101-105, 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.

Embodiment 108. A conjugate according to any of embodiments 1-100 for use as a pharmaceutical excipient, or for use as in a medicament.

Embodiment 109. A therapeutic composition comprising a conjugate of any of embodiments 1-100 and a therapeutic agent.

Embodiment 110. A composition for use in the treatment of a subject having a condition, the composition comprising a conjugate of any of embodiments 1-100 and a therapeutic agent suitable for treating the condition.

Embodiment 111. A method for treating a subject having a condition, the method comprising administering to the subject a composition of embodiment 110, for example, wherein the administration is oral, intranasal, topical or parenteral. Embodiment 112. A composition comprising a conjugate according to any of embodiments

1-100 and a therapeutic agent for use as a medicament.

Embodiment 113. A method for preparing a composition of embodiment 112, 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.

Embodiment 114. Use of a conjugate according to any of embodiments 1-100 for increasing bioavailability of a therapeutic agent.

Embodiment 115. Use of a conjugate according to any of embodiments 1-100 for increasing solubility of a therapeutic agent in an aqueous system.

Embodiment 116. Use of a conjugate according to any of embodiments 1-100 as a pharmaceutical excipient, or as a therapeutic.

Embodiment 117. The composition, method or use of any of embodiments 109-116, 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.

Embodiment 118. The composition, method or use of any of embodiments 109-116, 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.

Embodiment 119. The composition, method or use of any of embodiments 109-116, 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.

Embodiment 120. The composition, method or use of any of embodiments 109-116, 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.

Embodiment 121. The composition, method or use of any of embodiments 109-116, 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. Embodiment 122. The composition, method or use of any of embodiments 109-116, 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.

Embodiment 124. The composition, method or use of any of embodiments 109-116, wherein the therapeutic agent has a log D7.4 value (or a log P value) of at least 2, e.g., at least

2.25, at least 2.5 or at least 2.75.

Embodiment 125. The composition, method or use of any of embodiments 109-116, wherein the therapeutic agent has a log D74 value (or a log P value) of at least 3, e.g., at least

3.25, at least 3.5 or at least 3.75.

Embodiment 126. The composition, method or use of any of embodiments 109-116, wherein the therapeutic agent has a log D7.4 value (or a log P value) of at least 4, e.g., at least

4.25, at least 4.5 or at least 4.75.

Embodiment 127. The composition, method or use of any of embodiments 109-116, wherein the therapeutic agent has a log Dx value of at least 2, e.g., at least 2.25, at least 2.5 or at least 2.75.

Embodiment 128. The composition, method or use of any of embodiments 109-116, wherein the therapeutic agent has a log Dx value of at least 3, e.g., at least 3.25, at least 3.5 or at least 3.75.

Embodiment 129. The composition, method or use of any of embodiments 109-116, wherein the therapeutic agent has a log Dx value of at least 4, e.g., at least 4.25, at least 4.5 or at least 4.75.

Embodiment 130. The composition, method or use of any of embodiments 109-116, wherein the therapeutic agent has a water solubility in a buffer of pH X of no more than 5 mg/mL, e g., no more than 2 mg/mL at 37 °C.

Embodiment 131. The composition, method or use of any of embodiments 109-116, wherein the therapeutic agent has a water solubility in a buffer of pH X 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.

Embodiment 132. The composition, method or use of any of embodiments 109-116, wherein the therapeutic agent has a water solubility in a buffer of pH X 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. Embodiment 133. The composition, method or use of any of embodiments 127-132, wherein X is 3, or 3.5, or 4, or 4.5.

Embodiment 134. The composition, method or use of any of embodiments 127-132, wherein X is 5, or 5.5, or 6, or 6.5, or 7.

Embodiment 135. The composition, method or use of any of embodiments 127-132, wherein X is 8, or 8.5, or 9.

Embodiment 136. The composition, method or use of any of embodiments 127-135, having a pH in the range of 3-9, e.g., in the range of 3-4.5, or 4-5.5, or 5-6.5, or 6-7.5, or 7-8.5, or 8- 9.

Embodiment 137. The composition, method or use of any of embodiments 109-136, wherein the therapeutic agent is selected from Apixaban, Atorvastatin, Cabazitaxel, Celecoxib, Docetaxel, Dolutegravir, Edaravone, Etomidate. Everolimus. Midazolam. Paclitaxel, Propofol (oral), Rivaroxaban, Tacrolimus, Tenofovir Alafenamide and Ticagrelor.

Embodiment 138. The composition, method or use of any of embodiments 109-137, wherein the conjugate is present in an amount above its critical micelle concentration.

Embodiment 139. The composition, method or use of embodiments 109-137, wherein the conjugate is present in aqueous solution in an amount above its critical micelle concentration or less than 0.1 mmol.

Embodiment 140. The composition, method or use of any of embodiments 109-139, 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.

Embodiment 141. The composition, method or use of any of embodiments 109-139, 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.

Embodiment 142. The composition, method or use of any of embodiments 109-139, 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.

Embodiment 143. The composition, method or use of any of embodiments 109-139, 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.

Embodiment 144. The composition, method or use of any of embodiments 109-143, 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%.

Embodiment 145. The composition, method or use of any of embodiments 109-143, wherein the therapeutic agent is present in the composition in an amount of at least 0.5 wt%, e.g., 1 wt%.

Embodiment 146. The composition, method or use of any of embodiments 109-143, wherein the therapeutic agent is present in the composition in an amount of at least 2 wt%, e.g., at least 5 wt%.

Embodiment 147. The composition, method or use of any of embodiments 109-143, wherein the therapeutic agent is present in the composition in an amount of at least 10 wt%, e.g., at least 20 wt%.

Embodiment 148. The composition, method or use of any of embodiments 109-143, 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%.

Embodiment 149. The composition, method or use of any of embodiments 109-143, 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%.

Embodiment 150. The composition, method or use of any of embodiments 109-143, 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%.

Embodiment 151. The composition, method or use of any of embodiments 109-143, 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%. Embodiment 152. The composition, method or use of any of embodiments 109-151, wherein the conjugate is present in an amount of at least 1 wt%, e.g., at least 2 wt%.

Embodiment 153. The composition, method or use of any of embodiments 109-151, wherein the conjugate is present in an amount of at least 5 wt%, e g., at least 10 wt%.

Embodiment 154. The composition, method or use of any of embodiments 109-151, 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%.

Embodiment 155. The composition, method or use of any of embodiments 109-151, 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 156. The composition, method or use of any of embodiments 109-151, 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%.

Embodiment 158. The composition, method or use of any of embodiments 109-151, 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%.

Embodiment 159. The composition, method or use of any of embodiments 109-151, 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%.

Embodiment 160. The composition, method or use of any of embodiments 109-158, wherein the composition is in the form of an aqueous solution or suspensions.

Embodiment 161. The composition, method or use of any of embodiments 109-158, wherein the composition is in the form of a concentrate for dilution into an aqueous solution or suspension.

Embodiment 162. The composition, method or use of any of embodiments 109-158, wherein the composition is in the form of a cream or gel, e g., for topical administration. Embodiment 151. The composition, method or use of any of embodiments 109-158, wherein the composition is in the form of a solid formulation, for example, in the form of a tablet, a capsule, or granules.

Claims

CLAIMS What is claimed is:

1. A lipid/PEG/saccharide conjugate having the structural formula

wherein m has a number-average value in the range of 2-10;

2. The conjugate of claim 1, wherein m has a number-average value in the range or 2-4.

3. The conjugate of claim 1, wherein m has a number-average value in the range of 5-10.

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

5. 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.

6. The conjugate of claim 1, wherein S has the structural formula

in which -(C_XIH_2XIO_XI-I)-CO- is a sugar acyl residue derived from a sugar acid in which xl is 4 or 5, and (C_X2H_2X2-IOX2-I)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof.

7. The conjugate of claim 1, wherein S has the structure

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

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

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

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

12. The conjugate of claim 1, wherein L is -C(O)-R^J, and wherein - Oj-R¹ is at least 85 mol% of a single chemical identity.

13. The conjugate of claim 1, wherein L includes (or is) a steroid acyl group (e.g., a bile acyl group).

14. The conjugate of claim 1, wherein n has a number-average value in the range of 8- 45.

15. The conjugate of claim 1, wherein n has a number-average value in the range of 9- 13.

16. The conjugate of claim 1, wherein R² is methyl.

17. The conjugate of claim 1, wherein P has a polydispersity index of no more than 1.1.

18. The conjugate of claim 1, wherein m is 3;

S has the structural formula as below:

in which -(C_xiH2xiO_xi-i)-CO- is a sugar acyl residue derived from a sugar acid in which xl is 4 or 5, and (C_X2H2_X2-IO_X2-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)-R' is at least 80 mol% of cis-CH₃(CH2)7CH=CH(CH₂)7C(O)-, e.g., at least 85 mol%;

P has a polydispersity index of no more than 1.1, e.g., no more than 1.07.

19. The conjugate of claim 1, wherein the conjugate is Oleoyldiaminopropane- monomethoxypolyethylene-glycol-ether-lactobionate (DOPS), represented by the Chemical Structure 2:

Chemical Structure 2 (DOPS) wherein m(PEG)_n is a methylated PEG residue, and n is in the range of 9-13.

20. The conjugate of claim 1, having one of the following structures:

21. The conjugate of claim 1, wherein the conjugate has a purity of at least 90 wt% as measured by HPLC.

22. The conjugate of claim 1, wherein R¹-C(O) is fatty acyl and the conjugate when assayed by HPLC, resembles the peak profile of Figure 1, 2 or 3 and the following relative retention time (RRT):

¹ in the range of RRT ± 0.2 to ± 0.5

² RRT of oleic acid is set as 1.00

23. A process for making a conjugate of any of claims 1-22, the process comprising coupling a poly(ethylene)glycol, a saccharide and an R¹-C(O)- acyl group to a diamine backbone.

24. 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(ethylene glycol) 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.

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

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

27. 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.

28. A method for preparing a composition of claim 27, 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.

29. A method for treating a subject having a condition, the method comprising administering to the subject a composition of claim 27, for example, wherein the administration is oral, intranasal, topical or parenteral.

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

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

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

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

34. 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.

35. 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.