Polyoxazoline-carbohydrate-lipid conjugates

Abstract

The disclosure provides compounds, methods of making, and methods of using of novel Polyoxazoline-Carbohydrate-Lipid Conjugates. Polyoxazoline with less immunogenicity potential may be a favorable alternative to the traditional PEG-based polymers for clinical applications. The compounds have a backbone and three or four appended functional groups: one or two lipophilic compounds including fatty acids or sterols or lipophilic vitamins, one or two hydrophilic polyoxazoline, and one or two carbohydrate. The conjugate may have a fatty acid or cholesterol as the primary lipophilic carrier associated with a polyoxazoline and a carbohydrate. Specific functional groups may be selected for specific applications in formulating pharmaceuticals, cosmetics, nutriceuticals, and the like. Typical coupling reaction of the conjugates may involve one or more or combinations or in series of alkylation including N-alkylation or O-alkylation, etherification, esterification and amidation chemical processes. Shorter chain of polyoxazoline can be synthesized by "cationic ring-opening polymerization" or living CROP. A variety of linkers between the backbone and functional groups may also be selected to modify the carriers or center backbones for the coupling reactions and optimize performance of the conjugates.

Description

POLYOXAZOLINE-CARBOHYDRATE-LIPID CONJUGATESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims the benefit of priority of U.S. Provisional Patent Application Numbers: 63 / 612,877 filed on December 20, 2023, the disclosure of which is hereby incorporated herein by reference in its entirety.BACKGROUND OF THE DISCLOSURE1. Field of the Disclosure

[0002] The present disclosure relates to polymer conjugate materials useful as pharmaceutical excipients, as well as their use in various compositions such as pharmaceutical (including nutraceutical) compositions, as well as in therapeutic methods.2, Technical Background

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

[0004] Hence there remains a need for improved pharmaceutical carriers for water insoluble drugs.SUMMARY OF THE DISCLOSURE

[0005] The present inventor has noted that poly(2-alkyl-2-oxazoline)s can provide a higher stability and tenability with its functionalization as compared to polyethylene glycol (PEG), while retaining desirable features of biocompatibility, stealth behavior, and relatively low poly dispersity when used in pharmaceutical excipients. Thus, the present inventor has determined that these excellent properties of substituted oxazoline polymers enable their potential for applications in a wide variety of different biomedical applications, e.g., targeted drug delivery and from drug formulation to tissue engineering or tissue adhesives. Especially, the extraordinary synthetic versatility of substituted oxazoline polymers allows the construction of desirable polymeric architectures with finely tunable physical properties in a defined manner, making it an attractive platform for developing new approaches in drug delivery technology.

[0006] One aspect of the disclosure provides a polymer of poly(2-alkyl-2-oxazoline)- carbohydrate-lipid conjugates made or being made as a solubility or bioavailability enhancer for safely delivering hydrophobic or lipophilic compound or compounds, said polymer is a conjugation comprising a molecular structure represented by the formula (I):formula (I) wherein:L is a lipid or lipophilic carrier that is a residue of a compound selected from fatty acids (e.g., including lauric acid, myristic acid, linoleic acid, palmitic acid, oleic acid, elaidic acid, stearic acid), cholesterol, steroid acids, retinoids, carotenoids, tocopherols, and tocotrienolsSugar is a residue of a carbohydrate or an analog or derivative thereof (e.g., a saccharide);POZ is a residue of a polymer selected from poly(2-methyl-2-oxazoline), poly(2-ethyl-2- oxazoline), poly(2-propyl-2-oxazoline) and poly(2-isopropenyl-2-oxazoline);B is a residue of a compound having three or four available binding positions comprising selected from a group of molecules including glycerol, diamines, triamines, tetraamines, diaminoalcohols, aminoalcohols, aminodiols, aminotriols, amino acids, triols, tetraols, triacids, tetracids, halogen-containing diols, halogen-containing amines, carboxyl-containing diols and polyamines; and,D is residue as defined for L, Sugar or POZ.

[0007] It is noted that throughout the specification, the various residues are typically identified with reference to a base compound that can nominally react to provide the residue (e.g., an acid for an acyl residue, an amine for an amide nitrogen). As a short-hand, the term “residue” is omitted from various identifications of such components in this specification; the person of ordinary skill in the art will be familiar with reactivities of such compounds and will readily identify the appropriate residues.

[0008] In one aspect, the disclosure provides a conjugate of Formula I suitable for parenteral applications having the structure:wherein:Lipid is a residue of a fatty acid (e.g., including lauric acid, myristic acid, linoleic acid, palmitic acid, oleic acid, elaidic acid, stearic acid) or a steroid acid; the POZ polymer residue has a degree of polymerization ranging from 5 to 50 of (2-alkyl- 2-oxazoline) subunits; and m is in the range of 1 to 6.

[0009] In another aspect, the disclosure provides a process for making a conjugate as described herein, the process comprising coupling a poly(2-alkyl-2-oxazoline), a saccharide and an R1- C(O)- acyl group to a diamine backbone.

[0010] In another aspect, the disclosure provides a conjugate as described herein for use as a pharmaceutical excipient, or for use in a medicament.

[0011] In another aspect, the disclosure provides a therapeutic composition comprising a conjugate as described herein and a therapeutic agent.

[0012] 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.

[0013] 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.

[0014] In another aspect, the disclosure provides a use of a conjugate as described herein as a pharmaceutical excipient.

[0015] In another aspect, the disclosure provides a composition comprising a conjugate as described herein and a therapeutic agent for use as a medicament.

[0016] In another aspect, the disclosure provides a use of a conjugate as described herein for increasing bioavailability of a therapeutic agent.

[0017] 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.

[0018] Various aspects of the disclosure are described herein using the following chemical nomenclature:POZ Poly(2-alkyl- 2-oxazoline)xPEOZx: Poly(2-ethyl-2-oxazoline)xPMOZx: Poly(2-methyl-2-oxazoline)xPPOZx Poly(2-propyl-2-oxazoline)xPEOZ50: Poly(2-ethyl-2-oxazoline) hydroxy terminated, x =50, number-average molecular weight ~ 5,000 g / mol; e.g., 2-ethyl-2-oxazoline = 99.13 g / mol aminoPEOZio Poly(2-ethyl-2-oxazoline)nhydroxy ethyl amine terminated, x = 10, number-average molecular weight ~ 10,000 g / molDCPL-20: Cholesteryl(ethyleneglycol)diaminopropane-POZ2o-lactobionate.DEPL-20: ElaidoylpropanediaminoPOZ2o-lactobionate.DMPL- 10 : Myristoylpropanediamino- POZ 10-lactobionate.DMPL-20: Myristoylpropanediamino- POZ2o-lactobionate.DOPL-B20 Oleoylbutanediamino- POZ2o-lactobionate.DOPL-E20: Oleoylethylenediamino- POZ2o-lactobionate.DOPL-20: Oleoylpropanediamino- POZ2o-lactobionate.DOPL-10: Oleoylpropanediamino- POZ 10-lactobionate.DOPL-25: Oleoylpropanediamino- POZ25-lactobionate.DOPL-50: Oleoylpropanediamino- POZs-lactobionate.DOPL-H20: Oleoylhexanediamino- POZ2o-lactobionateDLPL-20: Linoleoylpropanediamino- POZ2o-lactobionateDSPL-20: Stearoylpropanediamino- POZ2o-lactobionateTOPL-20: 01eoylbis(3-aminopropyl)amino-POZ2o-lactobionateWherein: POZ in each instance can be PMOZ, PEOZ or PPOZ.

[0019] Additional aspects of the disclosure will be apparent in view of the disclosure and claims below.BRIEF DESCRIPTION OF THE DRAWINGS

[0020] 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.

[0021] Figure l is a ball-and-stick diagram of an example of a compound of the disclosure.

[0022] Figure 2 depicts a chart of solubility comparison study of oleoyl based lipid with different polymers: Poly(2-ethyl-2-Oxazoline) = DOPES-F02; Poly(2-propyl-2-Oxazoline) = DOPPS-F02; Poly(2-methyl-2-Oxazoline)= DOPMS-F02; Polysorbate 80 = PS80 and Cremophor® RH 40 = RH40. All made as a 10% solution in saline (0.9% of sodium chloride).

[0023] Figure 3 depicts disolution profile of atorvastatin in oleoylpropanediaminopoly(2- ethyl-2-oxazoline)io-lactobionate (DOPL-10) at a ratio of 1 to 3 (API / polymer) or oleoylpropanediaminopoly(ethylene-glycol)i2monomethoxy ether-lactobionate (DOPS-12) at a ratio of 1 to 3. The content of the API (active pharmaceutical ingredient) is 10 mg / capsule.

[0024] Figure 4 depicts HPLC chromatogram of Cholesteryl(ethyleneglycol)diaminopropane-POZio-lactobionate (DCPL-10): Impurities of peak 1 and 2 = positional isomers and 3 - intermediate product of cholesterol-ethylene glycol.DETAILED DESCRIPTION

[0025] Embodiments of the present disclosure are described herein in the context of varying POZ-carbohydrate-lipid conjugates for drug delivery. 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. Reference will now be made in detail to implementation of the compounds, compositions and methods of the present disclosure.

[0026] In the interest of clarity, not all of the routine features of the implementations herein are described. It will be appreciated that in the development of such actual implementation, numerous implementation-specific details may need to be made in order to achieve the developer’s specific goals, and that these specific goals may vary.

[0027] Polyoxazoline (POZ) is a water soluble polymer having the following general structure:The sidechain “Rs” is derived from the 2-substituent of the 2-R-2-oxazoline monomer. In various embodiments, Rs can be methyl (PMOZ), ethyl (PEOZ) or propyl (PPOZ). The “n” is a number of the subunits ranging from 5 to up to more than 500. However for biomedical applications, the “n” is preferably less than 100.

[0028] POZ is a biocompatible polymer that may be used in drug delivery in a number of complex formats; it can be attached directly to drug molecules as a prodrug, or conjugated to lipids where it can become part of the liposomal delivery system, or linked with cationic molecules where it can become part of a nucleic acid-complexing polymer. POZ has existed for over 50 years; development has lagged several decades behind polyethylene glycols. It was first developed as a food additive in the early 1980s and initial animal safety studies were completed in 1980’s by Dow Chemicals. Other studies reports showed that POZ was potential useful in multiple clinical applications. For instance, it can be conjugated to protein and small molecule drugs or grafted onto liposomal bilayers for extended blood circulation or formulated into micelles or surface modifications. In all these applications, POZ has similar “stealth” properties as PEG without any adverse effects in animal models. Radiolabeled POZ also suggested that this polymer is rapidly excreted by the kidney with no significant accumulation in tissues.

[0029] A number of processes for making and modifying polyoxazoline polymers have been reported in the literature. One method discusses the stoichiometric addition of an electrophile initiator such as an alkyltosylate or alkytriflate to the oxazoline monomer that is dissolved in a dry organic solvent and in an inert atmosphere. The propagation phase is conducted at 80 °C for approximately 1 to 3 days. In the second method, the polymerization is carried out with microwave energy to reduce the propagation time from days to hours. In both cases, the living cation is terminated by the introduction of a nucleophile such as OH , NH , COO , or S . Termination is conducted with aqueous sodium carbonate to give a hydroxyl terminal group or by reacting with a secondary amine such as morpholine or piperidine to give a terminal tertiary amine. POZ can be mono-functionalized at one end of the chain during the initiation step or at the termination step with the use of carboxylate ions. POZ has also been synthesized withpendant functional aldehyde and amine groups and terminated with inert groups. These chemistries can allow for higher drug loading than that possible with linear polymers, e.g., PEG.

[0030] POZ has emerged as a useful polymer class with a peptidomimetic structure belonging to the polyamide family for multiple potential applications, as they offer an unprecedented combination of properties and functionalities. However, there is no regulatory approval for use as pharmaceutical excipients at the present time. POZ are tertian' polyamides with the amide group in the methyl, ethyl or propyl side chain and are therefore structural isomers of polypeptides and thus are also considered pseudopeptides. The living cationic ring-opening polymerization of 2-substituted-2-oxazoiines was first reported in 1960s by researchers, enables the preparation of engineered POZ with defined structure, functionalities and adjustable physicochemical properties depending on the 2-substituent of the monomer which forms the side chain of POZ in this isomerization-polymerization. It is also considered as a potential useful platform polymer for drag delivery.

[0031] Over the last four decades, some of the promising drag carriers that have been investigated in systemic delivery systems include liposomes, polymeric nanoparticles, polymeric micelles, ceramic nanopartides and dendrimers. Systemic drug delivery may be achieved by intravenous or intraperipheral injection and therefore is non-invasive. The drugs may be administered repeatedly as needed. However, in order to achieve therapeutic concentrations at the target site, systemic administration requires large dosages with relatively high vehicle contents which may cause side effects such as allergic reactions.

[0032] The important role of sugars in many specific interactions in living systems is well recognized. Large molecular weight carriers such as proteins or liposomes may be modified with sugars for specific drug delivery. Lipid-sugar particles have been used for drug delivery to the brain for providing prolonged duration local anesthesia when injected at the sciatic nerve in rats. Since sugar-lipids are composed of materials that occur naturally in the human body suggests potential advantages over some other polymer-based controlled-release terms of biocompatibility. Lipid-sugars have a good biocompatibility as shown by the results of in vitro and in vivo studies.

[0033] Sterol in additional to fatty acids is classified as a lipid in one of the eight lipid categories. The lipid classification scheme is chemically based and driven by the distinct hydrophobic and hydrophilic elements that compose the lipid. Sterols and related compounds play essential roles in the physiology of eukaryotic organisms are a subgroup of the steroids.They occur naturally in plants, animals, and fungi, the most familiar type of animal sterol is cholesterol. Cholesterol is vital to animal cell membrane structure and function and forms part of the cellular membrane in animals, where it affects the cell membrane's fluidity and serves as secondary messenger in developmental signaling.

[0034] The human body has a natural tendency to maintain homeostasis, and may be elaborated from substances present in the diet, sometimes exclusively, for vitamins, minerals, essential amino-acids and essential fatty acids including polyunsaturated fatty acids which play a significant role in the prevention of cardiovascular disease in human. Lipophilic vitamins, e.g., vitamin E, are the general term for all tocopherols and tocotrienols, of which alpha-tocopherol is the natural and biologically most active form. The antioxidant function of vitamin E is considered to be critical for the prevention of oxidation of tissue. While these molecules are essential for the human body, the present inventor has determined that they may be utilized as safer ingredients to design for an ideal POZ-carbohydrate-lipid conjugate.

[0035] The conjugates of the present disclosure include as a carrier group of lipophilic components including but not limited to residues of fatty acids, steroidic acid, and sterols (both unsaturated and saturated fatty acids or steroid alcohols and hydrogenated sterols). Fatty acids and sterols are biological importance as a highly compatible vehicle for drug delivery, for instance fatty acids make up to 70 % of lipids and cholesterol makes up about 10-50 percent of the total lipid in natural cell membranes, the conjugates containing fatty acid or sterol or a lipophilic vitamins may increase the drug permeation for cell targeted delivering.

[0036] The conjugates of various embodiments of the present disclosure often include as a carrier group of a lipophilic component that is a residue of a fatty acid or steroid acid or sterol or lipophilic vitamin.

[0037] As another carrier group the conjugates of various embodiments of the disclosure included is a hydrophilic component of a carbohydrate molecule or water soluble vitamin such as ascorbic acid.

[0038] The third carrier is a polyoxazoline (e.g., a water-soluble polyoxazoline).

[0039] The three carrier groups are attached covalently to a central backbone where at least three bonding positions or sites available. The conjugation may be achieved via one or more types of reactions or combination of alkylation including N-alkylation or O-alkylation, etherification, esterification and amidation.

[0040] The solubility of organic molecules is often summarized by the phrase, "like dissolves like." This means that molecules with many polar groups are more soluble in polar solvents,and molecules with few or no polar groups (i.e., nonpolar molecules) are more soluble in nonpolar solvents. Lipophilic components in the present disclosure are predominantly nonpolar and hence are soluble in nonpolar solvents such as the fatty (nonpolar) tissue of the body. Solubility is a complex phenomenon that depends on the change in free energy (AG) of the process. For a process, i.e., a vitamin dissolving in a solvent, to be spontaneous, the change in free energy must be negative (i.e., AG < 0).

[0041] While there is no official definition of poor water-solubility, a poorly soluble compound typically has a water-solubility < 1 mg / mL over the physiological pH range or in deionized water at physiologic temperature, e.g., 37 °C.

[0042] In many embodiments of the disclosure, the poly(2-alkyl-2-oxazoline) has a relatively narrow molecular weight distribution (i.e., a relatively low poly dispersity (PDI)). The present inventor has noted that this can be highly desirable for biomedical applications, especially if used for intravenous injections.

[0043] In various embodiments of the disclosure, the conjugate includes a backbone having three or four appended carrier groups: one or two lipophilic groups, one or two hydrophilic POZ polymers, and one or two carbohydrates which may be substituted by a water soluble vitamin. By combining these functionalities all into one compound, it is possible to achieve improved formulations of many active agents. The general structure of the family of compounds is shown in a three-dimensional (3D) drawing in Figure 1 (white ball indicated hydrogen; grey = carbons; black = oxygen or nitrogen) where “B” indicates the backbone, “P” indicates the polymer or POZ, “L” indicates lipophilic compound, and “S” indicates the carbohydrate. As shown in the 3D drawing, the POZ chain has a bulky conformation. In aqueous solutions, the novel conjugates act as a solubility enhancer of poor water soluble agents resulting in either a true solution or a very stable emulsified suspension with those of active agents. In certain cases, the carbohydrate may be substituted by a water soluble sugar acid or vitamin such as ascorbic acid, which is also classified as aldonic acid or sugar acid.

[0044] In another aspect, the disclosure provides compounds having a backbone and four appended carrier groups: one or two of fatty acids or sterols, one or two hydrophilic polymers, and one or two carbohydrates which may be substituted by a water soluble vitamin. By doubling one of these three functionalities all into one compound, it may be possible to achieve more enhanced formulations of many poor water soluble or poor permeable active agents as shown in the formula I, wherein the fourth carrier “D” is a duplicate any of the three carriers or alternatively a mPEG (monomethoxypolyethylene glycol ether), all is bonded to the centralbackbone. However when combine a mPEG to the conjugate, the PEG chain may be smaller or equal to the size of the primary POZ chain.

[0045] In various embodiments, the present disclosure provides conjugates having various physical parameters, e.g., different coefficients of the oil / water phase partition (LogP) or the values of Hydrophilic-Lipophilic Balance (HLB), in which a large difference is among POZs utilized in present conjugates, where the Log Ps and HLBs were calculated with a computer program of Marvin Sketch (ChemAxon Kft, Budapest, Hungary). A positive value of Log P indicates more oil soluble and a negative value indicates more water soluble. Similarly, the HLB value calculated based on Griffin method to predict the conjugate properties of a molecule: < 10: more lipid soluble and > 10: more water soluble. Thus the water solubility or lipophilicity is solely based on the inherited character of the hydrocarbon carrier groups, which showed a magnitude difference among POZ-carbohydrate-conjugates and between POZ- carbohydrate-conjugates and PEG-carbohydrate-conjugates. The further chemistry difference between POZ and PEG is that PEG contain only have replicated ethylene groups which is more water soluble and POZ contain replicated groups of 2-methyl-2-oxazoline or 2-ethyl-2- oxazoline or 2-isopropenyl-2-oxazoline or 2-phenyl-2-oxazoline which have various water solubility. Hence the two types of the conjugates are different classes of molecules in the chemical structures and physical characters. In addition, PEG based conjugates may be a liquid or semisolid and the POZ based conjugates are all solid.

[0046] Table 1. Log P and HLB comparison between different type polymers or subchains on an identical back frame design:

[0047] As shown in Table 1, while the oil / water phase partition (LogP) coefficient of the POZ- carbohydrate-lipid conjugate is significantly different among the three POZ-carbohydrate-lipid conjugates, While PEOZ-carbohydrate-lipid conjugate is relatively closer to an otherwise similar PEG-carbohydrate-lipid conjugate, PMOZ-carbohydrate-lipid conjugate or PPOZ- carbohydrate-lipid conjugate is relatively different. However as a solubility enhancer, the variance of HLB values is relatively smaller. Even though PPOZ or PEOZ has only one or two carbons per structural unit more than PMOZ, the LogP value is significantly increased.

[0048] In one aspect of the present disclosure, the hydrophobic interaction of the POZ- carbohydrate-lipid conjugate may be tuned by the number of carbons in the POZ side chain. The water solubility is enhanced for those hydrophobes whereby the encapsulation of the lipophilic molecules into the POZ-carbohydrate-lipid conjugates. Differentiated from PEG- based polymers, the current disclosure provides polyoxazoline polymeric carrier having stronger hydrophobic interactions with lipophilic solutes. The same hydrophobic interaction may not be achieved with a PEG due to hydrophilic carbon clusters of PEG chains.

[0049] As another aspect of the present disclosure, the present inventor notes that POZ or POZ- like molecules increase hydrophobic interactions between the lipophilic carriers and hydrophobic solutes. The solubility is enhanced due to an increased interaction of POZ with hydrophobic solutes in addition to the lipophilic cores formed with the lipids in the conjugates.

[0050] In various embodiments of the novel POZ-carbohydrate-lipid conjugates of the disclosure, the central backbones are having three available binding sites, whereby two sites with polar groups attached and another site with nonpolar groups attached showed a good solubility enhancement as compared with a polymer directly attached to or terminated with a nonpolar group. The novel POZ-carbohydrate-lipid conjugates can aid in the formation of stable solution or emulsions or blends of water and lipophilic agents. These polymer conjugates can reduce the interfacial tension between hydrophobic molecules and water (e.g., by adsorbing the energy at the liquid-liquid interface).

[0051] In another aspect of the disclosure, the hydrophilic-lipophilic interaction is well balanced in the POZ-carbohydrate-lipid conjugates. For example, in various embodiments, the hydrophilic-lipophilic balance (HLB) number remains greater than 10 due to the large polymer portion in the conjugates; such materials can in various embodiments form translucent microemulsions spontaneously. Unlike other microemulsions formed by a mixture of surfactants or lipid polymers, co-surfactants and / or co-solvents which a surfactant or lipid polymer concentration is several times higher that significantly exceeds the concentration of the dispersed phase or mechanically produced translucent microemulsions for which specialized equipment is required, the polymer-carbohydrate-sterol / lipophilic conjugates of the present disclosure in many cases are able to form transparent solution or nanoemulsions spontaneously by a single POZ-carbohydrate-lipid conjugate and typically without co-solvent and external high energy input required.

[0052] In one aspect of the current disclosure, a stable aqueous solution or emulsion may be formed with minimal amounts of the POZ-carbohydrate-lipid conjugates, which is superiorover conventional surfactants or other lipid-polymers since many undesirable side effects can be caused by surfactants or lipid-polymers; indeed, higher concentrations of surfactants are disadvantageous or prohibitive in many applications. In addition, the stability of a microemulsion or mechanically formed nanoemulsion is often easily compromised by dilution, or heating, or by changing pH levels.

[0053] Though it is possible to use a variety of POZ in practicing the closure, polyoxazoline PEOZ (poly(2-ethyl-2-oxazoline)) or PMOZ (poly(2-methyl-2-oxazoline)) is preferred from its hydrophilic characteristics.

[0054] The General Structure 1 below shows an embodiment of a new POZ-carbohydrate- Lipid conjugate:(X4-D)0.IB* Sugar-X3^ / ^ XrPOZ L-X2

[0055] General Structure 1

[0056] The person of ordinary skill in the art will appreciate that general structure 1 is analogous to the structures of formula (I), but making explicit the identities of the “X” linkers. Notably, the “X” linkers can derive from the compounds used to make them (e.g., an amine backbone compound reacting with a fatty acid to form an amide linker), or can be provided by separate compounds (e.g., use of an amino acid or an acryloyl chloride to provide a linker).

[0057] In General Structure 1, B* is a residue of a compound that comprises at least three available binding positions or sites for the conjugation of a first carrier, a second carrier and a third carrier, each available binding position or site comprising an expendable amino, hydroxyl, or carboxylic group. The compound may be selected from the group consisting of glycerol and glycerol-like analogues, polyamines, diamines, triamines, tetraamines, aminodiol, aminotriols, aminoalcohols and amino acids having three available binding positions or sites, triols, tetraols, erythritol, triacids, tetracid, tetraacetic acid, glucoheptonic acid, and tartaric acid, including but not limited to ethanediamine, propanediamine, butanediamine, pentanediamine, hexanediamine, diethylenetriamine, 1,2-diaminoethane, 1,3-diaminopropane (propane-1, 3- diamine), 4-amino-3 -hydroxybutyric acid, 7V-(2-hydroxyethyl)ethylenediamine, 4-amino-2- hydroxybutyric acid, 2-hydroxy-4-aminobutylic acid, 1-B-homoserine, 1-threonine, 7V-B- aminoethyl-glycine, putrescine (butane- 1,4-diamine), cadaverine (pentane- 1,5-diamine),hexamethylenediamine (hexane- 1,6-diamine), 1,2-diaminopropane, diphenylethylenediamine, diaminocyclohexane, diethylenetriamine, bis(3-aminopropyl)amine, triethylenetetramine, tris(2-aminoethyl)amine, spermine, spermidine, norspermidine, bis(3-aminopropyl)-l,3- propanediamine, l,2-bis(3-aminopropylamino)ethane, 7V,7V'-bis(3-aminopropyl)-l,3- propanediamine, tris(hydroxy-methyl)aminomethane, diaminobenzidine, 7V-ethyl-7V'-(3- dimethylaminopropyl)carbodiimide, meso-erythritol, triazacyclononane, tetraazacyclododecane, threitol, dithiothreitol, trimethylcyclo-hexane-l,3,5-tricarboxylic acid, trimethylbis(hexamethylene)triamine, bis(hexamethylene)-triamine, arginine, oxylyldiamino- propionic acid, 3-amino-l,2-propanediol, 3-bromo-l,2-propanediol, 3-chloro-l,2-propanediol, 3 -fluoro- 1,2-propanediol, DL-gly ceric acid, diaminopropionic acid, glucoheptonic acid and, 1,2,4-butanetriol, 2,2-bis(hydroxymethyl)butyric acid, l,3-diamino-2-propanol and 2-(3- aminopropylamino)ethanol, and 3-((3-aminopropyl)-amino)propanol; aspartic acid, glutamic acid, asparagine, glutamine, lysine, ornithine, serine, and threonine or benzyl triols or aminohydroxybenzoic acids or benzenetriol, dihydroxybenzoic acid, di aminobenzoic acid, diaminophenol, diaminobenzoic acid, aminohydroxybenzoic acid, aminosalicylic acid, hydroxyanthranilic acid, hydroxyisophthalic acid, aminoisophthalic acid, 4- (hydroxymethyl)cyclopentane-l,3-diol, deoxy fuconojirimycin, deoxynojirimycin, prostaglandins, hydroxylmethylpiperidinol, dihydroxy(hydroxymethyl)aminocyclopentane, diaminophenol, benzenetetracarboxylic acid, benzenetricarboxylic acid, aminobenzenediol, dihydroxybenzoic acid, aminohydroxybenzoic acid, trihydroxyaniline, benzenetriol, dimethoxybenzenediamine, trihydroxyphenol, (diaminophenoxy)benzenediamine and aminobromophenol .

[0058] Sugar can be as described above. In many embodiments, Sugar is residue of a carbohydrate, such as monosaccharides or disaccharides or oligosaccharides, amino sugars and sugar acids.

[0059] L is a residue of a lipophilic compound or their diesters including but not limited to fatty acids or sterols or sterol-like compound or lipo-vitamin.

[0060] Xi, X2, X3 and X4 are the same or different linkers of carbon-nitrogen bond, ester or ether or amide between carrier groups and the backbone. Each linker may be as simple as oxygen or nitrogen or other single atom to form an ester or ether or amide bond between the carrier and center backbone. Alternatively, each linker may be single or replicate linkers. In some cases, the linker may be co-extensive with or a part of the backbone or functional group component used to synthesize the conjugates.

[0061] Typical coupling reaction of the conjugates involves with one or more or combination or in series of alkylation including A-alkylation or O-alkylation, etherification, esterification and amidation chemical processes. The general structure is meant to include all racemers or structural isomers of the structure, as they may be functionally equivalent.

[0062] The POZ chain preferably consists of between about 5 and 50 subunits, and the number of carbons in the side chain Rs groups is typically not more than 3 including methyl, ethyl or propyl. The terminal group on the POZ chain may be selected from a wide variety of chemical moieties. Hydroxy and alkoxy (e.g., C1-C20 alkoxy) is commonly selected as the terminal groups.

[0063] The Linkers on the in the conjugates may be selected from a wide variety of chemical compounds. Such linkers preferably have a molecular weight of less than 650, including but not limited to -OH, -NH2, -COOH, -OCH2CH2OH, -OCH2CH2NH2. The link group may facilitate linking the backbone and each carrier groups. Amino acids, maleinimidopropionate, methylcarbamate, tosylhydrazone salts, azide, propargyl-amine, propargyl alcohol, succinimidyl (NHS) esters or NHS carbonate, hydrazide, succinimidyl ester, succinimidyl tartrate, succinimidyl succinate, and toluenesulfonate salt are useful for such linking. Additionally, the link group may include neutral or either negatively or positively charged head-groups such as decanolamine, octadecylolamine, octanolamine, butanolamine, dodecanolamine, hexanolamine, tetradecanolamine, hexadecanolamine, oleylamine, decanoltrimethylammonium, octadecy-loltrimethylammonium, octanoltrimethylammonium, butanoltrimethylammonium, dodecanol -trimethylammonium, hexanoltrimethylammonium, tetradecanoltrimethylammonium, hexadecanol -trimethylammonium, oleyltrimethylammonium, for example.

[0064] The present disclosure contemplates that linking chemical groups that may be selected to optimize and improve POZ-carbohydrate-lipophilic group based formulations. Selecting an appropriate linker between lipo-portion or POZ or carbohydrate and backbone may be important for several reasons, described as following.

[0065] It is well understood that many drugs are xenobiotic, i.e., the normal human body doesn't need it. Ideally, a drug should reach the site of action intact, cure the disease, and leave the body after it completes its mission. However, drug developers often face the dilemma that 70 to 90% of drugs under development have water solubility or permeability problem, so that the drug may not reach its site of action and achieve its therapeutic effect, or do so too slowly, so that it stays in the body for a long time causing side effects. An object of the disclosure isto develop polymer-carbohydrate-lipids with appropriate linkers to help drugs to achieve therapeutic goals.

[0066] Of the three linked carbohydrate and lipophilic components and carbohydrates are digestible by humans while POZ is not. Breaking the linkage among the three components may result in increased clearance for all. It is therefore desirable to use various biodegradable linkers in large POZ-carbohydrate-lipid conjugates (i.e., a molecular weight > 5000) for improving clearance rates of lipid vesicles and lipids used for drug delivery.

[0067] When attached to a conjugate, any inherit property of the molecules may be inactive. It is therefore can be desirable to use less biodegradable linkers for bioactive carrier groups to stabilize the bond between the central backbone and the potential bioactive carrier groups, especially when a portion of the conjugates alone may be relatively toxic.

[0068] One aspect of the present disclosure involves coupling reactions of the conjugates with one or more or combination or in series of alkylation including 7V-alkylation or (9-alkylation, etherification, esterification and amidation chemical processes. For practical and economic reasons, it is preferable making those conjugates from simple processes whenever possible at low cost.

[0069] The retaining power of lipids is important in drug formulations and preventing drug precipitation from dilution or circulation in the body fluids. The present disclosure provides a way to enhancing retaining power or loading capacity by inclusion of relatively hydrophobic side chains of POZ into the polymer-carbohydrate conjugates. In addition, the use of preservative may be eliminated for parenteral products since the sterile filtration is possible with a relative low concentration of the conjugates in the dosage forms which typically form a true solution product.

[0070] The sugar groups in the various conjugates of the disclosure can have larger surface polarity than polymer chains or lipophilic carriers. For instance, those POZ-carbohydrate conjugates provide a better drug dispersion for their applications in nano-suspension or nanoparticles, especially for some amphipathic drugs or other compounds; this provides a better equilibrium for the drug or other compounds to partition into the lipophilic bilayers of the vesicles.

[0071] In various desirable embodiments of the disclosure, the POZ polymer chains in the conjugates are mono-disperse or narrowly-dispersed. For example, preferably 80% or more of the POZ chains in the range of the targeted molecular weights.

[0072] While various POZs are commercially available, but limited to larger size of the polymers. However smaller POZs, e.g., 1000 - 2000 g / mol (number average), can be readily prepared in the lab. POZ can be synthesized via cationic ring opening polymerization (CROP) or living CROP. Ring-opening polymerization is a mature technology that has been used since the beginning of the 1900s to produce polymers, e.g., synthesis of polypeptides. CROP of 2- oxazoline proceeds by nucleophilic attack of the chain end on the monomer molecule bearing a positive charge. The polymer size is controlled by the ratio of monomer and initiator, a high monomer to initiator ratio is typically used. A higher ratio leads to a higher molecular weight polymer. A key feature of a living polymerization is the ability to add more monomer to an active chain end to further extend the polymer chain, which is facilitated by a high monomer to initiator ratio.

[0073] In various embodiments, the POZ 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 POZ that has low poly dispersity can provide improved results, especially with respect to providing good dispersion of water-insoluble materials in aqueous systems. Polydispersity Index (PDI) is defined by the equation below:where Mwis the weight average molecular weight and Mnis the number average molecular weight. For example, in various embodiments, the “P” group has a PDI (poly dispersity index) of no more than 1.5, e.g., no more than 1.3. In various embodiments, the “P” group has a PDI of no more than 1.5, or no more than 1.2. The poly dispersity index of the “P” group is understood to be the same as the poly dispersity index of the POZ used to make the conjugate.

[0074] Commercial available POZs are generally of relatively high molecular weight, e.g., 10,000 to over 500,000 g / mol. However, the present inventor has noted that it is preferable to use a smaller POZ, e.g., 1,000 to 50,000 (number average), due to potential hypersensitive immune response, especially when used for intravenous administration. Smaller chain POZs can be synthesized by design of reaction conditions. The Cationic Ring-Opening Polymerization (CROP) of 2-Oxazolines follows a typical chain-growth polymerization mechanism, via initiation, propagation and termination. The CROP of 2-oxazolines enables the process in a living or quasi-living manner under appropriate conditions with less or no undesirable termination or chain transfer occurs during the polymerization. The poly dispersity of poly(2-oxazoline) is highly dependent on the synthesis method used, allowing for precisecontrol over molecular weight and a narrow poly dispersity, meaning the polymer chains have a relatively uniform size distribution when done properly; making it a key factor in determining the final characteristics of the polymer. Polymers with low polydispersity are desirable for many applications, especially in biomedical fields, as they exhibit more predictable and consistent properties. Suitable POZ materials may be available from the commercial sources, whereby a PDI is less than 1.5 for polymers with a number-average molecular weight less than 10,000 g / mol, e.g., < 1.3.

[0075] Generally, the present disclosure provides in some embodiments compositions and methods for synthesizing POZ-carbohydrate-sterol / (or lipophilic vitamin) conjugates comprising a central backbone with one POZ chain and one carbohydrate group and one lipophilic group bonded to the backbone. The conjugation undergoes alkylation including N- alkylation or (9-alkylation, etherification, esterification and amidation chemical processes. Selected linkers may be used to form ester or ether or amide bonds between the backbone and the POZ chain or the carbohydrate or the lipophilic group or prior to the conjugation to the center backbones. The backbone comprises glycerol or glycerol-liking having three available binding positions or diamines, triamines, tetraamine and polyamines or diaminoalcohol or amino acids having three available binding positions.

[0076] Examples of lipophilic carrier groups include residues of fatty acids ranging from carbon chain lengths of about C8 to about C22, preferably between about CIO and about Cl 8, such as capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, myristoleic acid palmitoleic acid, sapienic acid, oleic acid, elaidic acid, stearic acid, vaccenic acid, linoleic acid, linoelaidic acid and a-linolenic acid, as well as residues of cholesterol or cholesterol-like compounds having a single hydroxyl group, tocopherol, tocotrienol, cholecalciferol, retinol, retinal, and retinoic acid.

[0077] The person of ordinary skill in the art will appreciate from the present disclosure that a number of variations are possible, including a variety of compounds as for the central backbone with at least three available binding positions. Molecules having two available binding positions, such as diamines, aminoalcohols or amino acids may be chemically extended to three binding sites.

[0078] While positional isomers may be produced during synthesis of the polymer- carbohydrate-lipid conjugates, such isomers may be functionally equivalent. However, the choice of isomer may have implications in a variety of delivery process such as intracellular transport of lipophilic molecules as well as their use as vehicles in pharmaceutical applications.For example, isomers may differ in the ability to stabilize a compound during solubilizing and storage.

[0079] Though it is possible to use a variety of central backbone for the preparation of a polymer-carbohydrate conjugates, incorporating linear or cyclic central backbones in practicing the compounds, compositions and methods of the disclosure is demonstrated to be very powerful, because of a sterol or tocopherol or cholecalciferol may largely increase handling ability of “like dissolves like.” In various embodiments of General Structure 1, the backbone may be selected from glycerol or glycerol-like analogues, polyamines (di- or tri-or tetra- or penta- amines), amino acids having three available binding sites, and triols and triacids such as glucoheptonic acid and tartaric acid. The lipophilic component may in various embodiments be selected from a group of compounds including but not limited to cholesterol, stigmasterol, ergosterol, hopanoids, phytosterol, sitosterol, campesterol, brassicasterol, avenasterol adosterol, and stanols (saturated steroid alcohols or hydrogenated sterols), retinoids, retinals, retinoic acid, tretinoin, carotenoids, P-carotene, a-tocopherol, tocotrienols, cholecalciferol, ergocalciferol, astaxanthin, auroxanthin, capsanthin, capsorubin, chrysanthemaxanthin, cryptoxanthin, fucoxanthin, lutein, neoxanthin, rubixanthin, violaxanthin, zeaxanthin. The carbohydrate in various embodiments is a sugar including monosaccharides or disaccharides or oligosaccharides or animo sugars or sugar acids. Xi, X2, X3 and X4 are the same or different linkers of carbon-nitrogen bond, ester or ether or amide between carrier groups and center backbones. Each linker may be as simple as oxygen or other single atom. In some cases, the linker may be co-extensive with or a part of the backbone or functional group component used to synthesize the conjugate. Though not shown, the disclosure also provides compounds in which the carbohydrate is in the center position of the backbone. However, it is more practical to have carbohydrates at the terminus instead of the center of the backbones due to the routes of synthetic chemistry. The general structure is meant to include all racemers or structural isomers of the structure, as they may be functionally equivalent. The POZ chain preferably consists of between about 10 and 50 subunits, and is preferably substantially monodisperse. R is the terminal group on the POZ chain may be selected from a wide variety of chemical moi eties. R preferably has a molecular weight of less than about 650.

[0080] Preferable amino acid linkers are proline, glycine, alanine, lysine, cysteine, valine, isoleucine, leucine, methionine, phenylalanine, histidine, tryptophan, tyrosine, selenocysteine,and arginine, more preferable are proline, glycine, alanine, lysine, cysteine, valine, isoleucine, leucine, methionine, most preferable are proline, glycine, and alanine.

[0081] In various embodiments of the general structure 1, each X group may comprise one or more carbon atoms in addition to the linker forming an A-alkylation or (9-alkylation, ester or ether or amide bond between the carriers and center backbone. Whenever suitable, a simple and low cost coupling process should be chosen to void multiple linkers such as forming a peptide and the linker is preferably oriented so that the backbone is readily coupling to the carrier groups.

[0082] The compounds of the present disclosure may be practiced using a variety of central backbones. Preferable backbones have at least three available or two expandable positions for carbohydrate or lipid or POZ attachments through alkylation, esterification, etherification or amidation. For those suitable molecules may be used as the backbone including but not limited to the group consisting of ethylenediamine (1,2-diaminoethane, 1,3 -diaminopropane (propane- 1,3-diamine), putrescine (butane- 1,4-diamine), cadaverine (pentane- 1,5-diamine), hexamethylene-diamine (hexane-l,6-diamine), ethylenediamine, 1,3-diaminopropane, 1,2- diaminopropane, 1,4-diaminobutane, diphenylethylenediamine, diaminocyclohexane, 3- amino-l,2-propanediol, 3-bromo-l,2-propanediol, 3-chloro-l,2-propanediol, 3 -fluoro- 1,2- propanediol, DL-glyceric acid, diaminopropionic acid, tartaric acid, glucoheptonic acid and, 1,2,4-butanetriol, 2,2-Bis(hydroxymethyl)butyric acid, l,3-diamino-2-propanol and 2-(3- aminopropylamino)ethanol, 3-((3-aminopropyl)amino)propanol, di ethylenetriamine, spermidine, triethylene-tetramine, spermine, norspermidine, bi s(3 -aminopropyl)- 1,3- propanediamine, and bis(hexamethylene)triamine, aspartic acid, glutamic acid, asparagine, glutamine, ornithine, serine and threonine, benzyl triols or aminohydroxybenzoic acids or phenol-like analogues, phenyl diols with a carboxy group or amine, and diamines with a hydroxyl or carboxy group, diaminobenzoic acid, aminohydroxybenzoic acid, aminosalicylic acid, hydroxyanthranilic acid, hydroxyisophthalic acid, aminoisophthalic acid. For example, a suitable center backbone may be selected from 4-(hydroxymethyl)cyclopentane-l,3-diol, deoxy fuconojirimycin, deoxynojirimycin, prostaglandins, hydroxymethylpiperidinol, dihydroxy(hydroxymethyl)aminocyclopentane, diaminophenol, benzene-tetracarboxylic acid, benzenetricarboxylic acid, aminobenzenediol, dihydroxybenzoic acid, aminohydroxybenzoic acid, trihydroxyaniline, benzenetriol, dimethoxybenzenediamine, trihydroxyphenol, (diaminophenoxy)-benzene-diamine or aminobromophenol.

[0083] Suitable carbohydrates for the polymer-carbohydrate conjugates include monosaccharides or disaccharides or oligosaccharides as listed in Table 2. In addition to carbohydrates listed in Table 1, their analogues or derivatives are also suitable for making the conjugates including but not limited to sugar alcohol, sugar acids (saccharides with a carboxyl group), ascorbic acid, steviol glycoside (Rebaudioside A), sucralose, lactitol, maltitol, isomalt, maltotriitol, maltotetraitol, mogrosides, glycyrrhizin, inulin, glucoheptonic acid and osladin.

[0084] Table 2. Examples of Carbohydrates

[0085] The polymer-carbohydrate conjugates of the present disclosure may be used for many applications. Formulation and delivery of pharmaceutical and cosmetic agents have been described. Additionally, the polymer-carbohydrate conjugates of the present disclosure may be used in other contexts where water soluble lipids are advantageous, for example industrial and food processes.

[0086] The terminal group on the POZ chain may be selected from a wide variety of chemical moieties. Such moieties preferably have a molecular weight of less than 650. Such moieties include -OH, -NH2, -COOH, -OCH2CH3, -OCH2CH2OH, -COCH=CH2, -OCH2CH2NH2, -OSO2CH3, -OCH2C6H6, -OCH2COCH2CH2COONC4H4O2, -CH2CH2=CH2, C10H16N2O3S and -OCeHe. The terminal group may be a functional group that facilitates linking therapeutic or targeting agents to the surface of micro vesicle aggregates. Amino acids, amino alkyl esters, biotins, maleimide, diglycidyl ether, maleinimido propionate, methylcarbamate, tosylhydrazone salts, azide, propargyl-amine, propargyl alcohol, succinimidyl (NHS) esters (e.g., propargyl NHS ester, NHS-biotin, sulfo-NHS-LC-biotin, or NHS carbonate), hydrazide, succinimidyl ester, succinimidyl tartrate, succinimidyl succinate, and toluenesulfonate salt are useful for such linking. Linked therapeutic and targeting agents may include Fab fragments, cell surface binding agents, and the like. Additionally, the terminal group may include functional cell-targeting ligands such as folate, transferrin and molecules such as monoclonal antibodies, ligands for cellular receptors or specific peptide sequences may be attached to the liposomal surface to provide specific binding sites. The terminal group may be neutral or include either negatively or positively charged head-groups such as 10-aminodecanoxy, 18- aminooctadecyloxy, 8-aminooctanoxy, 4-aminobutoxy, 12-aminododecanolamine, 6- aminohexanoxy, 14-aminotetradecanoxy, 16-aminohexadecanoxy, 10- (trimethylammonium)decanoxy, 18-(trimethylammonium)octadecoxy, 8-(trimethylammonium)octanoxy, 4-(trimethylammonium)butoxy, 12-(trimethylammonium)dodecanoxy, 6-(trimethylammonium)hexanoxy, 14-(trimethylammonium)tetradecanoxy, 16-(trimethylammonium)hexadecanoxy. Other useful R groups include alkyl groups such as alkoxy moieties (e.g., C1-C20 alkoxy), amino acids, and sugars including monosaccharides, ascorbic acid, gluconic acid, glucaric acid, glucuronic acid, galacturonic acid, disaccharides, trisaccharides and the oligosaccharides containing 1, 2, 3, and 4 or more monosaccharide units respectively. Additionally, targeting moieties such as antibody fragments and vitamins may also be used as R groups. In some embodiments, the R group is highly soluble in water. The molecular weight of the R group is preferably less than about 650, and for most applications the R group is preferably easily polarized, in order to increase the binding and interaction with proteins at the targeted sites. However, well balanced ionic R groups are advantageously employed for certain modes of administrations such as topical gels and oral solutions targeting the mouth and throat.

[0087] Depending on the choice of backbone, functional groups and linkers, the compounds of the disclosure may be categorized into several classes. These classes include fattyacid- carbohydrate-POZ or cholesteryl-carbohydrate-POZ or tocopherylglycerolcarbohydrate-POZ and tocopheryl-carbohydrate-POZ.

[0088] In another aspect the disclosure provides a POZ-carbohydrate conjugate with three carriers having the General Structures:

[0089] General Structure 2 to 6

[0090] where the backbone is selected from residues of glycerol or glycerol-like analogues or linear amines (di- or tri-or tetra-amines) or amino acids having three available binding sites including and not limited to selected from the group consisting of 1,3 -propanediamine, diethylenetriamine, bis(3-aminopropyl)-amine or bis(3-aminopropyl)-l,3-propanediamine or 7V,7V'-bis(3-aminopropyl)-l,3-propanediamine, triethylenetetramine or l,2-bis(3- aminopropylamino)ethane, spermine, tris(2-aminoethyl)amine, spermidine, norspermidine,bis(hexamethylene)triamine, tris(hydroxymethyl)-aminomethane, diaminobenzidine, triazacyclononane, tetraazacyclododecane, threitol, meso-erythritol, dithiothreitol, trimethylcyclohexane-l,3,5-tricarboxylic acid or 1,3,5-cyclohexane-tricarboxylic acid, trimethylbis(hexa-methylene)triamine, arginine, oxylyldiaminopropionic acid having three or four available binding positions or sites, triols, triacids, glucoheptonic acid, and tartaric acid; where the L is with saturated or unsaturated chains ranging from 6 and 22 carbons, steroid acids including but not limiting to cholic acid, deoxycholic acid and glycocholic acid or sterol or fat soluble vitamin or alike selected from a group of lipophilic compounds or their esters including and not limited to cholesterol, stigmasterol, ergosterol, hopanoids, phytosterol, sitosterol, campesterol, brassicasterol, avenasterol adosterol, and stanols (saturated steroid alcohols or hydrogenated sterols), retinoids, retinals, retinoic acid, tretinoin, carotenoids, P- carotene, tocopherols, tocotrienols, cholecalciferol, ergocalciferol, astaxanthin, auroxanthin, capsanthin, capsorubin, chrysanthemaxanthin, cryptoxanthin, fucoxanthin, lutein, neoxanthin, rubixanthin, violaxanthin, zeaxanthin; the Sugar is a carbohydrate including monosaccharides ascorbic acid, gluconic acid, glucaric acid, glucuronic acid, galacturonic acid or disaccharides or oligosaccharides; where the three substitutable groups are covalently bond to the backbone through a etherification or esterification or amidification or similar substitution reactions. The General Structure is meant to include all racemers or structural isomers of the structure, as they may be functionally equivalent. Where the POZ (POZi or POZ2 or POZ3 may be the same of different polymer) chain may consist of between about 5 and 45 subunits. More preferably the POZ chain consists of between about 4 and 25 subunits. Where R (or Ri) is the terminal group on the POZ chain may be selected from a wide variety of chemical moieties. R preferably has a molecular weight of less than about 650. The POZ-carbohydrate-sterol conjugates are useful for applications other than liposomes, e.g., as a solubility enhancer in water solution. Even though no linker group is presented in the General Structures, modifications of carrier groups or center backbones may be necessary prior to the coupling reactions, those chemical modifications may be required for alkylation, etherification, esterification or amidation chemical processes between the carrier groups and the center backbone. Ideally selected carriers or center backbones may be used for the coupling reactions directly without a modification. Where X (Xi, X2 X3 or X4) may be the same or different linkers) is one or more linkers selected from the Table 2 or 3 or groups consisting of oxy, amino acids, amino, succinylamino, acetamido, aminopentanamido, aminoacetyl, thiopropanoayl, 7V-(mercapto- methyl)propionamido, mercapto-propylthio)propanoyl, (l,2-dihydroxy-3-mercapto-propythio)-propanoyl, succinyl, acetyl, oxopentanoyl, carbamoyl, aminoalkyl, glutaramido, aminoethanethiol, mercaptopropanol, (hydroxypropylthio)propanoayl, 3-((2-propion- amidoethyl)disulfanyl)-propanoayl, (((acetamido-ethyl)disulfanyl)propanoyloxy)glutaramido, aminoethanethioate, and 2-hydroxyacetic proprionic anhydride.

[0091] In another aspect the disclosure provides a molecule comprising a compound represented by the following General Structure 8:Sugars bPOZ^Backbone / 'L

[0092] General Structure 8

[0093] Where the backbone is described as above for “B,” e.g., selected from glycerol or glycerol -like analogues or linear amines (di- or tri-or tetra-amines) or amino acids having three available binding sites selected from a group of molecules including but not limited to glycerol or glycerol-like analogues, polyamines, triamines, tetraamines, aminodiol, aminotriols, aminoalcohols and amino acids having three available binding positions or sites, triols, tetraols, erythritol, triacids, tetracid, tetraacetic acid, glucoheptonic acid, and tartaric acid, including but not limited to 1,3 -propanediamine, ethylenediamine (1,2-diaminoethane, 1,3-diaminopropane (propane-1, 3-diamine), 4-amino-3 -hydroxybutyric acid, 7V-(2-hydroxyethyl)-ethylenediamine, 4-amino-2-hydroxybutyric acid, 2-hydroxy-4-aminobutylic acid, 1-B-homoserine, 1-threonine, 7V-B-aminoethyl-glycine, putrescine (butane- 1,4-diamine), cadaverine (pentane- 1,5-diamine), hexamethylenediamine (hexane- 1,6-diamine), ethylenediamine, 1,3-diaminopropane, 1,2- diaminopropane, 1,4-diaminobutane, diphenylethylenediamine, diamino-cyclohexane, diethylenetriamine, bis(3-aminopropyl)-amine, triethylenetetramine, tris(2-aminoethyl)amine, spermine, spermidine, norspermidine, bis(3-aminopropyl)-l,3-propanediamine, l,2-bis(3- aminopropylamino)ethane, 7N,7N'-bis(3-aminopropyl)-l,3-propanediamine, 3-amino-l,2- propanediol, aminoalcohols, tris(hydroxymethyl)aminomethane, diaminobenzidine, A-ethyl- Af'-(3-dimethylaminopropyl)carbodiimide, mesoerythritol, triazacyclononane, tetraazacyclododecane, threitol, dithiothreitol, trimethylcyclohexane-l,3,5-tricarboxylic acid, trimethylbis(hexa-methylene)triamine, bis(hexamethylene)triamine, arginine, oxylyldiaminopropionic acid, 3-bromo-l,2-propanediol, 3-chloro-l,2-propanediol, 3-fluoro- 1,2-propanediol, DL-glyceric acid, diaminopropionic acid, glucoheptonic acid and, 1,2,4- butanetriol, 2,2-bis(hydroxymethyl)-butyric acid, l,3-diamino-2-propanol and 2-(3-Aminopropylamino)-ethanol, and 3-((3-aminopropyl)-amino)propanol; aspartic acid, glutamic acid, asparagine, glutamine, lysine, ornithine, serine, and threonine or benzyl triols or aminohydroxybenzoic acids or benzenetriol, dihydroxybenzoic acid, diaminobenzoic acid, diaminophenol, diaminobenzoic acid, aminohydroxybenzoic acid, aminosalicylic acid, hydroxyanthranilic acid, hydroxyisophthalic acid, aminoisophthalic acid, 4- (hydroxymethyl)cyclopentane-l,3-diol, deoxy fuconojirimycin, deoxynojirimycin, prostaglandins, hydroxylmethylpiperidinol, dihydroxy(hydroxymethyl)-aminocyclopentane, diaminophenol, benzenetetracarboxylic acid, benzenetricarboxylic acid, aminobenzenediol, dihydroxybenzoic acid, aminohydroxybenzoic acid, trihydroxyaniline, benzenetriol, dimethoxybenzenediamine, trihydroxyphenol, (diaminophenoxy)benzenediamine and aminobromophenol; where the Lipid (L) is selected from a group of lipophilic compounds or their diesters including and not limited to fatty acids, e.g., lauric acid, myristic acid, linoleic acid, iso-linoleic acid, palmitic acid, oleic acid, elaidic acid, stearic acid and sterol including cholesterol, stigmasterol, ergosterol, hopanoids, phytosterol, sitosterol, campesterol, brassicasterol, avenasterol adosterol, and stanols (saturated steroid alcohols or hydrogenated sterols), retinoids, retinoic acid, tretinoin, carotenoids, P-carotene, a-tocopherol, tocotrienols, cholecalciferol, ergocalciferol, astaxanthin, auroxanthin, capsanthin, capsorubin, chrysanthemaxanthin, cryptoxanthin, fucoxanthin, lutein, neoxanthin, rubixanthin, violaxanthin, zeaxanthin; Sugar is a carbohydrate including monosaccharides or disaccharides or oligosaccharides or amino sugars or sugar acids including but not limited to ascorbic acid, gluconic acid, glucaric acid, glucuronic acid, galacturonic acid; where the three substitutable groups are covalently bond to the backbone through a etherification or esterification or amidification or similar substitution reactions. The General Structure is meant to include all racemers or structural isomers of the structure, as they may be functionally equivalent. Where the bPOZ is a branched POZ with 2 or more POZ chains and each POZ chain may consist of between about 5 and 45 subunits. For example, a branched POZ contains two hydroxy POZ- chains linked to a central core such as a glycerol, forming a so called "Y-shaped" POZ. . Where Ri is the terminal group on each POZ chain which may be the same or different and that may be selected from a wide variety of chemical moieties. Ri preferably has a molecular weight of less than about 650. The POZ-carbohydrate conjugates are useful for applications other than liposomes, e.g., as a solubility enhancer of poor water soluble agents in aqueous solutions.

[0094] In another aspect the disclosure provides a POZ-carbohydrate conjugate with four carriers having the following General Structures:

[0095] General Structures 9 -10

[0096] where L or Li and L2 may be the same or different lipophilic carrier) is fatty acids, e.g., lauric acid, myristic acid, linoleic acid, iso-linoleic acid, palmitic acid, oleic acid, elaidic acid, stearic acid and sterol including cholesterol or sterols or lipophilic vitamins or alike selected from a group of lipophilic compounds or their diesters including and not limited to cholesterol, stigmasterol, ergosterol, hopanoids, phytosterol, sitosterol, campesterol, brassicasterol, avenasterol adosterol, and stanols (saturated steroid alcohols or hydrogenated sterols), retinoids, retinals, retinoic acid, tretinoin, carotenoids, P-carotene, tocopherols, tocotrienols, cholecalciferol, ergocalciferol, astaxanthin, auroxanthin, capsanthin, capsorubin, chrysanthemaxanthin, cryptoxanthin, fucoxanthin, lutein, neoxanthin, rubixanthin, violaxanthin, zeaxanthin; if Li and L2 are different carriers other than sterols or fat soluble vitamins, one (the fourth carrier) of the two may be selected from residues of saturated fatty acids or unsaturated fatty acids as listed in Table 3 and also including native polyunsaturated alcohols such as farneol, solanesol and dodecaprenol, however fatty acids may only be selected as the secondary lipophilic carrier in the presence of a sterol as the primary lipophilic carrier and restrictedly avoided to be utilized as the primary lipophilic carrier due to their potential hemolytic property; where the backbone is selected from triamines, tetramines or polyamines or compounds having four available binding sites; where the fourth carrier is selected from diesters including and not limited to sterol-acylglycerols or disterolglycerols; Sugar (sugar 1 and 2 may be the same or different) is a carbohydrate including monosaccharides, ascorbic acid, gluconic acid, glucaric acid, glucuronic acid, galacturonic acid or disaccharides or oligosaccharides or amino sugars and sugar acids; where the three substitutable groups are covalently bond to the backbone through a etherification or esterification or amidification or similar substitution reactions. The General Structure is meant to include all racemers or structural isomers of the structure, as they may be functionally equivalent. Where the POZ chain (POZi andPOZ2 chain may be the same or different in length) may consist of betweenabout 5 and 50 subunits. Where R (Ri and R2 may be the same of different) is the terminal group on the POZ chain may be selected from a wide variety of chemical moieties. R preferably has a molecular weight of less than about 650. The POZ-carbohydrate conjugates are useful for applications other than liposomes, e.g., as a solubility enhancer in water solutions.

[0097] Table 3. Unsaturated fatty acids

[0001] Similar to the three carrier conjugates, synthesis of the new conjugates may be controlled so that there is a single linker in each POZ-carbohydrate conjugate. In some situations, however, it may be useful to have multiple copies of the same linker, or combinations of different linkers in a single molecule in the General Structures.

[0098] In one aspect of the present disclosure, coupling reactions of alkylation, etherification, esterification or amidation between the carriers and center backbone may be achieved with or without added-on linker groups depending on particular center backbones and carrier groups of the conjugates as summarized in the General Structure 11 :Suga

[0100] where Xi and X2 may be the same or different linkers that consist of one or more linkers selected from the group of oxy, amino, succinylamino, acetamido, aminopentanamido, aminoacetyl, thiopropanoayl, acryloyl, N-(mercaptomethyl)propionamido, mercaptopropylthiopropanoyl, (l,2-dihydroxy-3-mercapto-propylthio)propanoyl, succinyl, acetyl, oxopentanoyl, carbamoyl, aminoalkyl, glutaramido, aminoethanethiol, mercaptopropanol, (hydroxypropylthio)propanoayl, 3-((2-propionamidoethyl)- di sulfanyl jpropanoayl, (((acet-amidoethyl)disulfanyl)propanoyloxy)-glutaramido, aminoethane-thioate, and 2-hydroxyacetic proprionic anhydride.

[0101] In various embodiments, the present disclosure provides a method of linking the central backbone to any of the three carrier groups via an amino acid linkage (alkylation or amidation process), e.g., the hydroxyl in the carrier groups may be activated by reacting it with disucccimidylcarbonate (DCS) or mesylate or tosylate or strong base (etherification or esterification).

[0102] Example of the synthesis of the POZ-carbohydrate conjugates from amino acids is

[0103] Reaction Scheme 1

[0104] Wherein, THF = Tetrahydrofuran; DMAP = N, A-Dimethylformamide; DCC = N,N'- Dicyclohexylcarbodiimide; DCM = methylene chloride; MeOH = methanol and RT = room temperature. The reaction scheme is applicable to carrier groups having all kinds of hydrocarbon groups and amino acids with three available binding positions as demonstrated in the in Reaction Scheme 1 where the center backbone is Lysine.

[0105] The boc-lysine is commercially available which may be directly reacted with cholesterol acrylate via Michael addition reaction to create a new carbon-nitrogen bond. The carboxyl group of carboxylic acid from Sterol-AA may react with the terminal hydroxy group of POZ forms an ester linkage and then the protection group on the primary amine is removed and reacted with the activated carbohydrate to form the POZ-carbohydrate-sterol conjugates as depicted in Chemical Structure 2, where the sterol may be cholesterol. This reaction scheme is suitable for carrier groups with all kinds of lipophilic compounds or POZ chains. The generalstructures shown in the application are meant to include all racemers and structural isomers of the structures, as they may be functionally equivalent.

[0106] Chemical Structure 2: 7V-lactobionylysinate-cholestol(ethylene glycol)-POZ

[0107] In chemical structure 2, a linker of ethylene glycol was used on both POZ and cholesterol. Example of the synthesis of the POZ-carbohydrate-sterol conjugates from linear multi-amine central backbones is shown below in Reaction below in Reaction Scheme 2.Which is suitable for amines or carrier groups with all kinds of lipophilic compounds or POZ chains or carbohydrates as demonstrated in Reaction Scheme 3.

[0108] Reaction Scheme 2

[0109] Reaction Scheme 3

[0110] As showed in the Reaction Scheme 4, O-acetylation procedures are one of the most common synthetic strategies for the protection and purification of various natural and synthetic carbohydrate substructures. The free hydroxide groups may react with acetic anhydride of acetic chloride in the presence of acid scavenger i.e. pyridine or EtsN, smoothly at room temperature overnight to form acetate ester (R-O-Ac) in high yield. If catalytic amount of 4-Dimethylaminopyridine (~5%) was applied, the reaction was completed in less than 2 hours. The final product was further purified by washed with saturated NH4C1 aqueous solution, followed by saturated NaHCO3 aqueous solution, dried over MgSCU or ISfeSCU and condensed. This reaction scheme is suitable for carbohydrates or sugar carrier groups with all kinds of lipophilic compounds or POZ chains or backbones.

[0111] Reaction Scheme 4

[0112] The present disclosure also demonstrates the using of a branched-POZ as the polymer carrier. Branched POZs with smaller POZ chains may be used to prepare a branched POZ. As demonstrated in the Reaction Scheme 1 to 4, there are multiple chemical processes of alkylation, etherification, esterification or amidation involved for making each final product, the steps of each conjugation were designed accordingly.

[0113] In various embodiments, the present disclosure provides POZ-carbohydrate conjugates comprised of three carrier groups and a central backbone having at three positions available for the conjugation, and one or more linker(s) between one of the carrier groups and the central backbone. Such POZ-carbohydrate conjugates are represented by the General Structures 1 to 11, where the conjugates may comprise a linker or a link group consisting of di-tri-, tetra-, ethylene glycol, succinylamino, acetamido, aminopentanamido, aminoacetyl, acryloyl, thiopropanoayl, N-(mercaptomethyl)-propionamido, mercaptopropylthiojpropanoyl, (l,2-dihydroxy-3-mercaptopropylthio)propanoyl, succinyl, acetyl, oxopentanoyl, carbamoyl, aminoalkyl, glutaramido, aminoethanethiol, mercaptopropanol,(hydroxypropylthio)propanoayl, 3-((2-propionamidoethyl)disulfanyl)-propanoayl,(((acetamido-ethyl)disulfanyl)propanoyloxy)-glutaramido, amino-ethanethioate, and 2- hydroxyacetic proprionic anhydride. The Table 4 shows certain samples of the POZ- carbohydrate conjugates and in the event of variations of chemical names, the structures shown are meant to be controlling.

[0114] Table 4: Sample of POZ-Carbohydrate-Sterol Conjugates

[0115] In Table 4, the types of coupling reaction between the carriers and the center backbone as well as any chemical modification of a carrier or center backbone prior to the conjugation are alkylation including A-alkylation or (9-alkylation, esterification, etherification and amidation. For example, a POZ may be modified with acryloyl chloride then reacted withcenter backbone, thus two types of reaction may be involved; esterification and V-alkylation, e.g., Michael addition reaction.

[0116] The present disclosure provides a novel POZ polymer-carbohydrate conjugate system having at least one of lipophilic moiety that may be used as a safe and biocompatible vehicle for drug or molecule delivery. A therapeutic, diagnostic or cosmetic agent may be solubilized or encapsulated in those polymer-carbohydrate conjugates to form a solution or microsuspension as presented below:Wherein, Lipid is being selected from a group consisting of fatty acids including lauric acid, myristic acid, linoleic acid, palmitic acid, oleic acid, elaidic acid, stearic acid, sterols, tocopherols or retinoid acids and steroid acids; POZ is a polymer of Poly(2-alkyl -2-oxazoline); “n” ranges from 5 to 50 of 2-alkyl -2-oxazoline) subunits; the central backbone is a diamine; “m” = 1 to 6 of CEE.

[0117] Embodiments of the present disclosure are described herein in the context of preparation of pharmaceutical compositions including POZ-carbohydrate-lipid conjugates for increasing the solubility and enhancing the delivery of active agents. The approximate preferable compositions for formulated drug products are generally described herein, though different drugs typically have differing optimal formulations.

[0118] For intravenous (IV) solutions, the preferable concentration of drug is 0.1% to 30%. More preferable is 0.5 to 10%. Most preferable is 0.5 to 5%. The preferable weight ratio of POZ-carbohydrate lipid conjugate (PLC) to the drug (PLC / drug) in the final drug solution for the injection is 1 to 30, w / w (weight / weight). More preferable is 1 (drug) to 25 (PLC). Most preferable is 1 to 10.

[0119] It is preferable POZ-carbohydrate conjugates having narrow-disperse POZ chains for intravenous administration of pharmaceutical agents. The narrow-disperse POZ chains may consist of a few POZ oligomers, e.g., 1 to 5; wherein the total oligomer purity from individual oligomers may be as high as 80%. For instance, a monodisperse POZ with 10 subunits may contain 50% of POZio and 50% of species with other numbers of subunits, e.g.., 10 to 25% each of POZ9 or POZn species. It is preferable to have a narrow-disperse POZ chain containinga few numbers of oligomers. The preferable number of oligomers is 3 to 10, more preferable is 1 to 10. Most preferable is 1 to 5.

[0120] For ophthalmic preparations, the preferable concentration of drug is 0.01 to 5%. More preferable is 0.05 to 2%. Most preferable is 0.1 to 2%. The preferable ratio of POZ- carbohydrate to the drug (PLC / drug) is 1 to 50, w / w (weight / weight). More preferable is 1 (drug) to 20 (PLC). Most preferable is 1 to 5.

[0121] For topical solutions, the preferable concentration of drug is 0.05 to 5%. More preferable is 0.1 to 5%. Most preferable is 0.1 to 2%. The preferable ratio of POZ- carbohydrate conjugates to the drug (PLC / drug) is 1 to 100, w / v. More preferable is 3 (drug) to 50 (PLC). Most preferable is 1 to 10.

[0122] For oral dosages, the preferable content of drug is 2 mg to 500 mg. More preferable is 2 mg to 200 mg. Most preferable is 2 mg to 100 mg. The preferable ratio of POZ- carbohydrate conjugates to the drug (PLC / drug) is 1 to 300, w / w. More preferable is 1 (drug) to 100 (PLC). Most preferable is 1 to 50.EXAMPLES

[0123] Chemicals and Reagents: N,N-Dimethylformamide (DMAP), N, N’- di cyclohexylurea, N, TV’-dicyclohexylcarbo-diimide (DCC), ascorbic acid, lactobionic acid, fatty acids, cholecalciferol, cholesteryl choloformate, cholesterol, glucuronic acid, retinoic acid, a-tocopherol, 2-Methyl-2-oxazoline, 2-ethyl-2-oxazoline, 2-propyl-2-oxazoline, trifluoromethanesulfonic acid and other solvents or chemicals, e.g., Trifluoromethanesulfonic acid, were obtained from Sigma-Aldrich (St. Louis, MO, USA) or Alfa Aesar (Ward Hill, MA, USA).

[0124] Example 1. Preparation of tert-Butyl Carbamates (Boc)-Protected Amino Groups

[0125] A high yield and effective synthetic method under a catalyst-free and room temperature was reported previously [Chankeshwara, SV and Chakraborti, AK (2006). Org. Lett., 8: 3259] and used with some modifications. To a solution of starting compound containing amino benzoate in MeOH, di-Lbutyl dicarbonate was added as one to one molar ratio. The resulting mixture was stirred overnight at room temperature. When the reaction was done, solvent was removed under vacuum; the residue was dissolved into EtOAc and washed with saturated NH4CI aqueous solution once, then dried over ISfeSCU and condensed to yield the expected product (> 90%). Example of this reaction is demonstrated in Reaction Scheme5, where R is a main structure of the central backbone. This method gives A-Z-Boc derivatives chemoselectively without any side products (such as isocyanate, urea, A,A-di-Z-Boc).

[0126] Reaction Scheme 5

[0127] Example 2. Deprotection of Boc-Protected Amino Groups

[0128] 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 very convenient [Li, B. Berliner, M., et al (2006). J. Org. Chem.. 71: 9045], Equal volumes of trifluoroacetic acid were added to a solution of Boc-carbamate (10% of crude product) in CH2Q2. The resulting solution was stirred at room temperature for overnight and the solvent was evaporated and the residue was re-dissolved into CH2CI2, then washed with saturated NaHCCh and dried over MgSC4. Solvent was evaporated and was used in next step without further purification.

[0129] Example 3. Preparation of cholesterol acrylate

[0130] Dichloromethane (DCM) 500 mL was transferred into a 1 -liter round-bottomed flask equipped with a mechanic stirrer and an ice water bath. Cholesterol 387g (1 mol) was dissolved in DCM in the flask. Triethylamine 120g (1.2 mol) was added to the solution. The reaction mixture was cooled to 0-10 °C. Acryloyl chloride 91g (~ 81 mL, 1 mol) was added to the flask through addition funnel under constant stir. Water bath was removed after addition finished; the reaction mixture was continually stirred for 2 hours at room temperature. The reaction solution was washed with 2 x lOOmL water and then lOOmL brine, the organic layer was dried over sodium sulfate, filtered and solvent was evaporated to afford the product.

[0131] Example 4. Preparation of A-Boc-lysine-cholesterol

[0132] 74 g (0.3 mol) of W-Boc-lysine was constantly stirred under nitrogen in 500 mL of chloroform. 132 g (0.3 mol) of cholesterol acrylate from Example 3 was dissolved with 100 mL of chloroform and added to this heterogeneous mixture of A-tert-butyloxycarbonyl-lysine and followed by adding 10 mL of anhydrous pyridine. The reaction for 30 minutes under constantly stirring at room temperature, the mixture turned to homogeneous and the reaction was completed when no cholesterol acrylate was detected in the mixture. The bulk solvent wasremoved under vacuum and the crude product was used to next step without further purification. The resulting product (% of yields 70-80) is showed in Chemical Structure 3.

[0133] Chemical Structure 3

[0134] Example 5. Preparation of POZs

[0135] While synthesis of POZs is a mutual methodology over the last 4 decades, various processes can be found in literature. In general, polymerizations are carried out in a suitable solvent, e.g., acetonitrile or chlorobenzene with a desirable ratio of monomer (M) to initiator (I), e.g., the monomer to initiator ratio ([M] / [I]) of 10, 20, and 50 is corresponding to a degree of polymerization and molar masses, 1000 g / mol, 2000 g / mol , and 5000 g, respectively. Following procedure is an example for the preparation of 2-ethyl-2-oxazoline. A solution of 2- ethyl-2-oxazoline (298 g, 3 mol) and Trifluoromethanesulfonic acid (45 g, 0.3 mmol) was prepared in chlorobenzene (1200 mL) in a pre-cleaned and dried round-bottom flask under continuous N2 purge resulting in a monomer concentration of 3 moles and this mixture was heated at 120 °C for 120 min and resulting in pEtOx. The monomer conversion of the polymerization was over 95% (confirmed byJH NMR spectroscopy). Cooling the reaction mixture to room temperature using an ice bath, polymerizations were terminated with KOH / MeOH solution overnight to introduce a hydroxyl terminal group. The solvents of the reaction mixture (chlorobenzene and methanol) were evaporated under Vacuo. DCM was added to the crude product. The mixture was filtered to remove the excess KOH, and the resulting solution was extracted with dichloromethane (3x300 mL) and the combined organic layers were dried with magnesium sulphate. The resulting POZ-OH was obtained by evaporation of the solution under vacuum to dryness. The averaged molecular weight was in the range of 1000 g / mol.

[0136] In various some embodiments, Example 5 is suitable for the preparation of poly(2- methyl-oxazoline) or poly(2-propyl-oxazoline), whereby the monomer of 2-methyl-2- oxazoline or 2-propyl-2-oxazoline is used instead of 2-ethyl-oxazoline as the startingmonomer. However a monomer to initiator ratio has to be kept the same. A higher ratio produces a POZ with a high molecular weight; a ratio of 20 or 50 is to obtain polymerization and molar masses of 2000 g / mol or 5000 g / mol and so on.

[0137] Example 6. Preparation of Boc-'A- Lysine-cholestolpropionate-PEOZ

[0138] 0.1 moles of PEOZio (100 g, 0.1 mmol) was dissolved with 500 mL of anhydrous CH2Q2, 0.1 mole of dicyclohexylcarbodiimide (21g) and cholesterolpropionate-Boc-'A-lysine (67g) from Example 4 were added. The resulting mixture was stirred at 0-10 °C for 3 hours, then allowed to warm up to room temperature and stirred for additional 48 hours. When the reaction was complete, the white precipitate was filtered off over celite. The residue was rinsed with small amount of CH2Q2 twice and washed with sutured NH4CI, then dried over MgSC Solvent was evaporated to afford off-white solid as showed in Chemical Structure 4. The crude product’s purity was determined by 'H NMR and ESI-MS and HPLC-UV (>70%).

[0139] Chemical Structure 4 (n = 10)

[0140] Example 7. Preparation of - Lysine-cholesterolpropionate-PEOZ lactobionate

[0141] The protection group of tert-butyl carbonyl on the amino group was removed according to the method described in Example 2. 0.1 moles of Boc-'A-Lysine- cholesterolpropionate-PEOZ (157.5g) from Example 6 was dissolved with 500 mL of anhydrous N-methyl-2-pyrrolidinone, 0.1 moles of Lactobionolactone was added. The resulting mixture was stirred at 50-60 °C for overnight, and allowed to cool to the room temperature. The reaction solution was precipitated into isopropyl alcohol (IP A) and methyl t- butyl ether (MTBE) was added to maximize the isolated yield of precipitate. The crude product was washed well with 50 / 50 (v / v) IPA / MTBE and dried under vacuum at 30-40° C. The purity (> 90%) of the final product (Chemical Structure 5) was determined by LC-MS.

[0142] Chemical Structure 5 (n= 10)

[0143] Example 8. Preparation of Boc-protected 1,3-propanediamines

[0144] Following the same steps in Example 3 and the crude product obtained with a yield of 85-105% (Chemical structure 6)

[0145] Chemical structure 6

[0146] Example 9. Preparation of mesylated Polyoxazoline

[0147] Poly(2-ethyl-oxazoline)io (100 g, 0.1 mol) was transferred into a 5-liter round- bottomed flask equipped with a mechanic stirrer and placed in ice -bath. 500 mL THF and triethylamine (12 g, 0.12 mol) were added. The reaction mixture was cooled to 0-10 °C and mesyl chloride (12 g, 0.1 mol) 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 (50 g) for 1 hour. The salt was removed by filtration and the solvent was removed in vacuo to yield a yellowish liquid (Chemical Structure 7, 85-105% yield).

[0148] Chemical Structure 7

[0149] Example 9. Preparation of Boc-aminopropylamine-POZ

[0150] Formation of the C-N bond was by the N-alkylation of amine of the center backbone with the activated hydroxyl of the POZ. In a 1 -liter round-bottomed flask equipped with amechanic stirrer and a heating mantle, Boc-aminopropyleneamine from Example 8 (23 g, 0.13 mol) was mixed with the activated PEOZ from Example 8 (109 g, 0.1 mol) in 200 ml of a mixture of THF and water (1 / 1, v / v). The reaction was continually stirred for 2-4 hours under reflux and nitrogen purging protection. The solvent was removed in vacuo and 500mL of CH2Q2 was added to the residue. The solution was washed with 50 mL each of water and IN NaOH. The Organic layer was collected and dried over Na2SO4, solvent removed to afford Boc-aminopropaneamine-PEOZ (Chemical Structure 8), the crude product was transferred to the next step without further purification.

[0151] Chemical Structure 8

[0152] Example 10. Preparation of Preparation of Boc-aminopropaneamine-PEOZ-Oleate

[0153] The crude product (127 g, 0.1 mol) from the Example 9 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 (36 g, 0.12 mol) was dissolved in methylene chloride (200 mL) and slowly added to Boc-aminopropaneamino-PEOZ via a funnel. After the addition was completed, the reaction was continued for 2 hours under constant stirring at ambient room temperature. The ending reaction was judged by the completely 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 9: 65-75% yields).

[0154] Chemical Structure 9

[0155] Example 11. Preparation of Preparation of 1,3-propanediamine-lactobionate-POZ- 01 eate

[0156] Following the steps in Examples of 2 to remove the protection group on Boc- aminopropaneamine-POZ-oleate and free the amino group on N1position of aminopropaneamine-POZ-oleate. The product yield (~ 150g) was dissolved in 400 mL of CH2Q2 and transferred to a IL round-bottomed flask equipped with a mechanical stirrer. Tri ethylamine (20 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 Lactobionolactone (68 g, 0.2 mol) was added. The reaction was completed in 2 hours under constant stirring at ambient room temperature. The ending reaction was monitored by checking the peak profile using HPLC. The final product was washed with diluted HC1 (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 white solid (Chemical Structure 10: 70-80% yields).

[0157] Chemical Structure 10

[0158] Example 12. Preparation of lactobionyldi ethylenetriamine

[0159] Diethylenetriamine (0.1 mol) was dissolved in 50 mL of dry (molecular sieve) N- methyl-2-pyrrolidinone and lactobionolactone (0.05 mol) was added. The resulting mixture was stirred for 6 hours at 50-60 °C and allowed to cool to the room temperature when the reaction was completed. The reaction solution was precipitated into isopropyl alcohol (IP A) and methyl t-butyl ether (MTBE) was added to maximize the isolated yield of precipitate. The cake was washed well with 50 / 50 (v / v) IPA / MTBE and dried under vacuum at 30-40° C. The crude product (Chemical Structure 11) and was used in next step without further purification.

[0160] Chemical Structure 11

[0161] Example 12. Preparation of Lactobionyloleoyldiethylenetriamine-POZ

[0162] 0.1 mole of the starting material from Example 11, lactobionyldi ethylenetriamine(44.4g), was dissolved in 50 mL of dimethylformamide (DMF) at 20 to 30° C. The slightly excess active oleic acid / f-hydroxysuccinimide ester (42 g, 0.11 mol) was dissolved in 100 mL of tetrahydrofuran (THF), then mixed with lactobionyldiethylenetriamine and adding triethylamine (TEA, 3%, v / v) as a base, stirred for 2 hrs at room temperature. An assay was performed to verify the yield and moves to next step without purification. The active mesyl- PEOZ io- (101g, 0.1 mol) was dissolved in 200 mL THF, and then mixed with the above reactants, stirred for overnight at room temperature. After the completion of the reaction, solvents were removed by vacuo and 50 mL of acetone was added to the crude product and filtered and washed with 50 mL of acetone three times. The reaction solution was precipitated into isopropyl alcohol (IP A) and methyl t-butyl ether (MTBE) was added to maximize the isolated yield of precipitate. The crude product was washed well with 50 / 50 (v / v) IPA / MTBE and dried under vacuum at 30-40° C. The purity (> 95%) of the final product (Chemical Structure 12) was determined by HPLC-UV andLC-MS.00163] Chemical structure 12

[0164] Examples 1 to 12 are suitable for making a POZ-carbohydrate-lipid conjugate with all kinds of available POZs and 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, cholesterol, bile acid or its analogues including but limited to cholic acid, deoxycholic acid and glycocholic acid and cholesterol or retinoic acids or tocopherols. While large POZs are possible, the preferable POZ is ranging from 5 to 50 subunits for the clinical prospect.

[0165] 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 POZ-carbohydrate-lipid conjugate comprising the following structures:wherein, the “n” is ranging from 5 to 50, whereby PEOZ can be replaced by PMOZ or PPOZ.

[0151] Example 13 Preparation of Bulk Powder by Spray-drying

[0152] The polymer can be dried using a spray drying process, e.g., a 10% to 20% ofPOZOcarbohydrate-lipid concentrates in ethanol was flowed into a dryer which was set with following parameters:Spray dryer: 5L / hrAir Blower: 40HzInlet 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: 300Spray Pressure: 0.2MPaNeedle Pressure: 0.3MPaCooling water setting: 10°CNitrogen generator setting: As needed

[0153] In various embodiments, a drying process can be used in the compounding process, for example, using a lyophilizer or a spray dryer. Active pharmaceutical ingredients (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.

[0154] Example 14 Preparation of Water Soluble Bulk Pharmaceutical Products

[0155] Pre-mixed solution of active pharmaceutical ingredient (API) and polymer at requisite ratio, e.g., 1 to 5 or 1 to 3, in ethanol. The solvent removed after completely solubilized and USP water was added to produce a 20 to 30% of the product solution. The bulk solutions are transferred into glass or stainless steel trays or lyophilization trays, i.e., 1.2L or 1.8L of Lyoguard® freeze-drying trays (W.L. Gore & Associates, Elkton, MD, USA) and following the same freeze drying cycle described in Example 12 and the bulk lyophilized powder can will used for making granules with compression or loss powder for solution. A sample composition is listed in Tablet 5:

[0156] Table 5

[0157] In Table 5, The API is a poor water soluble substance including but limited to antifungals, antiretrovirals or anticoagulants or antitumor antibiotics or anti-inflammatory or antibacterials or cardiovascular agents or central nervous system agents or analgesics or a combination thereof.

[0158] In Table 5, POZ-lipid may be POZ-carbohydrate-lipid may be selected from Table 4 or paragraph 143. Extra amounts of said polymer may be required to solubilize the API and the side alky group is interchangeable among methyl, ethyl and propyl as a suitable alternative to achieve the solubility enhancement. Other surfactants, e.g., as a tablet filler, may be polyvinylpyrrolidone, poloxamers or cyclodextrin derivative, Polyoxyl 40 hydrogenated castor oil, polysorbates, polyethylene glycols or a combination thereof, the sweeteners include but not limited to sucrose, dextrose, fructose, glucose and maltose or polyhydric alcohols such as sorbitol, mannitol, isomalt and maltitol, the sweeteners may be from natural sources including stevia extra or monk fruit extract or artificial compounds such as acesulfame potassium, arginine acid, aspartame, cyclamate, erythritol, saccharin, sorbitol, sucralose and xylitol or a combination thereof; Superdisintegrants include but not limited to Mg stearate, Sodium starch, glycolate, crospovidone, microcrystalline cellulose and crospovidone; Coloring agents include but not limited to FD&C approved coloring agents, EU colors, natural coloring agents or pigments can be incorporated up to 1%; Flavoring agents include but not limited to cinnamon ,wild cherry, mint, anise, walnut, chocolate, vanilla, fruit, berry, butterscotch, peach, vanilla, wintergreen mint, maple, apricot, raspberry, citrus and licorice root.

[0159] Example 15 Solubility Profiles of POZ-carbohydrate conjugates

[0166] The water solubility of the POZ-carbohydrate conjugates may be estimated by the LogP calculations. In addition, the HLB value is a logP-like property indicating the lipophilicity. An overall hydrophilic-lipophilic balance (HLB) is dependent on the each of the carrier groups. The samples of the conjugates are listed in Table 6. While the solubility is increased with PMOZ as the polymer carrier but the loading capacity may be lower, in other hand, the solubility of the conjugates is lower with PPOZ carrier with increase loading capacity. The PMOZ or PEOZ is more suitable for parenteral applications and PPOZ is more useful for oral dosages and sustained-release delivery in oral and injectable applications. 01eoylpropanediamino-Poly(2-methyl-2-Oxazoline)io-lactobionate also shows approximately 3-fold more soluble than DOPS-F02. However, optimization of the solubility and loading capacity has to be from experimental results not only by a prediction.

[0167] Table d1DOPES-F02 = Oleoylpropanediamino-Poly(2-ethyl-2-Oxazoline)i0-lactobionate2DOPMS-F02 = Oleoylpropanediamino-Poly(2-methyl-2-Oxazoline)i0-lactobionate3DOPPS-F02 = Oleoylpropanediamino-Poly(2-propyl-2-Oxazoline)i0-lactobionate4DOPS-F02 = Oleoylpropanediamino-mPEGn-lactobionate5Calculated from the chemical drawing with MarvinSketch (Chemaxon, Budapest, Hungary)

[0168] Example 16 Solubility Study of Paclitaxel

[0169] The aqueous solubility of POZ with small side chains is based on the hydrophilicity of the polyamide backbone structure. Paclitaxel (PXT) was used as a model molecule to test the solubility enhancement. The test compound was mixed and dissolved with the requisite amounts of tested polymers in methanol and then the solvent was removed under vacuum. PTX samples were dissolved in a saline with individual polymer compositions at assay concentrations of 0.6 mg / mL and measured at different time points to determine the stability or retainability of individual polymers showed in Table 7.

[0170] Paclitaxel concentration in all samples was directly analyzed by a HPLC system (Alliance 2695, Milford, MA, USA) equipped with Waters 2996 Photodiode Array Detector. Inertsil ODS-3, 150 mm x 4.6 mm, 3 pm particle size column (GL Sciences, Torrance, CA, USA) was used at column temperature was set at 35 °C. The detector wavelength was set at 227 nm and injection volume was 10 p L. The mobile phase was a mixture of acetonitrile and water (50 / 50, v / v) at a flow rate of 1.0 mL / min.

[0171] Table 71Refer Table 9 for polymer abbreviation

[0172] While demonstrated the lowest molar concentration for solublizing paclitaxel, relative high amount of DOPES-F02 was still required. The physical stability was more favorable with DOPES-F02. DOPMS-F02-PXT is less stable due to a lower loading capacity and DOPPS-F02 itself has a lower solubility, precipitation occurred from a longer holding time.

[0173] Example 17: Solubility Comparison of Different Polymers

[0174] 10% (w / v) of tested polymers were prepared in a saline, 10 mL each of POZ- carbohydrate conjugates, DOPS-F02 and polysorbate 80 or Cremophor (EL or RH40) was placed into 20 mL glass vials, to ensure a complete solubilization; initially requisite APIs(dolutegravir, appixaban and celecoxib) were dissolved in dimethyl sulfoxide (DMSO) solvent, 150 mg equivalent APIs (3x) in DOMS solutions were added and well mixed with the polymer solutions. For the control, 50 mg of the APIs (lx) was added to vials containing 10% Cremophor® EL (10 mL). All tested samples were prepared in duplicate and the vials were incubated at 37 °C for 72 hours under constant stirring. The samples were cooled down to the room temperature and then a portion of the samples was diluted in methanol to assay concentrations of 0.5 mg / mL to 1.0 mg / mL, the assay was performed by HPLC-UV (refer Example 20) and solubility enhancement of individual polymers was compared to the control samples in which lx APIs were added in 10% Cremophor® EL (“Cr-EL”) as follows: Performance 100

[0175] As demonstrated in Figure 2, DOPES-12 showed the highest enhancement power on three tested APIs, following by DOPPS-F02 DOPMS-12. While it demonstrated that the lowest polymer to drug concentration ratio was DOPES-12 for solubilizing these APIs, much high concentration of Polysorbate 80 (“PS80”) or Cremophor® RH 40 (“RH40”) was required for the sample solution with the same API contents. This is largely due to a relative stronger hydrophobic interactions of poly (2-oxazoline) to the solute than those of PEG chains, The example further demonstrated the significant lipophilic effects of poly (2-oxazoline) for solubilizing hydrophobic compounds, even though the POZ conjugates with fatty acids have more variable values of LogP, and thus a small difference in HLB values may have a large impact in the solubilization of lipophilic compounds since a low HLB number implies a strong lipophilic affinity.

[0176] Examplel8: Dissolution Profile of Atorvastatin Dissolution studies were performed in a phosphate buffer (pH 6.5) at 37 ± 0.5°C, using a 708-DS Dissolution Apparatus 1 (Agilent Technologies, Santa Clara, California) - the rotating baskets were set at 50 rpm in the first 60 min, then speed up to 250 min at the end. The conjugate based formulations; oleoylpropanediaminopoly(2-ethyl-2-oxazoline)io-lactobionate (DOPL-10) or oleoylpropane- diaminopoly(ethylene-glycol)i2monomethoxy-ether-lactobionate (DOPS-12) containing 10 mg of atorvastatin with a API to polymer ratio of 1 to 3, and 10 mg of pure atorvastatin powder were filled in size 1 hypromellose capsules (Capsugel, Morristown, New Jersey) and each of these capsules were placed into individual basket and 900 mL of the dissolution media where release of atorvastatin API was considered as the baseline. 10 mL of sample was withdrawnfrom each basket at predesigned sampling points, filtered through a 0.45-pm filter paper and then analyzed at 247 nm in a UV-VIS spectrophotometer (Perkin-Elmer Lambda 10). Each test was performed in triplicate (n = 3) and calculated mean values of cumulative drug release were used to plot the release curve. The results in Figure 3 demonstrated the dissolution profile of atorvastatin was highly similar from the two conjugates based formulas.

[0177] Example 19: Stability Profile of POZ-carbohydrate-lipid Conjugate

[0178] The analytical procedure for assay and related compounds of POZ-carbohydrate-lipid conjugates was a reversed-phase, isocratic HPLC method and a representative HPLC chromatogram of cholestorylethylenepropanediaminopoly(2-ethyl-2-oxazoline)io- lactobionate (DCPL-10) is showed in Figure 4. The sample was from a kilogram batch prepared in house. The chromatographic conditions are presented in Table 8:

[0179] Table 8

[0180] This batch was stored in a wide mouth HPDE (High-density polyethylene) jar (1000 mL) and placed on a 12-month stability program at 25 °C / 60% relative humidity (25H) and 40 °C / 75% relative humidity (RH4) storage conditions. The moisture level of the samples was reduced from 3.9% to 3.0 % after storage at 25H conditions for up to 12 months and approximately 60% increased from 3.9 % to 2.2 % after storage at RH4 conditions for up to 6 months. As demonstrated in Table 9, the polymer was very stable and no significant changewas observed in related analogs or impurities and physical description after 6 months at RH4 and 12 months at 25H.

[0181] Table 9

[0182] One aspect of the disclosure provides a method of solubilizing a water-insoluble agent, i.e., a drug compound that, because of low solubility in water, typically requires formulation with a pharmaceutically acceptable carrier for effective delivery to an intended site of action. Such delivery may be intravenous, oral, topical, subdermal, sublingual, or any other mode of drug delivery. The disclosure also provides compositions for such delivery. Both the methods and the compositions related to delivery of water-insoluble agents employ the POZ- carbohydrate conjugates of the present disclosure and the methods and materials described above.

[0183] Example 20: Molecular Weight Distribution / Polydispersity

[0184] Poly(ethyloxazoline)5ooo or pEtOxsooo samples with averaged molecular weights of 5,000 g / mol made from the Example 5 were used for this experiment. Size exclusion chromatography (SEC) was conducted on the materials to measure molecular weight distributions or PDI. Agilent (Santa Clara, CA) PL aquagel-OH 20, 5 pm, 300 x 7.5 mm was used. A Waters Alliance 2695 Separations Module HPLC System (Waters Corp., Milford, MA) including autosampler and column oven was used for mobile phase delivery and sample injection, the system associated Waters Empower Software was used for the data process. A system of multiple detectors connected in series was used for the analysis. A (ELSD) Evaporative Light Scattering detection (Waters 2420) and a refractive index (RI) detector operating at a wavelength of 870 nm (Waters 2414). Tetrahydrofuran (THF) was the mobile phase and the column temperature was set at 40 °C and the injection volume was 50 uL and flow rate was 1 mL / min with a run time of 35 min. The samples were prepared in methanol at a concentration level of 0.5 -1% and filtered through a 0.2 pm PTFE filter before injection. The ELSD signals were normalized using with a polystyrene standard of 4,840 g / mol in a Polystyrene (low molecular) Standard ReadyCal Set, for GPC (Catalog Number 76552)obtained from Sigma-Aldrich (St. Louis, MO). A universal calibration curve was constructed using seven polystyrene standards with molecular weights ranging from 1,300 to 15,000 g / mol according to the targeted range of the polymers studied. Five standards in the range of 2,000 to 9,000 g / mol were used to cover this range. Size exclusion chromatography (SEC) was conducted on the samples of PEtOx oligomers in the range of 5,000 g / mol. The results are present in the Table 10. Table 10

[0185] The PDI is estimated approximately 1.08 (Mw / Mn: 5,461 / 5,060). The Mwvalue is always greater than the Mnvalue unless the polymer is completely monodisperse. The PDI directly influences the performance or solubility enhancement; hence it is always a challenge for producing narrow PDI polymers from large scale productions, whereby reaction can be varied by the physical conditions. Unsurprisingly, the PDI value of smaller batches is typically narrower than the values from large batches or commercial products which the PDI of pEtOxsooo is specified at < 1.3.

[0186] Generally, the present disclosure provides compositions and methods for synthesizing polymer-carbohydrate conjugates comprising a glycerol backbone or a multiamine or amino acid with a polymer (POZ) chain, a sugar (carbohydrate) and a sterol or “lipophilic” vitamin or alike group bonded to the backbone. Spacer or linker groups including amino acids may be included between the backbone and the POZ chains, carbohydrates or lipophilic groups. Furthermore, the terminal end of POZ chain may be a charged or polar moiety. For example, in at least one aspect of the present disclosure, a chemical compound carrier for improving the biocompatibility of a therapeutic agent and for increasing the solubility of a hydrophobic or lipophilic agent in water is disclosed. The carrier may comprise a molecular structure represented by the formula:wherein: L is a lipophilic carrier of steroid and fatty acids; Sugar is a carbohydrate comprises saccharide; POZ is a polymer of polyozazoline; D is a secondary sterol or lipophilic vitamin or POZ or carbohydrate; Backbone is a molecule having three or four available binding positions and being void of a drug moiety, said Backbone comprising at least one of glycerol, glycerol-like analogues, diamines, triamines, tetraamine, diaminoalcohol, aminoalcohols, aminodiol, aminotriols, amino acids, and polyamines; and L is a coupler comprising at least one of glycerol or glycerol-like analogues having three avaible binding positions, diamines, triamines, diaminoalcohol, aminoalcohols, aminodiols, aminotriols, and amino acids having three available binding positions.

[0187] One aspect of the disclosure provides a chemical compound and a method of making a compound represented by the formula:

[0188] where Xi, X2, X3 and X4 represent a type of linking process of alkylation, etherification, esterification or amidation, B* is a central backbone, P is a fatty acid or sterol or a lipo-vitamin selected from the group including and not limited to fatty acids, cholesterol or sterols, carotenoids, cholecalciferol, retinoids and tocopherols, or alike molecule; S is acarbohydrate, P is a polymer and D is a duplication of L, S or P. In presence of cholesterol as the primary lipophilic carrier, the fourth carrier (D) may be a fatty acid or polyunsaturated alcohol or lipid molecule inditional to sterols or lipo-vitamins, preferably the fatty acid is consisting of 5 to 22 carbons. The order of conjugating position for each carrier is not restricted on the backbone. Wherein “B*” is a residue of a backbone molecule selected from glycerol or glycerol-liking having three avaible binding positions or diamines, triamines, tetraamine and polyamines or diaminoalcohol or amino acids having three available binding positions and “L” comprises fatty acids, cholesterol or sterols having a single hydroxyl group or tocopherols or tocotrienols or cholecalciferol or retinols, retinals, and retinoic acid.

[0189] Another aspect of the disclosure provides a chemical compound and a method of making a compound wherein a polymer-carbohydrate conjugate with defined carriers is made by a method comprising the 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 polymer as the first career; c. selecting a terminal group on the polymer carrier; d. selecting a fatty acid or sterol or lipophilic vitamin as the second carrier; e. selecting a carbohydrate as the third carrier; f. selecting a polymer or lipophilic carrier or carbohydrate as the fourth carrier; g. selecting a linker or linkers for coupling reactions of alkylation including A-alkylation or (9-alkylation or esterification or etherification or amidation between carriers and center backbones

[0190] Yet another aspect of the disclosure is a chemical compound and a method of making a compound where the order of each conjugation step is not restricted and may further comprise the steps of alkylation, etherification, esterification or amidation: a. protecting the hydroxyl or amino group; b. bonding the first carrier to the central backbone; c. bonding the second carrier to the central backbone; d. removing the hydroxyl or amino protecting group; and e. bonding the third carrier to the central protecting group.

[0191] Still another aspect of the disclosure is a chemical compound and a method of making a compound wherein short chains of Poly(2-oxazoline)s can be synthesized by cationic ring-opening polymerization or living CROP and the polymer size can be designed bycontrolling the ratio of monomer (M) to initiator (I), e.g., the monomer to initiator ratio ([M] / [I]) of 10, 20, and 50 is corresponding to a degree of polymerization and molar masses, 1000 g / mol, 2000 g / mol, and 5000 g, respectively. As demonstrated in Example 5, it is very useful process especially for those of smaller POZs which are not commercially available.

[0192] Yet another aspect of the disclosure is a chemical compound and a method of making a compound wherein suitable molecules may be used as the backbone including glycerol or glycerol-like analogues or multiamines or amino acids or triols or diols with a carboxy group or amine or diamines with a hydroxyl or carboxyl group and extensible amines or alcohols, wherein the hydrophobic carrier is a sterol or lipophilic vitamin.

[0193] Another aspect of the disclosure is a chemical compound and a method of making a compound wherein the polymer is a POZ having subunits between 5 and 50. The POZ chain may consist of between about 5 and 15 subunits. More preferably the POZ chain consists of between about 10 and 50 subunits. Still more preferably the POZ chain consists of between about 10 and 20 subunits.

[0194] In various embodiments of the present disclosure, monosaccharides, disaccharides included but not limited to sucrose, lactulose, galactose, lactose, galactose, maltose, trehalose, cellobiose, kojibiose, nigerose, isomaltose, trehalose, sophorose, laminaribiose, gentiobiose, turanose, maltulose, palatinose, gentiobiulose, mannobiose, melibiose, melibiulose, rutinose, rutinulose and xylobiose, trisaccharides included but limited to isomaltotriose, nigerotriose, maltotriose, melezitose, maltotriulose, raffinose and kestose, are all suitable to make a polymer-carbohydrate conjugate. Due to a weaker solubility enhancement of monosaccharides and significantly higher costs of production with trisaccharides, disaccharides such as lactobionic acid is most suitable for chemical development strategies, developing a robust synthetic route that yields appropriate phy si cal / chemi cal properties and clinically suitable in medical formulations.

[0195] Yet another aspect of the disclosure is a chemical compound and a method of making a compound where the polymer is a branched POZ having 2 or more subchains each chain having POZ subunits between 5 and 20.

[0196] Still another aspect of the disclosure is a chemical compound and a method of making a compound wherein the POZ-carbohydrate conjugate is a compound represented by the formulas of the General Structure 1 through 11.

[0197] Further aspect of the disclosure is a chemical compound and a method of making a compound wherein the sugar is a carbohydrate including monosaccharides or disaccharides oroligosaccharides selected from Table 4 and their analogues or derivatives are 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 (Rebaudioside A), sucralose, lactitol, maltitol, isomalt, maltotriitol, maltotetraitol, mogrosides, glycyrrhizin, inulin and osladin.

[0198] Yet another aspect of the disclosure is a chemical compound and a method of making a compound wherein the linker is selected from the group consisting of -S-, -O-, -N-, -OCOO- , and the linkers to form covalent bonds of ester or ether or amide between carriers and center backbones. While a conjugation reaction of alkylation or etherifcation or esterification or amidation is preferable with or without adding linker group, the carriers or center backbones may be chemically modified prior to the final coupling reactions. Those of chemical modifications may be carried out with one or more of the linker groups.

[0199] Another aspect of the disclosure is a chemical compound and a method of making a compound wherein preferable amino acid linkers are proline, glycine, alanine, lysine, cysteine, valine, isoleucine, leucine, methionine, phenylalanine, histidine, tryptophan, tyrosine, selenocysteine, and arginine.

[0200] Another aspect of the disclosure is a chemical compound and a method of making a compound wherein the POZ chain is substantially monodisperse for intravenous administration of pharmaceutical agents and the monodisperse POZ chain may contain a few numbers of oligomers. The preferable number of oligomers is 1 to 10, more preferable is 3 to 10.

[0201] Yet another aspect of the disclosure is a chemical compound and a method of making a compound wherein the POZ chain is substantially monodisperse for intravenous administration of pharmaceutical agents and the monodisperse POZ chain ranging from 65% to 110% of averaged (or targeted) molecular weights.

[0202] Yet another aspect of the disclosure is a chemical compound and a method of making a compound wherein the POZ chains are replaced by polymers selected from the group consisting of monomers selected from the group consisting of methyl, ethyl and propyl or isopropyl.

[0203] Still another aspect of the disclosure is a chemical compound and or a method of making a compound wherein the terminal (R) group is preferably easily polarized or negatively or positively charged head-groups such as alkoxy moieties, amines, amino acids, and oligosaccharides.

[0204] Yet another aspect of the disclosure is a method of preparing a pharmaceutical formulation of a therapeutic agent, the method comprising: a. determining a therapeutic target; b. determining a mode of administration; c. determining the physiological conditions of the POZ-carbohydrate conjugates based formulation will encounter in reaching the therapeutic target using the mode of administration; and selecting a POZ-carbohydrate conjugate having one or more linkers between the three carriers including one or two POZ chains, one or two carbohydrates and one or two hydrophobic carriers (at least one sterol or lipophilic vitamin) and a central backbone, where such selecting is informed by the physiological conditions; and combining the POZ-carbohydrate conjugates and the therapeutic agent in a pharmaceutical formulation.

[0205] Yet another aspect of the disclosure is a chemical compound and a method of making a composition including therapeutic agents wherein the weight ratio of the POZ-carbohydrate conjugate to the drug compound is between about 1 and about 300 (w / w).

[0206] Various aspects of the disclosure are illustrated by the following enumerated embodiments, which may be combined in any number and in any combination not logically or technically inconsistent.Embodiment 1. A conjugate of poly(2-alkyl-2-oxazoline)-carbohydrate-lipid represented by the formula:wherein:L is a lipid or lipophilic carrier that is a residue of a compound selected from fatty acids, cholesterol, steroid acids, retinoids, carotenoids, tocopherols, and tocotrienolsSugar is a residue of a carbohydrate or an analog or derivative thereof;POZ is a residue of a polymer selected from poly(2-methyl-2-oxazoline), poly(2-ethyl- 2-oxazoline), poly( 2-propyl-2-oxazoline) and poly(2-isopropenyl-2-oxazoline);B is a residue of a compound having three or four available binding positions selected from glycerol, diamines, triamines, tetraamines, diaminoalcohols, aminoalcohols,aminodiols, aminotriols, amino acids, triols, tetraols, triacids, tetracids, halogencontaining diols, halogen-containing amines, carboxyl-containing diols and polyamines; andD is a residue as defined for L, Sugar, POZ, or is an mPEG (monomethoxypolyethylene glycol ether) residue.Embodiment 2. The conjugate of embodiment 1, wherein L is a residue of lauric acid, myristic acid, linoleic acid, palmitic acid, oleic acid, elaidic acid or stearic acid.Embodiment 3. The conjugate of claim 1, having the structure:whereinLipid is a residue of a fatty acid or a steroid acid; the POZ polymer residue has a degree of polymerization ranging from 5 to 50 (2-alkyl- 2-oxazoline) subunits; and m is in the range of 1 to 6.Embodiment 4. The conjugate of embodiment 3, that is suitable for parenteral applications.Embodiment 5. The conjugate of embodiment 3 or embodiment 4, wherein Lipid is a residue of an acid selected from lauric acid, myristic acid, linoleic acid, palmitic acid, oleic acid, elaidic acid, stearic acid, and steroid acids.Embodiment 6. The conjugate of embodiment 1, having one the following structures:Embodiment 7. The conjugate of claim 1 wherein:B is a residue of a compound comprising at least three available binding positions or sites for the conjugation of a first carrier, a second carrier, and a third carrier, each said available binding position or site comprising an expendable amino, hydroxyl, or carboxylic group; said first carrier comprising said lipid or lipophilic carrier and an expendable amino, hydroxyl, or carboxylic group; said second carrier comprising said residue of a polymer and an expendable amino, hydroxyl, or carboxylic group; and said third carrier comprising said residue of a carbohydrate and an expendable amino, hydroxyl, or carboxylic group.Embodiment 8. The conjugate of claim 1 wherein:B is a residue of a compound comprising at least four available binding positions or sites for the conjugation of a first carrier, a second carrier, a third carrier, and a fourth carrier,each said available binding position or site comprising an expendable amino, hydroxyl, or carboxylic group.Embodiment 9. The conjugate of claim 1 wherein B is a residue of a compound comprising three available binding positions or sites for the conjugation of a first carrier, a second carrier, and a third carrier, each said available binding position or site comprising an expendable amino, hydroxyl, or carboxylic group, wherein: said first carrier has said lipid or lipophilic carrier bound thereto; said second carrier has said polymer residue bound thereto; said polymer residue comprising a terminal (R) group; and said third carrier has said carbohydrate residue bound thereto.Embodiment 10. The conjugate of embodiment 1 wherein B is residue of one of a) through d): a) a compound selected from the group consisting of glycerol and glycerol-like analogues, polyamines, diamines, triamines, tetraamines, aminodiols, aminotriols, aminoalcohols, amino acids having three available binding positions or sites, triols, tetraols, erythritol, triacids, tetracid, tetraacetic acid and tartaric acid; b) a compound selected from the group consisting of ethanediamine, propanediamine, butanediamine, pentanediamine, hexanediamine, diethylenetriamine, diethylenetriamine, bis(3-aminopropyl)-amine, bi s(3 -aminopropyl)- 1,3 -propanediamine, 7V,7V'-bis(3-aminopropyl)-l,3-propanediamine, triethylenetetramine, l,2-bis(3- aminopropylamino)ethane, spermine, tris(2-aminoethyl)amine, spermidine, norspermidine, bis(hexamethylene)triamine, tris(hydroxymethyl)-aminomethane, diaminobenzidine, triazacyclononane, tetraazacyclododecane, threitol, meso-erythritol, dithio-threitol, trimethylcyclohexane-l,3,5-tricarboxylic acid, 1,3,5-cyclohexane-tricarboxylic acid, trimethylbis(hexa-methylene)triamine, arginine, oxylyldiaminopropionic acid having three or four available binding positions or sites, triols, triacids, glucoheptonic acid, and tartaric acid; c) a compound selected from the group consisting of 3-amino-l,2-propanediol, 3- bromo-l,2-propanediol, 3-chloro-l,2-propanediol, 3 -fluoro- 1,2-propanediol, DL-gly ceric acid, diamino-propionic acid, tartaric acid, glucoheptonic acid, 2,4-butanetriol, 2,2- bis(hydroxymethyl)butyric acid, l,3-diamino-2-propanol and 2-(3- aminopropylamino)ethanol, and 3-((3-aminopropyl)-amino)propanol; andd) a compound selected from the group consisting of aspartic acid, glutamic acid, asparagine, glutamine, lysine, ornithine, serine, and threonine.Embodiment 11. The conjugate of embodiment 1 wherein two said accessible binding positions or sites are selected from the group consisting of aminoalcohols, diamines, ethylenediamine, diaminopropane, ethanolamine, aminopropanol, aminobutanol, aminopentanol, amino- 1 -hexanol; and said polymer being chemically extended and modified to provide said third or a fourth available binding position or site.Embodiment 12. The conjugate of embodiment 1 wherein three said available binding positions or sites are selected from the group consisting of glycerol or glycerol-like analogues, diamines, triamines, triols, triacids, amino acids; and said polymer being chemically extended and modified to provide a fourth available binding position or site.Embodiment 13. The conjugate of embodiment 1 wherein said POZ comprises a single POZ chain having between 5 and 45 subunits or a branched POZ having 2 or more subchains, wherein each said subchain has between 5 and 45 subunits, and a terminal group (R) comprising a hydroxyl or alkane.Embodiment 14. The conjugate of embodiment 1 wherein L is a residue of a compound selected from the group consisting of caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, myristoleic acid, palmitoleic acid , sapienic acid, oleic acid, elaidic acid, stearic acid, vaccenic acid, linoleic acid, linoelaidic acid, a-linolenic acid, cholic acid, glycocholic acid, deoxycholic acid, chenodeoxycholic acid, glycochenodeoxycholic acid, lithocholic acid, cholesterol, stigmasterol, ergosterol, hopanoids, phytosterol, sitosterol, campesterol, brassicasterol, avenasterol adosterol, stanols, retinols, retinoids, retinal, retinoic acid, tretinoin, carotenoids, P-carotene, tocopherols, tocotrienols, cholecalciferol, and ergocalciferol.Embodiment 15. The conjugate of embodiment 1 wherein said carbohydrate is selected from the group consisting of monosaccharide, di saccharides, trisaccharides, tetrasaccharides,fructooligo-saccharide, galacto-oligosaccharides, mannanoligosaccharides, polysaccharides, carbohydrate analogues or derivatives.Embodiment 16. The conjugate of embodiment 15 wherein the carbohydrate analogues or derivatives comprise at least one of ascorbic acid, cellobiose, galactose, galacturonic acid, gentiobiose, gentiobiulose, glucaric acid, gluconic acid, glucuronic acid, glucoheptonic acid, glycyrrhizin, inulin, isomalt, isomaltose, isomaltotriose, kestose, kojibiose, lactitol, lactulose, lactose, lactobionic acid, laminaribiose, maltitol, maltose, maltotriose, maltotriitol, maltotetraitol, maltotriulose, maltulose, melibiose, melibiulose, melezitose, mannobiose, mogrosides, nigerose, nigerotriose, osladin, palatinose, raffinose, rutinose, rutinulose, sophorose, steviol glycoside (Rebaudioside A), sucrose, sucralose, trehalose, trehalose, turanose, and xylobiose.Embodiment 17. The conjugate of embodiment 1 wherein D comprises a fatty acid consisting of 5 to 22 carbons in presence of cholesterol as the primary lipophilic carrier.Embodiment 18. The conjugate of embodiment 1 that is selected from the group consisting of oleoylpropanediamineisomaltotriose-POZ, -lactobionyl-A'-oleoyl-POZ- lysinate oleoylpropane-diaminelactobionate-POZ, oleoylpropanediaminelaminaribiose-POZ, oleoylpropanediamine-gluconate-POZ, oleoylpropanediamineascorbate-POZ, myristoylpropanediaminelactobionate-POZ, myristoyldiethylenetriamineisomaltotriose-POZ, myristoyldiethylenetriamineisomaltotriose-POZ, oleoyldiethylenetriamine-POZ-lactobionate, ascorboylstearoylethylenediamine-POZ-amino-salicylate, myristoylascorboyldiethylenetriamine-POZ-lactobionate, myristoyldiethylenetriamine-POZ- lactobionate, oleoyldiethylenetriaminetryptophanyl-lactobionate, oleoylaspartate-POZ- lactobionate, oleoylmyristoyldiethylenetriamine-POZ-lactobionate, oleoylmyristoyl- diethylenetriamine-POZ-lactobionate, oleoyltriethylenetetramine-bisPOZ-lactobionate, lactobionoylmyristoyl-POZ-lysinate, oleoylascorboyldiethylenetriamine-POZ-lactobionate, A-bis-POZ-serinol-7V-oleoyl-A ’-lactobionoylpropanediamine, N,N-1,3- bislactobionoyldiamino-2-propanol-oleoyl-POZ-propanediamine, myristoyldiethylenetri amineisomaltotriose-POZ. cholesterypropanediamineisomaltotriose-POZ, AMactobionyl-Na-cholesterol-POZ-lysinate, cholesterypropanediaminelactobionate-POZ, a-tocopheroltriethylenetetramine-bis-POZ-lactobionate, cholesterolpropionatetriethylenetetraminelactobionatediPOZ, cholesterolpropionate-propane-diaminelaminaribiose-POZ, tocopherylpropanediaminelactobionate-POZ, tocopheryl-propanediamineisomaltotriose-POZ, retinoylpropanediaminelactobionate-POZ, retinoyl-diethylenetriamineisomaltotriose-POZ, cholecalciferol di ethylenetri amineisomaltotriose-POZ, cholesterolpropionatediethylenetriamine-POZ-lactobionate, cholesterylpropanediamine-POZ- gluconate, lactobionoylcholesterolpropionate-POZ-lysinate, cholesteryl-diethylenetriamine- POZ-glucuronate, tocopheryldiethylenetri-amine-POZ-lactobionate, tocopherylethylenediamine-POZ-ascorbate, ascorboyltocopherylethylenediamine-POZ- aminosalicylate, cholecalciferol-ascorboyldiethylenetriamine-POZ-lactobionate, cholecalciferol-diethylenetriamine-POZ-lactobionate, cholesterolpropionatediethylenetriaminetryptophanyl-lactobionate, cholesterol-POZ- propanediaminolactobionate, cholesterol-POZ-propanediaminoascorbate, cholesterol- aspartate-POZ-lactobionate, cholesterolpropionateoleoyldiethylenetriamine-POZ- lactobionate, cholesterolpropionate-retinoyldiethylenetriamine-POZ-lactobionate, cholesterolpropionate-triethylenetetraminebis-POZ-lactobionate, lactobionoyltocopherol- POZ-lysinate, cholesterolpropionatetriethylenetetramine-bisPOZ-lactobionate, cholesterolpropionateascorboyl-diethylenetriamine-POZ-lactobionate, A-bis-POZ-serinol-A- cholesterolpropionate-A’-lactobionoyl-propanediamine, A,A-l,3-bislactobionoyldiamino-2- propanol-cholesterolpropionate-POZ-propanediamine and cholecalciferol di ethylenetri amineisomaltotriose-POZ.Embodiment 19. A pharmaceutical composition that is an aqueous solution or mixture comprising an active pharmaceutical composition and the conjugate of any of claims 1-18.Embodiment 20. A method for treating a disease in a mammal, the method comprising administering to the mammal with the pharmaceutical composition of embodiment 19.Embodiment 21. A lipid / POZ / saccharide conjugate having the structural formulawherein 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)-R1in which R1is 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, a retinoid acyl group, or a carotenoid acyl group;P is a residue of a poly(2-methyl-2-oxazoline), a poly(2-ethyl-2-oxazoline), a poly(2- propyl-2-oxazoline) or a poly(2-isopropenyl-2-oxazoline).Embodiment 22. The conjugate of embodiment 21, 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 23. The conjugate of embodiment 21, wherein m has number-average value of 3.Embodiment 24. The conjugate of embodiment 21, wherein m has number-average value of 2, or m has a number-average value of 4.Embodiment 25. The conjugate of embodiment 21, wherein m has number-average value in the range of 5-10, e.g., 5-8 or 8-10.Embodiment 26. The conjugate of any of embodiments 21-25, wherein S is a disaccharide group.Embodiment 27. The conjugate of any of embodiments 21-25, wherein S is a monosaccharide group.Embodiment 28. The conjugate of any of embodiments 21-25, wherein S is a trisaccharide group.Embodiment 29. The conjugate of any of embodiments 21-28, wherein saccharide units of S are individually selected from hexoses and pentoses and sugar alcohol, sugar acid and amino sugar analogs thereof.Embodiment 30. The conjugate of any of embodiments 21-29 wherein saccharide units of S are individually selected from hexoses and sugar alcohol, sugar acid and amino sugar analogs thereof.Embodiment 31. The conjugate of any of embodiments 21-30, 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 32. The conjugate of embodiment 31, wherein any saccharide unit of S that is not directly bound to the nitrogen of the diamine is a sugar.Embodiment 33. The conjugate of any of embodiments 21-32, wherein S has the structural formulain which -(CxiEExiOxi-ij-CO- is a sugar acyl residue derived from a sugar acid in which xl is 4 or 5, and (CX2H2X2-IOX2-I)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof.Embodiment 34. The conjugate of embodiment 33, wherein xl is 5 and x2 is 6.Embodiment 35. The conjugate of any of embodiments 21-34, wherein S has the structureEmbodiment 36. The conjugate of any of embodiments 21-35, wherein S is lactobionyl or gluconyl, for example, lactobionyl.Embodiment 37. The conjugate of any of embodiments 21-35, 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 38. The conjugate of any of embodiments 21-37, wherein L includes (or is) -C(O)-RJ, wherein R1is an alkanyl and / or alkenyl group having a number-average number of carbons in the range of 6-22.Embodiment 39. The conjugate of any of embodiments 21-38, wherein R1has a numberaverage number of carbons in the range of 6-20, or 6-18.Embodiment 40. The conjugate of any of embodiments 21-38, wherein R1has a numberaverage number of carbons in the range of 10-22, e.g., 10-20 or 10-18.Embodiment 41. The conjugate of any of embodiments 1-38, wherein R1has a numberaverage number of carbons in the range of 12-22, e.g., 12-20 or 12-18.Embodiment 42. The conjugate of any of embodiments 21-38, wherein R1has a numberaverage number of carbons in the range of 14-22, e.g., 14-20 or 14-18.Embodiment 43. The conjugate of any of embodiments 21-42, wherein R1has a numberaverage number of carbons that is no more than 18.Embodiment 44. The conjugate of any of embodiments 21-43, wherein R1has a numberaverage number of unsaturations in the range of 0-3, e.g., 0-2.Embodiment 45. The conjugate of any of embodiments 21 -44, wherein R1is a linear alkyl or alkenyl group.Embodiment 46. The conjugate of any of embodiments 21-45 wherein R1is derived from one or more of caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, alpha-linoleic acid, arachidonic acid and erucic acid.Embodiment 47. The conjugate of any of embodiments 21-46, wherein L is -C(O)-R1, and wherein -C(O)-R1is at least 80 mol% of a single chemical identity, e.g., at least 85 mol%.Embodiment 48. The conjugate of any of embodiments 21-46, wherein L is -C(O)-R1, and wherein -C(O)-R1is at least 90 mol% of a single chemical identity, e.g., at least 95 mol%.Embodiment 49. The conjugate of embodiment 47 or embodiment 48, wherein the single chemical identity is cis-CH3(CH2)7CH=CH(CH2)7C(O)-.Embodiment 50. The conjugate of embodiment 47 or embodiment 48, wherein the single chemical identity is cis,cis-CH3(CH2)4CH=CHCH2CH=CH(CH2)7C(O)-.Embodiment 51. The conjugate of embodiment 47 or embodiment 48, wherein the single chemical identity is cis-CH3(CH2)3CH=CH(CH2)7C(O)-.Embodiment 52. The conjugate of embodiment 47 or embodiment 48, 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 53. The conjugate of embodiment 47 or embodiment 48, 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 54. The conjugate of any of embodiments 21-46, wherein L includes (or is) a steroid acyl group (e.g., a bile acyl group).Embodiment 55. The conjugate of any of embodiments 21-46 and 54, wherein the steroid acyl group is an acyl group derived from cholesterol, cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, taurochenodeoxy cholic acid, glycochenodeoxy cholic acid, chenodeoxy cholic acid, and lithocholic acid (e.g., cholic acid, deoxycholic acid, or glycocholic acid).Embodiment 56. The conjugate of any of embodiments 21-46, 54 and 55, wherein L includes (or is) a retinoid acyl group, or a carotenoid acyl group.Embodiment 57. The conjugate of any of embodiments 21-56, wherein POZ is a residue of a poly(2-methyl-2-oxazoline).Embodiment 58. The conjugate of any of embodiments 21-56, wherein POZ is a residue of a poly(2-ethyl-2-oxazoline).Embodiment 59. The conjugate of any of embodiments 21-56, wherein POZ is a residue of a poly(2-propyl-2-oxazoline)Embodiment 60. The conjugate of any of embodiments 21-56, wherein POZ is a residue of a poly(2-isopropenyl-2-oxazoline).Embodiment 61. The conjugate of any of embodiments 21-60, wherein POZ has a number-average degree of polymerization in the range of 5 to 50, e.g., in the range of 5-40, or 5-30, or 5-20, or 5-15, or 5-10.Embodiment 62. The conjugate of any of embodiments 21-60, wherein POZ has a number-average degree of polymerization in the range of 10 to 50, e.g., in the range of 10-40, or 10-30, or 10-20.Embodiment 63. The conjugate of any of embodiments 21-60, wherein POZ has a number-average degree of polymerization in the range of 15 to 50, e.g., in the range of 15-40, or 15-30, or 15-25.Embodiment 64. The conjugate of any of embodiments 21-60, wherein POZ has a number-average degree of polymerization in the range of 20 to 50, e.g., in the range of 20-40, or 20-30.Embodiment 65. The conjugate of any of embodiments 21-60, wherein POZ has a number-average degree of polymerization in the range of 30 to 50, e.g., in the range of 30-40, or 40-50.Embodiment 66. The conjugate of any of embodiments 21-65, wherein POZ is terminated with a hydrogen, a hydroxy, or a C1-C20 alkoxy.Embodiment 67. The conjugate of any of embodiments 21-65, wherein POZ is terminated with a group having a number-average molecular weight of no more than 650 g / mol.Embodiment 68. The conjugate of any of embodiments 21-65, wherein POZ has a poly dispersity index of no more than 1.5, e.g., no more than 1.3.Embodiment 67. The conjugate of any of embodiments 21-65, wherein POZ has a poly dispersity index of no more than 1.2, e.g., no more than 1.1.Embodiment 68. The conjugate of any not inconsistent embodiment above, wherein m is 2, 3 or 4;S has the structural formula as below:in which -(CxiEExiOxi-ij-CO- is a sugar acyl residue derived from a sugar acid in which xl is 4 or 5, and (CX2H2X2-IOX2-I)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof;R1is alkanyl or alkenyl group having a number-average number of carbons in the range of 6-22; and the POZ has a degree of polymerization in the range of 5-50 and a poly dispersity index of no more than 1.5, e.g., no more than 1.3.Embodiment 69. The conjugate of embodiment 68, wherein R1 has 12-22 carbons, e.g.,12-20 carbons.Embodiment 70. The conjugate of embodiment 68, wherein R1 has 16-20 carbons.Embodiment 71. The conjugate of any of embodiments 68-70, wherein R1 is at least 80 mol% of a single chemical identity, e.g., at least 85 mol%.Embodiment 72. The conjugate of any not inconsistent embodiment above, wherein m is 2, 3 or 4;S has the structural formula as below:in which -(CxiH2xiOxi-i)-CO- is a sugar acyl residue derived from a sugar acid in which xl is 4 or 5, and (CX2H2X2-IOX2-I)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof;-C(O)-R' is at least 80 mol% of cis-CH3(CH2)7CH=CH(CH2)?C(O)-, e.g., at least 85 mol%; the POZ has a degree of polymerization in the range of 5-50 and a poly dispersity index of no more than 1.5, e.g., no more than 1.3.Embodiment 73. The conjugate of embodiment 72, wherein -C(O)-R1is at least 90 mol% of cis-CH3(CH2)7CH=CH(CH2)7C(O)-, e.g., at least 95 mol%.Embodiment 74. The conjugate of any not inconsistent embodiment above, wherein m is 2, 3 or 4;S has the structural formula as below:in which -(CXIH2XIOXI-I)-CO- is a sugar acyl residue derived from a sugar acid in which xl is 4 or 5, and (CX2H2X2-IOX2-I)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof;-CXOj-R1is at least 80 mol% of -QOj-CEE-O-CEECEE-O-sterol e.g., at least 85 mol%; the POZ has a degree of polymerization in the range of 5-50 and a poly dispersity index of no more than 1.5, e.g., no more than 1.3.Embodiment 75. The conjugate of any not inconsistent embodiment above, wherein m is 2, 3 or 4;S has the structural formula as below:in which -(CXIH2XIOXI-I)-CO- is a sugar acyl residue derived from a sugar acid in which xl is 4 or 5, and (CX2H2X2-IOX2-I)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof;85 mol%; the POZ has a degree of polymerization in the range of 5-50 and a poly dispersity index of no more than 1.5, e.g., no more than 1.3.Embodiment 76. The conjugate of any of embodiments 68-75, wherein m is 3.Embodiment 77. The conjugate of any of embodiments 68-76, wherein xl is 5 and x2 is6.Embodiment 78. The conjugate of any of embodiments 68-76, wherein S has the structureor is an open-chain version thereof.Embodiment 79. The conjugate of any of embodiments 68-76, wherein S is lactobionyl.Embodiment 80. The conjugate of any of embodiments 68-79, wherein P has a poly dispersity index of no more than 1.2, e.g., no more than 1.1.Embodiment 81. The conjugate of any not inconsistent embodiment above, wherein the conjugate has a structural formula below:Embodiment 82. The conjugate of any of embodiments 21-81, wherein the conjugate has a purity of at least 85 wt% as measured by HPLC.Embodiment 83. The conjugate of any of embodiments 21-81, wherein the conjugate has a purity of at least 90 wt% as measured by HPLC.Embodiment 84. The conjugate of embodiment 82, wherein the conjugate is used in an oral application.Embodiment 85. The conjugate of embodiment 83, wherein the conjugate is used in a parenteral application.Embodiment 86. The conjugate of any of embodiments 21-85, wherein the R1-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 87. The conjugate of embodiment 86, wherein the single chemical identity is oleoyl, myristoyl, palmitoyl, stearoyl or linoleoyl.Embodiment 88. The conjugate of any of embodiments 21-87, having an HLB value in the range of 10-18, e.g., in the range of 10-16 or 10-15.Embodiment 89. The conjugate of any of embodiments 21-87, having an HLB value in the range of 11-18, e.g., in the range of 11-16 or 11-15.Embodiment 90. The conjugate of any of embodiments 1-20, as further described in any not-inconsi stent embodiment of embodiments 21-89.Embodiment 91. A therapeutic composition comprising a conjugate of any of embodiments 1-89 and a therapeutic agent.Embodiment 92. A composition for use in the treatment of a subject having a condition, the composition comprising a conjugate of any of embodiments 1-89 and a therapeutic agent suitable for treating the condition.Embodiment 93. A method for treating a subject having a condition, the method comprising administering to the subject a composition of embodiment 92, for example, wherein the administration is oral, intranasal, topical or parenteral.Embodiment 94. A composition comprising a conjugate according to any of embodiments 1-89 and a therapeutic agent for use as a medicament.Embodiment 95. A method for preparing a composition of embodiment 94, 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 96. Use of a conjugate according to any of embodiments 1-89 for increasing bioavailability of a therapeutic agent.Embodiment 97. Use of a conjugate according to any of embodiments 1-89 for increasing solubility of a therapeutic agent in an aqueous system.Embodiment 98. Use of a conjugate according to any of embodiments 1-89 as a pharmaceutical excipient, or as a therapeutic.Embodiment 99. The composition, method or use of any of embodiments 91-98, wherein a weight ratio of the conjugate of the disclosure to the therapeutic agent is in the range 300: 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 100. The composition, method or use of any of embodiments 91-98, 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 101. The composition, method or use of any of embodiments 91-98, wherein a weight ratio of the conjugate of the disclosure to the therapeutic agent is in the range of 300: 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 102. The composition, method or use of any of embodiments 91-98, wherein a weight ratio of the conjugate of the disclosure to the therapeutic agent is in the range of 300: 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 103. The composition, method or use of any of embodiments 91-102, 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 104. The composition, method or use of any of embodiments 91-102, wherein the therapeutic agent is present in the composition in an amount of at least 0.5 wt%, e.g., 1 wt%.Embodiment 106. The composition, method or use of any of embodiments 91-102, wherein the therapeutic agent is present in the composition in an amount of at least 2 wt%, e.g., at least 5 wt%.Embodiment 107. The composition, method or use of any of embodiments 91-102, wherein the therapeutic agent is present in the composition in an amount of at least 10 wt%, e.g., at least 20 wt%.Embodiment 108. The composition, method or use of any of embodiments 91-102, 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 109. The composition, method or use of any of embodiments 91-102, 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 110. The composition, method or use of any of embodiments 91-102, 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 111. The composition, method or use of any of embodiments 91-102, 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 112. The composition, method or use of any of embodiments 91-111, wherein the conjugate is present in an amount of at least 1 wt%, e.g., at least 2 wt%.Embodiment 113. The composition, method or use of any of embodiments 91-111, wherein the conjugate is present in an amount of at least 5 wt%, e.g., at least 10 wt%.Embodiment 114. The composition, method or use of any of embodiments 91-111, wherein the conjugate is present in an amount of at least 15 wt%, e.g., at least 20 wt%.Embodiment 115. The composition, method or use of any of embodiments 91-111, wherein the conjugate is present in an amount of at least 25 wt%, e.g., at least 30 wt%.Embodiment 116. The composition, method or use of any of embodiments 91-111, 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 117. The composition, method or use of any of embodiments 91-111, 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 118. The composition, method or use of any of embodiments 91-111, 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 119. The composition, method or use of any of embodiments 91-111, 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 120. The composition, method or use of any of embodiments 91-119, wherein the composition is in the form of an aqueous solution or suspensions.Embodiment 121. The composition, method or use of any of embodiments 91-119, wherein the composition is in the form of a concentrate for dilution into an aqueous solution or suspension.Embodiment 122. The composition, method or use of any of embodiments 91-119, wherein the composition is in the form of a cream or gel, e.g., for topical administration.Embodiment 123. The composition, method or use of any of embodiments 91-119, wherein the composition is in the form of a solid formulation, for example, in the form of a tablet, a capsule, or granules.Embodiment 124. A conjugate according to any of embodiments 1-89 for use as a pharmaceutical excipient, or for use as in a medicament.

[0207] While preferred embodiments of the present disclosure 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 disclosure, and all such changes and modifications should be understood to fall within the scope of the disclosure.

Claims

CLAIMS :Claim 1. A conjugate of poly(2-alkyl-2-oxazoline)-carbohydrate-lipid represented by the formula:Sugarwherein:L is a lipid or lipophilic carrier that is a residue of a compound selected from fatty acids, cholesterol, steroid acids, retinoids, carotenoids, tocopherols, and tocotrienolsSugar is a residue of a carbohydrate or an analog or derivative thereof;POZ is a residue of a polymer selected from poly(2-methyl-2-oxazoline), poly(2-ethyl- 2-oxazoline), poly(2-propyl-2-oxazoline) and poly(2-isopropenyl-2-oxazoline);B is a residue of a compound having three or four available binding positions selected from glycerol, diamines, triamines, tetraamines, diaminoalcohols, aminoalcohols, aminodiols, aminotriols, amino acids, triols, tetraols, triacids, tetracids, halogencontaining diols, halogen-containing amines, carboxyl-containing diols and polyamines; andD is a residue as defined for L, Sugar or POZ.Claim 2. A conjugate of claim 1, having the structural formulawherein 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)-R1in which R1is 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, a retinoid acyl group, or a carotenoid acyl group;P is a residue of a poly(2-methyl-2-oxazoline), a poly(2-ethyl-2-oxazoline), a poly(2- propyl-2-oxazoline) or a poly(2-isopropenyl-2-oxazoline).Claim 3. The conjugate of claim 2, wherein m has a number-average value of 3.Claim 4. The conjugate of claim 1, wherein S or Sugar is a disaccharide group.Claim 5. The conjugate of claim 1, wherein saccharide units of S or Sugar are individually selected from hexoses and sugar alcohol, sugar acid and amino sugar analogs thereof.Claim 6. The conjugate of claim 1, wherein S or Sugar has the structural formulain which -(CxiH2xi0xi-i)-C0- is a sugar acyl residue derived from a sugar acid in which xl is 4 or 5, and (CX2H2X2-IOX2-I)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof.Claim 7. The conjugate of claim 1, wherein S or Sugar has the structureopen-chain version thereof.Claim 8. The conjugate of claim 1, wherein S or Sugar is lactobionyl or gluconyl, for example, lactobionyl.Claim 9. The conjugate of claim 1, wherein L is -C(O)-RJ, wherein R1is an alkanyl and / or alkenyl group having a number-average number of carbons in the range of 6-22.Claim 10. The conjugate of claim 9, wherein R1has a number-average number of carbons in the range of 12-18.Claim 11. The conjugate of claim 9, wherein L is -C(O)-RJ, and wherein -QOj-R1is at least 80 mol% of a single chemical identity.Claim 12. The conjugate of claim 1, wherein the steroid acyl group is an acyl group derived from cholesterol, cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, taurochenodeoxy cholic acid, glycochenodeoxy cholic acid, chenodeoxy cholic acid, and lithocholic acid, or is a retinoid acyl group, or a carotenoid acyl group.Claim 13. The conjugate of claim 1, wherein POZ is a residue of a poly(2-methyl-2-oxazoline).Claim 14. The conjugate of claim 1, wherein POZ is a residue of a poly(2-ethyl-2-oxazoline).Claim 15. The conjugate of claim 1, wherein POZ is a residue of a poly(2-propyl-2-oxazoline)Claim 16. The conjugate of claim 1, wherein POZ has a number-average degree of polymerization in the range of 5 to 50.Claim 17. The conjugate of any claim 1, wherein POZ is terminated with a hydrogen, a hydroxy, or a C1-C20 alkoxy.Claim 18. The conjugate of claim 1, wherein POZ is terminated with a group having a numberaverage molecular weight of no more than 650 g / mol.Claim 19. The conjugate of claim 1, wherein POZ has a poly dispersity index of no more than 1.5.Claim 20. The conjugate of claim 1, wherein m is 2, 3 or 4;S has the structural formula as below:in which -(CxiH2xiOxi-i)-CO- is a sugar acyl residue derived from a sugar acid in which xl is 4 or 5, and (CX2H2X2-IOX2-I)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof;R1is alkanyl or alkenyl group having a number-average number of carbons in the range of 6-22; and the POZ has a degree of polymerization in the range of 5-50 and a poly dispersity index of no more than 1.3.Claim 21. The conjugate of claim 20, wherein R1has 12-20 carbons.Claim 22. The conjugate of claim 21, wherein m is 3.Claim 23. The conjugate of claim 1, wherein m is 2, 3 or 4;S has the structural formula as below:in which -(CXIH2XIOXI-I)-CO- is a sugar acyl residue derived from a sugar acid in which xl is 4 or 5, and (CX2H2X2-IOX2-I)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof;the POZ has a degree of polymerization in the range of 5-50 and a poly dispersity index of no more than 1.3.Claim 24. The conjugate of claim 1, wherein the conjugate has a structural formula below:Claim 25. The conjugate of claim 1, having an HLB value in the range of 12-18.Claim 26. A therapeutic composition comprising a conjugate of claim 1 and a therapeutic agent.Claim 27. A method for treating a subject having a condition, the method comprising administering to the subject a composition of claim 26.Claim 28. The composition of claim 26, wherein the therapeutic agent has a water solubility in deionized water of no more than 1 mg / mL at 37 °C.

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