Pharmaceutical compositions comprising antiviral agents and optionally steviol glycosides

Abstract

The disclosure in one aspect provides a pharmaceutical composition of an antiviral agent, the pharmaceutical composition comprising: the antiviral agent, which can be tenofovir; and a PEG-saccharide-lipid conjugate having the structural formula wherein m has a number-average value in the range of 2-10; S is a mono-, di- or trisaccharide group; L is -C(O)-R1 in which R1 is an alkanyl or alkenyl group having a number- average number of carbons in the range of 6-22, and / or is a steroid acyl group; P is -(CH2-CH2-O)nR2 in which n has a number-average value in the range of 5-50 and R2 is hydrogen and / or alkanyl and has a number average number of carbons in the range 0-4. Such compositions can be provided in a variety of forms. In various such embodiments, the pharmaceutical composition further includes one or more steviol glycosides mainly comprising one or more steviosides and / or rebaudiosides.

Description

[0001] PHARMACEUTICAL COMPOSITIONS COMPRISING ANTIVIRAL AGENTS AND OPTIONALLY STEVIOL GLYCOSIDES

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003]

[0001] This patent application claims the benefit of priority of each of U.S. Provisional Patent Applications Nos.: 63 / 516,214, filed on July 28, 2023; 63 / 518,178, filed on August 8, 2023; 63 / 578,425, filed on August 24, 2023; 63 / 578,817, filed on August 25, 2023; 63 / 567,267, filed on March 19, 2014, and 63 / 567,281, filed on March 19, 2024, the disclosure of each of which is hereby incorporated herein by reference in its entirety.

[0004] BACKGROUND OF THE DISCLOSURE

[0005] 1. Field

[0006]

[0002] The present disclosure relates to compositions of antiviral agents such as tenofovir and / or its related pharmaceutical products and related methods of treatment and uses, as well as pharmaceutical compositions including steviol glycosides.

[0007] 2, Technical Background

[0008]

[0003] Tenofovir is a common antiretroviral drug used in the treatment of HIV and AIDS. While tenofovir can be administered on its own, in general, the standard antiviral treatment consists of a combination of drugs to improve effectiveness. In the case of AIDS, a defined "highly active antiretroviral therapy" or HAART is to combine 2 to 4 antivirals that suppress HIV replication and provide more effective antiretroviral treatment even when mixtures of drug-resistant and drug-sensitive strains are present. In addition, tenofovir and its combinations with sofosbuvir and / or velpatasvir are effective treatments for Hepatitis B and C or coinfections.

[0009]

[0004] However, tenofovir and many other antiviral compounds are hydrophobic. Delivery of hydrophobic drug compounds to the site of action is an ongoing challenge in clinical research. It has been reported that 60-90% of new chemical entities in clinical and development are water insoluble or poorly soluble. Cyclodextrins, drug-lipid complexes, liposomes, and other solubilizing agents such as various PEG-lipid conjugates have been tested as the delivery vehicles for hydrophobic compounds. However, these are often found lacking, as they many not provide significant improvements in water solubility, large quantities may be required, and an undesirable degree of hemolysis may result.

[0010]

[0005] Further improvements in compositions and methods for administering hydrophobic antiviral agents are needed. SUMMARY OF THE DISCLOSURE

[0006] In one aspect, the present disclosure provides a pharmaceutical composition (for example, for oral administration) of an antiviral agent (e.g., an antiretroviral agent) dosage form, the pharmaceutical composition comprising: the antiviral agent, comprising an agent selected from the group consisting of tenofovir, dolutegravir, lopinavir, abacavir, bictegravir, cobicistat, darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, lamivudine, lenacapavir, lopinavir, rilpivirine, ritonavir, sofosbuvir, and any combination thereof; and a PEG-saccharide-lipid conjugate having the structural formula wherein m has a number-average value in the range of 2-10; S is a mono-, di- or trisaccharide group, in which each saccharide unit is a sugar, a sugar alcohol, an amino sugar or a sugar acid; L is -C(O)-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; P is -(CH2-CH2-O)nR2in which n has a number-average value in the range of 5- 50 (e.g., 8-45) and R2is hydrogen and / or alkanyl and has a number average number of carbons in the range 0-4. In various embodiments, the composition further includes one or more steviol glycosides mainly comprising one or more steviosides and / or rebaudiosides, for example, to reduce the intense bitterness of certain antivirals

[0007] Another aspect of the disclosure is pharmaceutical composition for oral administration of an antiviral agent (e.g., an antiretroviral agent), the pharmaceutical composition comprising: the antiviral agent, comprising an agent selected from the group consisting of tenofovir, dolutegravir, lopinavir, abacavir, bictegravir, cobicistat, darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, lamivudine, lenacapavir, lopinavir, rilpivirine, ritonavir, sofosbuvir, and any combination thereof; a solubility or bioavailability enhancer comprising PEG-saccharide-lipid conjugate represented by the chemical structure: wherein: L is a lipophilic residue selected from fatty acid residues and steroid acid residues (e.g., bile acid residues, cholesterol residues); S is a saccharide selected from monosaccharides, disaccharides and trisaccharides; P is a polyethylene glycol residue having from 4 to 45 subunits; and B is a backbone molecule having three or four available binding positions; and one or more steviol glycosides mainly comprising one or more steviosides and / or rebaudiosides.

[0008] Other aspects of the disclosure, including associated compositions, methods and uses, BRIEF DESCRIPTION OF THE DRAWINGS

[0009] The accompanying drawings, which are incorporated into and constitute a part of this specification, illustrate one or more embodiments of the present invention and, together with the detailed description, serve to explain the principles and implementations of the invention. In the drawings:

[0010] FIG.1 depicts HPLC chromatograms of fatty acid based conjugates: Peak 1 = lauroyl- propanediamino–mPEG(12)-lactobionate (DLOPS-12); Peak 2 = myristoylpropane-diamino– mPEG(12)-lactobionate (DMPS-12); Peak 3 = palmitoleoylpropanediamino–mPEG(12)- lactobionate (DPOPS-12); Peak 4 = linoleoyl-propanediamino–mPEG(12)-lactobionate (DLOPS-12); Peak 5 = palmitoylpropanediamino–mPEG(12)-lactobionate (DPPS-12); Peak 6 = oleoylpropanediamino–mPEG(12)-lactobionate (DOPS-12); Peak 7 = oleoypropaneldiamino–mPEG(12)-gluconate; Peak 8 = stearoylpropanediamino–mPEG(12)- lactobionate (DSPS-12). The concentrations injected onto the column were approximately 4 to 6 mg / mL each.

[0011] FIG.2 depicts an HPLC chromatogram of a sample of DOPS-12 made with USP grade mPEG (550) and the purity is > 95%. the concentration injected was approximately 5 mg / mL DEPS-12 = elaidoylpropanediamino–mPEG(12)-lactobionate.

[0012] FIG.3 depicts a HPLC chromatogram of linoleoylpropanediamino-mPEG-lactobionate (DLPS-12 and its isomer iso-DLPS-12) made with the USP grade of mPEG (550) and the purity is > 95%, the concentration injected was approximately 5 mg / mL.

[0013] FIG.4 depicts a long-term stability of a sample of DOPS-12 stored under 25 ºC and 65% relative humidity up to 36 months.

[0014] FIG.5 depicts a LC-MS / MS chromatogram of a sample of DOPS-12 at 50 ng / mL.

[0015] FIGS.6A and 6B depict the body weight profile of DOPS-12 for oral dosing up to 90 days in juvenile Beagle dogs (6A) female and (6B) male.

[0016] FIGS.7A and 7B depict Toxicokinetic profile of DOPS-12 for oral dosing in female (7A) and male (7B) juvenile Beagle dogs after Day-90.

[0017] FIG.8 depicts Pharmacokinetic profile of DOPS-12 from intravenous injection in female and male Beagle dogs.

[0018] FIG.9 depicts a finished conjugate product (DOPS-12).

[0019] FIG.10 depicts the curve fitting plot of the Critical Micelle Concentration test results of DOPS-12 in deionized (DI) water.

[0020] FIG.11 depicts the PEG distribution profile in a sample of DOPS-12 as determined by LC-MS

[0021] FIG.12 depicts representative HPLC chromatograms of 400 µg / mL of Emtricitabine (ETC) and 56 µg / mL of Tenofovir alafenamide (TAF) monitored at 265 nm.

[0022] FIG.13 depicts taste masking effects of TAF solution in a mixture of 80% of Rebaudioside M and 20% of Rebaudioside A

[0023] FIG.14 depicts taste masking effects of TAF solution with 95% of Rebaudioside A

[0024] FIG.15 depicts Solubility of Rebaudioside M in Oleoylpropanediamino-mPEG- lactobionate (namely “DOPS-12”) DETAILED DESCRIPTION

[0025] One aspect of the disclosure is a pharmaceutical composition (for example, for oral administration) of an antiviral agent (e.g., an antiretroviral agent), the pharmaceutical composition comprising: the antiviral agent, comprising an agent selected from the group consisting of tenofovir, dolutegravir, lopinavir, abacavir, bictegravir, cobicistat, darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, lamivudine, lenacapavir, lopinavir, rilpivirine, ritonavir, sofosbuvir, and any combination thereof; and a PEG-saccharide-lipid conjugate having the structural formula wherein m has a number-average value in the range of 2-10; S is a mono-, di- or trisaccharide group, in which each saccharide unit is a sugar, a sugar alcohol, an amino sugar or a sugar acid; L is -C(O)-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; P is -(CH2-CH2-O)nR2in which n has a number-average value in the range of 5-50 (e.g., 8-45) and R2is hydrogen and / or alkanyl and has a number average number of carbons in the range 0-4. Such compositions can be provided in a variety of forms, for example, for oral or other administration routes that may be developed as appropriate. In various such embodiments, the pharmaceutical composition further includes one or more steviol glycosides mainly comprising one or more steviosides and / or rebaudiosides.

[0026] Another aspect of the disclosure is a pharmaceutical composition for oral administration of an antiviral agent (e.g., an antiretroviral agent), the pharmaceutical composition comprising: the antiviral agent, comprising an agent selected from the group consisting of tenofovir, dolutegravir, lopinavir, abacavir, bictegravir, cobicistat, darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, lamivudine, lenacapavir, lopinavir, rilpivirine, ritonavir, sofosbuvir, and any combination thereof; a solubility or bioavailability enhancer comprising PEG-saccharide-lipid conjugate represented by the chemical structure: wherein: L is a lipophilic residue selected from fatty acid residues and steroid acid residues (e.g., bile acid residues, cholesterol residues); S is a saccharide selected from monosaccharides, disaccharides and trisaccharides; P is a polyethylene glycol residue having from 4 to 45 subunits; and B is a backbone molecule having three or four available binding positions; and one or more steviol glycosides mainly comprising one or more steviosides and / or rebaudiosides.

[0027] As noted above, a variety of antiviral compounds (and, in particular, antiretroviral compounds) can be suitably used in various compositions of the disclosure.

[0028] For example, in various embodiments, the antiviral agent is tenofovir. As used herein, the term “tenofovir” encompasses not only the tenofovir base compound, but also various salts thereof and various covalently-bonded analogs thereof (e.g., tenofovir alafenamide and tenofovir disoproxil). The same is true for other agents. In such embodiments, tenofovir can optionally be provided together with one or more additional antiviral agents. For example, in various embodiments, tenofovir (e.g., tenofovir alafenamide or tenofovir disoproxil) is provided together with one or more antiviral agents selected from abacavir, bictegravir, cobicistat, darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, lamivudine, lenacapavir, lopinavir, rilpivirine, ritonavir, sofosbuvir, velpatasvir and voxilaprevir.

[0029] In various embodiments, the antiviral agent is dolutegravir. In such embodiments, dolutegravir can optionally be provided together with one or more additional antiviral agents. For example, in various embodiments, dolutegravir is provided together with one or more antiviral agents selected from abacavir, bictegravir, cobicistat, darunavir, efavirenz, elvitegravir, emtricitabine, lamivudine, lenacapavir, lopinavir, rilpivirine, ritonavir, sofosbuvir, tenofovir, velpatasvir and voxilaprevir.

[0030] In various embodiments, the antiviral agent is lopinavir. In such embodiments, lopinavir can optionally be provided together with one or more additional antiviral agents. For example, in various embodiments, dolutegravir is provided together with one or more antiviral agents selected from abacavir, bictegravir, cobicistat, darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, lamivudine, lenacapavir, rilpivirine, ritonavir, sofosbuvir, tenofovir, velpatasvir and voxilaprevir.

[0031] The pharmaceutical compositions of the disclosure can be provided with a variety of total amounts of antiviral agent. The person of ordinary skill in the art can, based on the present disclosure, adjust the amount of the antiviral agent together with the amount of the conjugate in order to provide a desirable antiviral dose with a desirable degree of solubilization by the conjugate.

[0032] For example, in various embodiments, the pharmaceutical composition includes in the range of 1-800 mg of the antiviral agent per dosage or per discrete dosage form. As used herein, a dosage is an amount of the antiviral agent to be administered to a patient at a given time. A discrete dosage form is a discrete portion of the pharmaceutical composition, provided, for example, as a solid dosage form such as a tablet or a capsule, or provided as a defined aliquot of a solid or liquid dosage form. In various embodiments, the pharmaceutical composition includes in the range of 1-600 mg antiviral agent, e.g., in the range of 1-600 mg, or 1-300 mg, or 1-200 mg, or 1-100 mg. In various embodiments, the pharmaceutical composition includes in the range of 5-800 mg of the antiviral agent per dosage or per discrete dosage form, e.g., in the range of 5-600 mg, or 5-300 mg, or 5-200 mg, or 1-100 mg. In various embodiments, the pharmaceutical composition includes in the range of 15-800 mg of the antiviral agent per dosage or per discrete dosage form, e.g., in the range of 15-600 mg, or 15-300 mg, or 15-200 mg, or 15-100 mg. As described below, the antiviral agent can be provided in a variety of concentrations in the pharmaceutical composition.

[0033] For example, in various embodiments, the antiviral agent comprises (or is) tenofovir alafenamide, present, for example, in an amount of 5-40 mg per dosage or discrete dosage form.

[0034] In various embodiments, the antiviral agent comprises (or is) dolutegavir (e.g., 30-50 mg per dosage or discrete dosage form); emtricitabine (e.g., 120-200 mg per dosage or discrete dosage form), and tenofovir alafenamide (e.g., 15-25 mg per dosage or discrete dosage form).

[0035] In various embodiments, the antiviral agent comprises (or is) emtricitabine (e.g., 120- 200 mg per dosage or discrete dosage form), and tenofovir alafenamide (e.g., 15-25 mg per dosage or discrete dosage form).

[0036] In various embodiments, the antiviral agent comprises (or is) bictegravir (e.g., 30-50 mg per dosage or discrete dosage form), emtricitabine (e.g., 120-200 mg per dosage or discrete dosage form), and tenofovir alafenamide (e.g., 15-25 mg per dosage or discrete dosage form).

[0037] In various embodiments, the antiviral agent comprises (or is) cobicistat (e.g., 5 mg per dosage or discrete dosage form), 150 mg of elvitegravir (e.g., 150 mg per dosage or discrete dosage form), emtricitabine (e.g., 200 mg per dosage or discrete dosage form), and tenofovir alafenamide (e.g., 10 mg per dosage or discrete dosage form).

[0038] In various embodiments, the pharmaceutical composition comprises 150 to 400 mg of sofosbuvir and 15 to 25 mg of tenofovir alafenamide.

[0039] In various embodiments, the pharmaceutical composition comprises 100 to 200 mg of lopinavir and 25 to 50 mg of ritonavir

[0040] In various embodiments, the antiviral agent comprises (or is) sofosbuvir (e.g., 150-400 mg per dosage or discrete dosage form), and tenofovir alafenamide (e.g., 15-25 mg per dosage or discrete dosage form).

[0041] In various embodiments, the antiviral agent comprises (or is) lopinavir (e.g., 100-200 mg per dosage or discrete dosage form), and ritonavir (e.g., 25-50 mg per dosage or discrete dosage form).

[0042] The present inventor has noted that some antiviral agents, such as tenofovir alafenamide, can have an intense bitter taste. This can especially complicate pediatric oral administration of liquid formulations; children strongly reject such oral medications due to their intense bitterness. According to one aspect, the present disclosure provides compositions in the bitterness of the antiviral agent can be effectively modified or reduced.

[0043] In various such embodiments, the pharmaceutical composition includes one or more steviol glycosides mainly comprising one or more steviosides or rebaudiosides or their analogues, e.g., rubusoside. As the person of ordinary skill in the art will appreciate, these will generally be the most useful in compositions for oral administration. The present inventor has determined that such compounds can act as taste modifiers, and significantly modify or reduce the bitterness of such pharmaceutical compositions, making them more acceptable to patients in oral administration.

[0044] The steviol glycosides mainly comprise steviosides and / or rebaudioside. The person of ordinary skill in the art is familiar with steviol glycosides, and their use as sweeteners and sugar substitutes. They can be, for example, extracted from the plant Stevia rebaudiana, optionally with bioconversion or other modification of extract. Steviol glycosides can be, for example, 200 to 300 times sweeter than sugar.

[0045] However, many native steviol glycosides (i.e., as extracted from a plant) can produce a bitter aftertaste. While bioconversion of rebaudioside A (4 sugar units) to rebaudioside D (5 sugar units) or rebaudioside M (6 sugar units) can improve sweetness intensity and improve the aftertaste, molecules can have lower solubility in aqueous and alcoholic systems. Generally, rebaudioside A must be provided in higher amounts, about 2-3 times, than rebaudioside D and M to arrive at the same degree of sweetness, due to the varying degrees of the sweetness.

[0046] Steviol glycosides are generally metabolized to steviol, and so it is the safety evaluation of steviol itself that is of primary importance for risk assessment, so called steviol equivalence. For instance, based on their relative molecular weights, stevioside quantities are multiplied by 0.40 and rebaudioside A quantities by 0.33 to convert both to steviol equivalence, defined by the Joint FAO / WHO Expert Committee on Food Additives (JECFA).

[0047] Since the content of commercial grades of steviol glycosides can vary from different sources, the person of ordinary skill will determine the appropriate amount of conjugate for use with a particular steviol glycoside product. Typically, more conjugate is necessary for less pure products and for more hydrophobic steviol glycosides.

[0048] The data provided in the disclosure demonstrate that the bitter taste of antiviral agents can be addressed using steviol glycosides, especially those of relatively high purity. However, in some cases a higher amount of PEG-saccharide-lipid conjugate may be necessary to co- solubilize both the antiviral agent and the steviol glycosides, especially for less-soluble steviol glycosides like Rebaudioside M and D. Many high-potency sweetening steviol glycosides are relatively poorly-water soluble; i.e., less than 0.13 wt% in room temperature water.For instance Rebaudioside M, for example, is only sparingly soluble in water or alcohol. The sweetness of individual rebaudiosides is correlated to their solubility. Rebaudioside A is the sweetest of all the natural compounds in the stevia leaf which is more water soluble with a sweetness potency approximately 80 to 100 times versus sucrose. The enzymatically-modified products Rebaudioside M and D are poorly water soluble and have a more rounded and balanced sweetness profile compared to Rebaudioside A.

[0049] The present inventor has determined that the conjugates described herein can help improve the solubility of such steviol glycosides like rebaudioside D and rebaudioside M. Without intending to be bound by theory, the inventor suggests that the surfactant-like properties of the conjugates can be used to encapsulate steviol glycosides to form a conjugate- steviol glycoside complex, either together with the antiviral agent or separately. While in some cases the steviol glycosides will be sufficiently solubilized by the amount of the conjugate used in conjunction with the antiviral agent, in other cases it may be desirable to use a larger amount of the conjugate. In various embodiments, a weight ratio of the one or more steviol glycosides to the conjugate is in the range of about 1 to about 10, e.g., in the range of 1-10. In various embodiments, a weight ratio of a total amount of rebaudioside D or rebaudioside M to the conjugate is in the range of 0.5-10 This can, in some embodiments, depend on the purity and manufacturing process used for the preparation of the steviol glycoside. A purer steviol glycoside may require relatively more of the conjugate.

[0050] In various embodiments, wherein the one or more steviol glycosides are present in the composition in an amount in the range of 0.5-50 wt%, e.g., 1-50 wt%, or 5-50 wt%, or 0.5-25 wt%, or 1-25 wt%, or 5-25 wt%, or 0.5-10 wt%, or 1-10 wt%, or 5-10 wt%..

[0051] Without intending to be bound by theory, the present inventor suggests that the use of the conjugates of the disclosure can provide a higher amount of steviol glycosides to a composition, and thus provide more perceived sweetness to mask the bitter taste of the antiviral agent. Moreover, without intending to be bound by theory, the present inventor suggests that the conjugate-steviol glycoside complex can preferentially mask the bitter components of the steviol glycosides by more strongly complexing them, making them less likely to be perceived by the patient.

[0052] Some steviol glycosides with a higher water solubility, such as reboudioside A, can be useful in the compositions of the disclosure. In such cases, the steviol glycosides can be used in relatively higher amounts without as high a need for solubilization by the conjugate. Nonetheless, use of such steviol glycosides is specifically contemplated by the disclosure.

[0053] In some embodiments of the disclosure, the one or more steviol glycosides are provided in a purity of at least 75 wt%, e.g., at least 85 wt% or at least 90 wt% or at least 95 wt% (i.e., as a fraction of steviol glycosides extracts from the leaves of Stevia rebaudiana ), e.g., a commercial steviol glycoside mixture extracted from the plant was found to have about 81% stevioside (containing 3 glucoses), 7.7% rebaudioside A (containing 4 glucoses), and 0.6% rebaudioside C (containing 3 glucoses and a deoxyglucose), enrichment of rebaudioside A can be done from further extraction. In some embodiments of the disclosure, a total amount of one or more of Rebaudiosides A or D or M is at least 75 wt% of a total amount of steviol glycosides, e.g., at least 85 wt% or at least 90 wt% or at least 95 wt%. In some embodiments of the disclosure, a total amount of one or more of Rebaudiosides D or M is at least 75 wt% of a total amount of steviol glycosides, e.g., at least 85 wt% or at least 90 wt% or at least 95 wt%. In some embodiments of the disclosure, a total amount of Rebaudioside A is at least 75 wt% of a total amount of steviol glycosides, e.g., at least 85 wt% or at least 90 wt% or at least 95 wt%.

[0054] In various embodiments of the disclosure, the pharmaceutical composition can further include one or more sweeteners (i.e., other than or more steviol glycosides). As the person of ordinary skill in the art will appreciate, these will generally be the most useful in compositions for oral administration. The present inventor has determined that in some cases it can be desirable to include one or more sweeteners to mask certain flavors in the composition. They can be especially desirable when used in combination with steviol glycosides (especially Rebaudioside A) to modify the aftertaste thereof.

[0055] In various embodiments, one or more of the one or more sweeteners is an artificial sweetener. In various embodiments, one or more of the one or more sweeteners is a natural sweetener. For example, in various embodiments, one or more of the one or more sweeteners is selected from acesulfame potassium, arginine acid, aspartame, cyclamate, monk fruit extract, saccharin, and sucralose. In various embodiments, one or more of the one or more sweeteners is selected from sugars such as sucrose, dextrose, fructose, glucose and maltose and sugar alcohols such as sorbitol, mannitol, isomalt, maltitol, erythritol and xylitol. The person of ordinary skill in the art will select, based on the present disclosure, desirable sweeteners in desirable amounts for particular compositions. In various embodiments, a total amount of the one or more sweeteners is in the range of 0.2-10 wt% of the composition.

[0056] In some embodiments, it can be desirable to include one or more flavoring agents in a pharmaceutical composition of the disclosure. Here, too, flavorings are most useful in compositions for oral administration. For example, in various embodiments, a pharmacuetical composition of the disclosure includes one or more flavoring agents selected from yerba mate (extract of Ilex paraguariensis A. St.-Hil.), cinnamon and its derivatives (e.g., cinnamic acid), wild cherry, mint, anise, Irish cream, tea, mocha, walnut, chocolate, coconut, vanilla, fruit, berry, butterscotch, peach, vanilla, wintergreen mint, maple, apricot, raspberry, citrus, monk fruit extract, pineapple extract and licorice root. Of course a wide variety of other flavorings are possible. The person of ordinary skill in the art will select, based on the present disclosure, desirable flavoring agents in desirable amounts for particular compositions. In various embodiments, a total amount of the one or more flavoring agents is in the range of 0.5-10 wt% of the composition.

[0057] The person of ordinary skill in the art will appreciate that many other components may be present in the compositions of the disclosure. For example, in various embodiments, a pharmaceutical composition of the disclosure includes one or more bulking fillers. The type of bulking filler and whether or not a bulking filler is a desirable component will depend on the particular form of the pharmaceutical composition; the person of ordinary skill in the art can determine this based on the present disclosure. For example, in various embodiments, one or more of the one or more bulking fillers is selected from polyvinylpyrrolidone, poloxamers, cyclodextrin derivatives, Polyoxyl 40 hydrogenated castor oil, polysorbates and polyethylene glycols (e.g., number average molecular weight in the range of 2-8 kDa). In various embodiments, one or more of the one or more bulking fillers is a saccharide, such as a a sugar alcohol (such as mannitol) or a sugar (such as lactose).

[0058] In various embodiments, the pharmaceutical compositions of the disclosure can further include an antioxidant. As the person of ordinary skill in the art will appreciate, an antioxidant can be desirable in a number of contexts. For example, an antioxidant can help to prevent formation of or scavenge N-nitrosamine that may be formed during manufacturing or storage of the pharmaceutical composition, the one or more antiviral agents, or other components of the composition.

[0059] In various embodiments, the antioxidant is one or of ascorbic acid, α-tocopherol and TPGS (D-α-Tocopherol polyethylene glycol 1000 succinate).

[0060] In various embodiments, the antioxidant includes (or is) ascorbic acid. In various embodiments, the antioxidant includes (or is) α-tocopherol. Ascorbic acid (vitamin C) or α- tocopherol (vitamin E) are recommended by the FDA to be used for addressing nitrosamine formation.

[0061] In various embodiments, the antioxidant includes (or is) D-α-tocopherol polyethylene glycol 1000 succinate (TGPS), which is a chemically stable to heat, oxygen and light. TPGS has a better antioxidant activity than free vitamin E. Antioxidants are known blockers of nitrosamine formation; therefore TPGS works better with less toxicity concern as compared to pure vitamin E or vitamin C.

[0062] In some cases, it may be desirable to provide additional conjugate to help solubilize the antioxidant. For example, unlike TPGS, vitamin E is not water soluble which may require additional conjugate for solubility.

[0063] Of course, the person of ordinary skill in the art will be familiar with maximum recommended dosages of any antioxidants used, and can provide pharmaceutical compositions that acceptably address these maximum recommended dosages.

[0064] Of course, other components can be present in the pharmaceutical compositions of the disclosure. The person of ordinary skill in the art can determine other components for inclusion in the composition, including but not limited to those described below.

[0065] In various embodiments, a pharmaceutical composition of the disclosure (e.g., in a solid form) further includes a disintegrant. Examples of disintegrants include , microcrystalline cellulose and other so-called “superdisintegrants,” e.g., crospovidone or sodium starch glycolate, can be used in many cases.

[0066] In various embodiments, a pharmaceutical composition of the disclosure further includes a coloring agent such as a dye or a pigment. Examples include FD&C approved coloring agents, EU-approved coloring agents, natural coloring agents and pigments. In various embodiments, a coloring agent is present in an amount up to 2 wt% of the composition.

[0067] A pharmaceutical composition of the disclosure may further include an antimicrobial preservative, especially when the composition is in a liquid, gel or cream form. A variety of such preservatives can be used, typically in an amount in the range of 0.1-2 wt%.

[0068] The pharmaceutical compositions of the disclosure can be provided in a variety of forms, both liquid and solid, as well as semisolid forms like creams and gels.

[0069] For example, in various embodiments, especially those in which one or more of a steviol glycoside, a sweetener and a flavoring agent is present, the pharmaceutical composition is in the form of an oral dosage form. For example, in various embodiments, the pharmaceutical composition is in the form of a solid oral dosage form, such as a tablet, a capsule, or a film. The solid oral dosage forms can be configured to be swallowed in some embodiments. In other embodiments they can be configured to dissolve or disintegrate in the mouth, e.g., for sublingual or buccal administration. In other embodiments, the pharmaceutical composition is in the form of a liquid oral dosage form, such as an aqueous-based composition (e.g., solution or suspension) that can be drunk by a patient. In other embodiments, the pharmaceutical composition is the form of a dispersible solid, e.g., powder or granules, or a liquid concentrate that can be taken up in an aqueous liquid to form an aqueous-based composition that can be drunk by a patient.

[0070] But compositions of the disclosure can be used for other routes of administration. For example, in various embodiments, the composition of the disclosure is in a form for parenteral administration. The person of ordinary skill in the art can provide suitable parenteral compositions that include the conjugates of the disclosure. For example, in a 5 wt% PEG- saccharide-lipid conjugate aqueous solution, in some embodiments the concentration of the above drug substance can in some embodiments be up to 1 wt%. Formulations for parenteral administration can be, e.g., formulated with an appropriate amount of sodium chloride (e.g., 9 wt%) in purified water. pH adjustment can be provided as necessary, e.g., using sodium hydroxide and / or hydrochloric acid, or an appropriate buffer.

[0071] Compositions of the disclosure can be provided in a variety of other forms, for example, as liquids, creams or gels, e.g., for topical or intranasal administration.

[0072] The person of ordinary skill in the art can, based on the present disclosure, determine particular amounts of various components of the formulation. The person of ordinary skill in the art will understand from the present disclosure that the PEG-saccharide-lipid conjugates described herein can be used to solubilize not only an antiviral agent, but also, in some cases, a steviol glycoside that is added to address an undesirable taste of the antiviral agent, as well as, in some cases, an antioxidant. When more of these components are included, more of the conjugate may be necessary to solubilize the conjugate.

[0073] In various embodiments, a concentration of the PEG-saccharide-lipid conjugate in the range of 0.1-40 wt%, e.g., 0.5-40 wt%. In various embodiments, a concentration of the PEG- saccharide-lipid conjugate in the range of 0.5-40% (wt / vol) and a concentration of 60-99.5% (wt / vol) of a solid or an aqueous medium (e.g., water or a buffer or a flavored solution). In various embodiments, the composition is the form of an aqueous solution having an amount of water or a buffer or flavored solution in the range of 60-99 vol%. In various embodiments, drug solution products have an antiviral agent concentration in the range of 0.5 mg / mL to 50 mg / mL, and a conjugate concentration in the range of 0.5-30%(wt / vol) of PEG-saccharide-lipid conjugate.

[0074] Of course, a variety of other concentrations are possible, depending on particular components and form of the composition. For example, in various embodiments, the conjugate of the disclosure is present in the composition in an amount of at least 1 wt%, e.g., at least 2 wt%. In various embodiments, the conjugate of the disclosure is present in the composition in an amount of at least 5 wt%, e.g., at least 10 wt%. In various embodiments, the conjugate of the disclosure is present in the composition in an amount of at least 15 wt%, e.g., at least 20 wt%. In various embodiments, the conjugate of the disclosure is present in in the composition an amount of at least 25 wt%, e.g., at least 30 wt%.

[0075] In various embodiments, the conjugate of the disclosure is present in the composition in an amount in the range of 1-25 wt%, e.g., 2-25 wt%, or 1-15 wt%, or 2-15 wt%, or 1-10 wt%, or 2-10 wt%, or 1-5 wt%, or 2-5 wt%. In various embodiments, the conjugate of the disclosure is present in the composition in an amount in the range of 5-35 wt%, e.g., 10-35 wt%, or 5-25 wt%, or 10-25 wt%, or 5-15 wt%, or 10-20 wt%. In various embodiments, the conjugate of the disclosure is present in the composition in an amount in the range of 15-50 wt%, e.g., 20-50 wt%, or 15-40 wt%, or 20-40 wt%, or 15-30 wt%, or 20-35 wt%. In various embodiments, the conjugate of the disclosure is present in the composition in an amount in the range of 20-60 wt%, e.g., 25-60 wt%, or 20-50 wt%, or 25-50 wt%, or 20-40 wt%, or 25-45 wt%.

[0076] In various embodiments, the conjugate of the disclosure is present in an amount above its critical micelle concentration. For example, in some embodiments, the conjugate is present in aqueous solution in an amount above its critical micelle concentration or less than 0.1 mmol. Without intending to be bound by theory, it is believed that the conjugates of the disclosure work in part by forming micelles with the antiviral agent.

[0077] Similarly, the antiviral agent can be present in the composition in a variety of concentrations, depending on the antiviral agent and depending on the particular form of the composition. For example, in various embodiments, the antiviral agent is present in the composition in an amount of at least 0.1 wt%, e.g., at least 0.2 wt%. In various embodiments, the antiviral agent is present in the composition in an amount of at least 0.5 wt%, e.g., 1 wt%. In various embodiments, the antiviral agent is present in the composition in an amount of at least 2 wt%, e.g., at least 5 wt%. In various embodiments, the antiviral agent is present in the composition in an amount of at least 10 wt%, e.g., at least 20 wt%.

[0078] In various embodiments, the antiviral agent is present in the composition in an amount in the range of 0.1-10 wt%, e.g., 0.2-10 wt%, or 0.1-5 wt%, or 0.2-5 wt%, or 0.1-2 wt%, or 0.2- 2 wt%. In various embodiments, the antiviral agent is present in the composition in an amount in the range of 0.5-20 wt%, e.g., 1-20 wt%, or 0.5-10 wt%, or 0.5-10 wt%, or 0.5-5 wt%, or 1-5 wt%. In various embodiments, the antiviral agent is present in the composition in an amount in the range of 2-30 wt%, e.g., 5-30 wt%, or 2-20 wt%, or 5-20 wt%, or 2-10 wt%, or 5-15 wt%. In various embodiments, the antiviral 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%.

[0079] The person of ordinary skill in the art can determine an appropriate ratio of conjugate to antiviral agent based on the present disclosure. The amounts of the conjugate of the disclosure and the antiviral agent will vary depending on the particular dosage form and the particular dosage desired. The person of ordinary skill can select particular amounts based on the present disclosure and based on the identity of a desired antiviral agent.

[0080] For example, in various embodiments, a weight ratio of the conjugate of the disclosure to the antiviral agent is in the range of 1-100. In various embodiments, a weight ratio of the conjugate to the antiviral agent ranges from 0.5 to 50, or 0-5-10.

[0081] But a variety of other ratios are possible. In various embodiments, a weight ratio of the conjugate of the disclosure to the antiviral agent is in the range 500:1 - 1:2, e.g., 200:1 - 1:2, or 100:1 - 1:2, or 50:1 - 1:2, or 20:1 - 1:2. In various embodiments, a weight ratio of the conjugate of the disclosure to the antiviral agent is in the range of 500:1 - 1:1, e.g., 200:1 - 1:1, or 100:1 - 1:1, or 50:1 to 1:1, or 20:1 - 1:1, or 10:1 - 1:1, or 5:1 - 1:1. In various embodiments, a weight ratio of the conjugate of the disclosure to the antiviral agent is in the range of 500:1 - 2:1, e.g., 200:1 - 2:1, or 100:1 - 2:1, or 50:1 - 2:1, or 20:1 - 2:1, or 10:1 - 2:1, or 5:1 - 2:1. In various embodiments, a weight ratio of the conjugate of the disclosure to the antiviral agent is in the range of 500:1 - 4:1, e.g., 200:1 - 4:1, or 100:1 - 4:1, or 50:1 - 4:1, or 20:1 - 4:1, or 10:1 to 4:1.

[0082] Of course, the person of ordinary skill in the art can use the relative mass ratios described above to determine various suitable amounts of conjugate for a particular amount of antiviral agent.

[0083] The person of ordinary skill in the art can likewise determine an appropriate ratio of conjugate to steviol glycosides. Many steviol glycosides, like Rebaudioside A, are more soluble in water. The present inventor notes that a more important determination is a ratio of conjugate to poorly-soluble steviol glycosides (i.e., those having a water solubility at 23 °C of no more than 0.2 wt%). In various embodiments, a weight ratio of the conjugate of the disclosure to poorly-soluble steviol glycosides is in the range of 0.2-10. In various embodiments, a weight ratio of the conjugate of the disclosure to a total content of Rebaudioside D and Rebaudioside M is in the range of 0.2-10.

[0084] In various embodiments, a weight ratio of the conjugate of the disclosure to other excipients (including surfactants) is in the range of 0.5 to 5.

[0085] Another aspect of the disclosure is a pharmaceutical composition of the disclosure for use in the treatment of a subject having a viral condition, the antiviral agent of the composition being suitable for treating the viral condition.

[0086] Another aspect of the disclosure is a method for treating a subject having a viral condition, the method comprising administering to the subject a composition of the disclosure, the antiviral agent of the composition being suitable for treating the viral condition. The administration may be by any route suitable for the pharmaceutical composition and for the viral condition. For example, in some embodiments, the administration is an oral administration. In some embodiments, the administration is a parenteral administration, or a topical administration, or an intranasal administration.

[0087] The compositions and methods of the disclosure can be suitable for treatment of a variety of viral conditions. As the person of ordinary skill in the art appreciates, the antiviral agents discussed herein can be used to treat a variety of conditions. For example, in various embodiments, the viral condition is human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS). In various embodiments, the viral condition is hepatitis, e.g., hepatitis B or hepatitis C.

[0088] Another aspect of the disclosure provides a pharmaceutical composition of the disclosure for use as a medicament.

[0089] Another aspect of the disclosure is a use of a conjugate as described herein for increasing bioavailability of an antiviral agent selected from the group consisting of tenofovir, dolutegravir, lopinavir, abacavir, bictegravir, cobicistat, darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, lamivudine, lenacapavir, lopinavir, rilpivirine, ritonavir, sofosbuvir, and any combination thereof.

[0090] Another aspect of the disclosure is a use of a conjugate as described herein for increasing solubility in an aqueous system of an antiviral agent selected from the group consisting of tenofovir, dolutegravir, lopinavir, abacavir, bictegravir, cobicistat, darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, lamivudine, lenacapavir, lopinavir, rilpivirine, ritonavir, sofosbuvir, and any combination thereof.

[0091] Another aspect of the disclosure is a use of steviol glycosides (such as rebaudiosides, for example, Rebaudiosides A, D and / or M as described herein) for masking or modifying the bitterness taste of an antiviral agent.

[0092] Various embodiments of the disclosure are described herein with respect to the use of particular PEG-saccharide-conjugates as solubilizing agents. While the described PEG- saccharide-conjugates are useful solubilizing agents in compositions including one or more steviol glycosides and the described antivirals, the present disclosure specifically contemplates compositions, methods and uses as described here that do not require the use of the described conjugates. The person of ordinary skill in the art is aware of other solubilizing agents, such as fatty acid esters of sorbitans, fatty acid esters of polyethoxylated sorbitans, materials available under the name Chremophor™. Other solubilizing agents can include, in various embodiments, The pharmaceutical composition of claim 1, further comprising a bulking filler selected from polyethylene glycols, mannitol, lactose, polyvinylpyrrolidone, poloxamers or cyclodextrin derivatives, polysorbates, polyoxyl 40 hydrogenated castor oil, and combinations thereof. The person of ordinary skill in the art can determine other solubilizing agents effective to co-solubilize given amounts of antiviral agents and steviol glycosides. Specifically contemplated here is the replacement in any embodiment as described herein of the PEG- saccharide-conjugate with another solubilizing agent effective to solubilize the antiviral and the one or more steviol glycosides, in various amounts as described.

[0093] Another aspect of the disclosure is a use of a conjugate as described herein for increasing solubility of poorly-soluble steviol glycosides (e.g., rebaudiosides like Rebaudioside D and M) in an aqueous system. Similarly, the present inventor has found that poorly-soluble steviol glycosides can be effectively solubilized by the PEG-saccharide-lipid conjugates described herein. While the described PEG-saccharide-conjugates are useful solubilizing agents in compositions including one or more steviol glycosides and the described antivirals, the present disclosure specifically contemplates compositions, methods and uses as described here that do not require the use of the described antivirals. For example, specifically contemplated are compositions, methods and uses as described herein where the antiviral agent is substituted by some other active pharmaceutical agent, in various amounts as described, or where the antiviral agent is omitted without substitution by some other active pharmaceutical agent.

[0094] Another aspect of the disclosure is use of a conjugate as described herein as a pharmaceutical excipient together with an antiviral agent.

[0095] The person of ordinary skill in the art can adapt conventional techniques for making the compositions of the disclosure. In various embodiments, a drying process can be used in the compounding process, for example, using a lyophilizer or a spray dryer. The antiviral agent (and optionally, the steviol glycoside and / or the antioxidant, if present) 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.

[0096] In various embodiments, pharmaceutical compositions of the disclosure can desirably be formed by first combining the antiviral agent with a PEG-saccharide-lipid conjugate of the disclosure, which can be, e.g., liquid or semisolid at the temperature of solubilization. An aqueous solution of steviol glycoside (when present) and other excipients can later be mixed with the antiviral agent / conjugate mixture if an aqueous solution is desired. For solid dosage forms, an antiviral agent can be co-dissolved with the conjugate in a desirable solvent, then dried under vacuum or by a spry-drying process. For orally disintegrating tablets or granules, lyophilization may be a suitable process.

[0097] The present disclosure provides a variety of PEG-saccharide-lipid conjugates for use in the compositions of the disclosure. For example, in various embodiments, the PEG-saccharide- lipid conjugate has a structure according to the General Formula (I): wherein: m has a number-average value in the range of 2-10, which represents a distance between the terminal moieties of the center backbone; S is a saccharide such as a mono-, di-, or trisaccharide group, in which each saccharide unit is a sugar, a sugar alcohol, an amino sugar or a sugar acid; L is -C(O)-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, for example, those derived from cholesterol, cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, chenodeoxycholic acid, and lithocholic acid (for example, those derived from cholic acid, deoxycholic acid, glycocholic acid); P is -(CH2-CH2-O)nR2in which n has a number-average value in the range of 5-50 (e.g., 8-45) and R2is hydrogen and / or alkanyl and has a number average number of carbons in the range 0-4.

[0098] The person of ordinary skill in the art will appreciate that a real-world sample of the conjugates of the disclosure will often have a range of R1chain lengths, a range of R2chain lengths, and a range of n values, and as such various individual molecules within a sample may have different identifies of R1, R2and n. However, as described above, it can in many circumstances be desirable to control the variation, especially of the value of n. Thus, the definition of General Formula I contemplates that the materials can be in the form of mixtures of individual compounds each with their own particular definitions of S, L, P and m. General Formula I thus defines various substituents with number-average values of various substituents. But the disclosure also specifically contemplates various individual compounds with integral values for various substituents.

[0099] The present inventor has determined that maintaining a relatively small value of m, to provide a relatively short diamine backbone, can be desirable in some embodiments. Accordingly, in some embodiments as described herein, m has a number-average value in the range of 2-8. For example, in some embodiments, m has a number-average value in the range of 2-6, or 2-5, or 2-4. In some embodiments, m has a number-average value of 3. In some embodiments, m has a number-average value of 2, or a number average value of 4. The present inventor has noted that values of m in the range of 2-4 are especially suitable for parenteral administration, while values across the 2-10 range can be suitable for oral administration.

[0100] However, in other embodiments, a longer diamine backbone can be suitable. For example, in some embodiments as described herein, m has a number-average value in the range of 5-10. For example, in some embodiments, m has a number-average value in the range of 5-8 or 8-10. Without intending to be bound by theory, the present inventor suggests a longer diamine has a larger “space” or less steric hindrance for the synthesis, especially with longer PEG chains or bulkier lipids, and as such can offers a relative higher yield of the conjugate due to fewer steric effects.

[0101] The person of ordinary skill in the art can select a value of “m” based on the present disclosure, especially the showing that lower values of “m” can provide improved hemolytic stability and thus an improved safety profile.

[0102] “S” can be a variety of saccharide groups, such as mono-saccharides, disaccharides and trisaccharides. Each saccharide unit can be, e.g., a sugar, a sugar alcohol, a sugar acid, or an amino sugar.

[0103] In various embodiments as described herein, S is selected from a disaccharide, monosaccharide, or a trisaccharide group. For example, in some embodiments, “S” is a disaccharide group. In some embodiments, “S” is a monosaccharide group. In some embodiments, “S” is a trisaccharide group. The number of saccharide units can impact the HLB (Hydrophilic–lipophilic balance) value of the conjugate, and the person of ordinary skill in the art can, based on the disclosure herein, determine a particular saccharide group, along with particular “P” and “L” groups, to provide an overall desirable HLB value.

[0104] A variety of individual monosaccharide units can be present in the S groups, for example, sugars, sugar alcohols, amino sugars and sugar acids. In various embodiments, the saccharide units of S are individually selected from hexoses and pentoses and sugar alcohol, sugar acid and amino sugar analogs thereof. In various embodiments, saccharide units of S are individually selected from hexoses and sugar alcohol, sugar acid and amino sugar analogs thereof. Individual saccharide units of S can be interconnected by glycosidic bonds, as would be familiar to the person of ordinary skill in the art.

[0105] Notably, it can be desirable for saccharide unit of S that is directly bound to the nitrogen of the diamine central backbone to be derived from a sugar acid and to be bound to the nitrogen of the diamine as an amide. The present inventors have noted that linkage as an amide can provide especially stable compounds. In various such embodiments, any saccharide unit of S that is not directly bound to the nitrogen of the diamine is a sugar. However, other linkages are possible. For example, the linkage between the diamine central backbone and the saccharide can be in the form of an amine, for example, through amination of a sugar alcohol, or reaction of a aldehyde or ketone form of a saccharide unit with an amine to form an imine followed by Amadori rearrangement thereof:

[0106] In some embodiments as described herein, the structural formula of “S” is as follows: in which -(Cx1H2x1Ox1-1)-CO- is a sugar acyl residue derived from a sugar acid in which x1 is 4 or 5, and (Cx2H2x2-1Ox2-1)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof. In various such embodiments, x1 is 5 and x2 is 6.

[0107] In various embodiments, “S” has the following structure: or is an open-chain version thereof.

[0108] In various embodiments, “S” is lactobionyl or gluconyl or a combination thereof (e.g., in a molar ratio of at least 9:1 lactobionyl:gluconyl). In various embodiments, “S” is lactobionyl. In other embodiments, “S” is a residue from gluconolactone or neuraminic acid. In other embodiments, “S” is a residue from another disaccharide or trisaccharide, which can be modified (e.g., by oxidation). Examples include sucrose, lactose, maltose, trehalose, turanose, cellobiose raffinose, melezitose and maltotriose.

[0109] In various embodiments, “L” includes (or is) a fatty acyl group based on a saturated or unsaturated fatty acid (i.e., including all combinations thereof). Accordingly, in various embodiments, “L” is -C(O)-R1, wherein R1is an alkanyl or alkenyl group having a number- average number of carbons in the range of 6-22. The person of ordinary skill in the art will appreciate that in most real-world samples of fatty acids, the fatty group has a range of carbon chain lengths and degrees of unsaturation, and so the conjugates of the disclosure will likewise often have a range of carbon chain lengths and degrees of unsaturation in the fatty acyl component, especially those derived from natural sources.

[0110] In various such embodiments, R1has a number-average number of carbons in the range of 6-20, or 6-18. In various such embodiments, R1has a number-average number of carbons in the range of 10-22, e.g., 10-20 or 10-18. In various such embodiments, R1has a number- average number of carbons in the range of 12-22, e.g., 12-20 or 12-18. In various such embodiments, R1has a number-average number of carbons in the range of 14-22, e.g., 14-20 or 14-18. In various desirable embodiments as described above, R1has a number-average number of carbons that is no more than 18.

[0111] Both saturated and unsaturated R1groups can be suitable for use. In various embodiments as otherwise described herein, R1has a number-average number of unsaturation in the range of 0-3, e.g., 0-2. Of course, many real world samples will include R1 groups having more than one number of unsaturations. For example, some samples may have a distribution of stearoyl, oleoyl and linoleoyl residues. Others may include a combination of oleoyl and linoleoyl residues, for example, in a ratio of about 10:1.

[0112] In various desirable embodiments, R1is a linear alkanyl or alkenyl group.

[0113] In various embodiments as described herein, R1is derived from one or more of caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, alpha-linoleic acid, arachidonic acid and erucic acid. Various desirable fatty acids from which R1-C(O)- can be derived are further described in Table 1 and Table 2; mixtures of such fatty acids (e.g., as are present in various fatty acid materials derived from natural sources such as Tall tree oil and Sunflower oil) are specifically contemplated. Table 1 Saturated fatty acids Table 2 Unsaturated fatty acids

[0114] However, in many embodiments, it can be desirable for the -C(O)-R1group of a conjugate sample to largely have the same chemical identity, e.g., largely cis- CH3(CH2)7CH=CH(CH2)7-C(O)-, as would be the case for an R1-C(O)- Lipid group derived from oleic acid. In various embodiments as otherwise described herein, -C(O)-R1is at least 80 mol% of a single chemical identity, e.g., at least 85 mol%. In various embodiments as otherwise described herein, -C(O)-R1is at least 90 mol% of a single chemical identity, e.g., at least 95 mol%. In various embodiments as described herein, the single chemical identity is selected from n-hexanoyl, n-octanoyl, n-decanoyl, n-dodecanoyl, n-tetradecanoyl, n- hexadecanoyl, n-octadecanoyl, n-eicosanoyl and n-docosanoyl. In various embodiments as described herein, the single chemical identity is selected from: cis-CH3(CH2)5CH=CH(CH2)7C(O)-, cis,cisCH3CH2CH=CHCH2CH=CHCH2CH=CH(CH2)7C(O)-, cis,cis,cis-CH3(CH2)4CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)3C(O)-, and cis-CH3(CH2)7CH=CH(CH2)11C(O)-

[0115] For example, in various embodiments, that single chemical identity is cis-CH3(CH2)7CH=CH(CH2)7C(O)-. In various embodiments, that single chemical identity cis,cis-CH3(CH2)4CH=CHCH2CH=CH(CH2)7C(O)-. In various embodiments, that single chemical identity is cis-CH3(CH2)3CH=CH(CH2)7C(O)-. In other embodiments, that single chemical identity is any one of the other residues mentioned in Tables 1 and 2.

[0116] In other embodiments, “L” includes (or is) a steroid acyl group, such as a bile acid or a similar group. In various embodiments, the steroid acyl group is an acyl group derived from cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, chenodeoxycholic acid, and lithocholic acid. In various embodiments, the steroid acyl group is an acyl group derived from cholic acid, deoxycholic acid, and glycocholic acid.

[0117] As described above, “P” is -(CH2-CH2-O)nR2in which “n” has a number-average value in the range of 5-50 (e.g., 8-45) and R2is hydrogen and / or alkanyl and has a number average number of carbons in the range 0-4. In various embodiments, n has a number-average value in the range of 5-45, e.g., 5-40, or 5-30, or 5-20, or 5-15, or 5-10. In various embodiments, “n” has a number-average value in the range of 8-50, e.g., 8-45, or 8-40, or 8-30, or 8-20, or 8-15, or 8-12, or 8-10. In various embodiments, n has a number-average value in the range of 10-50, e.g., 10-45, or 10-40, or 10-30, or 10-20, or 10-15. In various embodiments, “n” has a number- average value in the range of 9-14, e.g., 9-13, or 10-14, or 10.5-13.5, or 11-13, or 11.5-12.5, or 11.8-12.2, or 10.2-13.8, or 10.8-13.2, or 11.4-12.6. In various embodiments, “n” has a number- average value in the range of 18-28, e.g., 20-26, or 22-24, or 22.5-23.5, or 22.8-23.2. In various embodiments, “n” has a number-average value in the range of 25-40. In various embodiments, n has a number-average value in the range of 40-50, e.g., 42-48, or 44-46, or 44.5-45.5, or 44.8-45.2.

[0118] The poly(ethylene glycol) is terminated with R2, which can be H (i.e., to provide a hydroxy) or an alkanyl group (i.e., to provide an ether). In various embodiments, R2has a number-average number of carbons of at least 0.95, e.g., at least 0.99 or at least 1 (e.g., free of hydroxyl). In various embodiments, R2has a number-average number of carbons in the range of 0.9-1.1, or 0.95-1.05, or 0.98-1.02. In various embodiments, R2is C1-C4alkanyl, e.g., methyl or ethyl. In various embodiments, R2is methyl. In various embodiments, R2has a number average number of carbons in the range 0-3, e.g., 0-2. In various embodiments, R2has a number-average number of carbons in the range of 0-0.94, e.g., 0-0.75, or 0-0.5, or 0-0.1, or 0-0.05; in such embodiments, there is a substantial amount of R2that is hydrogen.

[0119] When the -P group is a methylated PEG residue (i.e., R2is methyl), in various embodiments it has a number-average molecular weight in the range of 300-2200 g / mol. For example, in various embodiments, the -P group is a methylated PEG residue having a number- average molecular weight in the range of 300-1200 g / mol, e.g., 300-600 g / mol. In various embodiments, the -P group is a methylated PEG residue having a number-average molecular weight in the range of 500-2200 g / mol, e.g., 500-1200 g / mol, or 500-900 g / mol. In various embodiments, the -P group is a methylated PEG residue having a number-average molecular weight in the range of 700-2200 g / mol, e.g., 700-1200 g / mol, or 700-1100 g / mol. In various embodiments, the -P group is a methylated PEG residue having a number-average molecular weight in the range of 475-575 g / mol. In various embodiments, the -P group is a methylated PEG residue having a number-average molecular weight in the range of 475-525 g / mol or 525- 575 g / mol. In various embodiments, the -P group is a methylated PEG residue having a number-average molecular weight in the range of 710-790 g / mol. In various embodiments, the -P group is a methylated PEG residue having a number-average molecular weight in the range of 900-1100 g / mol, e.g., 950-1050 g / mol. In various embodiments, the -P group is a methylated PEG residue having a number-average molecular weight in the range of 1800-2200 g / mol, e.g., 1900-2100 g / mol. Methylated PEG residues and methylated PEGs are described variously in this disclosure as mPEG, as well as mPEGn and m(PEG)n, in which the n indicates a number-average number of ethylene glycol residues. The person of ordinary skill will understand from context whether a methylated PEG or a methylated PEG residue is being discussed.

[0120] In various embodiments, the PEG has a low degree of polydispersity, which can be especially important for those conjugates used in parenteral administrations. The present inventor has found that use of a PEG that has low polydispersity 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 ^^^^wis the weight average molecular weight and ^^^^nis the number average molecular weight. For example, in various embodiments, the “P” group has a PDI (polydispersity index) of no more than 1.1, e.g., no more than 1.07. In various embodiments, the “P” group has a PDI of no more than 1.06, or no more than 1.05. The polydispersity index of the “P” group is understood to be the same as the polydispersity index of the PEG used to make the conjugate. Molecular weights can be determined by liquid chromatography / mass spectrometry, either of the conjugates or of the P-H compound used to make the conjugates.

[0121] Commercial USP or EP grades of mPEG may be used in various embodiments. mPEG oligomers can also be made by a total synthesis.

[0122] In various desirable embodiments, the P group is a long chain, linear or branched synthetic polymer composed of ethylene oxide units, CH3OCH2CH2(OCH2CH2)nO-, in which n is typically between about 4 and about 45 or otherwise can vary to provide a narrow or mono- distributed polymer with molecular weights from 200-2000 Daltons.

[0123] In various embodiments as described herein, m is 3; S has the structural formula as below: in which -(Cx1H2x1Ox1-1)-CO- is a sugar acyl residue derived from a sugar acid in which x1 is 4 or 5, and (Cx2H2x2-1Ox2-1)- is a sugar residue-derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof; -C(O)-R1is at least 80 mol% of cis-CH3(CH2)7- CH=CH(CH2)7C(O)-, e.g., at least 85 mol%; R2is methyl; n has a weight-average value in the range of 11.5-12.5, e.g., 11.8-12.2; and P has a polydispersity index of no more than 1.1, e.g., no more than 1.07. For example, in some embodiments, x1 is 5 and x2 is 6. In some embodiments, S has the structure or is an open-chain version thereof. In some embodiments, S is lactobionyl. In some embodiments, -C(O)-R1is at least 90 mol% of cis-CH3(CH2)7CH=CH(CH2)7C(O)-, e.g., at least 95 mol%. In some embodiments, P has a polydispersity index of no more than 1.06, e.g., no more than 1.05.

[0124] In various embodiments as described herein, m is 3; S has the structural formula in which -(Cx1H2x1Ox1-1)-CO- is a sugar acyl residue derived from a sugar acid in which x1 is 4 or 5, and (Cx2H2x2-1Ox2-1)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof; -C(O)-R1is at least 80 mol% of cis- CH3(CH2)7CH=CH(CH2)7C(O)-, e.g., at least 85 mol%; and the -P group is a methylated PEG residue having a number-average molecular weight in the range of 525-575 g / mol and having a polydispersity index of no more than 1.1, e.g., no more than 1.07. For example, in some embodiments, x1 is 5 and x2 is 6. In some embodiments, S has the following structure: or is an open-chain version thereof. In some embodiments, S is lactobionyl. In some embodiments, -C(O)-R1is at least 90 mol% of cis-CH3(CH2)7CH=CH(CH2)7C(O)-, e.g., at least 95 mol%. In some embodiments, P has a polydispersity index of no more than 1.06, e.g., no more than 1.05.

[0125] In various embodiments as otherwise described herein, the conjugate has the structural formula of Chemical Structure 1: wherein m(PEG)nis a methylated PEG residue.

[0126] In various such embodiments of Chemical Structure 1, the fatty acyl residue -C(O)-R1is derived from one or more of lauric acid, myristic acid, palmitic acid, linoleic acid, Oleic acid and stearic acid. The m(PEG)nis a methylated PEG residue and “n” is any desirable value as described above.

[0127] In various embodiments, the conjugate is Oleoyldiaminopropane-monomethoxy- polyethylene-glycol-ether-lactobionate (DOPS), which can be represented by the Chemical Structure 2:

[0128] The “oleyl” group is understood to represent a -C(O)R1group that is at least 80 mol% derived from oleic acid. In Chemical Structure 2, m(PEG)nis methylated PEG residue, and “n” is any desirable value as described above. In some embodiments, the number-average value of “n” is in the range of 9.2-13.8, e.g., 10.2-13.2, or 11.4-13.6 (mPEG 550 (n = 12) or C58H112N2O24).

[0129] In various embodiments, the conjugate is Stearylpropanediaminomonomethoxy- polyethylene-glycol-ether-lactobionate, which can be represented by Chemical Structure 3:

[0011]

[0130] The “stearyl” group is understood to represent an R1group that is at least 80 mol% derived from stearic acid. In Chemical Structure 3, m(PEG)n is methylated PEG, and n is any desirable value as described above. In some embodiments, the number-average value of n is in the range of 9.2-13.8, e.g., 10.2-13.2, or 11.4-13.6 (mPEG 550 (n = 12), C58H114N2O24).

[0131] In various embodiments, the conjugate is represented by Chemical Structure 4: wherein m(PEG)nis methylated PEG (e.g., average number of carbons of R2in the range of 0.95-1.05, or 0.98-1.02), “n” is any desirable value as described above, and m is in the range of 2-6, e.g., is 3.

[0132] In various embodiments, the conjugate is choloylpropanediamino-mPEG-lactobionate (CDPS), which can be represented by Chemical Structure 5:

[0133] The “choloyl” group is understood to represent an R1group that is at least 65 mol% derived from choloic acid. In Chemical Structure 4, m(PEG)nis methylated PEG (e.g., average number of carbons of R2in the range of 0.95-1.05, or 0.98-1.02), and “n” is any desirable value as described above. In some embodiments, the number-average value of “n” is in the range of 9.2-13.8, e.g., 10.8-13.2, or 11.4-12.6 (mPEG 550 (n = 12) or C64H118N2O27). In various embodiments of Chemical Structures 3, 4, or 5, the number-average value of n is in the range of 11-13, e.g., 11.5-12.5, or 11.8-12.2.

[0134] In various embodiments as described herein, the conjugate has one of the following structures:

[0012]

[0135] The present inventor has determined that improved performance can be provided when one or more of various analytical targets are achieved for the conjugates of the disclosure.

[0136] In various embodiments of the conjugates as otherwise described herein, -P is provided from a P-H poly(ethylene glycol) source (e.g., an mPEG) that has a number-average molecular weight in the range of 95.0-105.0% of the labeled nominal value if the labeled nominal value is below 1000 g / mol, or in the range of 90.0-110.0% of the labeled nominal value if the labeled nominal value is in the range of 1000 and 2000 g / mol.

[0137] In various embodiments of the conjugates as otherwise described herein, the conjugate has a purity of at least 85 wt% as measured by HPLC. Such materials can be especially desirable for use in oral applications.

[0138] In various embodiments of the conjugates as otherwise described herein, the conjugate has a purity of at least 90 wt% as measured by HPLC. Such materials can be especially desirable for use in parenteral applications.

[0139] In various embodiments of the conjugates as otherwise described herein, when the R1- C(O)- group is a fatty acyl group, it is at least 65 mol% of a single chemical identity, e.g., at least 80 mol%, or at least 85 mol%, or at least 90%, or at least 95 mol%. In various embodiments, the single chemical identity is oleoyl, myristyl, palmitoyl, stearyl or linoleyl.

[0140] In various embodiments as otherwise described herein, the conjugate includes less than 5 mol% of fatty acid-related analogues (i.e., those having other than the primary R1-C(O)- identity, e.g., oleoyl).

[0141] In various embodiments of the conjugates as otherwise described herein, R1-C(O) is a fatty acyl and the conjugate of DOPS-12 (oleoylpropanediaminomonomethoxy-polyethylene- glycol-ether-lactobionate) when assayed by HPLC, resembles the peak profile of Figure 1, 2 or 3 and the following relative retention time (RRT), with particular analogs defined as how they differ from DOPS-12 (e.g., in the fatty acyl group, or in the saccharide as for gluconic acid):

[0142] In various embodiments, the conjugates of the present disclosure can be provided at relatively high levels of purity. For example, in various embodiments, the purity of the PEG- saccharide-lipid conjugates of the disclosure is greater than 80% by HPLC. In various embodiments, purity of the PEG-saccharide-lipid conjugates of the disclosure is greater than 90% by HPLC. In various embodiments, the purity of the PEG-saccharide-lipid conjugates of the disclosure is greater than 95% by HPLC. FIG.1 depicts HPLC chromatograms of fatty acid based conjugates: Peak 1 = lauroyl-propanediaminomPEG(12)-lactobionate (DLOPS-12); Peak 2 = myristoylpropanediaminomPEG(12)-lactobionate (DMPS-12); Peak 3 = palmitoleoylpropanediaminomPEG(12)-lactobionate (DPOPS-12); Peak 4 = linoleoyl- propanediaminomPEG(12)-lactobionate (DLOPS-12); Peak 5 = palmitoylpropane- diaminomPEG(12)-lactobionate (DPPS-12); Peak 6 = oleoylpropanediaminomPEG(12)- lactobionate (DOPS-12); Peak 7 = oleoypropaneldiaminomPEG(12)-gluconate; Peak 8 = stearoylpropanediaminomPEG(12)-lactobionate (DSPS-12). The concentrations injected onto the column were approximately 4 to 6 mg / mL each. FIG.2 depicts a HPLC chromatogram of DOPS-12 made with the USP grade of mPEG (550) and the purity is > 95%. The concentration injected was approximately 5 mg / mL. DEPS-12 = elaidoylpropanediamino-mPEG(12)- lactobionate. FIG.3 depicts a HPLC chromatogram of linoleoylpropane-diaminomPEG- lactobionate (DLPS-12 and its isomer iso-DLPS-12) made with the USP grade of mPEG (550) and the purity is > 95%, the concentration injected was approximately 5 mg / mL. In various embodiments, the HPLC peak profile of a conjugate of the disclosure resembles the peak profiles in the HPLC chromatograms of Figures 1, 2 and 3.

[0143] Notably, a superior solubility enhancement for poorly-soluble drugs can be provided by materials of the disclosure without co-solvents or co-emulsifiers. For example, in the case of a cyclosporine (0.09%) ophthalmic formulation, the particle size of cyclosporine in the marketed product (CEQUA®) is in the range of 12 to 20 nm, based on a SEDDS-like suspension using a mixture of polyoxyl 40 hydrogenated castor oil and polyalkoxylated alcohol. In the comparison, a true solution of 0.1% cyclosporine was obtained with approximately 1% of DOPS-12; the solution was stable for more than 4 years under room temperature. Without intending to be bound by theory, the present inventor believes that a higher purity and lower polydispersity of the said material contribute to the especially good performance.

[0144] In some embodiments as described herein, the conjugate has a hydrophilic-lipophilic balance (i.e. HLB) value in the range of 13-18, e.g., in the range of 13-15.

[0145] Another aspect of the disclosure provides a polyethylene glycol-saccharide-lipid conjugate useful, for example, as a solubility or bioavailability enhancer for safely delivering hydrophobic or lipophilic compound or compounds, represented by the formula: wherein: Lipid is selected from a group consisting of fatty acids including lauric acid, myristic acid, linoleic acid, palmitic acid, oleic acid, elaidic acid and steroid acids; m(PEG)n is a polymeric polyethylene glycols (i.e., which makes the conjugate polymeric in nature); n ranges from 8 to 45 of ethylene glycol subunits; and m* = 1 to 6 of CH2.

[0146] In some embodiments as described herein, the polymer has described herein has one or more of the following properties or specifications: a. the mPEG ranges between 95.0% and 105.0% of the labeled nominal value if the labeled nominal value is below 1000 or between 90.0% and 110.0% of the labeled nominal value if the labeled nominal value is between 1000 and 2000. b. Purity of the said polymeric conjugate is between 85% and 115.0 by HPLC assay if used for oral applications; c. Purity of the said polymeric conjugate is between 90% and 110.0% by HPLC assay if used for parenteral application; d. Purity of oleic acid if utilized is not less than 65% e. Individual related analogue or impurity is less than 5%; and f. Fatty acid based said polymers, resemble of the peak profile of Figures 1, 2 or 3 and the following relative retention time (RRT):

[0147] In various embodiments as described herein, the synthesis method for preparing the polymeric conjugate as described herein comprises the steps of: (1) coupling activated monomethoxypolyethylene glycol ether to the unprotected amino group of the center backbone; (2) conjugating a lipid or disaccharide to the backbone, thereby forming a PEG-saccharide- lipid conjugate having a high purity of conjugates in the range of 85% to 115% by HPLC assay.

[0148] In other embodiments as described herein, the synthesis method for preparing the polymeric conjugate as described herein comprises the steps of: (1) synthesizing a short-chain of ethylene glycol protected hydroxyl groups on the ethylene glycol and amino group of the center backbone; (2) extending the PEG chain by repeating the short ethylene glycol chain reaction. (3) conjugating a lipid or disaccharide to the backbone, thereby forming a PEG- saccharide-lipid conjugate having a high purity of PEG oligomer. wherein the sequence or order of coupling steps or sites is interchangeable.

[0149] In some embodiments of the polymeric conjugate as described herein, m* in the backbone is 0 or 1 thereby forming a PEG-saccharide-lipid conjugate with no or less hemolytic potential suitable for clinical parenteral administrations as well as oral applications having the following structure(s): wherein: when m* is 1, the backbone is propane; or when m* is zero, the backbone is ethylene; FA is a fatty acid which is selected from a group including but not limited to lauric acid, myristic acid, linoleic acid, palmitic acid, linoleic acid, oleic acid or stearic acids; and n is ranging from 8 to 45.

[0150] In some embodiments of the polymeric conjugate as described herein, the distance between the 2 terminal amines is less than 4 carbons if use for parenteral administrations.

[0151] In some embodiments of the polymeric conjugate as described herein, the m in the backbone is greater than 1 thereby forming a PEG-saccharide-lipid that is more suitable for oral administration of other applications.

[0152] In some embodiments of the polymeric conjugate as described herein, said PEG- saccharide-lipid conjugates are solid (low-water) or semisolid (higher moisturized) and stable for at least 36 months under room temperature storage conditions.

[0153] In some embodiments of the polymeric conjugate as described herein, the monomethoxypolyethylene glycol ether has an average molecular weight between 95.0% and 105.0% of the labeled nominal value if the labeled nominal value is below 1000 or between 90.0% and 110.0% of the labeled nominal value if the labeled nominal value is between 1000 and 2000.

[0154] In some embodiments of the polymeric conjugate as described herein, a monosaccharide-related impurity in said polymer is less than 5%. In some embodiments of the polymeric conjugate, the total fatty acid related impurities in said polymeric conjugate are less than 10% and individual fatty acid related impurity is less than 5%. For example, in various embodiments of the polymer as described herein, the purity of said polymeric conjugate is not least than (≥) 90% to be used for parenteral compositions. The polymeric conjugate as otherwise described herein can be purified by any means known in the art. For example, in some embodiments as described herein, the polymeric conjugate is purified or dried by lyophilization. In some embodiments of the polymeric conjugate as described herein, the polymeric conjugate is purified or dried by lyophilization if the polymer will be used for parenteral administration. In some embodiments of the polymeric conjugate as described herein, the purity of said polymeric conjugate is not less than (≥) 85% to be used for pharmaceutical oral compositions.

[0155] In some embodiments of the polymeric conjugate as described herein, the weight ratio of the PEG-saccharide conjugate to an oncology compound is between about 200 and about 1 for the drug delivery. In some embodiments of the polymeric conjugate as described herein, the weight ratio of the PEG-saccharide-lipid conjugate to a non-oncology compound is between about 200 and about 1 for the compound delivery.

[0156] In various embodiments of the polymer as described herein, the PEG-saccharide-lipid conjugate is selected from the following structures:

[0013] wherein n ranges from 8 to 45, or is as otherwise described herein.

[0157] Another aspect of the disclosure is a method for making a conjugate as described herein. Such a method includes coupling a poly(ethylene)glycol, a saccharide and an R1-C(O)- acyl group to a diamine backbone. For example, in various embodiments, the method includes providing a monoprotected diamine having a protected first amine group and an unprotected second amine group; coupling a poly(ethylene glycol) and an R1-C(O)- acyl group to the second amine group, and then deprotecting the protected first amine group and coupling a saccharide to the newly-unprotected first amine group. Notably, in various embodiments, the various process steps can be performed in the substantial absence of free-radical initiators.

[0158] In some embodiments, the coupling of the poly(ethylene glycol) can be performed before the coupling of the R1-C(O)- acyl group. When the poly(ethylene glycol) of the conjugate is to be hydroxy-terminated (i.e., R2in individual molecules being H), it can be desirable to have the hydroxy in a protected form (e.g., as a benzyl ether) at the time of the coupling of the R1-C(O)- acyl group.

[0159] In various embodiments, the coupling of the poly(ethylene glycol) to the second amine group can be performed in a stepwise fashion, e.g., by first coupling a shorter chain of PEG (or even a single ethylene glycol unit) to the central backbone, then by performing etherification to achieve a longer PEG chain. An example of this is shown in Reaction Scheme 1, below. Reaction Scheme 1 Synthesis of propanediaminomonomethoxydodecaethylene glycol

[0160] Here, a so-called “Boc” protecting group is used to protect the first amine of the diamine. The person of ordinary skill in the art will appreciate that Boc is a useful group for protecting the first amine in other methods of the disclosure. The person of ordinary skill in the art will appreciate that other protecting groups can also be used to protect the first amine.

[0161] Similarly benzyl (Bn) groups may be used for protecting the hydroxyl group. Removal of benzyl groups to free the hydroxyl group of the PEG-reagent can be achieved by any suitable reagents. For example, the benzyl group can be removed by hydrogenation in presence of palladium catalyst and the PEG chain can be extended by repeating the same etherification process. While a benzyl group is used in the example of Reaction Scheme 1, the person of ordinary skill in the art will identify other suitable alcohol protecting groups.

[0162] And while the extension of the poly(ethylene glycol) is shown in Scheme 1 as being performed before the coupling with the R1-C(O)- acyl group, in other embodiments the acylation can be performed with hydroxyl protecting group still in place, and the alcohol deprotection and extension can be performed after acylation.

[0163] Following the reaction in Reaction Scheme 1, prior to removing the protecting group on the terminal amine of the backbone, the second amine group can be acylated with a R1-C(O)- acyl group. One example of this is shown in Reaction Scheme 2. This can be done, for example, by reaction of an appropriate acid chloride. For example, in various embodiments as described herein, the coupling of the R1-C(O)- acyl group to the second amine group is performed using an R1-C(O)-halide. The person of ordinary skill in the art can determine suitable reaction conditions, e.g., in N-methyl-2-pyrrolidinone (NMP) at 20 to 30 °C. The acid chloride can be prepared separately by dissolving the corresponding acid in tetrahydrofuran (THF), adding excess triethylamine (TEA) as base and then adding isobutyl chloroformate (IBCF). Treatment with oxalyl chloride is another way to make acid chlorides suitable for the acylation. Reaction Scheme 2 Synthesis of N3- fatty acid propanediamino-mPEG-12 Reaction Scheme 3 Preparing of Myristoyl Chloride

[0164] With the PEG and the acyl group coupled to the second amine, the first amine can be deprotected using a suitable deprotection. Accordingly, in various embodiments, the coupling of the saccharide to the first amine group comprises deprotecting the first amine group and coupling the saccharide in the form of a sugar acid or a lactone version thereof. An example of the deprotection of Boc-protected amino groups can be found in Example 2 below. The saccharide can then be coupled to the central backbone via the first amine. An example of this is represented in the Reaction Scheme 4. In this method, any suitable saccharide, such as lactobionolactone can reacted with N3- fatty acid propanediamino-mPEG-12 in dichloromethane to produce the final product of N3- fatty acid propanediamino-mPEG-12-N1- lactobionate. Reaction Scheme 4 Synthesis of N3-fatty acid propanediamino-mPEG-12-N1-lactobionate

[0165] In various embodiments of the present disclosure, the synthetic methods described herein, e.g., those represented in various above reaction schemes, can be modified in any suitable manner. For example, the “backbone” 1,3-diaminopropane (propane-1,3-diamine) can be substituted by variety of agents, including but not limited to ethylenediamine, putrescine (butane-1,4-diamine), cadaverine (pentane-1,5-diamine), hexamethylenediamine (hexane-1,6- diamine) and the like.

[0166] In various embodiments, fatty acid residues range from carbon chain lengths of about C8 to about C22, for example about C10 and about C18, In various embodiments, the fatty acid residue is selected from the group consisting of capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, myristoleic acid palmitoleic acid, sapienic acid oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoelaidic acid and α-linolenic acid.

[0167] In various embodiments, when oleic acid is the lipid group, the purity of oleic acid should be in the range from 65% to 88% as defined in the current European Pharmacopoeia (EP). Further refining may be necessary when a purer oleic acid is desired.

[0168] The solvent for the PEG-saccharide-lipid conjugation reaction in the disclosed methods can be selected by the person of ordinary skill in the art. Polar solvents, e.g., polar aprotic solvents can be suitable in many embodiments. In some embodiments, the solvent is one or more of N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), pyridine, tetrahydrofuran (THF), dichloromethane (DCM), chloroform, 1,2-dichloroethane, ethyl acetate, isopropanol, methanol and the like.

[0169] The disclosed methods can be used to prepare a variety of novel PEG-saccharide-lipid conjugates. For example, the methods can be used to prepare N3-lipid propanediamino-mPEG- 12-N1-lactobionate in highly pure PEG form containing any lipophilic carrier groups.

[0170] While a monodisperse PEG is greatly useful for polymer characterization and profiling, the USP (US Pharmacopoeia) grade of polyethyleneglycols with a PDI no more than 1.1 is often used for the scale-up and commercial productions for the economic reasons since the process for the preparation of a pure oligomer PEG is both time and labor consuming. The USP grade materials are generally of sufficiently low polydispersity that they exhibit many of the same advantageous properties as materials made from monodisperse PEG products. Weight-average and number-average molecular weights of polyethylene glycols can be determined using mass spectrometry, and can be used in determining polydispersity.

[0171] The hemolytic activity of polyoxyethylene polymers may be ascribed to their tendency to form peroxides due to the synthetic processes of radical reactions. It should, however, be emphasized that hemolysis is only one form of cytotoxicity of polyoxyethylene polymers.

[0172] Notably, the synthetic methods described herein can provide the polymeric conjugates of the disclosure with a minimized degree of peroxide formation. Formation of peroxides can be largely minimized if a total synthesis is used for the polymer productions or the conjugation between the PEG and lipid is stepwise covalent bonding instead of “one-pot” randomized polymerization using free-radical-mediated processes.

[0173] The present disclosure provides synthetic methods for preparing PEG-saccharide-lipid conjugates that can provide several advantages such as simplified synthesis, high product yield and low cost of starting materials. In addition, the presently-described synthetic methods can be adapted to prepare a wide range of PEG-saccharide-lipid conjugates.

[0174] Often free radical polymerization, the molecular weight distributions are difficult to be narrowly controlled, typically within 50% of the targeted PEG molecular weight. Narrow- distribution may be achieved with size exclusion chromatograph, typically with 10% of the targeted PEG molecular weight. However it is extremely difficult to achieve a mono- distribution of purified PEGs for smaller PEG chains, i.e., the PEG molecular weights are 2000 or less.

[0175] Unlike free radical polymerization used for the production of polysorbates or Cremophors, in the present disclosure, the composition or structures of PEG-saccharide-lipid conjugates can be well defined and may include all the various functional linker groups described herein. Whenever is suitable, the USP grade polyethylene glycols or their monomethyl ethers with a narrower range of molecular weight distributions, i.e., a few oligomer or ranging ±10% of the mean PEG number-average molecular weight can be used. The synthetic methods described herein can be used to ensure a well-defined conjugate structure. The impurities in a well-defined mPEG product can be minimized, especially for the level of peroxides. Desirably, the level of hydroperoxide in a conjugate of the disclosure as measured by the FOX2 assay (see Wasylaschuk WR, et al (2007). “Evaluation of hydroperoxides in common pharmaceutical excipients. J Pharm Sci.96(1):106-16, which is hereby incorporated herein by reference in its entirety) is no more than 100 nmol / g, e.g., no more than 50 nmol / g, or no more than 30 nmol / g.

[0176] For the purpose of clarity, the molecular weight (MW) range of oligomers in commercially available polyethylene glycols is largely dependent on the quality or sources, for instance, the number-average molecular weight of the USP grade of Polyethylene Glycol Monomethyl Ether is between 95.0% and 105.0% of the labeled nominal value if the labeled nominal value is below 1000 g / mol (e.g., 750 ±); and it is between 90.0% and 110.0% of the labeled nominal value if the labeled nominal value is below 2000 g / mol. In the Examples of the present disclosure, only the USP grade of monomethyl polyethylene glycols was used for the synthesis of PEG-saccharide-lipid conjugates, in which the mPEG distribution range was within the USP specifications or the targeted number-average molecular weight (Mw) ± 5% (Mw ≤ 1000) to ±10% (up to 2000). Overall, a PDI of mPEG is desirably be less than 1.1.

[0177] The significance of purity in the PEG-saccharide-lipid conjugates disclosed in the present invention transcends mere quality control which is a fundamental assurance of patients’ safety. Reactive impurities in marketed pharmaceutical polymeric excipients could cause drug product instability, leading to decreased product performance, loss in potency, and / or formation of potentially toxic degradants, e.g., commercially available Polysorbates are chemically diverse mixtures, the expected structure for polyoxyethylene (20) sorbitan monolaurate and polyoxyethylene (80) sorbitan monooleate, only accounts for about 20% of the total polysorbate from some commercial sources. The composition of polysorbate may also vary between vendors with lot-to-lot variability likely resulting from different (radical) synthesis routes and raw materials used. Polysorbates 80 (PS80) and Cremophor (Cr-EL) are the leading PEG-lipid polymers approved for clinical use. The “maximum daily exposure” in intravenous products is 27,668 mg for Cr-EL and 4,739 mg for PS80 from the FDA database of “Ingredient Search for Approved Drug Products,” which corresponds to approximately 395 mg / kg of Cr- EL or 68 mg / kg of PS80 for a standard human of 70 kg. Often ethanol is used as a co-solvent with PS80 or Cr-EL (Descriptions of the compositions for “Paclitaxel” and “Taxotere” can be found at rxlist.com).

[0178] However, a single dose of 3% Cr-EL (in 5 % glucose, 6.3 mL / kg) or 3% PS80 (in 5% glucose, 6.3 mL / kg) with a 30 min infusion in minipigs was reported to cause transient erythema of skin or itching and anxiety. Other published studies also demonstrated the pseudoallergic sensitivity of the two excipients. These pseudoallergic reactions could be largely attributed from high levels of contaminants in the mixtures of Cr-El and PS80 which are impossible to be completely eliminated, and which are believed to result from radical synthesis.

[0179] Unlike Cr-EL or PS80 which are a complex mixtures of amphiphilic lipid molecules; the lot-to-lot variation of the PEG-saccharide-lipid conjugates disclosed here can be readily controlled. For instance, in various embodiments of the PEG-saccharide-lipid conjugates of the disclosure, the fatty acid-related impurities can be limited to 5 wt% or less. In contrast, the limits of the fatty acid-related impurities are up to 40% for PS80 and up to 25% for Cr-EL as defined in the polymer monographs of European Pharmacopoeia or US Pharmacopoeia.

[0180] Described below are toxicological and pharmacological safety evaluations of selected PEG-saccharide-lipid conjugates of the disclosure. For example, there was no pseudoallergic reaction observed from doses up to 200 mg / kg intravenously in minipig studies and up to 2000 mg / kg orally in dog studies.

[0181] The chemical stability of polysorbates versus the PEG-saccharide-lipid conjugates described herein is a major area of differentiation between the two polymeric materials. The ester bond in a pure oleic acid (i.e., 98%)-made polysorbate 80 (PS 80) is still more sensitive or degradable when compared to the amide bond in various PEG-saccharide-lipid conjugates of the disclosure, which can make PS80 more sensitive to degradation. For example, a study showed that the concentration of PS80 rapidly declined to levels <0.05% (v / v) of the plasma volume within 15 min after a bolus injection in mice and the recovery was only 66% of the initial concentration of PS 80. In direct comparison, the recovery of (intact) DOPS-12 was ~ 98% in mouse plasma, While the cause of pseudoallergy is unclear, it could be largely attributed to either high levels of contaminants in the mixtures of PS80 which are impossible to completely eliminate or polysorbate 80 undergoing intrinsic self-oxidation yielding reactive hydro- and alkyl-peroxides.

[0182] A variety of other PEG-saccharide-lipid conjugates are provided by the present disclosure. For example, in various embodiments, e.g., in compositions with one or more steviol glycosides, the PEG-saccharide-lipid conjugate is represented by the chemical structure: wherein: L is a lipophilic residue selected from fatty acid residues and steroid acid residues (e.g., bile acid residues, cholesterol residues); S is a saccharide selected from monosaccharides, disaccharides and trisaccharides; P is a polyethylene glycol residue having from 4 to 45 subunits; and B is a backbone molecule having three or four available binding positions.

[0183] For example, in some embodiments, L is a fatty acid residue, e.g., having 5-22 carbons. Examples include residues of stearic acid, oleic acid, palmitic acid, myristic acid, and lauric acid.

[0184] In some embodiments, the polyethylene glycol has from 5 to 45 subunits. In some embodiments, the polyethylene glycol has 5-25 subunits. In some embodiments, the polyethylene glycol residue is a is a monomethoxypolyethylene glycol residue, e.g., having 6- 45 subunits.

[0185] The backbone B is a molecule having three or four available binding positions. In some embodiments, the backbone B is one or more of (e.g., one of) glycerol, glycerol-like analogues having three binding positions, diamines, triamines, diaminoalcohols, aminoalcohols, aminodiols, aminotriols, amino acids, triols, tetraols, triacids, tetracids, halogen-containing diols, halogen-containing amines, carboxyl containing diols and polyamines. In other embodiments, B is one or more of diamines, triamines, glycerol and aminoacids.

[0186] Examples of PEG-saccharide-lipid conjugates include, for example, fatty acid diethylenetriaminemonomethoxypolyethyleneglycolether-lactobionate, fattyaciddipropylenetri- amine-monnomethoxypolyethyleneglycolether-lactobionate, fattyacidpropanediaminomono- methoxy-polyethyleneglycolether-lactobionate, fattyacidethylenediaminemonnomethoxypoly- ethylenegly-colether-lactobionate, cholesteroldiethylenetriamine-monnomethoxypolyethylene- glycol-ether-lactobionate, cholesteroldipropylenetriamine-monnomethoxypolyethyleneglycol- ether-lactobionate, cholesterolpropanediamine-monnomethoxypolyethyleneglycolether- lactobionate, cholesterolethylenediaminemonnomethoxypolyethyleneglycolether-lactobionate.

[0187] In various embodiments, the PEG-saccharide-lipid conjugate has one of the following structures:

[0014] wherein n = 8 to 45.

[0188] Other PEG-saccharide-lipid conjugates suitable for use in the compositions of the disclosure are described in United States Patent No.9,175,027 and United States Patent No. 10,835,608, each of which is hereby incorporated herein by reference in its entirety. EXAMPLES

[0189] The following non-limiting examples further illustrate various aspects and embodiments of the present disclosure.

[0190] Chemicals and Reagents: lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, lactobionic acid, bile acids, glucuronic acid, methoxypolyethylene glycols or polyethylene glycol (PEG) and other chemicals or reagents were obtained from Sigma-Aldrich (St. Louis, MO, USA) or Alfa Aesar (Ward Hill, MA, USA) or Thermo Fisher Scientific (Rockford, IL) and other commercial sources. All PEG-saccharide-lipid conjugates used in the studies were made in-house by LipoSeuticals Inc. (Monmouth Junction, NJ, USA).

[0191] Example 1. Preparation of tert-Butyl Carbamates (Boc)-Protected Amino Groups

[0192] A high yield and effective catalyst-free and room temperature synthetic method was reported previously (Weiszhár Z., et al (2012). Eur J Pharm Sci.45(4):492-8) and used with slight modification. To a solution of starting compound in MeOH, di-t-butyl dicarbonate was added in a one to one molar ratio. The resulting mixture was stirred overnight at room temperature. When the reaction was complete, solvent was removed under vacuum; the residue was dissolved into EtOAc and washed with saturated NH4Cl aqueous solution once, then dried over Na2SO4 and condensed to yield the expected product (> 90%). Example of this reaction is demonstrated in Reaction Scheme 5, where R is a main structure of the central backbone. This method gives N-t-Boc derivatives chemoselectively without substantial amounts of side products (such as isocyanate, urea). Reaction Scheme 5

[0193] Example 2. Deprotection of Boc-Protected Amino Groups

[0194] Effective reagents for the deprotection of tert-butyl carbamates or tert-butyl esters include phosphoric acid and trifluoroacetic acid. The reactions give high yields and are very convenient. Equal volumes of trifluoroacetic acid were added to a solution of Boc-carbamate (10% of crude product) in CH2Cl2. The resulting solution was stirred at room temperature for overnight and the solvent was evaporated and the residue was re-dissolved into CH2Cl2, then washed with saturated NaHCO3and dried over MgSO4. Solvent was evaporated and was used in next step without further purification.

[0195] Example 3. Preparation of Boc-1-animohexamethyleneamine

[0196] Hexamethylenediamine (20 mol) is transferred to a 30-liter round-bottomed flask equipped with a mechanic stirrer. A solvent mixture of 15 L containing methylene chloride / methanol (4 / 1, v / v, totally 10 L) is charged into the flask and the reaction flask is placed in an ice-water bath to maintain solution temperature 0-10 ºC. Boc2O (5 mol) in methylene chloride (1.0L) was slowly added. After the addition is completed, the reaction mixture is allowed to continue 2 more hours under vigorous stirring. The consumption of Boc2O is monitored by TLC method. The unreacted hexamethylenediamine is removed by washing with sodium bicarbonate solution (10% NaHCO3in water). The organic layer is collected and dried over sodium sulfate for 1-2 hours. Sodium sulfate is removed by filtration and the solvent is removed under reduced pressure by rotary evaporator. The crude product obtained is refrigerated (4-8 ºC) (85-105% yield). The resulting compound (Chemical Structure 6) is stable for at least 1 week in the refrigerator. Chemical Structure 6

[0197] Example 4. Preparation of cholic chloride

[0198] Cholic acid (150 g) was transferred into a 5-liter round-bottomed flask and dissolved in methylene chloride (500 mL). The reaction flask was placed in an ice-water bath to maintain a temperature between 0-10 °C. Oxalyl chloride (55g) was added slowly into the reaction flask via a funnel. The reaction was continued for 2 hours under constant stirring. The solvent was removed in vacuo and unreacted oxalyl chloride was further removed by co-evaporation with hexanes (500 mL) in vacuo to yield a yellowish solid (Chemical structure 7, 150-165g, 85- 100% yield), the resulting product is used for the next step without further purifications. Chemical structure 7

[0199] Example 5 Preparation of Boc-protected 1,3-propanediamines

[0200] Following the same steps in Example 3 and the crude product obtained with a yield of 85-105% (Chemical structure 8) Chemical structure 8

[0201] Example 6. Preparation of mesylated polyethylene glycol monomethoxyl ether

[0202] Polyethylene glycol monomethoxyl ether (mPEG)-550 (100 g) was transferred into a 5- liter round-bottomed flask equipped with a mechanic stirrer and placed in ice -bath. 500 mL THF and triethylamine (24 g) were added. The reaction mixture was cooled to 0-10 °C and mesyl chloride (24 g) was added through a funnel and the mixture was kept at 0-10 °C. The reaction was continued under constant stirring and kept at 0-10 ⁰C for 1 hour. The mixture was washed with 300 mL of 0.5N HCl twice. The organic layers were collected and dried over sodium sulfate (10 g) for 1 hour. The salt was removed by filtration and the solvent was removed in vacuo to yield a yellowish liquid (Chemical Structure 9: 100-110 g, 90-110% yield). Chemical Structure 9

[0203] Example 7. Preparation of Boc-aminopropylamine–mPEG

[0204] Formation of the C-N bond was by the N‐alkylation of amine of the center backbone with the activated hydroxyl of the PEG. In a 1-liter round-bottomed flask equipped with a mechanic stirrer and a heating mantle, Boc-aminopropyleneamine from Example 5 (135 g) was mixed with the mesylated mPEG from Example 6 (114 g) in 200 ml of a mixture of THF and water (1 / 1, v / v). The reaction was continually stirred for 2-4 hours under reflux and nitrogen purging protection. The solvent was removed in vacuo and 500mL of CH2Cl2was added to the residue. The solution was washed with 50 mL each of water and 2N NaOH. The Organic layer was collected and dried over Na2SO4, solvent removed to afford Boc-aminopropaneamine- mPEG (Chemical Structure 10), the crude product was transferred to the next step without further purification. Chemical Structure 10

[0205] Example 8. Preparation of Preparation of Boc-aminopropaneamine-mPEG-Oleate

[0206] The crude product (90 g) from Example 7 was dissolved in methylene chloride (800 mL) in a round bottom flask (2 L) equipped with a mechanical stirrer. In a separate container, oleoyl chloride (100g) was dissolved in methylene chloride (200 mL) and slowly added to the Boc-aminopropaneamino-mPEG via a funnel. After the addition was completed, the reaction was continued for 2 hours under constant stirring at ambient room temperature. The completion of reaction was determined by the complete disappearance of oleoyl chloride on TLC. The reaction mixture was washed with 300 mL of 0.5 N NaOH, 3 times and the methylene chloride layer was collected and dried over sodium sulfate (100 g) for approximately 2 hours. The salt was removed by filtration and the solution was removed under vacuum (Chemical Structure 11 70-75% yields). Chemical Structure 11

[0207] Example 10. Preparation of Preparation of 1,3-propanediamine-lactobionate-mPEG Oleate (DOPS-12)

[0208] The steps of Example 2 were followed to remove the protection group from the Boc- aminopropaneamine-mPEG-oleate product of Example 8 to free the N1-amino group. The resulting product (200g) was dissolved in 400 mL of CH2Cl2(DCM) and transferred to a 1L round-bottomed flask equipped with a mechanical stirrer. Triethylamine (24 g) was added to the flask and the mixture was cooled down to 0 and 10 °C in ice-water bath under constant stirring. Predried lactobionic acid (81 g) was added. The reaction was completed in 2 hours under constant stirring at ambient room temperature. The ending reaction was monitored by checking the peak profile using HPLC. The final product was washed with diluted HCl (0.1N) or NaOH (0.1N) to yield a neutral pH (7), then extracted with methylene chloride (DCM), repeated the steps of water wash and DCM extraction steps until the desired purity was achieved in the HPLC chromatogram. The DCM layer was collected and dried over sodium sulfate (100 g) for approximately 2 hours. The salt was removed by filtration and the solution was removed under vacuum. The product was further lyophilized to a yellowish wax (Chemical Structure 2: 70-80% yields).

[0209] Using the intermediate from the Example 5 and following the steps in Examples 7, 8 and 9, Choloypropanediamino-mPEG-lactobionate conjugate (Chemical Structure 5) was prepared:

[0210] Examples 3 to 10 are suitable for making a PEG-saccharide-lipid conjugate with all kinds of available lipids including but not limited to fatty acids such lauric acid, myristic acid, palmitic acid, stearic acid, myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, bile acid or its analogues including but limited to cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, chenodeoxycholic acid, and lithocholic acid. As described above, in various desirable embodiments the mPEG group has in the range of 8 to 45 subunits.

[0211] One feature or aspect of an embodiment is demonstrated at the time of the filing of this patent application to possibly reside broadly in a method of making a polymer including but not limited to the following said PEG-saccharide-lipid conjugate comprising the following structures:

[0015] where n is as descried in any embodiment above .

[0212] Example 11 Chromatography Profile of PEG-saccharide-lipid Conjugates

[0213] Individual fatty acid based FA-propanediamino-mPEG(12)-lactobionate conjugates were made according the synthesis described in the present disclosure. The analytical procedure for assay and related compounds of PEG-saccharide-lipid conjugates was a reversed- phase, isocratic HPLC method. The chromatographic conditions are presented in Table 3: Table 3

[0214] The purity and related analogues among these fatty acids may be monitored by the same method. concentrations of approximately 5 mg / mL each of the said polymers were prepared in pure methanol and injected 10 µL each onto the column. Figure 1 shows the resulting chromatogram. A chromatograph of a large-scale batch of DOPS-12 (DOPS-F02) prepared according to Example 10 is provided in Figure 2 and similarly linoleoylpropanediamino-mPEG-lactobionate conjugate and its isoform prepared as the same manner as for DOPS-12 is provided in Figure 3.

[0215] The relative retention times (RRT) of individual peaks to DOPS-12 (as the RT reference) of each of the fatty acid based PEG-saccharide-lipid conjugates is calculated with the following equation: in which the RRT of DOPS-12 = 1.00; the retention time of individual fatty acid is in minutes, the comparison should be in the same chromatogram or same sequence run. Representative RRT is listed in Table 4, with particular analogs defined as how they differ from DOPS-12 (e.g., in the fatty acyl group, or in the saccharide as for gluconic acid): Table 4

[0216] In some embodiments, the HPLC profile of the PEG-saccharide-lipid conjugates made by the present disclosure can exhibit the relative retention time to match the same in Table 4 using the assay procedure described in Example 11.

[0217]

[0218] Example 12 Long-term Storage Stability

[0219] Product stability is another key for clinical applications. Bulk samples from a pilot batch of DOPS-12 were evaluated in a formal stability study. 500-600 grams samples of DOPS-12 were packaged in a package configuration that is representative of a commercial package at a ratio (weight to volume) of 0.6 to 1.1 (kg / L). The materials of construction for the polyethylene containers are representative of commercial packaging. Three sets of DOPS-12 were packaged in this manner and tested by the HPLC procedure described in Example 11. No significant change was observed in related analogs or impurities and physical description after 6 months at 40ºC / 75% RH (relative humidity) and 36 months at 25ºC / 60% RH (Figure 4).

[0220]

[0221] Example 13 DOPS-12 Oral Toxicity in Juvenile Beagle Dogs

[0222] The study was under a GLP study protocol approved by the institutional Animal Care and Use Committees (IACUCs). The animals were aged at 11 to 13 weeks and randomly assigned to 4 groups, with 3 to 5 dogs / sex each dose groups. The dose levels were selected after initially dosing at 2000 mg / kg and 1000 mg / kg. While both dose strengths were well tolerated, 1000 mg / kg was chosen for the continued study due to the sample availability. They were orally administered with control article (sterile water for injection) or DOPS-12 (or DOPS-F-2) dose formulations (DOPS-12 in sterile water) at 600, 800 and 1000 mg / kg once daily for 90 consecutive days, using a dose volume of 5, 3, 4 and 5 mL / kg, respectively.

[0223] Body weights in the dosed female and male dogs exhibited no abnormalities in body weight or food consumption during the dosing phase and the recovery phase (Figures 6A and 6B). All of the dogs were grown at a normal pace during the study period and no remarkable adverse reaction was found in the juvenile dogs in the study.

[0224] Example 14 DOPS-12 Oral TK in Juvenile Beagle Dogs

[0225] Following the general procedure of Example 14, blood samples of animals in DOPS-12 groups were collected at predose and 0.5 h, 2 h, 4 h, 12 h, 24 h and 36 h (selectively on the last dose on the Day 90) post-dose. The actual body exposure to DOPS-12 between female and male groups was similar based on the mean AUC values (Figures 7A and 7B), the dose exposure was 10,50010,600 and 18,400 h∙ng / mL in females and 12,100, 12,900 and 12,700 h∙ng / mL in males corresponding to 600, 800 and 1,000 mg / kg on Day 1; the dose exposure was 19,600, 19,700 and 23,900 h∙ng / mL in females and 17,700, 22,000 and 23,200 h∙ng / mL in males corresponding to 600, 800 and 1,000 mg / kg on Day 90, respectively. Therefore, the difference in DOPS-12 exposure was considered to be insignificant between the female and male groups. A dose accumulation was observed and the mean AUC value was increased with a narrow AUC range. The dose exposure was slightly increased from 600 mg / kg to 800 or 1000 mg / kg on Day 90; this may be largely attributable to the dose accumulative effects.

[0226] DOPS-12 exhibited no remarkable adverse signs during the 90-day repeated dosing study. In contrast, mild and transient clinical signs of hypersensitivity reaction including erythema, edema, and scratching were observed from approximately 20 to 60 min post-dose in 1 / 3 animals at 10 mg / kg oral doses of Polysorbate 80.

[0227] Using nonrodent animal models for the safety evaluations on new molecules is always preferable since the concordance rates between animal and human toxicity have been shown to be about 71% when all species are considered, with nonrodents alone predictive for 63% and rodents for 43% of the events. Notably, the data for the animal models presented here is much more probative than rodent data, and as such cannot be directly compared with rodent data in prior studies.

[0228] Example 15 DOPS-12 Oral Bioavailability in Juvenile Beagle Dogs

[0229] The study was under a study protocol approved by the institutional Animal Care and Use Committees (IACUCs). The animals were administered with DOPS-12-saline solution intravenously by a short infusion at a dosing level of 3 mg / kg or a dosing volume of 0.2 mL / kg. Blood samples were collected at predose, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h and 24 h postdose. A LC-MS / MS method was used to determine the concentration of DOPS-12 in the dog plasma. Related PK parameters were calculated with a non-compartment analysis model using Phoenix WinNonlin 8.2 (Certara, Princeton, New Jersey). Following a single intravenous dose of DOPS-12 at 3 mg / kg level (Figure 8), AUC0-24of plasma DOPS-12 was 90600 and AUC0-∞was 91200 for the female dog; AUC0-24was 133000 h∙ng / mL and AUC0-∞was 135000 h∙ng / mL for the male dog, respectively. Cmaxwas 27200 ng / mL, CL was 32.9 mL / h / kg for the female dog; Cmaxwas 43300 ng / mL, CL was 22.3 mL / h / kg for the male dog, respectively. The half-life (t1 / 2) was very similar; 3.72 h for the female and 3.97 h for the male respectively. The absolute oral availability (Fabs) can be estimated using the following equation: Based on the dose exposures (Example 15), the bioavailability of DOPS-12 is 0.03% on Day 1 and 0.05% on Day 90 for male dogs; the bioavailability of DOPS-12 is 0.06% on Day 1 and 0.05% on Day 90 for female dogs, respectively. A low bioavailability of the polymer as a solubility enhancer is especially beneficial for clinical applications.

[0230] Example 16 Experiments on Solubility Enhancement

[0231] To establish the solubility enhancement, a determination of the amounts of a polymer required to solubilize a hydrophobic solute was made. Direct comparisons made with the solubility of 1% propofol in variable concentrations or polymers and the results from different polymers and concentrations presented in the Table 5 below and judged by whether a clear solution was achieved. Table 5

[0232] In some embodiments, conjugates of the disclosure have one or both of the following features: • Oligomer purity of a PEG-saccharide-lipid conjugate is greater than 85% or a labeled nominal value of the polymer is between 85.0% and 115.0%; and • Individual related analogue or impurity is less than 5%.

[0233] Every PEG-saccharide-lipid conjugate has its unique characteristics affecting safety and solubility enhancement, surprisingly certain short diamine as the center backbones exhibited less biological activity than others, even if the difference is only by a few methylene groups between the two terminal amines for the same configuration and carriers, e.g., DOPS-12 (1,3- Diaminopropane centered) versus DOPS-H12 (Hexamethylenediamine centered). The polymer structures based on the shorter diamines exhibit a lower hemolytic potential in comparison with materials based on triamine (TOPS-12) or longer-chain diamines (DOPS-H12) or bulkier lipid moiety (DCPS-12).

[0234] Example 17 Purification of PEG-saccharide-lipid Conjugates

[0235] After most impurities removed by “work-up” at end of the synthesis, solvent residual is often a safety concern. Since the polymers are highly soluble in both organic solvent and water, hence a cleanup process was developed for removing any hazardous residual solvents for the polymers. First the polymer was re-dissolved in pure USP grade ethanol at a weight to weight ratio of 1 to 1, and then removed under vacuum at 35 – 40 ºC. The alcohol rinsed polymer was then re-dissolved in pure water (USP grade or better) at a weight to weight ratio of 1 to 3. The polymer solution was transferred into suitable drying trays and placed into a – 45ºC freezer overnight.

[0236] Cooled the shelves of the Lyophilizer to approximately - 50 ºC and loaded the trays which were kept below - 45 ºC for a minimum of 8 hours. Set the vacuum to between 50 and 100 millitorr, the shelves to between -30 and -35 ºC and maintained at - 32 ±3ºC for at least 55- 65 hours. When the system pressure reached - 50 mtorr or lower; reduced the chamber pressure and heated the shelves to between 22 and 25ºC. Maintained at 22 ±3ºC until the product temperature was above 20ºC for at least 6 hours, then vented the chamber to partial vacuum Brought the chamber to atmospheric pressure, and unloaded the trays. Figure 9 showed a sample freezing dried polymer (DOPS-12) with a solid and pleasant appearance, only trace amounts of alcohol (< 0.5%) was detected and all other solvents were almost completely removed; either no detectable (USP class II residual solvents) or < 0.5% (USP class III solvents).

[0237] Alternatively the polymer can be dried using a spray drying process, e.g., a 10% to 20% of DOPS-12 concentrate in ethanol was flowed into a dryer which was set with following parameters: Spray dryer: 5L / hr Air Blower: 40Hz Inlet Temperature: 79 °C (76 to 82°C) Outlet Temperature: 30°C (25°C - 35°C) Flow Rate: 10 to 15 gm / min (or 600g to 900g / hr) De-Block piston setting: 300 Spray Pressure: 0.2Mpa Needle Pressure: 0.3Mpa Cooling water setting: 10°C Nitrogen generator setting: As needed.

[0238] In various embodiments, a drying process can be used in the compounding process, for example, using a lyophilizer or a spray dryer. Active pharmaceutical ingredient (API) is co- dissolved with the conjugate in a solvent such as water, alcohol or acetone, and then dried as appropriate using a lyophilizer (when water is used as the solvent) or a spray dryer.

[0239] In various embodiments of the disclosure it can be desirable to control the starting materials with specified qualities. One of the three main components in PEG-saccharide-lipid conjugates is fatty acid such as oleic acid which is from a natural source. Even though the manufacturers certified that content of oleic acid is in in upper 80% range, a refining process may be desirable to remove other saturated and unsaturated fatty acids. The second component is a saccharide acid such as lactobionic acid, an oxidative product of lactose which is also from a natural source, therefore certain monosaccharides such as galactose or glucose may be co- existed in lactose, which produces a small quantity of other sugar acids, e.g., galacturonic acid or glucuronic acid, upon oxidation. In addition, monomethoxypolyethylene glycol ether is a mixture of polyethylene chains which is typically ranging from 5 to 10% of the targeted molecular weight per the USP limits. Hence a set of specifications is desirable to control the polymer quality, e.g., the purity assay by the HPLC as demonstrated in Example 11.

[0240] Example 18 Active Systemic Anaphylaxis Study in Mice

[0241] The study was for the determination of any potential of PEG-saccharide-lipid conjugate to induce or prevent anaphylactic reaction by intravenous administrations. The mouse models of systemic anaphylaxis are important tools for the elucidation of the pathomechanisms of anaphylaxis, and for identifying and characterizing potential therapies for anaphylaxis. Hypothermia serves as the primary quantifiable indicator of anaphylaxis in these models.

[0242] This study was under a study protocol approved by the institutional Animal Care and Use Committees (IACUCs). Groups (G#) of 6 animals received single sensitizing injections of Normal saline (G1), Positive Control-Ovalbumin [OVA]- 100 µg / animal (G2), test article, 350 mg DOPS-12 / kg (G3) to 500 mg / kg body weight (G4) by the intraperitoneal route. Adjuvants- pertussis toxin and aluminum potassium sulfate were used for sensitization of G1, G2 and G3 groups. After a rest period of 21 days, the animals were challenged with 500 μg OVA / animal (G1 and G2 group), 350 mg / kg test article (G3 and G4 group), by the intravenous route. Clinical signs and mortality were observed twice daily on sensitization day and once a day on other days. On the day of challenge, rectal temperature was measured at pre-treatment and 5, 15 and 30 minutes or until death and observed for clinical signs at 5, 10, 15, 20, 25 and 30 minutes or until death, post challenge.

[0243] Ataxia, recumbency, slight tremors, slight lacrimation (clear discharge), dyspnea, slight piloerection was observed in G2 (positive control) animals at 5 to 25 minutes. All animals died at 10 to 25 minutes, post challenge. All mice of G2 group developed anaphylactic symptoms and experienced a steep decrease in body temperature. There were no clinical signs or mortality, change in the rectal temperature in G1, G3 and G4 groups, post challenge. There was no effect on body weight gain and no abnormalities on gross necropsy. The experiment validity was confirmed via a positive response using positive control Ovalbumin, which elicited signs of anaphylaxis, hypothermia resulting in mortality. No response was observed in the vehicle and test article treated groups. These results concluded that test article DOPS-12 did not demonstrate the potential to produce IgE (reagenic) antibody in the mouse active systemic anaphylaxis model under the testing conditions employed.

[0244] Example 19 Passive Systemic Cutaneous Anaphylaxis Study in Rats

[0245] The study was under a study protocol approved by the institutional Animal Care and Use Committees (IACUCs). This study of passive systemic anaphylaxis (PSA) was to assess the presence of IgE (reagenic) antibody as the primary quantifiable indicator of anaphylaxis for identifying and characterizing potential clinical applications of PEG-saccharide-lipid conjugates.

[0246] Groups of 4 animals received three sensitizing injections of Vehicle control- Normal saline (G1), Positive Control- Ovalbumin (OVA) +Aluminum potassium sulfate dodecahydrate (ALH) [OVA+ALH]- 100 mg of OVA + 12 mg ALH / rat (G2), test article, DOPS-12 – 10 mg / rat [200 μL / rat of 50 mg / mL test article formulation] (G3). On days 1, 3 and 5, the respective groups were administered with vehicle control and positive control through intraperitoneal route and test article by intravenous route. On day 10, all the sensitized animals were euthanized using Isoflurane anesthesia, blood collected, serum separated, pooled and stored under 2 to 8 ºC for 4 days, for use to challenge. Five naïve animals / group- G1a, G2a and G3a were passively sensitized by intradermal injection (0.1 mL / site at two sites) of sera [1:2 (50%) and 1:4 (25%) dilutions of serum with normal saline and undiluted serum] from the donor animals-G1, G2 and G3, respectively. Approximately, 24 hours later the intradermal sensitized animals were injected with 0.6 mL of vehicle control or positive control (10 mg / mL OVA) or test item (50 mg / mL) + 0.4 mL of Evan’s blue (1% w / v in normal saline) together by intravenous route. Approximately 30 minutes postdose, the animals were euthanized using Isoflurane anesthetic, the skin excised, inverted and the diameter of blue spots were measured, recorded and photographed.

[0247] There were no clinical signs of toxicity or mortality, no effect on body weight gain and no abnormalities on gross necropsy in any DOPS-12 treated animals. The Passive Cutaneous Anaphylaxis response [PCA] (Mean ± SD) as measured by the blue spot diameter (mm) listed in Table 6: Table 6

[0248] The experimental validity was confirmed via a positive response using positive control Ovalbumin, which elicited positive PCA response of 1.68 mm, 7.35 mm and 12.18 mm blue spot diameter corresponding to 25% serum, 50% serum and undiluted serum, in comparison to vehicle-treated group. No response was observed in the test article treated group. Based on these results it is concluded that test article DOPS-12 did not demonstrate the potential to produce IgE (reagenic) antibody in the rat passive cutaneous anaphylaxis model under the testing conditions employed.

[0249] Example 20: Preparation of Bulk Powder by Lyophilization

[0250] The following procedure can be adapted for the preparation of a bulk powder of an antiviral agent and a PEG-saccharide-lipid conjugate: Dissolve appropriate amounts of antiviral agent with a desired amounts of a selected conjugate in ethanol and remove the solvent under vacuum. Charge a portion of purified water to a suitable container equipped with an agitating device. Disperse with agitation the requisite amount of a bulking filler (e.g., mannitol or lactose) and mix with other pre-dissolved excipients using a suitable mixer. Cool down the solution to 21- 23 °C. Filter the solution into a suitable vessel and transfer back into the original container. If necessary, adjust the pH of the mix to pH 5 – 7 with diluted NaOH and add any additional Purified Water while stirring. Transfer the dispersion into suitable intermediate storage vessels (ISV) and stir at 25 – 55 rpm. Maintain temperature at 20°C - 24°C during the filling operation. The ISV and associated control unit are used to maintain dispersion homogeneity and temperature before and during the filling operation. Connect the ISV to suitable dosing pumps. 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. Freeze the product in a suitable freeze chamber. Transfer the frozen trays from the freeze chamber to suitable refrigerated storage cabinets (temperature below -25 ° C) prior to freeze drying and keep the product frozen. Load the frozen trays from the refrigerated storage cabinets into the freeze dryer and start the freeze drying cycle. Appropriate lyophilization is to set according to available equipment. For instance, program a freeze dryer (i.e., Epsilon 2-6D LSCPlus) to: • Precool the freeze-dryer shelves to 10 °C. • Load the blisters placed inside a Lypoprotect lyophilization bag. • Decrease the temperature of the shelves to 5 °C and maintain the trays at that temperature for 1 h. • Decrease the temperature of the shelves to -50°C in 1h and 30 min. • Keep the shelves at -50°C for 10 h. • Set up the vacuum pump to 0.133 mbar. • Increase the temperature of the shelves to -25°C in 1h. • Decrease the temperature of the shelves to -34°C. in 1min. • Keep the temperature of the shelves at -34°C and the pressure 0.133 mbar for 56 h. • Set up the vacuum pump to 0.001mbar and increase the temperature of the shelves to 25°C in 1 h. • Keep the temperature of the shelves at 25°C and the pressure at 0.001 mbar for 14h.

[0251] When the freeze drying cycle is completed, unload the product into suitable dry storage cabinets (i.e., 35% of relative humidity at 25°C) awaiting next steps. The bulk lyophilized powder can be used for making oral table forms with compression, or can be used to provide a powder for solution. A sample composition is listed in Table 7: Table 7

[0252] In Table 7, steviol glycoside includes but not limited to Rebaudioside A extracted from natural sources and / or Rebaudioside M or D by bioconversion of Steviol glycoside. The various components can be, for example, as described above.

[0253] Example 21: Preparation of Oral Thin Films

[0254] While there are several methods for the preparation of oral thin films, solvent casting methods are the most convenient method because their simplicity, low processing cost, and ease of application. In one such method, the antiviral agent and a PEG-saccharide-lipid conjugate are dissolved in ethanol and small amounts (i.e., less than 10% of the total volume) of pre-dissolved water-soluble excipients are added to this mixture to obtain a viscous solution. The solution is poured into a suitable tray and solvents are allowed to evaporate under vacuum at 35 - 40°C for 2 to 8 hours, depending in part on vacuum capacity. The films obtained after evaporation of the solvents and careful separation from the tray can be, e.g., 4 x 2cm or 5x 2 cm in diameter, 20 to 500 mm thick. A single or combined multiple layers may be used and cut into pieces of the desired dosing size according to the content of the active substance. A sample composition is showed in Table 8: Table 8

[0255] In Table 8, steviol glycoside includes but not limited to Rebaudioside A extracted from natural sources and / or Rebaudioside M or D by bioconversion of Steviol glycoside. The various components can be, for example, as described above.

[0256] Example 22: Preparation of Bulk Powder by Spray Drying

[0257] Spray drying can also be used to prepare powders. The following procedure is an example: Charge the requisite amounts of antiviral agent into a suitably-sized container and add a desired amount of conjugate (e.g., DOPS-12) in alcohol to the container. Maintain the mixture at 45 °C ± 5 °C and mix until substantially clear. Add pre-dissolved rebaudioside (e.g.., A or M) and mix well. Spray-dry the resulting mixture using a suitable spray dryer, e.g., 5L Spray Dryer with the following parameters: Temperature: inlet 78 ± 2°C and outlet 40 °C Aspirator flow: 60-65 Nm3 / hr (e.g., ~ 1.7 m3 / min under ambient conditions) Flow rate: 2 mL / min Continue drying spray-dried mixture in a vacuum oven at 40 °C ± 5°C until the solvent level is below 0.2%. The dried mixture is sieved manually through a No.30 mesh screen and blended for 10 minutes using a suitable mixer, e.g., V blender. Other excipients are sieved manually through a No.30 mesh screen. The dried mixture with the requisite amounts of screened excipients is blended for 10 minutes then compacted with a roller compactor, e.g., Vector Freund Compactor for 20 minutes. Compress the blend on a rotary tablet for a unit dosage size or pack the granules into individual sachet with desired strength. A sample formula is shown in Table 9. Table 9

[0016]

[0258] In Table 9, steviol glycoside includes but not limited to Rebaudioside A extracted from natural sources and / or Rebaudioside M or D by bioconversion of Steviol glycoside. The various components can be, for example, as described .

[0259] Example 23: Preparation of Bulk Granules

[0260] The compositions can also be formed as granules. For example, in one such procedure, the antiviral agent is dissolved in 5 to 20 fold of denatured alcohol and mixed with a predissolved aqueous solution of PEG-sacchrade-lipid conjugate and mannitol (the alcohol content is typically 5% or less of the final volume). For freeze granulation, the premixed solution is drawn into a syringe through a 10 µm filter to avoid obstruction of the granulation nozzle. The syringe is then inserted into a syringe pump, shaken periodically throughout the granulation process to avoid segregation, and the freeze granulation process started. The freeze granulation is performed with a lab-scale freeze granulator, i.e., PowderPro AB (Göteborg, Sweden) or Encapsulator (Inotech Encapsulation AG, Dottikon, Switzerland). The pumping speed is approximately 2 mL / min, with a membrane vibration frequency of approximately 2 kHz and a ring potential around 1 kV. The granules are loosened from the liquid N2 container and filled into flasks for freeze-drying for approximately 48 h while the condenser temperature is set to−50 ◦C at 0.08–0.1 mbar. A sample formula is described in Table 10. Table 10

[0261] In Table 10, steviol glycoside includes but not limited to Rebaudioside A extracted from natural sources and / or Rebaudioside M or D by bioconversion of Steviol glycoside The various components can be, for example, as described above.

[0262] Example 24: Preparation of Tenofovir Granules

[0263] Following the Example 22, a sample formulation as described in Table 11 is prepared. Table 11

[0264] The various components can be, for example, as described above. In Table E, the PEG- saccharide-lipid conjugate may in some embodiments be oleoylpropanediamino-mPEG- lactobionate (DOPS-12).

[0265] Example 24: Preparation of Tenofovir Tablets

[0266] Following Example 20, 22 or 23, a formulation as described in Table 12 is prepared: Table 12

[0267] The various components can be, for example, as described above. In Table 12, the PEG-saccharide-lipid conjugate may in some embodiments be oleoylpropanediamino-mPEG- lactobionate (DOPS-12).

[0268] Example 25: Preparation of Tenofovir and Emtricitabine Tablets

[0269] Following Example 20, 22 or 23, a formulation as described in Table 13 is prepared: Table 13

[0270] The various components can be, for example, as described above. In Table 13, the PEG-saccharide-lipid conjugate may in some embodiments be oleoylpropanediamino-mPEG- lactobionate (DOPS-12).

[0271] Example 26: Preparation of Tenofovir / Emtricitabine / Dolutegavir Tablets / Granules

[0272] Following Example 20, 22 or 23, a formulation as described in Table 14 is prepared: Table 14

[0273] The various components can be, for example, as described above. In Table 14, the PEG-saccharide-lipid conjugate may in some embodiments be oleoylpropanediamino-mPEG- lactobionate (DOPS-12).

[0274] Example 27: Preparation of Tenofovir, Emtricitabine and Bictegravir Tablets

[0275] Following Example 20, 22 or 23, a formulation as described in Table 15 is prepared: Table 15

[0276] The various components can be, for example, as described above. In Table 15, the PEG-saccharide-lipid conjugate may in some embodiments be oleoylpropanediamino-mPEG- lactobionate (DOPS-12).

[0277] Example 28: Preparation of Tenofovir and Sofosbuvir Tablets / Granules

[0278] A combination of Tenofovir and Sofosbuvir is a potential treatment for Hepatitis B virus (HBV) and hepatitis C virus (HCV) or co-infection with HIV. Following Example 20, 21 or 22, a formulation as described in Table 16 is prepared . Table 16 steviol glycosides

[0279] The various components can be, for example, as described above. In Table 16, the PEG-saccharide-lipid conjugate may in some embodiments be oleoylpropanediamino-mPEG- lactobionate (DOPS-12).

[0280] Example 29: Preparation of Cobicistat, Elvitegravir, Emtricitabine and Tenofovir Tablets / Granules

[0281] Following Example 20, 22 or 23, a formulation as described in Table 17 is prepared: Table 17

[0282] The various components can be, for example, as described above. In Table 17, the PEG-saccharide-lipid conjugate may in some embodiments be oleoylpropanediamino-mPEG- lactobionate (DOPS-12).

[0283] Example 30: Preparation of Lopinavir and Ritonavir Tablets / Granules

[0284] Following Example 20, 22 or 23, a formulation as described in Table 18 is prepared: Table 18

[0285] The various components can be, for example, as described above. In Table 18, the PEG-saccharide-lipid conjugate may in some embodiments be oleoylpropanediamino-mPEG- lactobionate (DOPS-12).

[0286] Example 31 Determination of Critical Micelle Concentration of DOPS-12

[0287] The testing instrument used for performing the critical micelle concentration (CMC) tests was a Surface Tensiometer model DY-700 (Kyowa Interface Science Co., Ltd., Tokyo, Japan). DI water (50 mL) was placed in a testing container, and the corresponding DOPS-F02 solution was placed in the Auto Buret to control the addition volume. The DOPS-F02 solution (0.6 mg / mL) was then added by controlled volumetric additions to the testing solution. After each addition, the testing solution was stirred for 30 seconds and allowed to rest for 60 seconds before measuring the surface tension. This process was repeated until the end of the titration.

[0288] The results of the CMC tests are shown in numerically and graphically in Figure 12. To calculate the CMC, two lines were fit to plots and the intersection of the two lines was determined (Figure 10). The lines were fit such that the R2 values of the fits were ≥ 0.999. The data points used for the fitting and the actual fitted lines are indicated in the Figure 10. The CMC was determined to be 12.67 mg / L or approximately 0.01 mmol. For optimal solubility enhancements, the conjugate present in aqueous solution in an amount above its critical micelle concentration since a lower critical micelle concentration (CMC) can be preferable for enhancing solubility because it indicates that micelles form more easily and are more stable. Therefore a CMC of the conjugate in the present disclosre is preferably less than 0.1 mmol, e.g., 0.005- 0.01 or 0.02 – 0.05.

[0289] Example 32. PEG distribution in DOPS-12

[0290] A LC-MS was used for the determination of the PEG distribution profile in DOPS-12. The method parameter are summarized as follows: Chromatography Conditions

[0291] As shown in Figure 11, the PEG distribution was in a narrow range as described throughout the present disclosure, e.g., ± 5% of the targeted molar mass.

[0292] Example 33: Product Stability of Tenofovir and Emtricitabine Solution

[0293] An aqueous combined drug product solution was prepared as in Example 25.2 wt% of oleoylpropyldiamino-monomethoxypolyethyleneglycol-lactobionate (DOPS 12) was used. The sample concentration was 3.1 mg / mL of tenofovir alafenamide monofumarate (TAF) and 20 mg / mL of Emtricitabine (ETC) in water were stored in capped 6 mL glass vials set on the bench top under lab ambient temperature between 21 and 25 °C. The samples were diluted to 56 µg / mL of TAF and 400 µg / mL of ETC in methanol (Figure 12) for HPLC assay. An HPLC system included of an on-line degasser, binary pumps, an injector, and a diode array or ultraviolet detector set at 265 nm. The HPLC analytical column was 5 µm inertsil 3V C18 (GL Sciences, Inc. Torrance, CA 90503), 25 cm x 4.6 mm inner dimension at ambient column temperature. A gradient method was used; mobile phases were (A) 30 mM KH2PO3(pH 3.2 ±0.2) and (B) methanol. The flow rate was set at 1.5 mL / min and sample injections were 10 µL. A separation was achieved from gradient of 90 % A / 10% B to 10 % A / 90 % B in 12 min. The chromatograms were processed with the Waters Empower software (ver.2). The samples were tested duplicate at initial, 3, 6, 9 and 12 months. The stability results (Table 19) demonstrated that the PEG-saccharide-lipid conjugate based formula very stable during the storage period. Table 19

[0294] Example 34: Oral Solution Compositions

[0295] A PEG-saccharide-lipid conjugate is added to a stainless steel vessel equipped with propeller type mixing blades and appropriate volumes of ethanol were added to the vessel with mixing. The drug substance was charged into the vessel with constant mixing at a temperature to 40° – 50 °C. Mixing continued until the drug was visually dispersed fully and a homogenous solution was achieved. Ethanol was removed by vacuum at a temperature to 35° – 45 °C; the wax-like mixture was solidified when cooled. Premixed solution of excipients were added into the dried mixture of API and polymer and re-dissolved under constantly stirring at 40 to 50 °C and mixed properly to obtain uniform mixture. A sample formulation is described in Table 20. Table 20

[0296] The various components can be, for example, as described above. In Table 20, the PEG-saccharide-lipid conjugate may in some embodiments be oleoylpropanediamino-mPEG- lactobionate (DOPS-12) and steviol glycoside includes but not limited to Rebaudioside A extracted from natural sources and / or Rebaudioside M or D by bioconversion of Steviol glycoside

[0297] Example 35: Preparation of Cobicistat, Darunavir, Emtricitabine and Tenofovir solution

[0298] Following Example 29, a formulation as described in Table 21 is prepared: Table 21

[0299] The various components can be, for example, as described above. In Table 21, the PEG-saccharide-lipid conjugate may in some embodiments be oleoylpropanediamino-mPEG- lactobionate (DOPS-12).

[0300] Example 36: Preparation of Cobicistat, Elvitegravi, Emtricitabine and Tenofovir solution

[0301] Following Example N, a formulation as described in Table 22 is prepared: Table 22

[0302] The various components can be, for example, as described above. In Table 22, the PEG-saccharide-lipid conjugate may in some embodiments be oleoylpropanediamino-mPEG- lactobionate (DOPS-12).

[0303] Example 37 Evaluation of Taste Masked Tablets of Tenofovir

[0304] Solutions were prepared by dissolving Orally Disintegrating Tablets (ODT) of Tenofovir alafenamide (TAF) monofumarate via the procedure in Example F in water to a fixed concentration of 5 mg / mL TAF. The first steviol glycosides used was a mixture of approximately 80% of Rebaudioside M and approximately 20% of Rebaudioside A having a minimum content of steviol glycosides above 98% and the second one was water soluble having content of Rebaudioside A approximately 95%. Highly-purified Rebaudiosides are commercially available, e.g., GLG Life Tech Corporation (Richmond, Canada) or Cargill (Wayzata, MN, USA). Identical sample concentrations of a fixed amount of TAF with variable stevia contents were used in these parallel series. A fixed concentration of 5 mg / mL of TAF solution with variable amounts of stevia extracts from high concentration to low concentration was adopted to avoid the delaying effect of bitterness. The sample concentrations used are shown in Table 23: Table 23

[0305] Perceived bitterness of TAF was assessed on a ten-point scale, divided into five regions, i.e., 0–2, 2–4, 4–6, 6–8, and 8–10. Each of approximate 10 mL of testing sample solutions was put into a transparent glass cup at room temperature. Each panelist tasted 1 mL solution by swirling in their mouth for 8–10 s before recording the bitterness score and subsequently spitting the solution. After 5-10 s, a second bitterness score was recorded. The oral cavity was washed with pure water three times before the next sample was tasted. The interval between samples was 5 to 10 min. Panelists were also required to take a 45 min break every 3 to 4 samples to prevent sensory evaluation fatigue and adaptation.

[0306] As demonstrated in Figures 13 and 14, stevia extract can effectively reduce the perceived bitterness of tenofovir alafenamide . Notably, lower amounts were required for Rebaudioside M than for Rebaudioside A. For instance the weight ratio of stevia extra to TAF is about 3 to 1 for 90% Rebaudioside M versus 6 to 1 for 95% Rebaudioside A, respectively. Additional sweetener was found to be helpful to modify the aftertaste of steviol glycosides, especially for Rebaudioside A.

[0307] Example 38 Solubility of Steviol Glycosides

[0308] A solubility test was performed for a steviol glycoside sample having a Rebaudioside M content greater than 95%, solubilized by oleoylpropanediamino-mPEG-lactobionate (DOPS- 12) in pure water, at a variety of concentrations of each. Sample solutions were mixed and rested on a laboratory bench top overnight. The solutions that remained visually clear were used as a guide for a minimum concentration of DOPS-12 needed to solubilize a given amount of the steviol glycoside. Figure 15 presents a plot of the maximum concentration solubilized by a given concentration of DOPS-12 in the samples tested. Solubility of the steviol glycoside in this experiment was achieved at a molar ratio of about 1:5 and a weight ratio of about 1:10 of steviol glycoside to DOPS-12. Of course, in real-world samples the amount of a PEG- saccharide-lipid conjugate necessary to co-solubilize is largely depending on a concentration of rebaudioside, particular type of steviol glycosides and compositions from different sources or extraction process, a pre-assessment may be necessary. For instance, a concentration of 2 mg / mL of 95% Rebaudioside M may need about 3 to 4 mg / mL of DOPS-12.

[0309] While preferred embodiments of the present invention have been described, those skilled in the art will recognize that other and further changes and modifications may be made without departing from the spirit of the invention, and all such changes and modifications should be understood to fall within the scope of this invention.

[0310] Various aspects and embodiments of the disclosure are provided by the following claims, which may be combined in any number and in any combination that is not logically or technically inconsistent. Embodiment 1. A pharmaceutical composition (for example, for oral administration) of an antiviral agent (e.g., an antiretroviral agent), the pharmaceutical composition comprising: the antiviral agent, comprising an antiviral agent selected from the group consisting of tenofovir, dolutegravir, lopinavir, abacavir, bictegravir, cobicistat, darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, lamivudine, lenacapavir, lopinavir, rilpivirine, ritonavir, sofosbuvir, and any combination thereof; and a PEG-saccharide-lipid conjugate having the structural formula wherein m has a number-average value in the range of 2-10; S is a mono-, di- or trisaccharide group, in which each saccharide unit is a sugar, a sugar alcohol, an amino sugar or a sugar acid; L is -C(O)-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; P is -(CH2-CH2-O)nR2in which n has a number-average value in the range of 5- 50 (e.g., 8-45) and R2is hydrogen and / or alkanyl and has a number average number of carbons in the range 0-4. Embodiment 2. A pharmaceutical composition for oral administration of an antiviral agent (e.g., an antiretroviral agent), the pharmaceutical composition comprising: the antiviral agent, comprising an agent selected from the group consisting of tenofovir, dolutegravir, lopinavir, abacavir, bictegravir, cobicistat, darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, lamivudine, lenacapavir, lopinavir, rilpivirine, ritonavir, sofosbuvir, and any combination thereof; a solubility or bioavailability enhancer comprising PEG-saccharide-lipid conjugate represented by the chemical structure: wherein: L is a lipophilic residue selected from fatty acid residues and steroid acid residues (e.g., bile acid residues, cholesterol residues); S is a saccharide selected from monosaccharides, disaccharides and trisaccharides; P is a polyethylene glycol residue having from 4 to 45 subunits; and B is a backbone molecule having three or four available binding positions; and one or more steviol glycosides mainly comprising one or more steviosides and / or rebaudiosides. Embodiment 3. The pharmaceutical composition of embodiment 1 further comprising one or more steviol glycosides mainly comprising one or more steviosides and / or rebaudiosides. Embodiment 4. The pharmaceutical composition of any of embodiments 1-3, wherein the antiviral agent includes (or is) tenofovir. Embodiment 5. The pharmaceutical composition of embodiment 4, wherein the tenofovir is tenofovir alafenamide and tenofovir disoproxil. Embodiment 6. The pharmaceutical composition of embodiment 4 or embodiment 5, wherein the antiviral agent further includes one or more antiviral agents selected from abacavir, bictegravir, cobicistat, darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, lamivudine, lenacapavir, lopinavir, rilpivirine, ritonavir, sofosbuvir, velpatasvir and voxilaprevir. Embodiment 7. The pharmaceutical composition of any of embodiments 1-3, wherein the antiviral agent includes (or is) dolutegravir. Embodiment 8. The pharmaceutical composition of embodiment 7, wherein the antiviral agent further includes one or more antiviral agents selected from abacavir, bictegravir, cobicistat, darunavir, efavirenz, elvitegravir, emtricitabine, lamivudine, lenacapavir, lopinavir, rilpivirine, ritonavir, sofosbuvir, tenofovir, velpatasvir and voxilaprevir. Embodiment 9. The pharmaceutical composition of any of embodiments 1-3, wherein the antiviral agent includes (or is) lopinavir. Embodiment 10. The pharmaceutical composition of embodiment 9, wherein the antiviral agent further includes one or more antiviral agents selected from abacavir, bictegravir, cobicistat, darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, lamivudine, lenacapavir, rilpivirine, ritonavir, sofosbuvir, tenofovir, velpatasvir and voxilaprevir. Embodiment 11. The pharmaceutical composition of any of embodiments 1-10, wherein the antiviral agent is present in the range of 1-800 mg of the antiviral agent per dosage or per discrete dosage form, e.g., in the range of 1-600 mg, or 1-300 mg, or 1-200 mg, or 1-100 mg. Embodiment 12. The pharmaceutical composition of any of embodiments 1-10, wherein the antiviral agent is present in the range of 5-800 mg of the antiviral agent per dosage or per discrete dosage form, e.g., in the range of 5-600 mg, or 5-300 mg, or 5-200 mg, or 5-100 mg. Embodiment 13. The pharmaceutical composition of any of embodiments 1-10, wherein the antiviral agent is present in the range of 15-800 mg of the antiviral agent per dosage or per discrete dosage form, e.g., in the range of 15-600 mg, or 15-300 mg, or 15-200 mg, or 15-100 mg. Embodiment 14. The pharmaceutical composition of any of embodiments 1-10, wherein the antiviral agent comprises (or is) tenofovir alafenamide, present, for example, in an amount of 5-40 mg per dosage or discrete dosage form. Embodiment 15. The pharmaceutical composition of any of embodiments 1-10, wherein the antiviral agent comprises (or is) dolutegavir (e.g., 30-50 mg per dosage or discrete dosage form); emtricitabine (e.g., 120-200 mg per dosage or discrete dosage form), and tenofovir alafenamide (e.g., 15-25 mg per dosage or discrete dosage form). Embodiment 16. The pharmaceutical composition of any of embodiments 1-10, wherein the antiviral agent comprises (or is) emtricitabine (e.g., 120-200 mg per dosage or discrete dosage form), and tenofovir alafenamide (e.g., 15-25 mg per dosage or discrete dosage form). Embodiment 17. The pharmaceutical composition of any of embodiments 1-10, wherein the antiviral agent comprises (or is) bictegravir (e.g., 30-50 mg per dosage or discrete dosage form), emtricitabine (e.g., 120-200 mg per dosage or discrete dosage form), and tenofovir alafenamide (e.g., 15-25 mg per dosage or discrete dosage form). Embodiment 18. The pharmaceutical composition of any of embodiments 1-10, wherein the antiviral agent comprises (or is) cobicistat (e.g., 5 mg per dosage or discrete dosage form), 150 mg of elvitegravir (e.g., 150 mg per dosage or discrete dosage form), emtricitabine (e.g., 200 mg per dosage or discrete dosage form), and tenofovir alafenamide (e.g., 10 mg per dosage or discrete dosage form). Embodiment 19. The pharmaceutical composition of any of embodiments 1-10, wherein the pharmaceutical composition comprises 150 to 400 mg of sofosbuvir and 15 to 25 mg of tenofovir alafenamide. Embodiment 20. The pharmaceutical composition of any of embodiments 1-10, wherein the pharmaceutical composition comprises 100 to 200 mg of lopinavir and 25 to 50 mg of ritonavir Emodiment 21. The pharmaceutical composition of any of embodiments 1-10, wherein the antiviral agent comprises (or is) sofosbuvir (e.g., 150-400 mg per dosage or discrete dosage form), and tenofovir alafenamide (e.g., 15-25 mg per dosage or discrete dosage form). Embodiment 22. The pharmaceutical composition of any of embodiments 1-10, wherein the antiviral agent comprises (or is) lopinavir (e.g., 100-200 mg per dosage or discrete dosage form), and ritonavir (e.g., 25-50 mg per dosage or discrete dosage form). Embodiment 23. The pharmaceutical composition according to any of embodiments 2- 22, wherein a weight ratio of the one or more steviol glycosides to the conjugate is in the range of about 1 to about 10, e.g., in the range of 1-10. Embodiment 24. The pharmaceutical composition according to any of embodiments 2- 22, wherein a weight ratio of a total amount of rebaudioside D and rebaudioside M to the conjugate is in the range of 0.5-10. Embodiment 25. The pharmaceutical composition according to any of embodiments 2- 24, wherein the one or more steviol glycosides are present in the composition an amount in the range of 0.5-50 wt%, e.g., 1-50 wt%, or 5-50 wt%, or 0.5-25 wt%, or 1-25 wt%, or 5-25 wt%, or 0.5-10 wt%, or 1-10 wt%, or 5-10 wt%. Embodiment 26. The pharmaceutical composition according to any of embodiments 2-25 wherein the one or more steviol glycosides are provided in a purity of at least 75 wt%, e.g., at least 85 wt% or at least 90 wt% or at least 95 wt%%. Embodiment 27. The pharmaceutical composition according to any of embodiments 2- 26, wherein a total amount of one or more of Rebaudiosides A, D and M is at least 75 wt% of a total amount of steviol glycosides, e.g., at least 85 wt% or at least 90 wt% or at least 95 wt%. Embodiment 28. The pharmaceutical composition according to any of embodiments 2- 26, wherein a total amount of one or more of Rebaudiosides D and M is at least 75 wt% of a total amount of steviol glycosides, e.g., at least 85 wt% or at least 90 wt% or at least 95 wt%. Embodiment 29 The pharmaceutical composition according to any of embodiments 2- 26, wherein a total amount of Rebaudioside A is at least 75 wt% of a total amount of steviol glycosides, e.g., at least 85 wt% or at least 90 wt% or at least 95 wt%. Embodiment 30. The pharmaceutical composition of any of embodiments 1-29, further comprising one or more sweeteners. Embodiment 31. The pharmaceutical composition of embodiment 30, wherein one or more of the one or more sweeteners is an artificial sweetener. Embodiment 32. The pharmaceutical composition of embodiment 30 or 31, wherein one or more of the one or more sweeteners is a natural sweetener. Embodiment 33. The pharmaceutical composition of any of embodiments 30-32, wherein one or more of the one or more sweeteners is selected from acesulfame potassium, arginine acid, aspartame, cyclamate, monk fruit extract, saccharin, and sucralose. Embodiment 34. The pharmaceutical composition of any of embodiments 30-33, wherein one or more of the one or more sweeteners is selected from sugars such as sucrose, dextrose, fructose, glucose and maltose and sugar alcohols such as sorbitol, mannitol, isomalt, maltitol, erythritol and xylitol. Embodiment 35. The pharmaceutical composition of any of embodiments 30-34, wherein a total amount of the one or more sweeteners is in the range of 0.2-10 wt% of the composition. Embodiment 36. The pharmaceutical composition of any of embodiments 1-35, further comprising one or more flavoring agents. Embodiment 37. The pharmaceutical composition of embodiment 36, wherein the one or more flavoring agents include one or more flavoring agents selected from yerba mate (extract of Ilex paraguariensis A. St.-Hil.), cinnamon and its derivatives (e.g., cinnamic acid), wild cherry, mint, anise, Irish cream, tea, mocha, walnut, chocolate, coconut, vanilla, fruit, berry, butterscotch, peach, vanilla, wintergreen mint, maple, apricot, raspberry, citrus, monk fruit extract, pineapple extract and licorice root. Embodiment 38. The pharmaceutical composition of any of embodiments 1-37, further comprising one or more bulking fillers. Embodiment 39. The pharmaceutical composition of embodiment 38, wherein one or more of the one or more bulking fillers is selected from polyvinylpyrrolidone, poloxamers, cyclodextrin derivatives, Polyoxyl 40 hydrogenated castor oil, polysorbates and polyethylene glycols (e.g., number average molecular weight in the range of 2-8 kDa). Embodiment 40. The pharmaceutical composition of embodiment 38 or embodiment 39, wherein one or more of the one or more bulking fillers is a saccharide, such as a sugar alcohol (such as mannitol) or a sugar (such as lactose). Embodiment 41. The pharmaceutical composition of any of embodiments 1-40, further comprising an antioxidant. Embodiment 42. The pharmaceutical composition of embodiment 41, wherein the antioxidant is present in an amount up to 10 wt% of the composition. Embodiment 43. The pharmaceutical composition of embodiment 40 or embodiment 41, wherein the antioxidant includes (or is) ascorbic acid. Embodiment 44. The pharmaceutical composition of any of embodiments 40-43, wherein the antioxidant includes (or is) α-tocopherol. Embodiment 45. The pharmaceutical composition of any of embodiments 40-44, wherein the antioxidant includes (or is) D-α-tocopherol polyethylene glycol 1000 succinate. Embodiment 46. The pharmaceutical composition of any of embodiments 1-45, in a liquid form. Embodiment 47. The pharmaceutical composition of any of embodiments 1-45, in a solid form. Embodiment 48. The pharmaceutical composition of any of embodiments 1-45, in a semisolid form, e.g., a cream or a gel. Embodiment 49. The pharmaceutical composition of any of embodiments 1-48, in the form of an oral dosage form. Embodiment 50. The pharmaceutical composition of embodiment 49, in the form of a tablet, a capsule or a film. Embodiment 51. The pharmaceutical composition of embodiment 49 or embodiment 50, configured to be swallowed. Embodiment 52. The pharmaceutical composition of embodiment 49 or embodiment 50, configured to dissolve or disintegrate in the mouth, e.g., for sublingual or buccal administration Embodiment 53. The pharmaceutical composition of embodiment 49, in the form of a liquid. Embodiment 54. The pharmaceutical composition of embodiment 53, in the form of an aqueous-based composition (e.g., solution or suspension). Embodiment 55. The pharmaceutical composition of embodiment 49, wherein the pharmaceutical composition is the form of a dispersible solid, e.g., powder or granules, or a liquid concentrate that can be taken up in an aqueous liquid to form an aqueous-based composition. Embodiment 56. The pharmaceutical composition of any of embodiments 1-48, in the form of a liquid, cream or gel, e.g., for topical or intranasal administration. Embodiment 57. The pharmaceutical composition of any of embodiments 1-56, having a concentration of the PEG-saccharide-lipid conjugate in the range of 0.1-40 wt%. Embodiment 58. The pharmaceutical composition of any of embodiments 1-56, having a concentration of the PEG-saccharide-lipid conjugate in the range of 0.5-50 wt%. Embodiment 59. The pharmaceutical composition of any of embodiments 1-56, wherein a concentration of the PEG-saccharide-lipid conjugate in the range of 0.5-40% (wt / vol) and a concentration of 60-99.5% (wt / vol) of a solid or an aqueous medium (e.g., water or a buffer or a flavored solution). Embodiment 60. The pharmaceutical composition of any of embodiments 1-53, wherein the composition is the form of an aqueous solution having an amount of water or a buffer or flavoed solution in the range of 60-99 vol%. Embodiment 61. The pharmaceutical composition of any of embodiments 1-53, having an antiviral agent concentration in the range of 0.5 mg / mL to 50 mg / mL, and a conjugate concentration in the range of 0.5-30%(wt / vol) of PEG-saccharide-lipid conjugate. Embodiment 62. The pharmaceutical composition of any of embodiments 1-58, wherein the conjugate is present in the composition in an amount of at least 1 wt%, e.g., at least 2 wt%. Embodiment 63. The pharmaceutical composition of any of embodiments 1-58, wherein the conjugate is present in the composition in an amount of at least 5 wt%, e.g., at least 10 wt%. Embodiment 64. The pharmaceutical composition of any of embodiments 1-58, wherein the conjugate is present in the composition in an amount of at least 15 wt%, e.g., at least 20 wt%. In various embodiments, the conjugate of the disclosure is present in an amount of at least 25 wt%, e.g., at least 30 wt%. Embodiment 65. The pharmaceutical composition of any of embodiments 1-58, 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 66. The pharmaceutical composition of any of embodiments 1-58, 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 67. The pharmaceutical composition of any of embodiments 1-58, 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 68. The pharmaceutical composition of any of embodiments 1-58, 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 69. The pharmaceutical composition of any of embodiments 1-58, wherein the conjugate is present in an amount above its critical micelle concentration. Embodiment 70. The pharmaceutical composition of any of embodiments 1-69, wherein the antiviral agent is present in the composition in an amount of at least 0.1 wt%, e.g., at least 0.2 wt%. Embodiment 71. The pharmaceutical composition of any of embodiments 1-69, wherein the antiviral agent is present in the composition in an amount of at least 0.5 wt%, e.g., 1 wt%. Embodiment 72. The pharmaceutical composition of any of embodiments 1-69, wherein the antiviral agent is present in the composition in an amount of at least 2 wt%, e.g., at least 5 wt%. Embodiment 73. The pharmaceutical composition of any of embodiments 1-69, wherein the antiviral agent is present in the composition in an amount of at least 10 wt%, e.g., at least 20 wt%. Embodiment 74. The pharmaceutical composition of any of embodiments 1-69, wherein the antiviral 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 75. The pharmaceutical composition of any of embodiments 1-69, wherein the antiviral 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 76. The pharmaceutical composition of any of embodiments 1-69, wherein the antiviral 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 77. The pharmaceutical composition of any of embodiments 1-69, wherein the antiviral 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 78. The pharmaceutical composition of any of embodiments 1-77, wherein a weight ratio of the conjugate of the disclosure to the antiviral agent is in the range of 1-100. Embodiment 79. The pharmaceutical composition of any of embodiments 1-77, wherein a weight ratio of the conjugate to the antiviral agent is in the range of 0.5-50, or 0.5-10. Embodiment 80. The pharmaceutical composition of any of embodiments 1-77, wherein a weight ratio of the conjugate of the disclosure to the antiviral agent is in the range 500:1 - 1:2, e.g., 200:1 - 1:2, or 100:1 - 1:2, or 50:1 - 1:2, or 20:1 - 1:2. Embodiment 81. The pharmaceutical composition of any of embodiments 1-77, wherein a weight ratio of the conjugate of the disclosure to the antiviral 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 82. The pharmaceutical composition of any of embodiments 1-77, wherein a weight ratio of the conjugate of the disclosure to the antiviral agent is in the range of 500:1 - 2:1, e.g., 200:1 - 2:1, or 100:1 - 2:1, or 50:1 - 2:1, or 20:1 - 2:1, or 10:1 - 2:1, or 5:1 - 2:1. Embodiment 83. The pharmaceutical composition of any of embodiments 1-77, a weight ratio of the conjugate of the disclosure to the antiviral agent is in the range of 500:1 - 4:1, e.g., 200:1 - 4:1, or 100:1 - 4:1, or 50:1 - 4:1, or 20:1 - 4:1, or 10:1 to 4:1. Embodiment 84. The pharmaceutical composition of any of embodiments 1-83, wherein a weight ratio of the conjugate to poorly-soluble steviol glycosides is in the range of 1-10. Embodiment 85. The pharmaceutical composition of any of embodiments 1-83, wherein a weight ratio of the conjugate to a total content of Rebaudioside D and Rebaudioside M is in the range of 1-10. Embodiment 86. The pharmaceutical composition of any of embodiments 1-84, wherein a weight ratio of the conjugate to other excipients (including surfactants) is in the range of 0.5 to 5. Embodiment 87. The pharmaceutical composition of any of embodiments 1-86, for use in the treatment of a subject having a viral condition, the antiviral agent of the composition being suitable for treating the viral condition. Embodiment 88. A method for treating a subject having a condition, the method comprising administering to the subject the pharmaceutical composition of any of embodiments 1-86. Embodiment 89. The method of embodiment 87, wherein the administration is an oral administration. Embodiment 90. The method or composition of any of embodiments 87-89, wherein the viral condition is human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS). Embodiment 91. The method or composition of any of embodiments 87-89, wherein the viral condition is hepatitis, e.g., hepatitis B or hepatitis C. Embodiment 92. Use of a conjugate as identified in embodiment 1 or embodiment 2, as a pharmaceutical excipient in a medicament comprising an antiviral agent selected selected from the group consisting of tenofovir, dolutegravir, lopinavir, abacavir, bictegravir, cobicistat, darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, lamivudine, lenacapavir, lopinavir, rilpivirine, ritonavir, sofosbuvir, and any combination thereof. Embodiment 93. Use of a conjugate as identified in embodiment 1 or embodiment 2, for increasing bioavailability of an antiviral agent selected from the group consisting of tenofovir, dolutegravir, lopinavir, abacavir, bictegravir, cobicistat, darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, lamivudine, lenacapavir, lopinavir, rilpivirine, ritonavir, sofosbuvir, and any combination thereof. Embodiment 94. Use of a conjugate as identified in embodiment 1 or embodiment 2, for increasing solubility in an aqueous system of an antiviral agent selected selected from the group consisting of tenofovir, dolutegravir, lopinavir, abacavir, bictegravir, cobicistat, darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, lamivudine, lenacapavir, lopinavir, rilpivirine, ritonavir, sofosbuvir, and any combination thereof. Embodiment 95. Use of a conjugate as identified in embodiment 1 or embodiment 2, for increasing solubility of poorly-soluble rebaudiosides in an aqueous system. Embodiment 96. Use of a conjugate as identified in embodiment 1 or embodiment 2, as a pharmaceutical excipient together with an antiviral agent. Embodiment 97. The composition, method or use of any of embodiments 1, 3 and 4-96 as they depend from embodiments 1 and 3, wherein m has a number-average value in the range of 2-8, e.g., in the range of 2-6, or 2-5, or 2-4. Embodiment 98. The composition, method or use of any of embodiments 1, 3 and 4-96 as they depend from embodiments 1 and 3, wherein m has a number-average value of 3. Embodiment 99. The composition, method or use of any of embodiments 1, 3 and 4-96 as they depend from embodiments 1 and 3, wherein m has a number-average value of 2, or m has a number-average value of 4. Embodiment 100. The composition, method or use of any of embodiments 1, 3 and 4-96 as they depend from embodiments 1 and 3, wherein m has a number-average value in the range of 5-10, e.g., 5-8 or 8-10. Embodiment 101. The conjugate, composition ,method or use of any of embodiments 1, 3, 97-100 and 4-96 as they depend from embodiments 1 and 3, wherein S is a disaccharide group. Embodiment 102. The conjugate, composition,method or use of any of embodiments 1, 3, 97-100 and 4-96 as they depend from embodiments 1 and 3, wherein S is a monosaccharide group. Embodiment 103. The conjugate, composition,method or use of any of embodiments 1, 3, 97-100 and 4-96 as they depend from embodiments 1 and 3, wherein S is a trisaccharide group. Embodiment 104. The composition, method or use of any of embodiments 1, 3, 97-103 and 4-96 as they depend from embodiments 1 and 3, wherein saccharide units of S are individually selected from hexoses and pentoses and sugar alcohol, sugar acid and amino sugar analogs thereof. Embodiment 105. The composition, method or use of any of embodiments 1, 3, 97-104 and 4-96 as they depend from embodiments 1 and 3, wherein saccharide units of S are individually selected from hexoses and sugar alcohol, sugar acid and amino sugar analogs thereof. Embodiment 106. The composition, method or use of any of embodiments 1, 3, 97-105 and 4-96 as they depend from embodiments 1 and 3, 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 107. The conjugate of embodiment 106, wherein any saccharide unit of S that is not directly bound to the nitrogen of the diamine is a sugar. Embodiment 108. The composition, method or use of any of embodiments 1, 3, 97-107 and 4-96 as they depend from embodiments 1 and 3, wherein S has the structural formula in which -(Cx1H2x1Ox1-1)-CO- is a sugar acyl residue derived from a sugar acid in which x1 is 4 or 5, and (Cx2H2x2-1Ox2-1)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof. Embodiment 109. The conjugate of embodiment 108, wherein x1 is 5 and x2 is 6. Embodiment 110. The composition, method or use of any of embodiments 1, 3, 97-109 and 4-96 as they depend from embodiments 1 and 3, wherein S has the structure or is an open-chain version thereof. Embodiment 111. The composition, method or use of any of embodiments 1, 3, 97-110 and 4-96 as they depend from embodiments 1 and 3, wherein S is lactobionyl or gluconyl, for example, lactobionyl. Embodiment 112. The composition, method or use of any of embodiments 1, 3, 97-110 and 4-96 as they depend from embodiments 1 and 3, 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), for example sucrose, lactose, maltose, trehalose , turanose, cellobiose raffinose, melezitose and maltotriose. Embodiment 113. The composition, method or use of any of embodiments 1, 3, 97-112 and 4-96 as they depend from embodiments 1 and 3, wherein L includes (or is) -C(O)-R1, wherein R1is an alkanyl and / or alkenyl group having a number-average number of carbons in the range of 6-22. Embodiment 114. The composition, method or use of any of embodiments 1, 3, 97-113 and 4-96 as they depend from embodiments 1 and 3, wherein R1has a number-average number of carbons in the range of 6-20, or 6-18. Embodiment 115. The composition, method or use of any of embodiments 1, 3, 97-113 and 4-96 as they depend from embodiments 1 and 3, wherein R1has a number-average number of carbons in the range of 10-22, e.g., 10-20 or 10-18. Embodiment 116. The composition, method or use of any of embodiments 1, 3, 97-113 and 4-96 as they depend from embodiments 1 and 3, wherein R1has a number-average number of carbons in the range of 12-22, e.g., 12-20 or 12-18. Embodiment 117. The composition, method or use of any of embodiments 1, 3, 97-113 and 4-96 as they depend from embodiments 1 and 3, wherein R1has a number-average number of carbons in the range of 14-22, e.g., 14-20 or 14-18. Embodiment 118. The composition, method or use of any of embodiments 1, 3, 97-117 and 4-96 as they depend from embodiments 1 and 3, wherein R1has a number-average number of carbons that is no more than 18. Embodiment 119. The composition, method or use of any of embodiments 1, 3, 97-118 and 4-96 as they depend from embodiments 1 and 3, wherein R1has a number-average number of unsaturations in the range of 0-3, e.g., 0-2. Embodiment 120. The composition, method or use of any of embodiments 1, 3, 97-119 and 4-96 as they depend from embodiments 1 and 3, wherein R1is a linear alkyl or alkenyl group. Embodiment 121. The composition, method or use of any of embodiments 1, 3, 97-120 and 4-96 as they depend from embodiments 1 and 3, wherein 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 122. The composition, method or use of any of embodiments 1, 3, 97-121 and 4-96 as they depend from embodiments 1 and 3, 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 123. The composition, method or use of any of embodiments 1, 3, 97-121 and 4-96 as they depend from embodiments 1 and 3, 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 124. The conjugate of embodiment 122 or embodiment 123, wherein the single chemical identity is cis-CH3(CH2)7CH=CH(CH2)7C(O)-. Embodiment 125. The conjugate of embodiment 122 or embodiment 123, wherein the single chemical identity is cis,cis-CH3(CH2)4CH=CHCH2CH=CH(CH2)7C(O)-. Embodiment 126. The conjugate of embodiment 122 or embodiment 123, wherein the single chemical identity is cis-CH3(CH2)3CH=CH(CH2)7C(O)-. Embodiment 127. The conjugate of embodiment 122 or embodiment 123, 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 128. The conjugate of embodiment 122 or embodiment 123, 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)11C(O)-. Embodiment 129. The composition, method or use of any of embodiments 1, 3, 97-128 and 4-96 as they depend from embodiments 1 and 3, wherein L includes (or is) a steroid acyl group (e.g., a bile acyl group). Embodiment 130. The composition, method or use of any of embodiments 1, 3, 97-122, 129 and 4-96 as they depend from embodiments 1 and 3, wherein the steroid acyl group is an acyl group derived from cholesterol,. cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, chenodeoxycholic acid, and lithocholic acid (e.g., cholic acid, deoxycholic acid, or glycocholic acid). Embodiment 131. The composition, method or use of any of embodiments 1, 3, 97-130 and 4-96 as they depend from embodiments 1 and 3, wherein n has a number-average value in the range of 5-45, e.g., 5-40, or 5-30, or 5-20, or 5-15, or 5-10. Embodiment 132. The composition, method or use of any of embodiments 1, 3, 97-130 and 4-96 as they depend from embodiments 1 and 3, wherein n has a number-average value in the range of 8-50, e.g., 8-45, or 8-40, or 8-30, or 8-20, or 8-15, or 8-12, or 8-10. Embodiment 133. The composition, method or use of any of embodiments 1, 3, 97-130 and 4-96 as they depend from embodiments 1 and 3, wherein n has a number-average value in the range of 10-50, e.g., 10-45, or 10-40, or 10-30, or 10-20, or 10-15. Embodiment 134. The composition, method or use of any of embodiments 1, 3, 97-130 and 4-96 as they depend from embodiments 1 and 3, wherein n has a number-average value in the range of 9-14, e.g., or 9-13, or 10-14, or 10.5-13.5, or 11-13, or 11.5-12.5, or 11.8-12.2, or 10.2-13.8, or 10.8-13.2, or 11.4-12.6. Embodiment 135. The composition, method or use of any of embodiments 1, 3, 97-130 and 4-96 as they depend from embodiments 1 and 3, wherein n has a number-average value in the range of 18-28, e.g., 20-26, or 22-24, or 22.5-23.5, or 22.8-23.2. Embodiment 136. The composition, method or use of any of embodiments 1, 3, 97-130 and 4-96 as they depend from embodiments 1 and 3, wherein n has a number-average value in the range of 25-40. Embodiment 137. The composition, method or use of any of embodiments 1, 3, 97-130 and 4-96 as they depend from embodiments 1 and 3, wherein n has a number-average value in the range of 40-50, e.g., 42-48, or 44-46, or 44.5-45.5, or 44.8-45.2. Embodiment 138. The composition, method or use of any of embodiments 1, 3, 97-137 and 4-96 as they depend from embodiments 1 and 3, wherein R2has a number-average number of carbons of at least 0.95, e.g., at least 0.99 or at least 1. Embodiment 139. The composition, method or use of any of embodiments 1, 3, 97-137 and 4-96 as they depend from embodiments 1 and 3, wherein R2has a number-average number of carbons in the range of 0.9-1.1, or 0.95-1.05, or 0.98-1.02. Embodiment 140. The composition, method or use of any of embodiments 1, 3, 97-137 and 4-96 as they depend from embodiments 1 and 3, wherein R2is C1-C4alkanyl, e.g., methyl or ethyl. Embodiment 141. The composition, method or use of any of embodiments 1, 3, 97-137 and 4-96 as they depend from embodiments 1 and 3, wherein R2is methyl. Embodiment 142. The composition, method or use of any of embodiments 1, 3, 97-137 and 4-96 as they depend from embodiments 1 and 3, wherein R2has a number average number of carbons in the range 0-3, e.g., 0-2. Embodiment 143. The composition, method or use of any of embodiments 1, 3, 97-137 and 4-96 as they depend from embodiments 1 and 3, wherein R2has a number-average number of carbons in the range of 0-0.94, e.g., 0-0.75, or 0-0.5, or 0-0.1, or 0-0.05. Embodiment 144. The composition, method or use of any of embodiments 1, 3, 97-130 and 4-96 as they depend from embodiments 1 and 3, wherein the -P group is a methylated PEG residue having a number-average molecular weight in the range of 300-2200 g / mol. Embodiment 145. The composition, method or use of any of embodiments 1, 3, 97-130 and 4-96 as they depend from embodiments 1 and 3, wherein the -P group is a methylated PEG residue having a number-average molecular weight in the range of 300-1200 g / mol, e.g., 300- 600 g / mol. Embodiment 146. The composition, method or use of any of embodiments 1, 3, 97-130 and 4-96 as they depend from embodiments 1 and 3, wherein the -P group is a methylated PEG residue having a number-average molecular weight in the range of 500-2200 g / mol, e.g., 500- 1200 g / mol, or 500-900 g / mol. Embodiment 147. The composition, method or use of any of embodiments 1, 3, 97-130 and 4-96 as they depend from embodiments 1 and 3, wherein the -P group is a methylated PEG residue having a number-average molecular weight in the range of 700-2200 g / mol, e.g., 700- 1200 g / mol, or 700-1100 g / mol. Embodiment 148. The composition, method or use of any of embodiments 1, 3, 97-130 and 4-96 as they depend from embodiments 1 and 3, wherein the -P group is a methylated PEG residue having a number-average molecular weight in the range of 475-525 g / mol. Embodiment 149. The composition, method or use of any of embodiments 1, 3, 97-130 and 4-96 as they depend from embodiments 1 and 3, wherein the -P group is a methylated PEG residue having a number-average molecular weight in the range of 525-575 g / mol. Embodiment 150. The composition, method or use of any of embodiments 1, 3, 97-130 and 4-96 as they depend from embodiments 1 and 3, wherein the -P group is a methylated PEG residue having a number-average molecular weight in the range of 710-790 g / mol. Embodiment 151. The composition, method or use of any of embodiments 1, 3, 97-130 and 4-96 as they depend from embodiments 1 and 3, wherein the -P group is a methylated PEG residue having a number-average molecular weight in the range of 900-1100 g / mol, e.g., 950- 1050 g / mol. Embodiment 152. The composition, method or use of any of embodiments 1, 3, 97-130 and 4-96 as they depend from embodiments 1 and 3, wherein the -P group is a methylated PEG residue having a number-average molecular weight in the range of 1800-2200 g / mol, e.g., 1900-2100 g / mol. Embodiment 153. The composition, method or use of any of embodiments 1, 3, 97-152 and 4-96 as they depend from embodiments 1 and 3, wherein P has a polydispersity index of no more than 1.1, e.g., no more than 1.07. Embodiment 154. The composition, method or use of any of embodiments 1, 3, 97-152 and 4-96 as they depend from embodiments 1 and 3, wherein P has a polydispersity index of no more than 1.06, e.g., no more than 1.05. Embodiment 155. The composition, method or use of any not inconsistent embodiment above, wherein m is 3; S has the structural formula as below: in which -(Cx1H2x1Ox1-1)-CO- is a sugar acyl residue derived from a sugar acid in which x1 is 4 or 5, and (Cx2H2x2-1Ox2-1)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof; -C(O)-R1is at least 80 mol% of cis-CH3(CH2)7CH=CH(CH2)7C(O)-, e.g., at least 85 mol%; R2is methyl; n has a weight-average value in the range of 11.5-12.5, e.g., 11.8-12.2; and P has a polydispersity index of no more than 1.1, e.g., no more than 1.07. Embodiment 156. The composition, method or use of any not inconsistent embodiment above, wherein m is 3; S has the structural formu la in which -(Cx1H2x1Ox1-1)-CO- is a sugar acyl residue derived from a sugar acid in which x1 is 4 or 5, and (Cx2H2x2-1Ox2-1)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof; -C(O)-R1is at least 80 mol% of cis-CH3(CH2)7CH=CH(CH2)7C(O)-, e.g., at least 85 mol%; and the -P group is a methylated PEG residue having a number-average molecular weight in the range of 525-575 g / mol and having a polydispersity index of no more than 1.1, e.g., no more than 1.07. Embodiment 157. The composition, method or use of embodiment 155 or embodiment 156, wherein x1 is 5 and x2 is 6. Embodiment 158. The composition, method or use of any of embodiments 155-157, wherein S has the structure or is an open-chain version thereof. Embodiment 159. The composition, method or use of any of embodiments 155-158, wherein S is lactobionyl. Embodiment 160. The composition, method or use of any of embodiments 155-159, wherein -C(O)-R1is at least 90 mol% of cis-CH3(CH2)7CH=CH(CH2)7C(O)-, e.g., at least 95 mol%. Embodiment 161. The composition, method or use of any of embodiments 155-160, wherein P has a polydispersity index of no more than 1.06, e.g., no more than 1.05. Embodiment 162. The composition, method or use of any not inconsistent embodiment above, wherein the conjugate has the structural formula of Chemical Structure 1: Chemical Structure 1, wherein m(PEG)nis a methylated PEG residue, and n is any value in any embodiment described above. Embodiment 163. The composition, method or use of embodiment 162, wherein the fatty acyl residue -C(O)-R1is derived from one or more of Lauric acid, Myristic acid, Palmitic acid, Linoleic acid, Oleic acid and Stearic acid. Embodiment 164. The composition, method or use of any not inconsistent embodiment above, wherein the conjugate is Oleoyldiaminopropane-monomethoxypolyethylene-glycol- ether-lactobionate (DOPS), which can be represented by the Chemical Structure 2: Chemical Structure 2 (DOPS) wherein m(PEG)nis a methylated PEG residue, and n is any value in any embodiment described above. Embodiment 165. The composition, method or use of any not inconsistent embodiment above, wherein the conjugate is Stearylpropanediamino-monomethoxypolyethylene-glycol- ether-lactobionate, which can be represented by Chemical Structure 3: Chemical Structure 3 (DSPS) wherein m(PEG)nis a methylated PEG residue, and n is any value in any embodiment described above. Embodiment 166. The composition, method or use of any not inconsistent embodiment described above, wherein the conjugate is represented by Chemical Structure 4: Chemical Structure 4 wherein m(PEG)nis a methylated PEG residue and n is any value in any embodiment described above, and m is in the range of 2-6, e.g., is 3. Embodiment 167. The composition, method or use of any not inconsistent embodiment described above, wherein the conjugate is Choloylpropanediamino-mPEG-lactobionate (CDPS), which can be represented by Chemical Structure 5: Chemical Structure 5 (CDPS) wherein m(PEG)n is methylated PEG residue, and n is any desirable value as described above. Embodiment 168. The composition, method or use of any of embodiments 162-167, wherein the number-average value of n is in the range of 9.2-13.8, e.g., 10.2-13.2, or 11-13, or 11.4-13.6, or 11.5-12.5, or 11.8-12.2. Embodiment 169. The composition, method or use of any not-inconsistent embodiment above, wherein the conjugate has one of the following structures:

[0017] . Embodiment 170. The composition, method or use of any of embodiments 1-169, wherein -P is provided from a P-H poly(ethylene glycol) source (e.g., an mPEG) that has a number- average molecular weight in the range of 95.0-105.0% of the labeled nominal value if the labeled nominal value is below 1000 g / mol, or in the range of 90.0-110.0% of the labeled nominal value if the labeled nominal value is in the range of 1000 and 2000 g / mol. Embodiment 171. The composition, method or use of any of embodiments 1-170, wherein the conjugate has a purity of at least 85 wt% as measured by HPLC. Embodiment 172. The composition, method or use of any of embodiments 1-170, wherein the conjugate has a purity of at least 90 wt% as measured by HPLC. Embodiment 173. The composition, method or use of embodiment 171, wherein the conjugate is used in an oral application. Embodiment 174. The composition, method or use of embodiment 172, wherein the conjugate is used in a parenteral application. Embodiment 175. The composition, method or use of any of embodiments 1-174, 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 176. The composition, method or use of embodiment 175, wherein the single chemical identity is oleoyl, myristoyl, palmitoyl, stearoyl or linoleoyl. Embodiment 177. The composition, method or use of any of embodiments 1-176, wherein R1-C(O) is fatty acyl and the conjugate when assayed by HPLC, resembles the peak profile of Figure 1, 2 or 3 and the following relative retention time (RRT): Embodiment 177. The conjugate of any of embodiments 1-177, having an HLB value in the range of 13-18, e.g., in the range of 13-15. Embodiment 178. The composition, method or use of any of embodiments 1-96, wherein the conjugate has the formula: wherein: Lipid is selected from a group consisting of fatty acids including lauric acid, myristic acid, linoleic acid, palmitic acid, oleic acid, elaidic acid and steroid acids; m(PEG)n is a polymer of polyethylene glycols; n ranges from 8 to 45 of ethylene glycol subunits; and m* = 1 to 6 of CH2. Embodiment 179. The composition, method or use of embodiment 178 or any of the above not-inconsistent embodiments, having one or more of the following properties or specifications: a. the mPEG ranges between 95.0% and 105.0% of the labeled nominal value if the labeled nominal value is below 1000 or between 90.0% and 110.0% of the labeled nominal value if the labeled nominal value is between 1000 and 2000. b. Purity of the said polymeric conjugate is between 85% and 115.0 by HPLC assay if used for oral applications; c. Purity of the said polymeric conjugate is between 90% and 110.0% by HPLC assay if used for parenteral application; d. Purity of oleic acid if utilized is not less than 65% e. Individual related analogue or impurity is less than 5%; and f. Fatty acid based said polymers, resemble of the peak profile of Figures 1, 2 or 3 and the following relative retention time (RRT): y Embodiment 180. The composition, method or use of embodiment 178 or embodiment 179 or any of the above not-inconsistent embodiments, wherein the synthesis method for preparing a said polymer comprises the steps of: (1) coupling activated monomethoxypolyethylene glycol ether to the unprotected amino group of the center backbone; (2) conjugating a lipid or disaccharide to the backbone, thereby forming a PEG- saccharide-lipid conjugate having a high purity of conjugates in the range of 85% to 115% by HPLC assay. Embodiment 181. The composition, method or use of embodiment 178 or embodiment 179, or any of the above not-inconsistent embodiments, wherein the synthesis method for preparing a said polymer comprises the steps of: (1) synthesizing a short-chain of ethylene glycol protected hydroxyl groups on the ethylene glycol and amino group of the center backbone; (2) extending the PEG chain by repeating the short ethylene glycol chain reaction. (3) conjugating a lipid or disaccharide to the backbone, thereby forming a PEG- saccharide-lipid having a high purity of PEG oligomer. wherein the sequence or order of coupling steps or sites is interchangeable. Embodiment 182. The composition, method or use of any of embodiments 178-181 or any of the above not-inconsistent embodiments, wherein the m* in the backbone is 0 or 1 thereby forming a PEG-saccharide-lipid conjugate with no or less hemolytic potential suitable for parenteral administrations as well as oral applications having the following structure(s): wherein when m* is 1, the backbone is propane; or when m* is zero, the backbone is ethylene; FA is a fatty acid which is select for a group consisting but not limited to lauric acid, myristic acid, linoleic acid, palmitic acid, linoleic acid, oleic acid or stearic acids; and n is ranging from 8 to 45 Embodiment 183. The composition, method or use of any of embodiments 178-182 or any of the above not-inconsistent embodiments, wherein the distance between the 2 terminal amines is less than 4 carbons if use for parenteral administrations. Embodiment 184. The composition, method or use of any of embodiments 178-182 or any of the above not-inconsistent embodiments, wherein the m* in the backbone is greater than 1 thereby forming a PEG-saccharide-lipid conjugate that is more suitable for oral administration or other applications Embodiment 185. The composition, method or use of any of embodiments 178-184 or any of the above not-inconsistent embodiments, wherein said PEG-saccharide-lipid conjugates are solid (low-water) or semisolid (higher moisturized) and stable for at least 36 months under room temperature storage conditions. Embodiment 186. The composition, method or use of any of embodiments 178-185 or any of the above not-inconsistent embodiments, wherein the monomethoxypolyethylene glycol ether having an average molecular weight between 95.0% and 105.0% of the labeled nominal value if the labeled nominal value is below 1000 or between 90.0% and 110.0% of the labeled nominal value if the labeled nominal value is between 1000 and 2000. Embodiment 187. The composition, method or use of any of embodiments 178-186 or any of the above not-inconsistent embodiments, wherein a monosaccharide-related impurity in said polymer is less than 5%. Embodiment 188. The composition, method or use of any of embodiments 178-183 or any of the above not-inconsistent embodiments, wherein the total fatty acid related impurities in said polymer are less than 10% and individual fatty acid related impurity is less than 5%. Embodiment 189. The composition, method or use of any of embodiments 178-183 and 186- 188 or any of the above not-inconsistent embodiments, wherein the purity of said polymer is not least than (≥) 90% to be used for parenteral compositions. Embodiment 190. The composition, method or use of any of embodiments 178-183 and 186- 188 or any of the above not-inconsistent embodiments, wherein said polymer is purified or dried by lyophilization if use for parenteral administrations. Embodiment 191. The composition, method or use of any of embodiments 178-183 and 186- 190 or any of the above not-inconsistent embodiments, wherein the purity of said polymer is not less than (≥) 85% to be used for pharmaceutical oral compositions. Embodiment 192. The composition, method or use of any of embodiments 178-191 or any of the above not-inconsistent embodiments, wherein the weight ratio of the PEG-saccharide conjugate to an oncology compound is between about 200 and about 1 for the drug delivery. Embodiment 193. The composition, method or use of any of embodiments 178-191 or any of the above not-inconsistent embodiments, wherein the weight ratio of the PEG-saccharide-lipid conjugates to a non-oncology compound is between about 200 and about 1 for the compound delivery. Embodiment 194. The composition, method or use of polymer of any of embodiments 178-193 or any of the above not-inconsistent embodiments, wherein said PEG-saccharide-lipid conjugate has a structure selected from the below:

[0018] wherein n ranges from 8 to 45. Embodiment 195. The composition, method or use of embodiment 2, or the composition, method or use of any of embodiments 4-96 as they depend from embodiment 2, wherein L is a fatty acid residue, e.g., having 5-22 carbons. Embodiment 196. The composition, method or use of embodiment 2 or 195, or the composition, method or use of any of embodiments 4-194 as they depend from embodiment 2, wherein L is a residue of stearic acid, oleic acid, palmitic acid, myristic acid, or lauric acid. Embodiment 197. The composition, method or use of embodiment 2, 195 or 196, or the composition, method or use of any of embodiments 4-194 as they depend from embodiment 2, wherein the polyethylene glycol has from 5 to 45 subunits, e.g., 5-25 subunits. Embodiment 198. The composition, method or use of embodiment 2 or any of 195-197, or the composition, method or use of any of embodiments 4-194 as they depend from embodiment 2, wherein the polyethylene glycol residue is a is a monomethoxypolyethylene glycol residue, e.g., having 6-45 subunits. Embodiment 199. The composition, method or use of embodiment 2 or any of embodiments 195-198, or the composition, method or use of any of embodiments 4-194 as they depend from embodiment 2, wherein the backbone B is one or more of (e.g., one of) glycerol, glycerol-like analogues having three binding positions, diamines, triamines, diaminoalcohols, aminoalcohols, aminodiols, aminotriols, amino acids, triols, tetraols, triacids, tetracids, halogen-containing diols, halogen-containing amines, carboxyl containing diols and polyamines. Embodiment 200. The composition, method or use of embodiment 2 or any of embodiments 195-198, or the composition, method or use of any of embodiments 4-194 as they depend from embodiment 2, wherein B is one or more of diamines, triamines, glycerol and aminoacids. Embodiment 201. The composition, method or use of embodiment 2 or 195, or the composition, method or use of any of embodiments 4-194 as they depend from embodiment 2, wherein the PEG-saccharide-lipid conjugates is one or more of fatty acid Embodiment 202. The composition, method or use of embodiment 2 or 195, or the composition, method or use of any of embodiments 4-194 as they depend from embodiment 2, wherein the PEG-saccharide-lipid conjugate is represented by one or the following structures: wherein n = 8 to 45 Embodiment 203. The composition, method or use of embodiment 2 or 195, or the composition, method or use of any of embodiments 4-194 as they depend from embodiment 2, as further described in any of embodiments 97-194. Embodiment 204. A pharmaceutical composition (for example, for oral administration), the pharmaceutical composition comprising: one or more steviol glycosides mainly comprising one or more steviosides and / or rebaudiosides, and a PEG-saccharide-lipid conjugate having the structural formula wherein m has a number-average value in the range of 2-10; S is a mono-, di- or trisaccharide group, in which each saccharide unit is a sugar, a sugar alcohol, an amino sugar or a sugar acid; L is -C(O)-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; P is -(CH2-CH2-O)nR2in which n has a number-average value in the range of 5- 50 (e.g., 8-45) and R2is hydrogen and / or alkanyl and has a number average number of carbons in the range 0-4 Embodiment 205. A pharmaceutical composition for oral administration, the pharmaceutical composition comprising: a solubility or bioavailability enhancer comprising PEG-saccharide-lipid conjugate represented by the chemical structure: wherein: L is a lipophilic residue selected from fatty acid residues and steroid acid residues (e.g., bile acid residues, cholesterol residues); S is a saccharide selected from monosaccharides, disaccharides and trisaccharides; P is a polyethylene glycol residue having from 4 to 45 subunits; and B is a backbone molecule having three or four available binding positions; and one or more steviol glycosides mainly comprising one or more steviosides and / or rebaudiosides. Embodiment 206. A composition as described in embodiment 204 or embodiment 205, wherein the PEG-saccharide-lipid conjugate and / or the one or more steviol glycosides is as identified in any one or more non-inconsistent embodiments above. Embodiment 207. A composition as described in any of embodiments 204-206, as further described with respect to any one or more non-inconsistent embodiment above. Embodiment 208. A composition as described in any of embodiments 204-207, lacking an antiviral agent as identified in embodiment 1. Embodiment 209. A composition as described in any of embodiments 204-208, further comprising an active pharmaceutical agent that is not an antiviral agent as identified in claim 1, e.g., in an amount as generally described for the antiviral agent in various above embodiments. Embodiment 210. A composition for use, method or use as identified in any one or more non-inconsistent embodiments above (e.g.., any embodiment not specifically requiring an antiviral agent), wherein the composition is as described in any of embodiments 204-209. Embodiment 211. Use of steviol glycosides (such as rebaudiosides, for example, Rebaudiosides A, D and / or M as described herein) for masking or modifying the bitterness taste of an antiviral agent, e.g., in a pharmaecueticual composition, method or use as described in any not-inconsistent embodiment above. Embodiment 212. A composition comprising:one or more steviol glycosides mainly comprising one or more steviosides and / or rebaudiosides, and an antiviral agent selected from the group consisting of tenofovir, dolutegravir, lopinavir, abacavir, bictegravir, cobicistat, darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, lamivudine, lenacapavir, lopinavir, rilpivirine, ritonavir, sofosbuvir, and any combination thereof. Embodiment 213. A composition as described in embodiment 212, wherein the antiviral agent and / or the one or more steviol glycosides is as identified in any one or more non- inconsistent embodiments above. Embodiment 214. A composition as described in any of embodiments 212 and 213, as further described with respect to any non-inconsistent embodiment above. Embodiment 215. A composition as described in any of embodiments 212-214, lacking a conjugate as identified in embodiment 1 or embodiment 2. Embodiment 216. A composition as described in any of embodiments 212-215, further comprising an active pharmaceutical agent that is not an antiviral agent as identified in claim 1, e.g., in an amount as generally described for the antiviral agent in various above embodiments. Embodiment 217. A composition as described in any of embodiments 212-216, further comprising a solubilizing agent. Embodiment 218. A composition as described in embodiment 217, wherein the solubilizing agent comprises one or more of fatty acid esters of sorbitans, fatty acid esters of polyethoxylated sorbitans, materials available under the name Chremophor™, polyethylene glycols, mannitol, lactose, polyvinylpyrrolidone, poloxamers and cyclodextrin derivatives, polysorbates, polyoxyl 40 hydrogenated castor oil. Embodiment 219. Use of steviol glycosides (such as rebaudiosides, for example, Rebaudiosides A, D and / or M as described herein) for masking or modifying the bitterness taste of an antiviral agent, e.g., in a pharmaecueticual composition, method or use as described in any not-inconsistent embodiment above.

Claims

What is claimed is:

1. A pharmaceutical composition (for example, for oral administration) of an antiviral agent (e.g., an antiretroviral agent), the pharmaceutical composition comprising: the antiviral agent, comprising an agent selected from the group consisting of tenofovir, dolutegravir, lopinavir, abacavir, bictegravir, cobicistat, darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, lamivudine, lenacapavir, lopinavir, rilpivirine, ritonavir, sofosbuvir, and any combination thereof; and a PEG-saccharide-lipid 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; P is -(CH2-CH2-O)nR2in which n has a number-average value in the range of 5- 50 (e.g., 8-45) and R2is hydrogen and / or alkanyl and has a number average number of carbons in the range 0-4.

2. A pharmaceutical composition for oral administration of an antiviral agent (e.g., an antiretroviral agent), the pharmaceutical composition comprising: the antiviral agent, comprising an agent selected from the group consisting of tenofovir, dolutegravir, lopinavir, abacavir, bictegravir, cobicistat, darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, lamivudine, lenacapavir, lopinavir, rilpivirine, ritonavir, sofosbuvir, and any combination thereof; a solubility or bioavailability enhancer comprising PEG-saccharide-lipid conjugate represented by the chemical structure:wherein: L is a lipophilic residue selected from fatty acid residues and steroid acid residues (e.g., bile acid residues, cholesterol residues); S is a saccharide selected from monosaccharides, disaccharides and trisaccharides; P is a polyethylene glycol residue having from 4 to 45 subunits; and B is a backbone molecule having three or four available binding positions; and one or more steviol glycosides mainly comprising one or more steviosides and / or rebaudiosides.

3. The pharmaceutical composition of claim 1 further comprising one or more steviol glycosides mainly comprising one or more steviosides and / or rebaudiosides.

4. The pharmaceutical composition of claim 1, wherein the antiviral agent includes (or is) tenofovir.

5. The pharmaceutical composition of claim 3, wherein a weight ratio of the one or more steviol glycosides to the conjugate is in the range of 1-10.

6. The pharmaceutical composition of claim 3, wherein the one or more steviol glycosides are present in the composition an amount in the range of 0.5-25 wt%.

7. The pharmaceutical composition of claim 3, wherein a total amount of one or more of Rebaudiosides A, D and M is at least 90 wt% of a total amount of steviol glycosides.

8. The pharmaceutical composition of claim 1, further comprising one or more sweeteners.

9. The pharmaceutical composition of claim 1, further comprising an antioxidant.

10. The pharmaceutical composition claim 9, wherein the antioxidant includes one or more of ascorbic acid, α-tocopherol and D-α-tocopherol polyethylene glycol 1000 succinate.

11. The pharmaceutical composition of claim 1, further comprising a bulking filler selected from polyethylene glycols, mannitol, lactose, polyvinylpyrrolidone, poloxamers or cyclodextrin derivative, polysorbates, polyoxyl 40 hydrogenated castor oil, polyethyleneglycols or a combination thereof.

12. The pharmaceutical composition of claim 1, in a liquid form.

13. The pharmaceutical composition of claim 1, in a solid form.

14. The pharmaceutical composition of claim 1, wherein a weight ratio of the conjugate to the antiviral agent is in the range of 0.5-50.

15. The pharmaceutical composition of claim 3 wherein a weight ratio of the conjugate to poorly-soluble steviol glycosides is in the range of 1-10.

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

17. The pharmaceutical composition of claim 1, wherein m has a number-average value in the range of 5-10.

18. The pharmaceutical composition of claim 1, wherein S is a disaccharide group.

19. The pharmaceutical composition of claim 1, wherein S has the structural formulain which -(Cx1H2x1Ox1-1)-CO- is a sugar acyl residue derived from a sugar acid in which x1 is 4 or 5, and (Cx2H2x2-1Ox2-1)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof.

20. The pharmaceutical composition of claim 1, wherein S is lactobionyl or gluconyl.

21. The pharmaceutical composition of claim 1, wherein L is -C(O)-R1, and R1is a linear alkyl or alkenyl group and has a number-average number of carbons in the range of 12-18.

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

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

24. The pharmaceutical composition of claim 1, wherein n has a number-average value in the range of 9-13 and R2is methyl.

25. The pharmaceutical composition of claim 1, wherein P has a polydispersity index of nomore than 1.

1.

26. The pharmaceutical composition of claim 1, wherein m is 3; S has the structural formula as below:in which -(Cx1H2x1Ox1-1)-CO- is a sugar acyl residue derived from a sugar acid in which x1 is 4 or 5, and (Cx2H2x2-1Ox2-1)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof; -C(O)-R1is at least 80 mol% of cis-CH3(CH2)7CH=CH(CH2)7C(O)-, e.g., at least 85 mol%; R2is methyl; n has a weight-average value in the range of 11.5-12.5, e.g., 11.8-12.2; and P has a polydispersity index of no more than 1.1, e.g., no more than 1.

07.

27. The pharmaceutical composition of claim 1, wherein the conjugate is Oleoyldiaminopropane-monomethoxypolyethylene-glycol-ether-lactobionate (DOPS), represented by the Chemical Structure 2:Chemical Structure 2 (DOPS) wherein m(PEG)nis a methylated PEG residue, and n is in the range of 9-13.

28. The pharmaceutical composition of claim 1, wherein the conjugate has one of the following structures:

29. The pharmaceutical composition of any claims 1-27, for use in the treatment of a subject having a viral condition, the antiviral agent of the composition being suitable for treating the viral condition.

30. A method for treating a subject having a condition, the method comprising administering to the subject the pharmaceutical composition of any claims 1-27.

31. The method of claim 29, wherein the administration is an oral administration.

32. The composition of claim 28, wherein the viral condition is human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS).

33. The composition of claim 28, wherein the viral condition is hepatitis, e.g., hepatitis B or hepatitis C.

34. Use of a conjugate as identified in any of claims 1, 2 and 15-27, as a pharmaceutical excipient in a medicament comprising an antiviral agent selected from the group consisting of tenofovir, dolutegravir, lopinavir, abacavir, bictegravir, cobicistat, darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, lamivudine, lenacapavir, lopinavir, rilpivirine, ritonavir, sofosbuvir, and any combination thereof.

35. Use of a conjugate as identified in any of claims 1, 2 and 15-27, for increasing bioavailability of an antiviral agent selected from the group consisting of tenofovir, dolutegravir, lopinavir, abacavir, bictegravir, cobicistat, darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, lamivudine, lenacapavir, lopinavir, rilpivirine, ritonavir, sofosbuvir, and any combination thereof.

36. Use of a conjugate as identified in embodiment 1 or embodiment 2, for increasing solubility in an aqueous system of an antiviral agent selected from the group consisting of tenofovir, dolutegravir, lopinavir, abacavir, bictegravir, cobicistat, darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, lamivudine, lenacapavir, lopinavir, rilpivirine, ritonavir,sofosbuvir, and any combination thereof.

37. Use of a conjugate as identified in any of claims 1, 2 and 15-27, for increasing solubility of poorly-soluble rebaudiosides in an aqueous system.

38. Use of a conjugate as identified in any of claims 1, 2 and 15-27, as a pharmaceutical excipient together with an antiviral agent.

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