Pharmaceutical compositions comprising edaravone

Abstract

The disclosure in one aspect provides a pharmaceutical composition of Edaravone, the pharmaceutical composition comprising: Edaravone which can be further combined with dexborneol; and a PEG-saccharide-lipid conjugate having the structural formula (I) wherein m has a number-average value in the range of 2-10; S is a mono-, di- or trisaccharide group; L is -C(O)-R1 in which R1 is an alkanyl or alkenyl group having a numberaverage number of carbons in the range of 6-22, and / or is a steroid acyl group; and 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. In various such embodiments, an amino acid is used as a co-solubilizer..

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING EDARA VONECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of 63 / 717,501, filed November 7,2024, and of U.S. Provisional Patent Application no. 63 / 750,913, filed January 29, 2025, each of which is hereby incorporated herein by reference in its entirety.BACKGROUND OF THE DISCLOSURE1. Field of the Disclosure

[0002] This disclosure relates to pharmaceutical compositions and methods for the administration of edaravone, optionally together with dexbomeol.2, Technical Background

[0003] Clinical studies have demonstrated that there is a synergistic effect of edaravone with dexborneol in the treatments of ischemic stroke. Edaravone (EDA) and dexbomeol are hydrophobic. The solid keto form of edaravone is very stable, in contrast to its anion which is very unstable in water or aqueous solution when pH is greater than 7, where it easily becomes an edaravone radical, resulting in formation of brownish or precipitates mainly composed of edaravone trimer. While a lower pH may reduce the formation of the anion, it further limits solubility. Sodium bisulfite (NaHSCh) or cysteine or glutathione or a combination thereof can be used as stabilizer(s) to reduce the formation of the dimer or trimer. However, the U.S. Food and Drug Administration (FDA) has cautioned that NaHSCh may cause allergic reactions. While basic amino acids (AA), e.g., arginine or lysine, can solubilized completely at a molar ratio of 1 (EDA) to 2 or 3 of (AA), the pH is greater than 7, e.g., pH 10 or 12, where the compound is largely in the anion form and thus unstable. It precipitates when the pH is lower than 7. Hence the amino acid alone is not a suitable solubilizer due to pH-induced destabilizing the edaravone active pharmaceutical ingredient (API).

[0004] Delivery of hydrophobic drug compounds to the site of action remains 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 may not provide significant improvements in water solubility, large quantities may be required, and an undesirable adverse effect, e.g., degree of hemolysis may result with high amounts of Cremophor.

[0005] Further improvements in compositions and methods for administering hydrophobic Edaravone agents are clinically significant for the treatments of amyotrophic lateral sclerosis (ALS) or stroke patients.SUMMARY OF THE DISCLOSURE

[0006] In one aspect, the present disclosure provides a pharmaceutical composition (for example, for oral administration) of edaravone (optionally together with dexbomeol), the pharmaceutical composition comprising: edaravone, optionally in combination with dexborneol; 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 numberaverage 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.

[0007] In various embodiments, the composition further includes one or more steviol glycosides mainly comprising one or more steviosides and / or rebaudiosides to reduce the bitterness taste of basic amino acids, e.g., arginine.

[0008] Another aspect of the disclosure is pharmaceutical composition for oral administration of edaravone that may further combine with dexbomeol, the pharmaceutical composition comprising: edaravone, optionally in combination with dexborneol; and a 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; andB is a backbone molecule having three or four available binding positions; and the composition further comprises one or more steviol glycosides (e.g., one or more steviosides and / or rebaudiosides and / or an amino acids (e.g., one or more of arginine, methylarginine, citrulline, homoarginine, canavanine, lysine, glutamine).

[0009] Another aspect of the disclosure is a method for treating a subject having amyotrophic lateral sclerosis, the method comprising administering to the subject a pharmaceutical composition as described herein.

[0010] Embodiment 150. Use of a conjugate as identified in any Embodiment above, as a pharmaceutical excipient in a medicament comprising edaravone, optionally in combination with dexbomeol.

[0011] Another aspect of the disclosure is a use of a conjugate as identified in anyEmbodiment above, for increasing bioavailability edaravone.

[0012] Another aspect of the disclosure is a use of a conjugate as identified in anyEmbodiment above, for increasing stability of edaravone in solid dosage forms of edaravone.

[0013] Another aspect of the disclosure is a use of a conjugate as identified in anyEmbodiment above, for increasing solubility in an aqueous system of edaravone.BRIEF DESCRIPTION OF THE DRAWINGS

[0014] 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:

[0015] FIG.l depicts HPLC chromatograms of fatty acid based conjugates: Peak 1 = lauroyl-propanediamino-mPEG(12)-lactobionate (DLOPS-12); Peak 2 = myristoylpropane- diamino-mPEG(12)-lactobionate (DMPS-12); Peak 3 = palmitoleoylpropanediamino- mPEG(12)-lactobionate (DPOPS-12); Peak 4 = linoleoyl-propanediamino-mPEG(12)- lactobionate (DLOPS-12); Peak 5 = palmitoylpropanediamino-mPEG(12)-lactobionate (DPPS- 12); Peak 6 = oleoylpropanediamino-mPEG(12)-lactobionate (DOPS-12); Peak 7 = oleoypropaneldiamino-mPEG(12)-gluconate; Peak 8 = stearoylpropanediamino-mPEG(12)-lactobionate (DSPS-12). The concentrations injected onto the column were approximately 4 to 6 mg / mL each.

[0016] 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.

[0017] FIG. 3 depicts a HPLC chromatogram of linoleoylpropanediamino-mPEG- lactobionate (DLPSFI-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.

[0018] FIG. 4 provides a cross-sectional schematic view of an oral dosage form according to one embodiment of the disclosure.

[0019] FIG. 5 provides a cross-sectional schematic view of an oral dosage form according to another embodiment of the disclosure.

[0020] FIG. 6 provides a cross-sectional schematic view of an oral dosage form according to another embodiment of the disclosure.

[0021] FIG. 7 depicts the curve fitting plot of the Critical Micelle Concentration test results of DOPS-12 in deionized (DI) water.

[0022] FIG. 8 depicts the PEG distribution profile in a sample of DOPS-12 as determined by LC-MS.DETAILED DESCRIPTION

[0023] One aspect of the disclosure is a pharmaceutical composition (for example, for oral administration) of edaravone, optionally in combination with dexbomeol, the pharmaceutical composition comprising: edaravone; 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; andP 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.

[0024] The present disclosure provides a variety of PEG-sacchari de-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):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); andP 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.

[0025] 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 Rl, R2 and n. However, as described above, it can in many circumstances be desirable to control the variation, especially of the value of n. Thus, the definition of General Formula I contemplates that the materials can be in the form of mixtures of individual compounds each with their own particular definitions of S, L, P and m. General Formula I thus defines various substituents with number-average values of various substituents.But the disclosure also specifically contemplates various individual compounds with integral values for various substituents.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] “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.

[0030] 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.

[0031] 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, thesaccharide 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.

[0032] 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:

[0033] In some embodiments as described herein, the structural formula of “S” is as follows:in which -(CxiH2xiOxi-i)-CO- is a sugar acyl residue derived from a sugar acid in which xl is 4 or 5, and (CX2H2X2-IOX2-I)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof. In various such embodiments, xl is 5 and x2 is 6.

[0034] In various embodiments, “S” has the following structure:or is an open-chain version thereof.

[0035] In various embodiments, “S” is lactobionyl or gluconyl or a combination thereof (e.g., in a molar ratio of at least 9:1 lactobionykgluconyl). In various embodiments, “S” is lactobionyl. In other embodiments, “S” is a residue from gluconolactone or neuraminic acid. In other embodiments, “S” is a residue from another disaccharide or tri saccharide, which can bemodified (e.g., by oxidation). Examples include sucrose, lactose, maltose, trehalose, turanose, cellobiose raffinose, melezitose and maltotriose.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] In various desirable embodiments, R1is a linear alkanyl or alkenyl group.

[0040] 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, alphalinoleic 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 acidsTable 2 Unsaturated fatty acids

[0041] 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 derivedfrom 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)i iC(O)-

[0042] 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.

[0043] 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.

[0044] The polyethylene 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 Ci-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.

[0045] 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. Forexample, in various embodiments, the -P group is a methylated PEG residue having a numberaverage 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.

[0046] 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. Poly dispersity Index (PDI) is defined by the equation below:where Mwis the weight average molecular weight and Mnis the number average molecular weight. For example, in various embodiments, the “P” group has a PDI (poly dispersity index) of no more than 1.1, 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.

[0047] Commercial USP or EP grades of mPEG may be used in various embodiments. mPEG oligomers can also be made by a total synthesis.

[0048] In various desirable embodiments, the P group is a long chain, linear or branched synthetic polymer composed of ethylene oxide units, CIEOCFhCFhlOCIECIEjnO-, in which n is typically between about 4 and about 45 or otherwise can vary to provide a narrow or monodistributed polymer with molecular weights from 200-2000 Daltons.

[0049] In various embodiments as otherwise described herein, the conjugate has the structural formula of Chemical Structure 1 :Chemical Structure 1 wherein m(PEG)nis a methylated PEG residue.

[0050] In various such embodiments of Chemical Structure 1, the fatty acyl residue - Oj-R1is derived from one or more of lauric acid, myristic acid, palmitic acid, linoleic acid, oleic acid and stearic acid. The m(PEG)nis a methylated PEG residue and “n” is any desirable value as described above.

[0051] 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).

[0052] In various embodiments, the conjugate is Oleoyldiaminopropane-monomethoxy- polyethylene-glycol-ether-lactobionate (DOPS), which can be represented by the Chemical Structure 2:Chemical Structure 2 (DOPS)

[0053] In various embodiments, the conjugate is Stearylpropanediaminomonomethoxy- polyethylene-glycol-ether-lactobionate, which can be represented by Chemical Structure 3 :Chemical Structure 3 (DSPS)

[0054] 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).

[0055] In various embodiments, the conjugate is represented by Chemical Structure 4: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.

[0056] In various embodiments, the conjugate is cholesterolethyleneglycolpropanediamino-mPEG-lactobionate (DCPS), which can be represented by Chemical Structure 5 a:Chemical Structure 5a (DCPS)

[0057] In the case when Cholic acid is the lipid group, the “choloyl” group is understood to represent an R1group that is at least 65 mol% derived from choloic acid. In various embodiments, the conjugate is Choloylpropanediamino-mPEG-lactobionate (CDPS), which can be represented by Chemical Structure 5b:Chemical Structure 5b (CDPS)

[0058] In Chemical Structure 4, m(PEG)n is 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 C64Hn8N2O27). In various embodiments of Chemical Structures 3, 4, 5a or 5b, the number-average value of n is in the range of 11-13, e.g., 11.5-12.5, or 11.8-12.2.

[0059] In various embodiments as described herein, the conjugate has one of the following structures:

[0060] 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.

[0061] In various embodiments of the conjugates as otherwise described herein, -P is provided from a P-H polyethylene glycol) source (e.g., an mPEG) that has a number-average molecular weight in the range of 95.0-105.0% of the labeled nominal value if the labeled nominal value is below 1000 g / mol, or in the range of 90.0-110.0% of the labeled nominal value if the labeled nominal value is in the range of 1000 and 2000 g / mol.

[0062] 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.

[0063] 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.

[0064] In various embodiments of the conjugates as otherwise described herein, when the RLC(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, myristoyl, palmitoyl, stearoyl or linoleoyl.

[0065] 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 Rl-C(O)- identity, e.g., oleoyl).

[0066] In various embodiments of the conjugates as otherwise described herein, Rl-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):1in the range of RRT ± 0.2 to ± 0.52RRT of oleic acid is set as 1.00

[0067] 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 concentrationinjected 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 FIGS. 1, 2 and 3.

[0068] Notably, a superior solubility enhancement for poorly-soluble drugs can be provided by materials of the disclosure without co-solvents or co-emulsifiers. For example, in the case of a cyclosporine (0.09%) ophthalmic formulation, the particle size of cyclosporine in the marketed product (CEQUA®) is in the range of 12 to 20 nm, based on a SEDDS-like suspension using a mixture of polyoxyl 40 hydrogenated castor oil and polyalkoxylated alcohol. In the comparison, a true solution of 0.1% cyclosporine was obtained with approximately 1% of DOPS-12; the solution was stable for more than 4 years under room temperature. Without intending to be bound by theory, the present inventor believes that a higher purity and lower poly dispersity of the said material contribute to the especially good performance.

[0069] 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.

[0070] Another aspect of the disclosure is a pharmaceutical composition for oral administration of edaravone, the pharmaceutical composition comprising: edaravone, optionally in combination with dexborneol; a solubility or bioavailability enhancer that is a 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 tri saccharides;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; andone or more steviol glycosides, for example, one or more steviosides and / or rebaudiosides.

[0071] Various improved conjugates as described herein are described in International Patent Applications nos. PCT / US2024 / 040087 and PCT7US2024 / 040092, which are hereby incorporated herein by reference in their entirety. The full text of International Patent Applications nos. PCT / US2024 / 040087 is provided at the end of this specification and constitutes a part of this specification. Any not-inconsistent embodiment described in these applications can be combined with any embodiment as described herein to provide additional embodiments of the disclosure.

[0072] The present inventor has noted that edaravone can have a bitter taste. Moreover, as described below, the present disclosure contemplates the optional inclusion of amino acids in the compositions; some amino acids, such as arginine, can have a bitter taste. Bitter taste can especially complicate oral administration of liquid formulations; children especially strongly reject such oral medications due to their intense bitterness. According to one aspect, the present disclosure provides compositions in which bitterness can be effectively modified or reduced.

[0073] In various embodiments, the pharmaceutical composition includes one or more steviol glycosides, for example, 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.

[0074] Desirable steviol glycosides for use herein include steviosides and / or rebaudiosides. 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.

[0075] However, many native steviol glycosides (i.e., as extracted from a plant) themselves 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. The conjugates described herein can also aid in the solubilization ofless-soluble steviol glycosides. 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.

[0076] 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).

[0077] 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.

[0078] The present inventor has recognized that the bitter taste of active pharmaceutical agent(s) agents and amino acids can be addressed using steviol glycosides, especially those of relatively high purity. However, in some cases a higher amount of PEG-sacchari de-lipid conjugate may be necessary to co-solubilize both the API(s) 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.

[0079] In various embodiments, 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%..

[0080] 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 active pharmaceutical agent(s) and, when present, the amino acid. Moreover, without intending to be bound by theory, the present inventor suggests that the conjugate-steviol glycoside complexcan preferentially mask the bitter components of the steviol glycosides by more strongly complexing them, making them less likely to be perceived by the patient.

[0081] Some steviol glycosides having higher water solubility, such as rebaudioside 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 much of a need for solubilization by the conjugate. Nonetheless, use of such steviol glycosides is specifically contemplated by the disclosure.

[0082] 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 extract 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%.

[0083] 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 active pharmaceutical agent(s) or separately. While in some cases the steviol glycosides will be sufficiently solubilized by the amount of the conjugate used in conjunction with the active pharmaceutical agent(s) 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.

[0084] In various embodiments of the disclosure as otherwise described herein, the pharmaceutical composition further comprises an amino acid. The present inventor has determined that various amino acids can be helpful in solubilizing the edaravone. In various embodiments, the amino acid is one or more of arginine, methylarginine, citrulline, homoarginine, canavanine, lysine and glutamine. In various embodiments, the amino acid includes (or is) arginine. In various embodiments, at least some of the amino acid and at least some of the edaravone are provided together as an amino acid salt of edaravone, e.g., an arginine salt of edaravone.

[0085] The amino acid can be provided in a variety of ratios with respect to the edaravone. For example, in various embodiments, the amino acid is provided in a weight ratio in the range of 0.5: 1 - 3:1, e.g., in a ratio of 50 mg AA to 100 mg EDA, or 200 mg AA to 100 mg EDA.

[0086] The pharmaceutical compositions of the disclosure can be provided with a variety of total amounts of pharmaceutical active ingredients (API). The person of ordinary skill in the art can, based on the present disclosure, adjust the amount of the active pharmaceutical agent(s) agent together with the amount of the conjugate in order to provide a desirable active pharmaceutical agent(s) dose with a desirable degree of solubilization by a particular conjugate, optionally in combination with a particular amino acid (AA) as described above.

[0087] In various embodiments, amounts of AA used can increase the pH of the final composition to basic, e.g., pH > 7. This can be undesirable in that it can cause edaravone to be less stable, forming a dimer / trimer quickly, e.g., in less than an hour. While a pH modifier, e.g., critic acid, may be used to adjust the pH, it may cause a lower solubility of the drug compound or precipitation. The person of ordinary skill in the art can, based on the present disclosure, balance the requisite amounts of a conjugate and AA having a neutral or acidic pH, e.g., pH 6; to enhance the drug solubility without destabilization of the drug compound.

[0088] In various embodiments, the edaravone is present in an amount in the range of 1- 1050 mg of edaravone per discrete package (e.g., bag or dilutable mixture for providing intravenous dosage) or per discrete dosage form (e.g., liquid dosage aliquot, tablet, or capsule). For example, in various embodiments, the edaravone is present in an amount in the range of 1- 105 mg, or 1-60, or 1-30 mg per discrete package or discrete dosage form. In various embodiments, the edaravone is present in an amount in the range of 5-1050 mg, e.g., 5-105 mg, or 5-60, or 5-30 mg per discrete package or discrete dosage form. In various embodiments, theedaravone is present in an amount in the range of 30-1050 mg, e.g., 30-600, or 30-300, or 30- 105 mg, or 30-60 mg per discrete package or discrete dosage form.

[0089] Based on the disclosure herein, the person of ordinary skill in the art can select a desirable weight ratio of edaravone (quantified as the free base compound per se) to a weight ratio of edaravone to the conjugate is in the range of 0.2-10, e.g., in the range of 0.2-7, or 0.2-4, or 0.2-2. In various embodiments, a weight ratio of edaravone to the conjugate is in the range of 0.5-10, e.g., in the range of 0.5-7, or 0.5-4, or 0.5-2. In various embodiments, a weight ratio of edaravone to the conjugate is in the range of 1-10, e.g., in the range of 1-7, or 1-4, or 1-3. In various embodiments, a weight ratio of edaravone to the conjugate is in the range of 2-10, e.g., in the range of 2-7, or 2-4. In various embodiments, a weight ratio of edaravone to the conjugate is in the range of 3-10, e.g., in the range of 3-7, or 3-5.

[0090] As described above, in various embodiments the pharmaceutical composition further comprises dexborneol. In various embodiments, a ratio of edaravone to dexbomeol is in the range of 3:1 to 10: 1, e.g., in the range of 3:1 to 6:1, such as 4 to 1 or 5 to 1. In various embodiments, an amount of dexbomeol is in the range of 1-100 mg per discrete package or per discrete dosage form. For example, in various embodiments the amount of dexbomeol is in the range of 1-50 mg, or 1-20 mg, or 1-10 mg per discrete package or per discrete dosage form. In various embodiments the amount of dexbomeol is in the range of 3-100 mg, e.g., 3-50 mg, or 3-20 mg, or 3-10 mg per discrete package or per discrete dosage form. In various embodiments, the amount of dexborneol is in the range of 5-100 mg, e.g., 5-50 mg, or 5-20 mg, or 5-10 mg, or 5-7.5 mg, or 6-7.5 mg per discrete package or per discrete dosage form.

[0091] For example, in various embodiments, edaravone is present, for example, in an amount of 30 to 105 mg per discrete package or discrete dosage form.

[0092] In various embodiments, the pharmaceutical composition comprises edaravone (e.g., 30-105 mg per discrete package or discrete unit dosage form) and dexbomeol (e.g., 5 to 10 mg per discrete package or discrete dosage form).

[0093] 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.

[0094] 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, 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.

[0095] 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 pharmaceutical composition of the disclosure includes one or more flavoring agents selected from yerba mate (extract of Ilex paraguariensis A. St.-Hill), 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.

[0096] 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 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 sugar alcohol (such as mannitol) or a sugar (such as lactose).

[0097] 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 A-nitrosamine that may be formed during manufacturing or storage of the pharmaceutical composition, the one or two APIs, or other components of the composition.

[0098] In various embodiments, the antioxidant is one or of ascorbic acid, a-tocopherol and TPGS (D-a-Tocopherol polyethylene glycol 1000 succinate).

[0099] In various embodiments, the antioxidant includes (or is) ascorbic acid. In various embodiments, the antioxidant includes (or is) a-tocopherol. Ascorbic acid (vitamin C) or a- tocopherol (vitamin E) are recommended by the FDA to be used for addressing nitrosamine formation.

[0100] In various embodiments, the antioxidant includes (or is) D-a-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.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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 approvedcoloring 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.

[0106] A pharmaceutical composition of the disclosure may further include an antimicrobial preservative, especially when the composition is in a liquid or gel form. A variety of such preservatives can be used, typically in an amount in the range of 0.1-2 wt%.

[0107] The pharmaceutical compositions of the disclosure can be provided in a variety of forms, liquid or solid, as well as semisolid forms like gels.

[0108] 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 granule or tablet or a film. The solid oral dosage forms can be configured to be quick soluble 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 (e.g., for a single dosage provided as a discrete dosage aliquot) that can be drunk by a patient.

[0109] 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., 0.9 wt%) in purified water. pH adjustment can be provided as necessary, e.g., using sodium hydroxide and / or citric acid, or an appropriate buffer.

[0110] 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 API, but also, in somecases, a steviol glycoside that is added to address an undesirable taste of any API or agents, e.g., amino acid, 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.[oni] 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 active pharmaceutical agent(s) 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-carbohydrate-lipid conjugate (PCL).

[0112] 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%.

[0113] In various embodiments, the conjugate of the disclosure is present in the composition and the ratio of the amount of amino acid to the conjugate in the range of 1 to 1 or 1 to 3 (w / w), e.g., 0.5 (AA) to 1 (PCL). In various embodiments, the conjugate of the disclosure is present in the composition in an amount in the range of 2-10 wt%, e.g., 2-6 wt%, or 3-5 wt%.

[0114] 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 APIs.

[0115] Similarly, the active pharmaceutical agent(s) agent can be present in the composition in a variety of concentrations, depending on API and depending on the particular form of the composition. For example, in various embodiments, the API is present in thecomposition in an amount of at least 1 wt%, e.g., at least 1.05 wt%. In various embodiments, the active pharmaceutical agent(s) agent is present in the composition in an amount of at least 0.5 wt%, e.g., 1 wt%. In various embodiments, the active pharmaceutical agent(s) agent is present in the composition in an amount of at least 2 wt%, e.g., at least 2.1 wt%. In various embodiments, the API is present in the composition in an amount of at least 5 wt%, e.g., at least 6 wt%.

[0116] The person of ordinary skill in the art can determine an appropriate ratio of conjugate to active pharmaceutical agent(s) agent based on the present disclosure. The amounts of the conjugate of the disclosure and the APIs 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 agent or agents.

[0117] For example, in various embodiments, a weight ratio of the conjugate of the disclosure to the API is in the range of 1-10. In various embodiments, a weight ratio of the conjugate to the active pharmaceutical agent(s) agent ranges from 0.5 to 10, or 0-5-5.

[0118] 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 active pharmaceutical agent(s) agent.

[0119] 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.

[0120] In various embodiments, a weight ratio of the conjugate of the disclosure to all other excipients including amino acid or surfactants (individually or totally) is in the range of 0.5 to 5.

[0121] Moreover, the present inventor has found that stability of oral solid dosage forms of edaravone can be further improved via tablet design, for example, through the use ofmultiple-layer tablets (e.g., bilayer or core-shell) using a barrier film to separate the API (EDA) in an API layer from one or more alkaline components in an alkaline-containing layer.

[0122] Accordingly, in various embodiments, an oral dosage form includes an API layer comprising the edaravone and the conjugate of the disclosure, an alkaline-containing layer containing at least one alkaline component, and a barrier layer disposed between the API layer and the alkaline-containing layer.

[0123] As used herein, an alkaline component is a component that has a pH of at least 8 at a 0.5 M concentration in water at 23 °C. In various embodiments, the alkaline component has a pH of at least 8.5 at a 0.5 M concentration in water at 23 °C, e.g., at least 9. In various embodiments, the alkaline component has a pH of at least 8.5 at a 0.5 M concentration in water at 23 °C, e.g., at least 9.

[0124] The alkaline component can be any of a number of pharmaceutically-acceptable components. In some embodiments the alkaline component is an alkaline amino acid. For example, in some embodiments, the alkaline component is selected from arginine, methylarginine, citrulline, homoarginine, canavanine, lysine and glutamine. In some embodiments, the alkaline component includes (or is) arginine.

[0125] The present inventor has noted that, while alkaline components like arginine can help to solubilize edaravone, as edaravone is hydrolysable and degradable by base, direct contact with alkaline components such as arginine can cause degradation during storage, especially in high-moisture conditions. Even tightly-sealed packaging does not exclude moisture from seeping into the container during the storage, especially after the packaging is opened and reopened during use. Accordingly, the present inventor has developed solid dosage forms that address the problem not at the package level but at the dosage form level, by including a barrier film between the edaravone-containing layer and the layer containing the alkaline component. Even if moisture makes it into the package, the barrier film can prevent the moisture from carrying the alkaline component to the edaravone.

[0126] An example of a core-shell solid dosage form is shown in FIG. 4. Here, tablet 400 has an API layer 410 that includes edaravone and a conjugate of the disclosure, and surrounding the API layer 410 is an alkaline-containing layer that includes an alkaline component such as arginine. Layer 410 is configured as a core, and layer 420 is configured as a shell. Disposed between layer 410 and layer 420 is a barrier later 430 configured to prevent moisture from carrying the alkaline component from layer 420 into layer 410. While the core-shell dosage form of FIG. 4 has the API layer surrounded by the alkaline-containing layer, the inventor notes that other embodiments have the

[0127] Similarly, an example of a bilayer dosage form is shown in FIG. 5. Here, tablet 500 has an API layer 510 that includes edaravone and a conjugate of the disclosure, and a parallel alkaline-containing layer 520. Between layers 510 and 520 is a barrier layer 530 configured to prevent moisture from carrying the alkaline component from layer 520 into layer 510.

[0128] Of course, other dosage form architectures are available. For example, in some embodiments, a barrier film-coated API core layer is disposed within a capsule containing granular alkaline component-containing material. Such a dosage form is shown in FIG. 6. Here, an API layer 610 is provided as an edaravone and conjugate-containing core layer, which is coated with barrier layer 630, and disposed within capsule 650 with an alkaline-containing granulate that provides the alkaline-containing layer 620. The capsule shell is typically water soluble or water dispersible; examples of materials include gelatin and hydroxypropyl methylcellulose (HPMC).

[0129] A variety of materials may be used as the barrier film. Examples include sodium carboxymethylcellulose, hydroxypropylcellulose (e.g., HPC EF), hydroxyethylcellulose, ethyl cellulose, hydroxypropylmethylcellulose, polyvinylalcohol, polyvinyl acetate, cellulose acetate, poly polyvinylalcohol-polyethyleneglycol copolymers (e.g., graft copolymers), and mixtures of polyvinyl alcohol and polyethyleneglycol. Commercial examples include Opadry® AMB, Methocel® E3, E5, E6 and El 5, Walocel® HM3 PA, Kollicoat® IR Protect, Klucel™, Kollicoat® SR 30 D. But the person of ordinary skill in the art will appreciate that other materials can be used. Desirably, the barrier film is water soluble (e.g., polyvinylalcohol, hydroxypropylmethylcellulose, hydroxyethylcellulose, PVA-PEG graft copolymer, or PVA / PEG mixture). The person of ordinary skill in the art can select a layer thickness to provide a desired degree of protection of migration of the alkaline component into the API layer.

[0130] To the extent that a barrier layer has less than desired adhesion to a layer of an oral dosage form, a thin film of PEG-saccharide-lipid conjugate may be used as a gluing agent.

[0131] Dosage forms can also or alternatively have an external barrier coating at an external surface thereof, to slow water ingression into the dosage form, and thus slow the rate of moisture carrying alkaline component the edaravone.

[0132] While a simple sugar-coating process requires low capital cost, unsophisticated equipment and is relatively easy to perform, it is labor-intensive and requires long processing time. Moreover, sugar coated tablets are not amenable to embossing, use of print for identification or labelling And sugar-coated tablets may further require preservatives for longterm storage. Hence a polymer film is a better alternative. The same materials described above for barrier layers can also be suitable for use as coating layers. The person of ordinary skill in the art can select suitable coatings and thicknesses thereof. The oral dosage form 500 of FIG. 5 includes a coating layer disposed about the outer surface of the dosage form.

[0133] Another aspect of the disclosure is a pharmaceutical composition of the disclosure for use in the treatment of a subject having a used to treat patients with amyotrophic lateral sclerosis (ALS), which is also known as Lou Gehrig's disease. This medical agent of the composition alone and / or dexborneol further suitable for treating the acute ischemic stroke condition. The administration may be by any route suitable for the pharmaceutical composition and for the disease condition. For example, in some embodiments, the administration is an oral administration. In some embodiments, the administration is a parenteral administration or an intranasal administration.

[0134] Another aspect of the disclosure provides a pharmaceutical composition of the disclosure for use as a medicament.

[0135] Another aspect of the disclosure is a use of a conjugate combining rebaudiosides as described herein for reducing or modifying the bitterness taste of amino acids used as the solubilizing agent

[0136] Another aspect of the disclosure is a use of a conjugate as described herein for increasing solubility of poorly-soluble rebaudiosides in an aqueous system.

[0137] Another aspect of the disclosure is use of an amino acid alone or combined with the conjugate as described herein as a pharmaceutical excipient together with the APIs.

[0138] 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 API (and optionally, the steviol glycoside and / or the antioxidant, if present) is co-dissolved with amino acid(s) or 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.

[0139] In various embodiments, pharmaceutical compositions of the disclosure can desirably be formed by first combining the active pharmaceutical agent(s) 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 active pharmaceutical agent(s) agent / conjugate mixture if an aqueous solution is desired. For solid dosage forms, the API can be co-dissolved with the conjugate or mixed with amino acid(s) 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.

[0140] 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)nis 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 CEE.

[0141] 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%; andf. Fatty acid based said polymers, resemble of the peak profile of Figures 1, 2 or 3 and the range of the relative retention time.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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 describedherein, 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.

[0146] In various embodiments, fatty acid residues range from carbon chain lengths of about C8 to about C22, for example about CIO 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 a-linolenic acid.

[0147] 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.

[0148] In various embodiments, the PEG-saccharide-lipid conjugate has one of the following structures:wherein n = 8 to 45.

[0149] 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

[0150] The following non-limiting examples further illustrate various aspects and embodiments of the present disclosure.

[0151] Chemicals and Reagents: All PEG-saccharide-lipid conjugates used in the studies were made in-house by LipoSeuticals Inc. (Monmouth Junction, NJ, USA). Amino acids, edaravone, dexbomeol and other excipients and chemicals were obtained from commercial sources such as Sigma-Aldrich (St. Louis, MO, USA), Alfa Aesar (Ward Hill, MA, USA) and Thermo Fisher Scientific (Rockford, IL).Example 1 Chromatography Profile of PEG-saccharide-lipid Conjugates

[0152] Individual fatty acid-based FA-propanediamino-mPEG(12)-lactobionate conjugates were made in-house. The analytical procedure for assay and related compounds of PEG-saccharide-lipid conjugates was a reverse-phase, isocratic HPLC method.Chromatography parameters are presented in Table 3:Table 3

[0153] 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 polymers were prepared in pure methanol and injected 10 pL each onto the column. Figure 1 shows the resulting chromatogram. A chromatograph of a large-scale batch of DOPS-12 (DOPS-F02) prepared according to Example 10 is provided in Figure 2 and similarly a chromatograph of linoleoylpropanediamino-mPEG-lactobionate conjugate and its isoform prepared as the same manner as for DOPS-12 is provided in Figure 3.

[0154] The relative retention times (RRT) of individual peaks to DOPS-12 (as the RT reference) of each of the fatty acid based PEG-saccharide-lipid conjugates is calculated with the following equation:> > „ > Retention time of individual FA R 1 -Retention time of DOPS-12 in which the RRT of DOPS-12 = 1.00; the retention time of individual fatty acid composition of the conjugates 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 41in the range of RRT ± 0.2 to ± 0.52positional isomer of Linoleic acid (a different double bond location)

[0155] 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 1.Example 2: Preparation of Bulk Powder by Lyophilization

[0156] The following procedure can be adapted for the preparation of a bulk powder of an active pharmaceutical agent(s) agent and a PEG-saccharide-lipid conjugate: Dissolve appropriate amounts of API 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., polyethylene glycol or 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 fromthe 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 Ih 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 Ih.• Decrease the temperature of the shelves to -34°C. in Imin.• Keep the temperature of the shelves at -34°C and the pressure 0.133 mbar for 56 h.• Set up the vacuum pump to O.OOlmbar 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.

[0157] 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 5:Table 5

[0158] In Table 5, PEG-saccharide-lipid can be any conjugate as described herein, e.g., any of the conjugates described in the Example 1. The amino acid can be selected from arginine, methyl arginine, citrulline, homoarginine, canavanine, lysine, glutamine or a combination thereof. Steviol glycoside can be, e.g., Rebaudioside A extracted from natural sources and / or Rebaudioside M or D made by bioconversion of steviol glycoside. The various components can be, for example, as described above.Example 3: Preparation of Oral Thin Films

[0159] 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 active pharmaceutical agent(s) 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 shown in Table 6:Table 6

[0160] In Table 6, the PEG-saccharide-lipid can be any of the conjugates described herein, e.g., any of the conjugates described in Example 1. Amino acid is selected from arginine, methyl arginine, citrulline, homoarginine, canavanine, lysine, glutamine or a combination thereof. Steviol glycoside can be, e.g., 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.Example 4: Preparation of Bulk Powder by Spray Drying

[0161] Spray drying can also be used to prepare powders. The following procedure is an example: Charge the requisite amounts of active pharmaceutical agent(s) 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 °CAspirator flow: 60-65 Nm3 / hr (e.g., ~ 1.7 m3 / min under ambient conditions)Flow rate: 2 mL / minContinue 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 aresieved 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 7.Table 7

[0162] In Table 7, the PEG-saccharide-lipid can be any of the conjugates described herein, e.g., any of the conjugates described in Example 1. Amino acid is selected from arginine, methyl arginine, citrulline, homoarginine, canavanine, lysine, glutamine or a combination thereof. Steviol glycoside can be, e.g., 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.Example 5: Preparation of Bulk Granules

[0163] The compositions can also be formed as granules. For example, in one such procedure, the active pharmaceutical agent(s) is dissolved in 5 to 20 fold of denatured alcohol and mixed with a predissolved aqueous solution of PEG-saccharide-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 pm filter to avoidobstruction 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 (Goteborg, 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 8.Table 8

[0164] In Table 8, the PEG-saccharide-lipid can be any of the conjugates described herein, e.g., any of the conjugates described in Example 1. Amino acid is selected from arginine, methyl arginine, citrulline, homoarginine, canavanine, lysine, glutamine or a combination thereof. Steviol glycoside can be, e.g., 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.Example 6: Preparation of Edaravone Solution

[0165] A lipid based formulation suitable for oral delivery of Edaravone was prepared. The requisite amounts of the API was added to a vessel equipped with a mixer propeller.Arginine was added with constant mixing at 40 - 45 °C. Mixing continued until the drug was visually dispersed in the lipids. Pre-dissolved other excipients in water were slowly added to the vessel with adequate mixing. Mixing continued until fully a homogenous solution was achieved. A sample formulation is described in Table 9.Table 91may be replaced by other amino acids or combinations thereof as described herein2PEG = Polyethylene glycol, e.g., PEG 3350 or PEG 80003e.g., acesulfame potassium4pH being adjusted to 7 to 85e.g., orange or pineapple6stabilizerExample 7: Preparation of Edaravone-Dexborneol Solution

[0166] Following Example 6, a formulation as described in Table 10 is prepared:Table 101= oleoylpropanediamino-mPEG-lactobionate (DOPS-12)2Steviol glycoside can be, but is not limited to Rebaudioside A extracted from natural sources and / or Rebaudioside M or D made by bioconversion of Steviol glycoside. Lower amounts may be required for Rebaudioside M as compared to Rebaudioside A, which may be needed up to 200 mg. Higher amounts are required for less purified steviol glycosides.3see Table 9

[0167] The various components can be, for example, as described above Examples 6 and 7. In other embodiments analogous to that of Table 10, oleoylpropanediamino-mPEG- lactobionate (DOPS-12) may be other PEG-sacchari de-lipid conjugates as described herein. Formulations can be provided with or without dexborneol and pH can be adjusted with citric acid. Instead of arginine, the amino acid can be selected from arginine, methylarginine, citrulline, homoarginine, canavanine, lysine, glutamine and combinations thereof.Example 8: Preparation of Edaravone Granules For Solution

[0168] Following Example 2 or 4, a formulation as described in Table 11 is prepared:Table 111Steviol glycoside can be, but is not limited to Rebaudioside A extracted from natural sources and / or Rebaudioside M or D made by bioconversion of Steviol glycoside. Lower amounts may be required for Rebaudioside M as compared to Rebaudioside A, which may be needed up to 200 mg. Higher amounts are required for less purified steviol glycosides.2e.g., orange or pineapple extractsExample 9: Preparation of Edaravone Powder For Solution

[0169] Following Example 2 or 4, a formulation as described in Table 12 is prepared:Table 12e.g., orange or pineapple extractsExample 10: Preparation of Edaravone Tablets

[0170] Following Example 2 or 4, a formulation as described in Table 13 is prepared:Table 131Oleoylpropanediamino-mPEG-lactobionate (DOPS-12) may be replaced by other PEG-saccharide-lipid conjugates described herein2The amino acid is selected from methylarginine, citrulline, homoarginine, canavanine, lysine, glutamine in addition to arginine3Steviol glycoside includes but not limited to Rebaudioside A extracted from natural sources and / or Rebaudioside M or D by bioconversion of Steviol glycoside Less amounts required for purer steviol glycosides, i.e., may need up to 250 mg of a 80% purity of steviol glycosides to replace approximately 150 mg of 95% purity of steviol glycosides

[0171] The various components can be, for example, as described above. In Table 13, the composition may be without dexbomeol.Example 11 Determination of Critical Micelle Concentration (CMC) of DOPS-12

[0172] Without intending to be bound by theory, the inventor believes that micellar solubilization is likely the primary mechanism of the enhancement of the solubility of poorly soluble drugs such as edaravone or dexbomeol in the compositions as described herein. Surfactants like the conjugates described herein can reduce the interfacial tension in aqueous medium and increase the dissolution of poorly soluble drugs. Hence the CMC is an important parameter related to solubilization. The testing instrument used for performing the CMC tests was a Surface Tensiometer model DY-700 (Kyowa Interface Science Co., Ltd., Tokyo, Japan). Deionized water (50 mL) was placed in a testing container, and the corresponding oleoylpropanediamino-mPEG-lactobionate (DOPS-F02) solution was placed in the Auto Buretto 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.

[0173] The results of the CMC tests are shown in numerically and graphically in FIG. 7. To calculate the CMC, two lines were fit to plots and the intersection of the two lines was determined. The lines were fit such that the R2values of the fits were > 0.999. The data points used for the fitting and the actual fitted lines are indicated. The CMC was determined to be 12.67 mg / L or approximately 0.01 mmol. It can be desirable for the conjugate to be present in aqueous solution in an amount above its critical micelle concentration. Use of a conjugate with a lower critical micelle concentration (CMC) can be desirable for enhancing solubility because it indicates that micelles form more easily and are more stable. Accordingly, in various embodiments of the disclosure, the CMC of the conjugate is preferably no more than 0.1 mmol, e.g., 0.005-0.01 mmol, or 0.005-0.05 mmol, or 0.02-0.01 mmol, or 0.02-0.05 mmol.Example 12. PEG distribution in DOPS-12

[0174] LC-MS was used for the determination of the PEG distribution profile in a sample of DOPS-12. The method parameter are summarized as follows:Chromatography ConditionsParameter SettingColumn ACQUITY UPLC BEH C8, 1.7pm, 2.1 50 mm, WatersMobile phase 0.1% formic acid / acetonitrile = 6 / 4Injection volume 0.5 pL (1 mg / mL)Flow rate 0.4 mL / minMass Spectrometry ConditionsParameter SettingIon source Electronic Spray Ion (ESI+) Scan time 3.5 minInterface temperature 300 °C DL temperature 250 °C Heater temperature 400 °C Nebulizer gas flow 2.50 L / min Heater gas flow 10.00 L / min Dry gas flow 10.00 L / minQI scan: 300-1500 m / z

[0175] As shown in FIG. 8, the PEG distribution was in a narrow range as described throughout the present disclosure, e.g., ± 5% of the targeted molar mass.Example 13: Product Stability of Edaravone (EDA) Tablet

[0176] EDA Tablets of 60 g / tablet were prepared in Example 10. Tablets were stored for various amounts of time. To determine product stability at various times, tablets were dissolved with methanol in a 200 mL volumetric flask. The samples were further diluted to 30 pg / mL of EDA in methanol 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 243 nm. The HPLC analytical column was 5 pm inertsil 3V Cl 8 (GL Sciences, Inc. Torrance, CA 90503), 25 cm x 4.6 mm inner dimension at ambient column temperature. An isocratic HPLC method was used; mobile phase was a mixture of methanol and water (9 / 1, v / v). The flow rate was set at 1.2 mL / min and sample injections were 20 pL. The chromatograms were processed with the Waters Empower software (ver. 2). The samples were tested duplicate at initial, 3, 6, 9 and 12 months stored at 25 °C / 60 relative humidity. The stability results (Table 14) demonstrated that the PEG-saccharide-lipid conjugate based formula was very stable during the storage period.Table 14Example 14: Oral Solution Compositions

[0177] 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 15.Table 151e.g., selected from Benzoic Acid 0.1 to 0.2% or Sorbic Acid 0.1 to 0.2% or Methyl Paraben 0.25% or Propyl Paraben 0.5 to 0.25% or Sodium Benzoate 0.1 to 0.2%.2 0.1 to 0.5% selected from xanthan gum; guar gum; locust bean gum; starch; carrageenan.

[0178] 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) and steviol glycoside can be, e.g., Rebaudioside A extracted from natural sources and / or Rebaudioside M or D made by bioconversion of Steviol glycosideExample 16: Multiple-Layer Tablets of Edaravone

[0179] A specialized rotary press with three feed hoppers and die pairs stacked vertically can be used to make multi-layer tablets, e.g., bi-layer tablets combining an API layer, a barrier layer and an alkaline-containing layer as described herein. Each layer is compressed sequentially to create one tablet with distinct layers according to the following steps: the granules for the first layer are fed from a hopper into a die cavity on the rotating turret; the lower and upper punches apply a light compression force to the powder. Air is removed and the layer is lightly consolidated, which creates a surface with enough roughness for suitable adhesion with the next layer. Granules for the second (barrier) layer are fed from a second hopper into the same die, on top of the first, pre-compressed layer as a thin and loose layer. Granules for the third layer are fed from a third hopper into the same die, on top of the second- loose layer. The turret moves to the main compression station where the final pressure is applied. This fuses the three layers together into a single, durable tablet. Then the lower punchlifts the finished tablet out of the die cavity, and tablets are removed from the turret by a scraper.

[0180] A sample composition is shown in Table 16Table 161steviol glycoside includes but is not limited to Rebaudioside A extracted from natural sources and / or Rebaudioside M or D by bioconversion of Steviol glycoside. Lower amounts may be required for Rebaudioside M as compared to Rebaudioside A which may be needed up to 100 mg. Higher amounts may be desirable for less purified steviol glycosides.2e.g., banana orange or pineapple extracts

[0181] The polymer of the barrier layer may be as described above. The bulking filler may be selected from various known fillers, e.g., polyethylene glycols, mannitol, lactose, poloxamers, cyclodextrin derivatives, polyoxyl 40 hydrogenated castor oil, polyethylene glycols or a combination thereof.Example 17: Multiple-Layer Tablets of Edaravone

[0182] Following Examples 10 and 16, a composition as described in Table 17 is prepared:Table 171Oleoylpropanediamino-mPEG-lactobionate (DOPS-12) may be replaced by other PEG-saccharide-lipid conjugates described herein2The amino acid is selected from arginine, methylarginine, citrulline, homoarginine, canavanine, lysine, and glutamine3Steviol glycoside includes but is not limited to Rebaudioside A extracted from natural sources and / or Rebaudioside M or D by bioconversion of Steviol glycoside Less amounts required for purer steviol glycosides, i.e., may need up to 250 mg of a 80% purity of steviol glycosides to replace approximately 150 mg of 95% purity of steviol glycosidesExample 18 Edaravone Capsules

[0183] The granulated EDA powders are made following the process described in Examples 2, 4 or 8, in which the portions or the API core and alkaline-containing layer are processed separately and accomplished at room temperatures. The API core is made following the Example 10 and coated with polyvinyl alcohol -polyethyleneglycol grafted copolymer using a perforated pan coater or a fluid bed coater. The manufacture of the oral capsules comprises first adding the coated API core, next the premixed alkaline-containing layer ingredients were filled into the capsule according to designed weights of capsule contents. The capsule shells can be made for example, from HPMC E-grade material to take advantage of its good water solubility. Aseptic conditions are maintained throughout the mixing and encapsulationoperations in accordance with standard manufacturing procedures for oral dosages. A sample of the composition is described in Table 18:Table 181Oleoylpropanediamino-mPEG-lactobionate (DOPS-12) may be replaced by other PEG-saccharide-lipid conjugates described herein2The amino acid is selected from methylarginine, citrulline, homoarginine, canavanine, lysine, glutamine in addition to arginine3Polyvinyl alcohol-polyethyleneglycol graft copolymer, e.g., 45,000 Daltons, ranging from 1 to 5% of the tablet weights

[0184] The various components can be, for example, as described above. In Tables 14 through 18, the PEG-saccharide-lipid conjugate may in some embodiments be oleoylpropanediamino-mPEG-lactobionate (DOPS-12) and steviol glycoside can be, e.g., Rebaudioside A extracted from natural sources and / or Rebaudioside M or D made by bioconversion of steviol glycoside, all other ingredients have been described, e.g., in Example 15.

[0185] While preferred embodiments of the present disclosure have been described, those skilled in the art will recognize that other and further changes and modifications may be made without departing from the spirit of the invention, and all such changes and modifications should be understood to fall within the scope of this invention.

[0186] Various aspects and embodiments of the disclosure are provided by the following enumerated embodiments, 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 edaravone, the pharmaceutical composition comprising: edaravone; 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 numberaverage number of carbons in the range of 6-22, and / or is a steroid acyl group; andP 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. The pharmaceutical composition of Embodiment 1, wherein m has a number-average value in the range of 2-8, e.g., in the range of 2-6, or 2-5, or 2-4.Embodiment s. The pharmaceutical composition of Embodiment 1, wherein m has a number-average value of 3.Embodiment 4. The pharmaceutical composition of Embodiment 1, wherein m has a number-average value of 2, or m has a number-average value of 4.Embodiment s. The pharmaceutical composition of Embodiment 1, wherein m has a number-average value in the range of 5-10, e.g., 5-8 or 8-10.Embodiment 6. The pharmaceutical composition of any of Embodiments 1-5, wherein S is a disaccharide group.Embodiment 7. The pharmaceutical composition of any of Embodiments 1-5, wherein S is a monosaccharide group.Embodiment 8. The pharmaceutical composition of any of Embodiments 1-5, wherein S is a trisaccharide group.Embodiment 9. The pharmaceutical composition of any of Embodiments 1-8, wherein saccharide units of S are individually selected from hexoses and pentoses and sugar alcohol, sugar acid and amino sugar analogs thereof.Embodiment 10. The pharmaceutical composition of any of Embodiments 1-9 wherein saccharide units of S are individually selected from hexoses and sugar alcohol, sugar acid and amino sugar analogs thereof.Embodiment 11. The pharmaceutical composition of any of Embodiments 1-10, wherein the saccharide unit of S that is directly bound to the nitrogen of the diamine central backbone is derived from a sugar acid and is bound as an amide.Embodiment 12. The pharmaceutical composition of Embodiment 11, wherein any saccharide unit of S that is not directly bound to the nitrogen of the diamine is a sugar.Embodiment 13. The pharmaceutical composition of any of Embodiments 1-12, wherein S has the structural formulain which -(CxiH2xiOxi-i)-CO- is a sugar acyl residue derived from a sugar acid in which xl is 4 or 5, and (CX2H2X2-IOX2-I)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof.Embodiment 14. The pharmaceutical composition of Embodiment 13, wherein xl is 5 and x2 is 6.Embodiment 15. The pharmaceutical composition of any of Embodiments 1-14, wherein S has the structureEmbodiment 16. The pharmaceutical composition of any of Embodiments 1-15, whereinS is lactobionyl or gluconyl, for example, lactobionyl.Embodiment 17. The pharmaceutical composition of any of Embodiments 1-15, whereinS is a residue from gluconolactone or neuraminic acid, or is a residue from another disaccharide or trisaccharide, which can be modified (e.g., by oxidation). Examples include sucrose, lactose, maltose, trehalose , turanose, cellobiose raffinose, melezitose and maltotriose.Embodiment 18. The pharmaceutical composition of any of Embodiments 1-17, whereinL includes (or is) -C(O)-R1, wherein R1is an alkanyl and / or alkenyl group having a numberaverage number of carbons in the range of 6-22.Embodiment 19. The pharmaceutical composition of any of Embodiments 1-18, whereinR1has a number-average number of carbons in the range of 6-20, or 6-18.Embodiment 20. The pharmaceutical composition of any of Embodiments 1-18, whereinR1has a number-average number of carbons in the range of 10-22, e.g., 10-20 or 10-18.Embodiment 21. The pharmaceutical composition of any of Embodiments 1-18, whereinR1has a number-average number of carbons in the range of 12-22, e.g., 12-20 or 12-18.Embodiment 22. The pharmaceutical composition of any of Embodiments 1-18, whereinR1has a number-average number of carbons in the range of 14-22, e.g., 14-20 or 14-18.Embodiment 23. The pharmaceutical composition of any of Embodiments 1-22, whereinR1has a number-average number of carbons that is no more than 18.Embodiment 24. The pharmaceutical composition of any of Embodiments 1-23, whereinR1has a number-average number of unsaturations in the range of 0-3, e.g., 0-2.Embodiment 25. The pharmaceutical composition of any of Embodiments 1-24, whereinR1is a linear alkyl or alkenyl group.Embodiment 26. The pharmaceutical composition of any of Embodiments 1-25 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 27. The pharmaceutical composition of any of Embodiments 1-26, 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 28. The pharmaceutical composition of any of Embodiments 1-26, 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 29. The pharmaceutical composition of Embodiment 27 or Embodiment 28, wherein the single chemical identity is cis-CH3(CH2)7CH=CH(CH2)7C(O)-.Embodiment 30. The pharmaceutical composition of Embodiment 27 or Embodiment 28, wherein the single chemical identity is cis,cis-CH3(CH2)4CH=CHCH2CH=CH(CH2)7C(O)-.Embodiment 31. The pharmaceutical composition of Embodiment 27 or Embodiment 28, wherein the single chemical identity is cis-CH3(CH2)3CH=CH(CH2)7C(O)-.Embodiment 32. The pharmaceutical composition of Embodiment 27 or Embodiment 28, wherein the single chemical identity is selected from n-hexanoyl, n-octanoyl, n-decanoyl, n- dodecanoyl, n-tetradecanoyl, n-hexadecanoyl, n-octadecanoyl, n-eicosanoyl and n-docosanoyl.Embodiment 33. The pharmaceutical composition of Embodiment 27 or Embodiment 28, wherein the single chemical identity is selected from cis-CH3(CH2)5CH=CH(CH2)7C(O)-, cis,cis-CH3CH2CH=CHCH2CH=CHCH2CH=CH(CH2)7C(O)-, cis,cis,cis-CH3(CH2)4CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)3C(O)- and cis-CH3(CH2)7CH=CH(CH2)nC(O)-.Embodiment 34. The pharmaceutical composition of any of Embodiments 1-26, wherein L includes (or is) a steroid acyl group (e.g., a bile acyl group).Embodiment 35. The pharmaceutical composition of any of Embodiments 1-26 and 34, wherein the steroid acyl group is an acyl group derived from cholesterol, cholic acid,deoxycholic acid, glycocholic acid, taurocholic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, chenodeoxycholic acid, and lithocholic acid (e.g., cholic acid, deoxycholic acid, or glycocholic acid).Embodiment 36. The pharmaceutical composition of any of Embodiments 1-35, 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 37. The pharmaceutical composition of any of Embodiments 1-35, 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 38. The pharmaceutical composition of any of Embodiments 1-35, 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 39. The pharmaceutical composition of any of Embodiments 1-35, 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 40. The pharmaceutical composition of any of Embodiments 1-35, 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 41. The pharmaceutical composition of any of Embodiments 1-35, wherein n has a number-average value in the range of 25-40.Embodiment 42. The pharmaceutical composition of any of Embodiments 1-35, 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 43. The pharmaceutical composition of any of Embodiments 1-42, wherein R2has a number-average number of carbons of at least 0.95, e.g., at least 0.99 or at least 1.Embodiment 44. The pharmaceutical composition of any of Embodiments 1-42, 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 45. The pharmaceutical composition of any of Embodiments 1-42, whereinR2is C1-C4 alkanyl, e.g., methyl or ethyl.Embodiment 46. The pharmaceutical composition of any of Embodiments 1-42, wherein R2is methyl.Embodiment 47. The pharmaceutical composition of any of Embodiments 1-42, wherein R2has a number average number of carbons in the range 0-3, e.g., 0-2.Embodiment 48. The pharmaceutical composition of any of Embodiments 1-42, 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 49. The pharmaceutical composition of any of Embodiments 1-35, wherein the -P group is a methylated PEG residue having a number-average molecular weight in the range of 300-2200 g / mol.Embodiment 50. The pharmaceutical composition of any of Embodiments 1-35, wherein the -P group is a methylated PEG residue having a number-average molecular weight in the range of 300-1200 g / mol, e.g., 300-600 g / mol.Embodiment 51. The pharmaceutical composition of any of Embodiments 1-35, wherein the -P group is a methylated PEG residue having a number-average molecular weight in the range of 500-2200 g / mol, e.g., 500-1200 g / mol, or 500-900 g / mol.Embodiment 52. The pharmaceutical composition of any of Embodiments 1-35, wherein the -P group is a methylated PEG residue having a number-average molecular weight in the range of 700-2200 g / mol, e.g., 700-1200 g / mol, or 700-1100 g / mol.Embodiment 53. The pharmaceutical composition of any of Embodiments 1-35, wherein the -P group is a methylated PEG residue having a number-average molecular weight in the range of 475-525 g / mol.Embodiment 54. The pharmaceutical composition of any of Embodiments 1-35, wherein the -P group is a methylated PEG residue having a number-average molecular weight in the range of 525-575 g / mol.Embodiment 55. The pharmaceutical composition of any of Embodiments 1-35, wherein the -P group is a methylated PEG residue having a number-average molecular weight in therange of 710-790 g / mol.Embodiment 56. The pharmaceutical composition of any of Embodiments 1-35, wherein the -P group is a methylated PEG residue having a number-average molecular weight in the range of 900-1100 g / mol, e.g., 950-1050 g / mol.Embodiment 57. The pharmaceutical composition of any of Embodiments 1-35, wherein the -P group is a methylated PEG residue having a number-average molecular weight in the range of 1800-2200 g / mol, e.g., 1900-2100 g / mol.Embodiment 58. The pharmaceutical composition of any of Embodiments 1-57, wherein P has a poly dispersity index of no more than 1.1, e.g., no more than 1.07.Embodiment 59. The pharmaceutical composition of any of Embodiments 1-57, wherein P has a poly dispersity index of no more than 1.06, e.g., no more than 1.05.Embodiment 60. The pharmaceutical composition of any not inconsistent Embodiment above, wherein m is 3;S has the structural formula as below:in which -(CxiH2xiOxi-i)-CO- is a sugar acyl residue derived from a sugar acid in which xl is 4 or 5, and (CX2H2X2-IOX2-I)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof;-C(O)-R.' is 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; andP has a poly dispersity index of no more than 1.1, e.g., no more than 1.07.Embodiment 61. The pharmaceutical composition of any not inconsistent Embodiment above, wherein m is 3;S has the structural formulain which -(CxiH2xiOxi-i)-CO- is a sugar acyl residue derived from a sugar acid in which xl is 4 or 5, and (CX2H2X2-IOX2-I)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof;-C(O)-R is at least 80 mol% of cis-CH3(CH2)7CH=CH(CH2)?C(O)-, e.g., at least 85 mol%; and the -P group is a 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 62. The pharmaceutical composition of Embodiment 60 or Embodiment 61, wherein xl is 5 and x2 is 6.Embodiment 63. The pharmaceutical composition of any of Embodiments 60-62, whereinS has the structureor is an open-chain version thereof.Embodiment 64. The pharmaceutical composition of any of Embodiments 60-63, wherein S is lactobionyl.Embodiment 65. The pharmaceutical composition of any of Embodiments 60-64, wherein -C(O)-R is at least 90 mol% of cis-CH3(CH2)7CH=CH(CH2)7C(O)-, e.g., at least 95 mol%.Embodiment 66. The pharmaceutical composition of any of Embodiments 60-65, wherein P has a poly dispersity index of no more than 1.06, e.g., no more than 1.05.Embodiment 67. The pharmaceutical composition 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.Embodiment 68. The pharmaceutical composition of Embodiment 67, wherein the fatty acyl residue - Oj-R1is derived from one or more of Lauric acid, Myristic acid, Palmitic acid, Linoleic acid, Oleic acid and Stearic acid.Embodiment 69. The pharmaceutical composition 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 desirable value as described above.Embodiment 70. The pharmaceutical composition 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 methylated PEG residue, and n is any desirable value as described above.Embodiment 71. The pharmaceutical composition of any not inconsistent Embodiment described above, wherein the conjugate is represented by Chemical Structure 4:Chemical Structure 4 wherein m(PEG)nis methylated PEG residue and n is any desirable value as described above, and m is in the range of 2-6, e.g., is 3.Embodiment 72. The pharmaceutical composition of any not inconsistent Embodiment described above, wherein the conjugate is cholesterolethyleneglycolpropanediamino-mPEG- lactobionate (DCPS), which can be represented by Chemical Structure 5a:Chemical Structure 5a (DCPS), or Choloylpropanediamino-mPEG-lactobionate (CDPS), which can be represented byChemical Structure 5b:Chemical Structure 5b (CDPS) wherein m(PEG)n is methylated PEG residue, and n is any desirable value as described above.Embodiment 73. The pharmaceutical composition of any of Embodiments 70-72, 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 74. The pharmaceutical composition of any not-inconsi stent Embodiment above, wherein the conjugate has one of the following structures:Embodiment 75. The pharmaceutical composition of any of Embodiments 1-74, wherein -P is provided from a P-H poly(ethylene glycol) source (e.g., an mPEG) that has a numberaverage molecular weight in the range of 95.0-105.0% of the labeled nominal value if thelabeled nominal value is below 1000 g / mol, or in the range of 90.0-110.0% of the labeled nominal value if the labeled nominal value is in the range of 1000 and 2000 g / mol.Embodiment 76. The pharmaceutical composition of any of Embodiments 1-75, wherein the conjugate has a purity of at least 85 wt% as measured by HPLC.Embodiment 77. The pharmaceutical composition of any of Embodiments 1-76, wherein the conjugate has a purity of at least 90 wt% as measured by HPLC.Embodiment 78. The pharmaceutical composition of any of Embodiments 1-77, 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 79. The pharmaceutical composition of Embodiment 80, wherein the single chemical identity is oleoyl, myristoyl, palmitoyl, stearoyl or linoleoyl.Embodiment 80. The pharmaceutical composition of any of Embodiments 1-79, 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):1in the range of RRT ± 0.2 to ± 0.52RRT of oleic acid is set as 1.00Embodiment 83. The pharmaceutical composition of any of Embodiments 1-82, wherein the conjugate has an HLB value in the range of 13-18, e.g., in the range of 13-15.Embodiment 84. A pharmaceutical composition for oral administration of edaravone, the pharmaceutical composition comprising: edaravone, optionally in combination with dexborneol; a solubility or bioavailability enhancer that is a 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; andB is a backbone molecule having three or four available binding positions; and one or more steviol glycosides, for example, one or more steviosides and / or rebaudiosides.Embodiment 85. The pharmaceutical composition of any of Embodiments 1-83, further comprising one or more steviol glycosides, for example, one or more steviosides and / or rebaudiosides.Embodiment 86. The pharmaceutical composition of Embodiment 84 or Embodiment 85, 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 87. The pharmaceutical composition according to any of Embodiments 84- 86 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 88. The pharmaceutical composition according to any of Embodiments 84- 87, 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 89. The pharmaceutical composition according to any of Embodiments 84-88, 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 90. The pharmaceutical composition according to any of Embodiments 84-89, 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 91. The pharmaceutical composition according to any Embodiments 84-90, 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 92. The pharmaceutical composition of any of Embodiments 84-il, 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 93. The pharmaceutical composition of any of Embodiments 1-92, further comprising an amino acid.Embodiment 94. The pharmaceutical composition of Embodiment 93, wherein the amino acid is selected from arginine, methylarginine, citrulline, homoarginine, canavanine, lysine and glutamine.Embodiment 95. The pharmaceutical composition of Embodiment 93, wherein the amino acid includes (or is) arginine.Embodiment 96. The pharmaceutical composition of any of Embodiments 93-95, wherein the amino acid (AA) is present in a weight ratio with edaravone (EDA) in the range of 0.5:1 - 3: 1, e.g., in a ratio of 50 mg AA to 100 mg EDA, or 200 mg AA to 100 mg EDA.Embodiment 97. The pharmaceutical composition of any of Embodiments 93-96, wherein a weight ratio of the conjugate to the amino acid (AA) is no more than 5: 1, e.g., no more than 3.5: 1.Embodiment 98. The pharmaceutical composition of any of Embodiments 93-96, wherein the weight ratio of the conjugate to the amino acid is in the range of 1 :1-5 :1, e.g., 2: 1-5:1, or 1 :1- 4: 1, or 2: 1-4: 1, for example, 3 (PCL) to 1 (AA) or 2.3 (PCL) to 1 (AA) or 2 (PCL) to 1 (AA).Embodiment 99. The pharmaceutical composition of any of Embodiments 93-98, wherein the pH is neutral or acidic.Embodiment 100. The pharmaceutical composition of any of Embodiments 1-99, wherein the edaravone is present in the range of 1-1050 mg of the edaravone per dosage package or per discrete dosage form, e.g., in the range of 1-105 mg, or 1-60 mg, or 1-30 mg per discrete package or discrete dosage form.Embodiment 101. The pharmaceutical composition of any of Embodiments 1-99, wherein the edaravone is present in the range of 5-1050 mg of the edaravone per dosage package or per discrete dosage form, e.g., in the range of 5-105 mg, or 5-60 mg, or 5-30 mg per discrete package or discrete dosage form.Embodiment 102. The pharmaceutical composition of any of Embodiments 1-99, wherein the edaravone is present in the range of 30-1050 mg of the edaravone per dosage package or per discrete dosage form, e.g., in the range of 30-600 mg, or 30-300 mg, or 30-105 mg, or 30-60 mg per discrete package or discrete dosage form.Embodiment 103. The pharmaceutical composition of any of Embodiments 1-102, wherein a weight ratio of edaravone to the conjugate is in the range of 0.2-10, e.g., in the range of 0.2-7, or 0.2-4, or 0.2-2.Embodiment 104. The pharmaceutical composition of any of Embodiments 1-102, wherein a weight ratio of edaravone to the conjugate is in the range of 0.5-10, e.g., in the range of 0.5-7, or 0.5-4, or 0.5-2.Embodiment 105. The pharmaceutical composition of any of Embodiments 1-102, wherein a weight ratio of edaravone to the conjugate is in the range of 1-10, e.g., in the range of 1-7, or1-4, or 1-3.Embodiment 106. The pharmaceutical composition of any of Embodiments 1-102, wherein a weight ratio of edaravone to the conjugate is in the range of 2-10, e.g., in the range of 2-7, or2-4.Embodiment 107. The pharmaceutical composition of any of Embodiments 1-102, wherein a weight ratio of edaravone to the conjugate is in the range of 3-10, e.g., in the range of 3-7, or3-5.Embodiment 108. The pharmaceutical composition of any of Embodiments 1-107, further comprising dexbomeol.Embodiment 109. The pharmaceutical composition of Embodiment 108, wherein a ratio of edaravone to dexborneol is in the range of 3: 1 to 10: 1, e.g., in the range of 3: 1 to 6: 1, such as 4 to 1 or 5 to 1.Embodiment 110. The pharmaceutical composition of Embodiment 108, wherein an amount of dexborneol is in the range of 1-100 mg per discrete package or per discrete dosage form, e.g., in the range of 1-50 mg, or 1-20 mg, or 1-10 mg per discrete package or per discrete dosage form.Embodiment 111. The pharmaceutical composition of Embodiment 108, wherein the amount of dexborneol is in the range of 3-100 mg, e.g., 3-50 mg, or 3-20 mg, or 3-10 mg per discrete package or per discrete dosage form.Embodiment 112. The pharmaceutical composition of Embodiment 108, wherein the amount of dexborneol is in the range of 5-100 mg, e.g., 5-50 mg, or 5-20 mg, or 5-10 mg, or 5-7.5 mg, or 6-7.5 mg per discrete package or per discrete dosage formEmbodiment 113. The pharmaceutical composition of any of Embodiments 1-112, further comprising one or more sweeteners.Embodiment 114. The pharmaceutical composition of Embodiment 113, wherein one or more of the one or more sweeteners is an artificial sweetener.Embodiment 115. The pharmaceutical composition of Embodiment 113 or Embodiment 114, wherein one or more of the one or more sweeteners is a natural sweetener.Embodiment 116. The pharmaceutical composition of any of Embodiments 113-115, wherein one or more of the one or more sweeteners is selected from acesulfame potassium, aspartame, cyclamate, monk fruit extract, saccharin, and sucralose.Embodiment 117. The pharmaceutical composition of any of Embodiments 113-116, 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 118. The pharmaceutical composition of any of Embodiments 113-117, wherein a total amount of the one or more sweeteners is in the range of 0.2-10 wt% of the composition.Embodiment 119. The pharmaceutical composition of any of Embodiments 113-118, further comprising one or more flavoring agents.Embodiment 120. The pharmaceutical composition of Embodiment 119, 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 121. The pharmaceutical composition of any of Embodiments 1-120, further comprising one or more bulking fillers.Embodiment 122. The pharmaceutical composition of Embodiment 121, 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 123. The pharmaceutical composition of Embodiment 121 or Embodiment 122, 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 124. The pharmaceutical composition of any of Embodiments 1-123, further comprising an antioxidant.Embodiment 125. The pharmaceutical composition of Embodiment 124, wherein the antioxidant is present in an amount up to 5 wt% of the composition.Embodiment 126. The pharmaceutical composition of Embodiment 124 or Embodiment 125, wherein the antioxidant includes (or is) ascorbic acid.Embodiment 127. The pharmaceutical composition of any of Embodiments 124-127, wherein the antioxidant includes (or is) a-tocopherol.Embodiment 128. The pharmaceutical composition of any of Embodiments 124-128, wherein the antioxidant includes (or is) D-a-tocopherol polyethylene glycol 1000 succinate.Embodiment 129. The pharmaceutical composition of any of Embodiments 1-128, in a liquid form, e.g., as a parenteral liquid or as drinkable liquid.Embodiment 130. The pharmaceutical composition of any of Embodiments 1-128, in a solid form.Embodiment 131. The pharmaceutical composition of any of Embodiments 1-130, in the form of an oral dosage form.Embodiment 132. The pharmaceutical composition of any of Embodiments 1-130, in the form of a tablet, a capsule or a film.Embodiment 133. The pharmaceutical composition of Embodiment 131 or Embodiment 132, configured to dissolve or disintegrate in the mouth, e.g., for sublingual or buccal administration.Embodiment 134. The pharmaceutical composition of any of Embodiments 1-128, in the form of a solid dosage form comprising: an API layer comprising the edaravone and the conjugate, an alkaline-containing layer containing at least one alkaline component, and a barrier layer disposed between the API layer and the alkaline-containing layer.Embodiment 135. The pharmaceutical composition of Embodiment 134, wherein the alkaline component has a pH of at least 8.5 at a 0.5 M concentration in water at 23 °C, e.g., at least 9.Embodiment 136. The pharmaceutical composition of Embodiment 134, wherein the alkaline component has a pH of at least 8.5 at a 0.5 M concentration in water at 23 °C, e.g., at least 9.Embodiment 137. The pharmaceutical composition of any of Embodiments 134-136, wherein the alkaline component is selected from arginine, methylarginine, citrulline, homoarginine, canavanine, lysine and glutamine.Embodiment 138. The pharmaceutical composition of any of Embodiments 134-137, wherein the alkaline component includes (or is) arginine.Embodiment 139. The pharmaceutical composition of any of Embodiments 134-138, wherein the barrier layer is selected from sodium carboxymethylcellulose, hydroxypropylcellulose (e.g., HPC EF), hydroxyethylcellulose, ethyl cellulose, hydroxypropylmethylcellulose, polyvinylalcohol, polyvinylacetate, cellulose acetate, polyvinylalcohol-polyethyleneglycol copolymers (e.g., graft copolymers), and mixtures of polyvinylalcohol and polyethyleneglycol. In various embodiments.Embodiment 140. The pharmaceutical composition of any of Embodiments 134-138, wherein the barrier layer is selected from polyvinylalcohol, hydroxypropylmethylcellulose, hydroxy ethylcellulose, PVA-PEG graft copolymer, or a PVA / PEG mixture.Embodiment 141. The pharmaceutical composition of any of Embodiments 134-140, wherein the oral dosage form is a core-shell dosage form having one of the API layer and the alkaline-containing layer configured as a core and the other of the API layer and the alkaline- containing layer configured as a shell.Embodiment 142. The pharmaceutical composition of any of Embodiments 134-140, wherein the oral dosage form is a core-shell dosage form having the API layer configured as a core and the alkaline-containing layer configured as a shell.Embodiment 143. The pharmaceutical composition of any of Embodiments 134-140, wherein the oral dosage form is a core-shell dosage form having the alkaline-containing layer configured as a core and the API layer configured as a shell.Embodiment 144. The pharmaceutical composition of any of Embodiments 134-140, in the form of a bilayer dosage form, wherein the barrier layer is disposed between the API layer and the alkaline-containing layer.Embodiment 145. The pharmaceutical composition of any of Embodiments 134-140, in the form of a capsule having disposed within the API layer coated with the barrier layer, and an alkaline-containing granulate as the alkaline-containing layer.Embodiment 145. The pharmaceutical composition of any of Embodiments 130-144, wherein the dosage form comprises an external barrier coating at an external surface thereof.Embodiment 146. A method for treating a subject having amyotrophic lateral sclerosis, the method comprising administering to the subject the pharmaceutical composition of any of Embodiments 1-145.Embodiment 147. The method of Embodiment 146, wherein the administration is an oral administration.Embodiment 148. The method of Embodiment 146, wherein the administration is a parenteral administration or an intranasal administration.Embodiment 149. A pharmaceutical composition of any of Embodiments 1-145, for use in treating amyotrophic lateral sclerosis (e.g., by oral administration, by parenteral administration, or by intranasal administration).Embodiment 150. Use of a conjugate as identified in any Embodiment above, as a pharmaceutical excipient in a medicament comprising edaravone, optionally in combination with dexbomeol.Embodiment 151. Use of a conjugate as identified in any Embodiment above, for increasing bioavailability edaravone.Embodiment 152. Use of a conjugate as identified in any Embodiment above, for increasing stability of edaravone in solid dosage forms of edaravone.Embodiment 153. Use of a conjugate as identified in any Embodiment above, for increasing solubility in an aqueous system of edaravone.Embodiment 154. The composition, method or use of any of the above Embodiments, wherein the pharmaceutical composition does not have an amount of edaravone in an amount of 100 mg per discrete dosage form or discrete package.Embodiment 155. The composition, method or use of any of the above Embodiments, wherein the pharmaceutical composition does not have an amount of edaravone in an amount of 95-105 mg per discrete dosage form or discrete package.Embodiment 156. The composition, method or use of any of the above Embodiments, wherein the pharmaceutical composition does not have a weight ratio of the conjugate to edaravone of 1 : 1.Embodiment 157. The composition, method or use of any of the above Embodiments, wherein the pharmaceutical composition does not have a weight ratio of the conjugate to edaravone in the range of 0.7: 1-1.3: 1.Embodiment 158. The composition, method or use of any of the above Embodiments, wherein the pharmaceutical composition does not have a weight ratio of DOPS-12 to edaravone of 1 : 1.Embodiment 159. The composition, method or use of any of the above Embodiments, wherein the pharmaceutical composition does not have a weight ratio of DOPS-12 to edaravone in the range of 0.7: 1-1.3: 1.

Claims

1. What is claimed is:

1. A pharmaceutical composition (for example, for oral administration) of edaravone, the pharmaceutical composition comprising: edaravone; and a PEG-saccharide-lipid conjugate having the structural formulaS 1,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 numberaverage number of carbons in the range of 6-22, and / or is a steroid acyl group; andP 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. The pharmaceutical composition of Claim 1, wherein m has a number-average value of3.

3. The pharmaceutical composition of Claim 1, wherein S is a disaccharide group.

4. The pharmaceutical composition of Claim 1, wherein S has the structural formulain which -(CxiH2xiOxi-i)-CO- is a sugar acyl residue derived from a sugar acid in which xl is 4 or 5, and (CX2H2X2-IOX2-I)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof.

5. The pharmaceutical composition of Claim 1, wherein S has the structure6. The pharmaceutical composition of Claim 1, wherein L is -C(O)-R1, wherein R1is an alkanyl and / or alkenyl group having a number-average number of carbons in the range of 6-22.

7. The pharmaceutical composition of Claim 6 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, alphalinoleic acid, arachidonic acid and erucic acid.

8. The pharmaceutical composition of Claim 1, wherein L is -C(O)-R1, and wherein - C(O)-R.' is at least 950 mol% of a single chemical identity.

9. The pharmaceutical composition of claim 8, 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)iiC(O)-.

10. The pharmaceutical composition of claim 9, wherein L is a steroid acyl group (e.g., a bile acyl group).

11. The pharmaceutical composition of claim 1, wherein “n” has a number-average value in the range of 8-50.

12. The pharmaceutical composition of claim 1, wherein R2is methyl.

13. The pharmaceutical composition of claim 1, wherein the -P group is a methylated PEG residue having a number-average molecular weight in the range of 300-1200 g / mol.

14. The pharmaceutical composition of claim 1, wherein P has a poly dispersity index of no more than 1.07.

15. The pharmaceutical composition of claim 1, wherein m is 3;S has the structural formula as below:in which -(CxiH2xiOxi-i)-CO- is a sugar acyl residue derived from a sugar acid in which xl is 4 or 5, and (CX2H2X2-IOX2-I)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof;-C(O)-R is at least 80 mol% of cis-CH3(CH2)7CH=CH(CH2)?C(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; andP has a poly dispersity index of no more than 1.1, e.g., no more than 1.07.

16. The pharmaceutical composition of claim 1, wherein m is 3;S has the structural formula ° in which -(CXIH2XIOXI-I)-CO- is a sugar acyl residue derived from a sugar acid in which xl is 4 or 5, and (CX2H2X2-IOX2-I)- is a sugar residue derived from a sugar in which x2 is 5 or 6, or is an open-chain version thereof;-C(O)-R is at least 80 mol% of cis-CH3(CH2)7CH=CH(CH2)7C(O)-, e.g., at least 85 mol%; and the -P group is a methylated PEG residue having a number-average molecular weight in the range of 525-575 g / mol and having a polydispersity index of no more than 1.1, e.g., no more than 1.07.

17. The pharmaceutical composition of claim 1, 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 desirable value as described above.

18. The pharmaceutical composition of claim 1, further comprising one or more steviol glycosides, for example, one or more steviosides and / or rebaudiosides.

19. The pharmaceutical composition according to claim 18, 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%.

20. The pharmaceutical composition of any of claims 1-92, further comprising an amino acid selected from arginine, methylarginine, citrulline, homoarginine, canavanine, lysine and glutamine.

21. The pharmaceutical composition of claim 20, wherein the amino acid is present in a weight ratio with edaravone in the range of 0.5 : 1 - 3 : 1.

22. The pharmaceutical composition of claim 1, wherein a weight ratio of edaravone to the conjugate is in the range of 0.2-10.

23. The pharmaceutical composition of claim 1, in a liquid form, e.g., as a parenteral liquid or as drinkable liquid.

24. The pharmaceutical composition of claim 1, in the form of an oral dosage form.

25. The pharmaceutical composition of claim 1, in the form of a solid dosage form comprising: an API layer comprising the edaravone and the conjugate, an alkaline-containing layer containing at least one alkaline component, and a barrier layer disposed between the API layer and the alkaline-containing layer.

26. The pharmaceutical composition of claim 25, in the form of a bilayer tablet or a coreshell tablet.

27. The pharmaceutical composition of claim 25, wherein the alkaline-containing component is arginine.

28. A method for treating a subject having amyotrophic lateral sclerosis, the method comprising administering to the subject the pharmaceutical composition of any of claims 1-27.

29. The method of claim 28, wherein the administration is an oral administration.

30. The method of claim 28, wherein the administration is a parenteral administration or an intranasal administration.

31. A pharmaceutical composition of any of claims 1-27, for use in treating amyotrophic lateral sclerosis (e.g., by oral administration, by parenteral administration, or by intranasal administration).

32. Use of a conjugate as identified in any of claims 1-27, as a pharmaceutical excipient in a medicament comprising edaravone, optionally in combination with dexborneol.

33. Use of a conjugate as identified in any of claims 1-27, for increasing bioavailability of edaravone.

34. Use of a conjugate as identified in any of claims 1-27, for increasing stability of edaravone in solid dosage forms of edaravone.

35. Use of a conjugate as identified in in any of claims 1-24, for increasing solubility in an aqueous system of edaravone.

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