Polyethylene glycol-sugar-lipid conjugate

Abstract

The present disclosure provides PEG-saccharide-lipid conjugates centered around various diamines. In various embodiments, these conjugates can be safely used as water-soluble or bioavailability enhancers. In one aspect, the present disclosure provides a PEG-saccharide-lipid conjugate having the following structural formula. JPEG2026528703000080.jpg27170Here The number average value of m ranges from 2 to 10. S is a monosaccharide, disaccharide or trisaccharide group, and each sugar unit is a sugar, sugar alcohol, amino sugar or sugar acid. L is -C(O)-R 1 where R 1 is an alkanoyl or alkenoyl group having an average carbon number of 6 to 22, and / or a steroid acyl group. P is -(CH2-CH2-O)nR 2 where "n" has a number average value in the range of 5 to 50 (e.g., 8 to 45), and R 2 is hydrogen and / or an alkane and has a number average carbon number in the range of 0 to 4.

Description

[Technical Field]

[0001] Cross-references to related applications This patent application claims priority to U.S. Provisional Patent Application No. 63 / 516,214 filed on 28 July 2023, 63 / 518,178 filed on 8 August 2023, 63 / 578,425 filed on 24 August 2023, 63 / 578,817 filed on 25 August 2023, 63 / 567,281 filed on 19 March 2014, and 63 / 567,267 filed on 19 March 2024, the disclosures of each application being incorporated herein by reference in their entirety.

[0002] Background of Disclosure 1. Areas of Disclosure This invention relates to novel polyethylene glycol (PEG) sugars, lipid conjugates, their analogues and variants, and their use in various compositions and therapeutics, such as pharmaceutical (including nutritional supplement) compositions.

[0003] 2.Technical background One of the major problems in new drug development is that many promising substances are insoluble in water. Often, even promising drug candidates are discontinued due to insufficient water solubility. As an alternative, other carriers such as polymers or oily derivatives are sometimes used. However, these carriers can often cause serious side effects.

[0004] Therefore, the need for improved pharmaceutical carriers for water-insoluble drugs remains.

[0005] Summary of Disclosure In one embodiment, the present disclosure provides a PEG-saccharide-lipid conjugate having a structural formula. JPEG2026528703000002.jpg2954 Here The average value of m is in the range of 2 to 10. S is a monosaccharide, disaccharide, or trisaccharide group, and each sugar unit is a sugar, sugar alcohol, amino sugar, or sugar acid. L is -C(O)-R 1 And here R 1 These are alkanyl or alkenyl groups and / or steroidacyl groups having an average number of carbon atoms of 6 to 22. P is -(CH2-CH2-O)nR 2 Here, "n" has a numerical mean in the range of 5 to 50 (for example, 8 to 45), and R 2 These are hydrogen and / or alkanes, with a number-average number of carbon atoms ranging from 0 to 4.

[0006] In another aspect, the present disclosure provides a method for producing the conjugate described herein, the method for which poly(ethylene) glycol, sugars and R 1 This involves attaching a -C(O)-acyl group to a diamine skeleton.

[0007] In another aspect, the present disclosure provides conjugates described herein for use as pharmaceutical excipients or for use in pharmaceuticals.

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

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

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

[0011] In another aspect, the disclosure provides the use of the conjugates described herein as pharmaceutical excipients.

[0012] In another aspect, the present disclosure provides compositions for use as pharmaceuticals, comprising a conjugate and a therapeutic agent as described herein.

[0013] In another aspect, the present disclosure provides the use of the conjugates described herein to enhance the bioavailability of therapeutic agents.

[0014] In another aspect, the Disclosure provides a method for using the conjugate described herein to increase the solubility of therapeutic agents in aqueous systems. Various aspects of the Disclosure are described herein using the following chemical nomenclature. mPEG(11): Monomethoxypolyethylene glycol ether 500 (i.e., nominal number average degree of polymerization = 11, nominal number average molecular weight 500 g / mol). mPEG(12): Monomethoxypolyethylene glycol ether 550. mPEG(17): Monomethoxypolyethylene glycol ether 750. mPEG(23): Monomethoxypolyethylene glycol ether 1,000. mPEG(45): Monomethoxypolyethylene glycol ether 2,000. CDPS-12: Chloroylpropanediamino-mPEG(12)-lactobionate. DCPS-12: Cholesteryl (oxyethoxy)acetyldiaminopropane-mPEG(12)-lactobionate. DEPS-12: Eliidoylpropanediamino-mPEG(12)-lactobionate. DMPS-11: Myristoylpropanediamino-mPEG(11)-lactobionate. DMPS-12: Myristoylpropanediamino-mPEG(12)-lactobionate. DOPS-B12 Oleoylbutanediamino-mPEG(12)-lactobionate. DOPS-E12: Oleoylethylenediamino-mPEG(12)-lactobionate. DOPS-12: Oleoylpropanediamino-mPEG(12)-lactobionate. DOPS-11: Oleoylpropanediamino-mPEG(11)-lactobionate. DOPS-23: Oleoylpropanediamino-mPEG(23)-lactobionate. DOPS-45: Oleoylpropanediamino-mPEG(45)-lactobionate. DOPS-G12: Oleoylpropanediamino-mPEG(12)-gluconate. DOPS-H12: Oleoylhexanediamino-mPEG(12)-lactobionate DOPS-P17: Oleoylpropanediamino-mPEG(17)-lactobionate DOPS-P24: Oleoylpropanediamino-mPEG(24)-lactobionate DOPS-P45: Oleoylpropanediamino-mPEG(45)-lactobionate DLPS-12: Linoleoilpropanediamino-mPEG(12)-lactobionate DSPS-12: Stearoylpropanediamino-mPEG(12)-lactobionate TOPS-12: Oleoylbis(3-aminopropyl)amine-mPEG(12)-lactobionate

[0015] Further aspects of this disclosure will become apparent when considering the following disclosures and claims. [Brief explanation of the drawing]

[0016] The accompanying drawings ("Figures") incorporated herein and forming part thereof illustrate one or more embodiments of the present disclosure and, together with the detailed description, are useful in illustrating the various principles and implementations of the present disclosure.

[0017] [Figure 1]Figure 1 shows the HPLC chromatograms of fatty acid-based conjugates. Peak 1 = Lauroylpropanediamino-mPEG(12)-lactobionate (DLOPS-12). Peak 2 = Myristoylpropanediamino-mPEG(12)-lactobionate (DMPS-12). Peak 3 = Palmitoylpropanediamino-mPEG(12)-lactobionate (DPOPS-12). Peak 4 = Linoleoylpropanediamino-mPEG(12)-lactobionate (DLOPS-12). Peak 5 = Palmitoylpropanediamino-mPEG(12)-lactobionate (DPPS-12). Peak 6 = Oleoylpropanediamino-mPEG(12)-lactobionate (DOPS-12). Peak 7 = oleylpropanediamino-mPEG(12)-gluconic acid; Peak 8 = stearoylpropanediamino-mPEG(12)-lactobionate (DSPS-12). The concentrations injected into the column were approximately 4-6 mg / mL, respectively.

[0018] [Figure 2] Figure 2 shows the HPLC chromatogram of a DOPS-12 sample prepared with mPEG(550) and with a purity exceeding 95%. The injected concentration was approximately 5 mg / mL DEPS-12 = elidoylpropanediamino-mPEG(12)-lactobionate.

[0019] [Figure 3] Figure 3 shows the HPLC chromatogram of linoleoylpropanediamino-mPEG-lacbionate (DLPS-12 and its isomer iso-DLPS-12) prepared using USP-grade mPEG(550), with a purity exceeding 95% and an injection concentration of approximately 5 mg / mL.

[0020] [Figure 4] Figures 4A and 4B show the hemolytic activity spectra of (4A)DOPS-12 and (4B)DCPS-12.

[0021] [Figure 5]Figure 5 shows the long-term stability of DOPS-12 samples stored at 25°C and 65% relative humidity for up to 36 months.

[0022] [Figure 6] Figure 6 shows the LC-MS / MS chromatogram of a 50 ng / ml DOPS-12 sample.

[0023] [Figure 7] Figure 7 shows the toxicological profiles of DOPS-12 administered intravenously to male and female Yucatan miniature pigs at a dose of 200 mg / kg of body weight over 90 minutes, 28 days after the last dose. Males are represented by black-filled symbols, and females by white-out symbols.

[0024] [Figure 8] Figures 8A and 8B show the body weight profiles of young beagle dogs (8A) female and (8B) male after oral administration of DOPS-12 for up to 90 days.

[0025] [Figure 9] Figures 9A and 9B show the toxicological profiles of DOPS-12 administered orally to young female (8A) and male (8B) beagle dogs from day 90 onwards.

[0026] [Figure 10] Figure 10 shows the pharmacokinetic profiles of DOPS-12 administered intravenously in female and male beagle dogs.

[0027] [Figure 11] Figure 11 shows the completed conjugate product (DOPS-12).

[0028] [Figure 12] Figure 12 shows the curve-fitting plot of the results of the critical micelle concentration test of DOPS-12 in deionized water.

[0029] [Figure 13]Figure 13 shows the PEG distribution profile in the DOPS-12 sample determined by LC-MS. [Modes for carrying out the invention]

[0030] Detailed explanation The inventors have demonstrated that polyethylene glycol (PEG)-saccharide-lipid conjugates have the ability to improve the pharmacological profile and solubility of lipophilic drugs in aqueous systems. They may also offer other advantages, such as minimizing therapeutic side effects and providing various new options in the formulation of active drugs. This disclosure is the first to reveal various unique safety and quality properties of specific PEG-saccharide-lipid conjugates. As shown in the following examples, representative polymers of this disclosure were repeatedly administered to miniature pigs up to 200 mg / kg (body weight) in intravenous toxicity studies over 4 weeks. To the best of the inventors' knowledge, comparable toxicity performance with PEG-lipid polymers such as polysorbate (Tween) or polyoxyethylated triglycerides (i.e., Cremophor®) has not been reported. In various embodiments, the materials described herein may help minimize anaphylactic attacks. In various embodiments, the materials of this disclosure may help avoid progressive proteolysis and reduce immunogenicity. Therefore, the materials of this disclosure can be used, for example, as a substitute for currently available compounds such as polysorbates and cremofoll. The materials of this disclosure can meet important needs while simultaneously providing differentiated clinical benefits to all stakeholders, including patients and physicians.

[0031] This specification specifically discloses the structure and method of manufacturing a PEG-saccharide-lipid conjugate having a suitable diamine central skeleton with at least three binding sites. PEG, carbohydrate, and lipid groups are covalently conjugated to the central skeleton. In particular, the novel PEG-saccharide-lipid conjugates disclosed herein can be manufactured with high purity and are useful for therapeutic drug delivery, cosmetics, and other compound delivery applications. Detailed results of in vitro and animal in vivo studies disclosed herein demonstrate the safety and quality profile of such conjugates.

[0032] The inventors have noted that it is desirable for PEG chain lengths to be provided in a highly monodisperse form. Therefore, in various embodiments of this disclosure, both safety and solubility can be ensured by specifying the purity and average molecular weight accuracy of these polymers. High-performance liquid chromatography (HPLC) can be performed for continuous quality control.

[0033] Embodiments of this disclosure are described herein in the context of PEG-sugar-lipid conjugates aimed at improving safety and enhancing the delivery of poorly water-soluble drugs. Those skilled in the art will understand that the following detailed description of this disclosure is for illustrative purposes only and is not intended to limit in any way. Other embodiments of this disclosure will be readily conceivable to those skilled in the art who benefit from this disclosure. Embodiments of this disclosure shown in the accompanying drawings will be described in detail below. Throughout the drawings and the following detailed description, the same reference numerals will be used to refer to the same or similar parts.

[0034] For clarity, not all routine features of the implementations described herein are illustrated and explained. Furthermore, while development work can be complex and time-consuming, it will be understood by those skilled in the art who benefit from this disclosure that it is still routine engineering work.

[0035] The inventors have surprisingly discovered that using a specific diamine central skeleton in PEG-saccharide-lipid conjugates significantly improves safety and biocompatibility. Furthermore, by using a relatively short diamine central skeleton, it is possible to provide conjugates with a safety profile suitable for parenteral administration. While not intending to be bound by theory, the inventors hypothesize that the longer the distance between the two amino bond sites, the stronger the interaction between the polymer and the cell surface, or the more likely red blood cells are to become unstable or destroyed.

[0036] Accordingly, this disclosure provides a diamine-centered PEG-sugar-lipid conjugate that, coupled with excellent solubility-enhancing properties, can exhibit an improved safety profile, including reduced immunogenicity / antigenicity. Results of in vitro and animal in vivo studies are disclosed herein for the first time. Furthermore, the relationship between the polymer structure and hemolytic activity is also disclosed herein for the first time. As shown herein, seemingly small structural differences between the diamine-centered skeleton described herein and the triamine-centered skeleton of conventional conjugates can have a significant impact on safety, as demonstrated in the examples of this disclosure.

[0037] The amide bond is the most widely found structure in peptides and proteins. While its therapeutic effects are very high, its toxicity (hemolytic effect) has limited the number of peptides that have been commercialized as pharmaceuticals. For example, a lipopeptide formed by linking the 37-amino acid peptide LL-37, which has leucine-leucine at its N-terminus, to a fatty acid chain with 7-10 carbon atoms has been shown to cause approximately 10% hemolysis at the micromolar level. Increasing the fatty acid chain length to 15 carbon atoms increased the hemolysis rate to 40%.

[0038] While bulky ring structures, longer alkyl chains, or more lipophilic carrier groups may in some cases result in higher hemolytic activity, the inventors have found that fatty acid groups with 18 or fewer carbon atoms reduce hemolytic activity. Therefore, in various preferred embodiments of this disclosure, the lipids are fatty acid acyl groups with an average of 18 or fewer carbon atoms. However, in certain situations, particularly in oral administration, longer acyl groups or steroid acyl groups may be desirable.

[0039] There are clear differences between fatty acid-based conjugates and cholesterol-based or cholesterol-like conjugates. The former exhibits significantly lower hemolytic activity, likely due to its low critical micelle concentration and poor distribution of fatty acid conjugates to the cell membrane. On the other hand, cholesterol-based conjugates, regardless of their central skeleton, exhibit higher hemolytic activity. Therefore, linear lipid acyl groups are considered more suitable for parenteral drug delivery due to their low hemolytic activity.

[0040] Therefore, another aspect of the various embodiments of this disclosure concerns the observation that selected PEG-sugar-fatty acid conjugates are often suitable for parenteral administration, while PEG-sugar-cholesterol conjugates may often be suitable only for specific oral administrations.

[0041] Polyoxyethylene-derived polymers have been widely used as drug delivery vehicles for decades, but their tendency to form peroxides is well known, and adverse effects on various drugs have been demonstrated. Like other surfactants, polyoxyethylene lipid polymers can cause hemolysis when in contact with red blood cells. Despite the side effects of polysorbate and polyethoxylated castor oil (marketed under the trade name "Cremofor"), these two major regulatory-approved intravenous excipients are accepted in cancer treatment because the drug is effective, otherwise the patient would not be able to receive treatment. The conjugates of this disclosure can often reduce hemolytic activity and thus may be even better than these currently available vehicles.

[0042] The inventors noted that most systemic toxicity studies of polymers such as polysorbates and cremofol in previous research have been conducted using rodents. Therefore, the potential immunogenicity of PEG-lipid polymers appears to have been overlooked. In contrast, multiple intravenous studies of the PEG-sugar-lipid conjugates described herein have been conducted using large animals (miniature pigs) and have been completed with favorable results. For the polymers under test, particularly oleoylpropylenediamino-mPEG-lactobionate ("DOPS-12," also called "DOPS-F02" depending on the synthesis process used), immunogenic reactions were reduced or not observed at all. In these in-house studies, no allergic reactions were observed in either Gottingen or Yucatan miniature pigs at intravenous doses up to 200 mg / kg (body weight).

[0043] Anaphylaxis is a severe systemic hypersensitivity reaction characterized by a rapid onset and life-threatening symptoms. Further studies using animal models of passive systemic cutaneous anaphylaxis and active systemic anaphylaxis have demonstrated that various embodiments of the PEG-saccharide-lipid polymers of this disclosure exhibit low immunogenicity.

[0044] In various embodiments, this disclosure provides PEG-saccharide-lipid conjugates with improved safety in many respects, and methods for synthesizing PEG-saccharide-lipid conjugates. In various embodiments, the conjugates may be based on PEG oligomers or USP-grade mPEG containing 5 to 50 (e.g., 8 to 45) ethylene glycol subunits. This disclosure also provides various methods for preparing PEG-saccharide-lipid conjugates having various saturated or unsaturated fatty acid or alkyl chain lengths. Such PEG-saccharide-lipid conjugates can be used for drug delivery and, in various specific embodiments, can be used for intravenous administration of poorly water-soluble or lipophilic drugs.

[0045] This disclosure provides a simple and economical synthetic method for preparing PEG-saccharide-lipid conjugates, in which each carrier group can be attached to the central diamine skeleton using various linear binding groups. The method of this disclosure offers several advantages, including simplified synthesis, high production yield, and low cost of starting materials, which are naturally desirable for commercialization. Therefore, the synthetic method described herein is desirable for the preparation of the wide range of conjugates of this disclosure.

[0046] This disclosure also describes the stability profiles of PEG-saccharide-lipid conjugates prepared by the synthesis methods described herein. In various embodiments, the PEG-saccharide-lipid conjugates exhibit long-term stability for at least 36 months in both liquid and solid states under room temperature conditions. The stability of the conjugates can be critical to ensuring safety in clinical applications.

[0047] PEG-saccharide-lipid conjugates can be incorporated into lyophilized powders, aqueous solutions, or solid dosage forms for drug delivery. While improved solubility of PEG-saccharide-lipid conjugates can be achieved by forming simple micelles in aqueous media, this is often distinguished from the improved solubility of so-called "self-emulsifying drug delivery systems" (SEDDSs), as SEDDS systems are typically isotropic mixtures of drugs, lipids, and surfactants containing two or more hydrophilic cosolvents or coemulsifiers. SEDDS mixtures typically require relatively more solubilizers compared to the same drug solution made with novel PEG-saccharide-lipid conjugates. The resulting reduction in dosage size is also beneficial for patients.

[0048] One aspect of the present disclosure provides a PEG-saccharide-lipid conjugate having the structure of general formula (I). JPEG2026528703000003.jpg3663 Here: m has an average value in the range of 2 to 10, which represents the distance between the terminal parts of the central skeleton. S is a sugar such as a monosaccharide, disaccharide, trisaccharide, etc., and each saccharide unit is a sugar, sugar alcohol, amino sugar, or sugar acid. L is -C(O)-R 1 where R 1 is an alkanil group or alkenyl group having an average carbon number in the range of 6 to 22, and / or a steroid acyl group, for example, those derived from cholesterol, cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, chenodeoxycholic acid, and lithocholic acid (for example, those derived from cholic acid, deoxycholic acid, glycocholic acid). P is -(CH2-CH2-O)nR 2 where n has a number average value in the range of 5 to 50 (for example, 8 to 45), and R 2 is hydrogen and / or an alkane, having a number average carbon number in the range of 0 to 4.

[0049] One of ordinary skill in the art will understand that real-world samples of the conjugates of the present disclosure will often have a range of R 1 chain lengths, a range of R 2 chain lengths, and a range of n values, and thus, various individual molecules within the sample may have different identifiers for R 1 , R 2 , and n. However, as noted above, in many cases, it may be desirable to control the variation in the value of n in particular. Thus, the definition of general formula I assumes that the material may be in the form of a mixture of individual compounds each having its own definitions of S, L, P, and m. Thus, general formula I defines various substituents in terms of the number average values of the various substituents. However, the present disclosure specifically contemplates various individual compounds having integer values for the various substituents as well.

[0050] The inventors have found that in some embodiments, it is desirable to keep the value of m relatively small in order to provide a relatively short diamine skeleton. Accordingly, in some embodiments described herein, the mean number of m is in the range of 2 to 8. For example, in some embodiments, the mean number of m is in the range of 2 to 6, or 2 to 5, or 2 to 4. In some embodiments, the mean number of m is 3. In some embodiments, the mean number of m is 2 or 4. The inventors have found that a value of m in the range of 2 to 4 is particularly suitable for parenteral administration, while a value of m in the range of 2 to 10 may be suitable for oral administration.

[0051] However, in other embodiments, longer diamine skeletons may be suitable. For example, in some embodiments described herein, the average number of m is in the range of 5 to 10. For example, in some embodiments, the average number of m is in the range of 5 to 8 or 8 to 10. While not intended to be theoretically bound, the inventors suggest that longer diamines result in relatively higher conjugate yields, as they provide more "space" in synthesis, less steric hindrance, and therefore less steric effect, especially when the PEG chain is long or the lipid is bulky.

[0052] Those skilled in the art can select a value for "m" based on the findings of this disclosure, particularly that a lower value for "m" improves hemolytic stability and therefore the safety profile.

[0053] This refers to various groups of sugars, such as trisaccharides. Each sugar unit is, for example, a sugar, a sugar alcohol, a sugar acid, or an amino sugar.

[0054] In the various embodiments described herein, S is selected from disaccharides, monosaccharides, or trisaccharides. For example, in some embodiments, "S" is a disaccharide. In some embodiments, "S" is a monosaccharide. In some embodiments, "S" is a trisaccharide. The number of sugar units may affect the HLB (hydrophilic-lipophilic balance) value of the conjugate, and those skilled in the art can obtain a desirable overall HLB value by determining specific sugars, as well as specific "P" and "L" groups, based on the disclosures herein.

[0055] The S group can contain various monosaccharide units, such as sugars, sugar alcohols, amino sugars, and sugar acids. In various embodiments, the sugar units of S are individually selected from hexoses, pentoses, sugar alcohols, sugar acids, and their amino sugar analogs. The individual sugar units of S can be linked to each other by glycosidic bonds, as is well known to those skilled in the art.

[0056] In particular, it is sometimes desirable that the S sugar unit directly bonded to the nitrogen of the diamine central skeleton originates from a sugar acid and is bonded to the nitrogen of the diamine as an amide. The inventors have focused on the fact that particularly stable compounds can be obtained by bonding as an amide. In various embodiments, the S sugar unit not directly bonded to the nitrogen of the diamine is a sugar. However, other bonding is also possible. For example, the bond between the diamine central skeleton and the sugar can take the form of an amine, for example, by amination of a sugar alcohol, or by the formation of an imine by the reaction of an aldehyde or ketone body of the sugar unit with an amine, followed by an Amadori rearrangement.

[0057] In some embodiments described herein, the structural formula of "S" is as follows: JPEG2026528703000004.jpg2076 Here, -(C x1 H 2x1 O x1 -1)-CO- is, x1A sugar acyl residue derived from a sugar acid where is 4 or 5, (C x2 H 2x2 -1O x2 -1)- is, x2 A sugar residue derived from a sugar in which is 5 or 6, or its open-chain form. In various embodiments, x1 It is 5, x2 It is 6.

[0058] In various embodiments, "S" has the following structure: JPEG2026528703000005.jpg3568 or its open-chain version.

[0059] In various embodiments, "S" is a lactobionyl group, a gluconyl group, or a combination thereof (e.g., a molar ratio of lactobionyl group:gluconyl group of at least 9:1). In various embodiments, "S" is a lactobionyl group. In other embodiments, "S" is a residue derived from gluconolactone, or neuraminic acid. In other embodiments, "S" is a residue of another disaccharide or trisaccharide that may be modified (e.g., oxidized). Examples include sucrose, lactose, maltose, trehalose, turanose, cellobiose, raffinose, melegitose, and maltotriose.

[0060] In various embodiments, "L" contains (or is an aliphatic acyl group) an aliphatic acyl group based on a saturated or unsaturated fatty acid (i.e., all combinations thereof). Thus, in various embodiments, "L" is -C(O)-R 1 And here, R 1 This is an alkanyl or alkenyl group with an average number of carbon atoms in the range of 6 to 22. Those skilled in the art will understand that in most real-world fatty acid samples, the aliphatic group has a variety of carbon chain lengths and degrees of unsaturation, and therefore the conjugates of this disclosure also often have a variety of carbon chain lengths and degrees of unsaturation in the aliphatic acyl component, particularly in conjugates of natural origin.

[0061] In various embodiments, R 1 It has an average number of carbon atoms in the range of 6 to 20, or 6 to 18. In various embodiments, R 1 It has an average number of carbon atoms in the range of 10 to 22, for example, 10 to 20 or 10 to 18. In various embodiments, R 1 It has an average number of carbon atoms in the range of 12 to 22, for example, 12 to 20 or 12 to 18. In various embodiments, R 1 R has an average number of carbon atoms in the range of 14 to 22, for example, 14 to 20 or 14 to 18. In the various preferred embodiments described above, R 1 It has an average number of carbon atoms of 18 or less.

[0062] Saturated and unsaturated R 1 Any of the bases are usable. In various embodiments described separately herein, R 1 R has an average unsaturated number in the range of 0 to 3, for example, 0 to 2. Of course, many samples in the real world have multiple unsaturated numbers. 1 The group is included. For example, some samples may contain stearoyl residues, oleoyl residues, and linoleyl residues. Some samples also contain combinations of oleoyl and linoleyl residues (for example, in a ratio of approximately 10:1).

[0063] In various desirable embodiments, R 1 This is a linear alkanyl group or alkenyl group.

[0064] In various embodiments described herein, R 1 It is derived from one or more of the following: 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. 1A variety of desirable fatty acids that can induce -C(O)- are further described in Tables 1 and 2, and mixtures of these fatty acids (e.g., those present in various fatty acid materials of natural sources such as sedge oil and sunflower oil) are of particular consideration. JPEG2026528703000006.jpg81170JPEG2026528703000007.jpg101166

[0065] However, in many embodiments, -C(O)-R 1 The base of the conjugated sample is R derived from oleic acid. 1 It is preferable that, as in the case of the -C(O)-lipid group, it has mostly the same chemical identity, for example, mostly cis-CH3(CH2)7CH=CH(CH2)7-C(O)-. In various embodiments described separately herein, -C(O)-R 1 This is at least 80 mol%, for example, at least 85 mol%, of a single chemical identity. In various embodiments described separately herein, -C(O)-R 1 This is at least 90 mol%, for example, at least 95 mol%, of a single chemical identity. In the various embodiments described herein, the single chemical identity is selected from n-hexanoyl, n-octanoyl, n-decanoyl, n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl, n-octadecanoyl, n-eicosaenoyl, and n-docosaenoyl. In the various embodiments described herein, the single chemical identity is selected from the following: Sys CH3(CH2)5CH=CH(CH2)7C(O)-, Sys, Sys CH3CH2CH=CHCH2CH=CHCH2CH=CH(CH2)7C(O)-, Sys, Sys, Sys CH3(CH2)4CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)3C(O)-, and Sys CH3(CH2)7CH=CH(CH2)11C(O)-

[0066] For example, in various embodiments, the single chemical identity is cis-CH3(CH2)7CH=CH(CH2)7C(O)-. In various embodiments, the single chemical identity is cis,cis-CH3(CH2)4CH=CHCH2CH=CH(CH2)7C(O)-. In various embodiments, the single chemical identity is cis-CH3(CH2)3CH=CH(CH2)7C(O)-. In other embodiments, the single chemical identity is any of the other residues listed in Tables 1 and 2.

[0067] In other embodiments, "L" includes (or is) a steroidacyl group such as a bile acid or similar group. In various embodiments, the steroidacyl group is an acyl group derived from cholesterol, cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, chenodeoxycholic acid, and litcholic acid. In various embodiments, the steroidacyl group is an acyl group derived from cholic acid, deoxycholic acid, and glycocholic acid.

[0068] As mentioned above, "P" is -(CH2-CH2-O)nR 2 And "n" has a numerical mean in the range of 5 to 50 (for example, 8 to 45), R 2n is hydrogen and / or alkanyl, with an average number of carbon atoms of 0 to 4. In various embodiments, n has an average number in the range of 5 to 45, for example, 5 to 40, 5 to 30, 5 to 20, 5 to 15, or 5 to 10. In various embodiments, n has an average number in the range of 8 to 50, for example, 8 to 45, 8 to 40, 8 to 30, 8 to 20, 8 to 15, 8 to 12, or 8 to 10. In various embodiments, the average number of n is in the range of 10 to 50, for example, 10 to 45, 10 to 40, 10 to 30, 10 to 20, or 10 to 15. In various embodiments, the mean value of "n" is in the range of 9 to 14, for example, 9 to 13, 10 to 14, 10.5 to 13.5, 11 to 13, 11.5 to 12.5, 11.8 to 12.2, 10.2 to 13.8, 10.8 to 13.2, or 11.4 to 12.6. In various embodiments, the mean value of "n" is in the range of 18 to 28, for example, 20 to 26, 22 to 24, 22.5 to 23.5, or 22.8 to 23.2. In various embodiments, the mean value of "n" is in the range of 25 to 40. In various embodiments, the mean value of "n" is in the range of 40 to 50, for example, 42 to 48, 44 to 46, 44.5 to 45.5, or 44.8 to 45.2.

[0069] Poly(ethylene glycol) is R 2 It is terminally modified with R 2 R can be H (i.e., forming a hydroxyl group) or an alkanyl group (i.e., forming an ether group). In various embodiments, R 2 R has an average carbon number of at least 0.95, for example, at least 0.99, or at least 1 (e.g., without hydroxyl groups). In various embodiments, R 2 R has an average carbon number in the range of 0.9 to 1.1, or 0.95 to 1.05, or 0.98 to 1.02. In various embodiments, R 2 The group is C1-C4. Examples include alkanyl groups, such as methyl or ethyl groups. In various embodiments, R 2 R is a methyl group. In various embodiments, R 2 The average number of carbon atoms is 0 to 3, for example, 0 to 2. In various embodiments, R2 The average number of carbon atoms is 0 to 0.94, for example, 0 to 0.75, 0 to 0.5, 0 to 0.1, or 0 to 0.05. In such embodiments, R 2 A significant portion of it is hydrogen.

[0070] - The P group is a methylated PEG residue (i.e., R 2 If the -P group is a methyl group, in various embodiments its number average molecular weight is in the range of 300 to 2200 g / mol. For example, in various embodiments, the -P group is a methylated PEG residue with a number average molecular weight in the range of 300 to 1200 g / mol, for example, 300 to 600 g / mol. In various embodiments, the -P group is a methylated PEG residue with a number average molecular weight in the range of 500 to 2200 g / mol, for example, 500 to 1200 g / mol, or 500 to 900 g / mol. In various embodiments, the -P group is a methylated PEG residue with a number average molecular weight in the range of 700 to 2200 g / mol, for example, 700 to 1200 g / mol, or 700 to 1100 g / mol. In various embodiments, the -P group is a methylated PEG residue with a number average molecular weight in the range of 475 to 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, for example, 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, for example, 1900–2100 g / mol. In this disclosure, methylated PEG residues and methylated PEG are described in various forms such as mPEG, mPEGn, and m(PEG)n, where n represents the number-average number of ethylene glycol residues. Those skilled in the art will understand from the context whether methylated PEG or methylated PEG residues are being discussed.

[0071] In various embodiments, PEG exhibits low polydispersity, which can be particularly important for conjugates used in parenteral administration. The inventors have found that using low polydispersity PEG yields better results, particularly regarding the good dispersibility of water-insoluble substances in aqueous systems. The polydispersity index (PDI) is defined by the following formula: JPEG2026528703000008.jpg1223 Here, Mw is the weight-average molecular weight and Mn is the number-average molecular weight. For example, in various embodiments, the PDI (polydispersion index) of the "P" group is 1.1 or less, e.g., 1.07 or less. In various embodiments, the PDI of the "P" group is 1.06 or less, or 1.05 or less. The polydispersion index of the "P" group is understood to be the same as the polydispersion index of PEG used in the manufacture of the conjugate. The molecular weight can be measured by liquid chromatography / mass spectrometry for either the conjugate or the PH compound used in the manufacture of the conjugate.

[0072] Commercially available USP or EP grade mPEG can be used in various embodiments. mPEG oligomers can also be prepared by total synthesis.

[0073] In various desirable embodiments, the P group is a long-chain linear or branched synthetic polymer composed of ethylene oxide units, CH3OCH2CH2-(OCH2CH2)nO-, where n is typically between about 4 and about 45, otherwise varying to provide a narrow or single-distribution polymer with a molecular weight of 200 to 2000 Daltons.

[0074] In the various embodiments described herein, m is 3, and S has the following structural formula. JPEG2026528703000009.jpg1971 Here, -(C x1 H 2x1 O x1 -1)-CO- is, x1 A sugar acyl residue derived from a sugar acid where is 4 or 5, (C x2 H 2x2 -1Ox2 -1)- is, x2 -C(O)-R, a sugar residue derived from a sugar where 5 or 6 is present, or its open-chain version. 1 This is at least 80 mol%, for example, at least 85 mol%, of cis-CH3(CH2)7-CH=CH(CH2)7C(O)-. 2 is methyl. The weight-average value of n is in the range of 11.5 to 12.5, for example, 11.8 to 12.2. The polyvariance index of P is 1.1 or less, for example, 1.07 or less. For example, in some embodiments, x1 It is 5, x2 It is 6. In some embodiments, S is structure JPEG2026528703000010.jpg3460 or their open-chain forms. In some embodiments, S is lactobionyl. In some embodiments, -C(O)-R 1 This is at least 90 mol%, for example, at least 95 mol%, of cis-CH3(CH2)7CH=CH(CH2)7C(O)-. In some embodiments, the polyvariance index of P is 1.06 or less, for example, 1.05 or less.

[0075] In the various embodiments described herein, m is 3 and S is a structural formula JPEG2026528703000011.jpg2382 Here, -(C x1 H 2x1 O x1 -1)-CO- is, x1 A sugar acyl residue derived from a sugar acid where is 4 or 5, (C x2 H 2x2 -1O x2 -1)- is, x2 -C(O)-R 1 cis-CH3(CH 27The CH=CH(CH2)7C(O)- is at least 80 mol%, for example, at least 85 mol%. The -P group is a methylated PEG residue having a number-average molecular weight in the range of 525 to 575 g / mol and a polydispersity index of 1.1 or less, for example, 1.07 or less. For example, in some embodiments, x1 It is 5, x2 It is 6. In some embodiments, S has the following structure. JPEG2026528703000012.jpg3459 or their open-chain forms. In some embodiments, S is lactobionyl. In some embodiments, -C(O)-R 1 This is at least 90 mol%, for example, at least 95 mol%, of cis-CH3(CH2)7CH=CH(CH2)7C(O)-. In some embodiments, the polyvariance index of P is 1.06 or less, for example, 1.05 or less.

[0076] In various embodiments described elsewhere in this specification, the conjugate has the structural formula of chemical structure 1. JPEG2026528703000013.jpg4297 Here, m(PEG)n is a methylated PEG residue.

[0077] In various embodiments, fatty acid acyl residues -C(O)-R 1 It is derived from one or more of the following: lauric acid, myristic acid, palmitic acid, linoleic acid, oleic acid, and stearic acid. m(PEG)n is a methylated PEG residue, where "n" is any desired value as described above.

[0078] In various embodiments, the conjugate is oleoyldiaminopropane-monomethoxy-polyethylene-glycol-ether-lacbionate (DOPS), represented by chemical structure 2. JPEG2026528703000014.jpg44115

[0079] The "oleyl" group is derived from oleic acid by at least 80 mol% -C(O)R 1It is understood to represent a group. In chemical structure 2, m(PEG)n is a methylated PEG residue, and "n" is any desired value as described above. In some embodiments, the mean number of "n" is in the range of 9.2 to 13.8, for example 10.2 to 13.2, or 11.4 to 13.6 (mPEG550 (n=12) or C 58 H 112 N2O 24 )

[0080] In various embodiments, the conjugate is stearylpropanediaminomonomethoxypolyethylene glycol etherlacbionate, represented by chemical structure 3. JPEG2026528703000015.jpg50115

[0081] The "stearyl" group is derived from stearic acid by at least 80 mol%. 1 It is understood to represent a group. In chemical structure 3, m(PEG)n is methylated PEG, and n is any desired value as described above. In some embodiments, the mean number of n is in the range of 9.2 to 13.8, for example 10.2 to 13.2, or 11.4 to 13.6 (mPEG550 (n=12), C 58 H 114 N2O 24 )

[0082] In various embodiments, the conjugate is represented by chemical structure 4. JPEG2026528703000016.jpg3991 Here, m(PEG)n is methylated PEG (for example, R 2 The average number of carbon atoms is 0.95–1.05, or 0.98–1.02, where "n" is any desired value as described above, and m is in the range of 2–6, for example, 3.

[0083] In various embodiments, the conjugate is chloroylpropanediamino-mPEG-lacbionate (CDPS), represented by chemical structure 5. JPEG2026528703000017.jpg53144

[0084] The "coloyl" group means that at least 65 mol% of the R 1 groups are derived from coloic acid. In Chemical Structure 4, m(PEG) n is methylated PEG (for example, the average number of carbon atoms of R 2 is in the range of 0.95 to 1.05, or 0.98 to 1.02), and "n" is any of the aforementioned desirable values. In some embodiments, the number average value of "n" is in the range of 9.2 to 13.8, for example 10.8 to 13.2, or 11.4 to 12.6 (mPEG550 (n = 12), or C 64 H 118 N2O 27 ). In various embodiments of Chemical Structures 3, 4, or 5, the number average value of n is in the range of 11 to 13, for example 11.5 to 12.5, or 11.8 to 12.2.

[0085] In various embodiments described herein, the conjugate has one of the following structures. JPEG2026528703000018.jpg97153JPEG2026528703000019.jpg194170JPEG2026528703000020.jpg167169

[0086] The inventor has determined that for the conjugates of the present disclosure, improved performance is obtained when one or more of various analysis goals are achieved.

[0087] In various embodiments of the conjugates described separately herein, -P is provided from a PH poly(ethylene glycol) source (such as mPEG) having a number average molecular weight in the range of 95.0 to 105.0% of the labeled nominal value when the labeled nominal value is less than 1000 g / mol, and having a number average molecular weight in the range of 90.0 to 110.0% of the labeled nominal value when the labeled nominal value is in the range of 1000 to 2000 g / mol.

[0088] In various embodiments of the conjugates described herein, the conjugate has a purity of at least 85% by weight as measured by HPLC. Such substances may be particularly desirable for oral use.

[0089] In various embodiments of the conjugates described herein, the conjugate has a purity of at least 90% by weight as measured by HPLC. Such substances may be particularly desirable for parenteral use.

[0090] In various embodiments of the conjugates described herein, R 1 When the -C(O)- group is an aliphatic acyl group, it is at least 65 mol% of a single chemical identity, such as at least 80 mol%, or at least 85 mol%, or at least 90%, or at least 95 mol%. In various embodiments, the single chemical identity is oleoyl, myristyl, palmitoyl, stearyl, or linoleyl.

[0091] In various embodiments described elsewhere herein, the conjugate contains less than 5 mol% of fatty acid-related analogs (i.e., those having other than the major R 1 -C(O)- identity, such as oleoyl).

[0092] In various embodiments of the conjugates described elsewhere herein, R 1 -C(O) is a fatty acyl, and when the conjugate of DOPS-12 (oleoylpropanediaminomonomethoxypolyethylene glycol ether lactobionate) is analyzed by HPLC, it is similar to the peak profiles and the following relative retention times (RRT) of Figures 1, 2, or 3, and the particular analogs are defined by how they differ from DOPS-12 (e.g., fatty acyl group, or in the case of gluconic acid, the saccharide). JPEG2026528703000021.jpg93170

[0093] In various embodiments, the conjugates of the Disclosure may be provided with relatively high purity. For example, in various embodiments, the purity of the PEG-sugar-lipid conjugates of the Disclosure exceeds 80% by HPLC. In various embodiments, the purity of the PEG-sugar-lipid conjugates of the Disclosure exceeds 90% by HPLC. In various embodiments, the purity of the PEG-sugar-lipid conjugates of the Disclosure exceeds 95% by HPLC. Figure 1 shows the HPLC chromatogram of the fatty acid conjugate. Peak 1 = Lauroylpropanediamino mPEG(12)-lactobionate (DLOPS-12); Peak 2 = Myristoylpropanediamino mPEG(12)-lactobionate (DMPS-12); Peak 3 = Palmitreylpropanediamino mPEG(12)-lactobionate (DPOPS-12). Peak 4 = linoleoylpropanediamino mPEG(12)-lactobionate (DLOPS-12); Peak 5 = palmitoylpropanediamino mPEG(12)-lactobionate (DPPS-12); Peak 6 = oleoylpropanediamino mPEG(12)-lactobionate (DOPS-12); Peak 7 = oleoylpropanediamino mPEG(12)-gluconic acid; Peak 8 = stearoylpropanediamino mPEG(12)-lactobionate (DSPS-12). The injection concentrations into the column were approximately 4-6 mg / mL for each. Figure 2 is an HPLC chromatogram of DOPS-12 prepared using USP grade mPEG(550), with a purity of over 95%. The injection concentration was approximately 5 mg / mL. DEPS-12 = elidoylpropanediamino-mPEG(12)-lactobionate. Figure 3 shows the HPLC chromatogram of linoleoylpropane-diamino-mPEG-lactobionate (DLPS-12 and its isomer iso-DLPS-12) prepared using USP-grade mPEG(550). The purity was 95% or higher, and the injection concentration was approximately 5 mg / mL. In various embodiments, the HPLC peak profiles of the conjugates of this disclosure are similar to the peak profiles of the HPLC chromatograms in Figures 1, 2, and 3.

[0094] In particular, the materials disclosed herein can achieve excellent solubility improvement of poorly soluble drugs without the use of cosolvents or coemulsifiers. For example, in the case of cyclosporine (0.09%) eye drops, the particle size of cyclosporine in the commercially available product (CEQUA®) is in the range of 12-20 nm, based on a SEDDS-like suspension using a mixture of polyoxyl 40 hydrogenated castor oil and polyalkoxylated alcohol. For comparison, by adding approximately 1% DOPS-12, a true 0.1% cyclosporine solution was obtained, and this solution was stable at room temperature for more than 4 years. While not intended to be theoretically bound, the inventors believe that the high purity and low dispersibility of the substance contribute to its particularly excellent performance.

[0095] In some embodiments described herein, the conjugate has a hydrophilic-lipophilic balance (i.e., HLB) value in the range of 13 to 18, for example, in the range of 13 to 15.

[0096] Another aspect of this disclosure provides a polyethylene glycol-sugar-lipid conjugate represented by the following formula, which is useful as a solubility or bioavailability enhancer for safely delivering hydrophobic or lipophilic compounds or groups of compounds. JPEG2026528703000022.jpg40170 Here: It is selected from the group consisting of fatty acids such as lauric acid, myristic acid, linoleic acid, palmitic acid, oleic acid, elaidic acid, and steroid acids. m(PEG)n is a high-molecular-weight polyethylene glycol (i.e., it makes the conjugate essentially a polymer). n is in the range of 8 to 45 ethylene glycol subunits. CH2's m * = 1 to 6. In some embodiments described herein, the polymers described herein have one or more of the following properties or specifications:

[0097] a. If the label's nominal value is less than 1000, the mPEG is in the range of 95.0% to 105.0% of the label's nominal value. If the label's nominal value is between 1000 and 2000, the mPEG is in the range of 90.0% to 110.0% of the label's nominal value. b. When used for oral applications, the purity of the polymer conjugate is 85% to 115.0% as determined by HPLC analysis. c. The purity of the polymer conjugate is 90% to 110.0% when used for parenteral administration, as determined by HPLC analysis. d. When using oleic acid, its purity must be 65% or higher. e. Each related analogue or impurity is less than 5%, f. The fatty acid-based polymer having a peak profile similar to that of Figures 1, 2, or 3 and the following relative retention times (RRT): JPEG2026528703000023.jpg90170

[0098] The synthesis method for preparing polymer conjugates includes the following steps: (1) Activated monomethoxypolyethylene glycol ether is coupled to the unprotected amino group of the central skeleton. (2) Lipids or disaccharides are attached to the backbone to form a PEG-saccharide-lipid conjugate in which the purity of the conjugate by HPLC assay is in the range of 85% to 115%.

[0099] In other embodiments described herein, the synthesis method for preparing the polymer conjugates described herein includes the following steps: (1) A short chain is synthesized consisting of an ethylene glycol group as the central skeleton and an ethylene glycol-protected hydroxyl group on an amino group. (2) The PEG chain is extended by repeating short ethylene glycol chain reactions. (3) Lipids or disaccharides are attached to the backbone to form a PEG-saccharide-lipid conjugate having high purity PEG oligomers. Here, the order of the coupling steps or coupling parts is interchangeable.

[0100] In some embodiments of the polymer conjugates described herein, m in the backbone * The value is 0 or 1, thereby forming a PEG-sugar-lipid conjugate with the following structure, suitable for clinical parenteral administration and oral application, with no or less hemolytic activity. JPEG2026528703000024.jpg35170 Here: m * If it is 1, the skeleton is propane, or m * If it is zero, the skeleton is ethylene. A fatty acid selected from the group including, but not limited to, lauric acid, myristic acid, linoleic acid, palmitic acid, linoleic acid, oleic acid, or stearic acid. n is in the range of 8 to 45.

[0101] In some embodiments of the polymer conjugates described herein, when used for parenteral administration, the distance between the two terminal amines is less than 4 carbon atoms.

[0102] In some embodiments of the polymer conjugates described herein, m in the backbone is greater than 1, thereby forming PEG-saccharide-lipids that are more suitable for oral administration in other applications.

[0103] In some embodiments of the polymer conjugates described herein, the PEG-saccharide-lipid conjugate is solid (low moisture) or semi-solid (high moisture) and is stable for at least 36 months under room temperature storage conditions.

[0104] In some embodiments of the polymer conjugates described herein, the average molecular weight of the monomethoxypolyethylene glycol ether is 95.0% to 105.0% of the nominal label value when the nominal label value is less than 1000, and 90.0% to 110.0% of the nominal label value when the nominal label value is between 1000 and 2000.

[0105] In some embodiments of the polymer conjugates described herein, the monosaccharide-related impurities in the polymer are less than 5%. In some embodiments of the polymer conjugates, the total amount of fatty acid-related impurities in the polymer conjugate is less than 10%, and the individual fatty acid-related impurities are less than 5%. For example, in various embodiments of the polymers described herein, the purity of the polymer conjugate is 90% or higher for use in parenteral compositions. The polymer conjugates described herein can be purified by any means known in the art. For example, in some embodiments described herein, the polymer conjugate is purified or dried by lyophilization. In some embodiments of the polymer conjugates described herein, if the polymer conjugate is used for parenteral administration, the polymer conjugate is purified or dried by lyophilization. In some embodiments of the polymer conjugates described herein, the purity of the polymer conjugate is 85% or higher for use in oral pharmaceutical compositions.

[0106] In some embodiments of the polymer conjugates described herein, the weight ratio of the PEG-saccharide conjugate to the oncological compound is approximately 200 to approximately 1 in drug delivery. In some embodiments of the polymer conjugates described herein, the weight ratio of the PEG-saccharide-lipid conjugate to the non-oncological compound is approximately 200 to approximately 1 in compound delivery.

[0107] In various embodiments of the polymers described herein, the PEG-saccharide-lipid conjugate is selected from the following structures. JPEG2026528703000025.jpg188170JPEG2026528703000026.jpg193170 Here, n is in the range of 8 to 45, or as otherwise stated herein.

[0108] Another aspect of this disclosure is a method for producing conjugates as described herein. Such a method involves poly(ethylene) glycol, sugars, and R 1 The method includes coupling a -C(O)-acyl group to a diamine skeleton. For example, in various embodiments, the method includes the steps of preparing a monoprotected diamine having a protected primary amine group and an unprotected secondary amine group, and poly(ethylene glycol) and R 1 The process includes the steps of coupling a -C(O)-acyl group to a secondary amine group, and then deprotecting the protected primary amine group and coupling a sugar to the newly unprotected primary amine group. In particular, in various embodiments, these various process steps can be carried out substantially without the use of a free radical initiator.

[0109] The coupling of poly(ethylene glycol) is R 1 This can be done before coupling the -C(O)-acyl group. If the poly(ethylene glycol) of the conjugate is hydroxy-terminated (i.e., R in the individual molecules) 2 If H, R 1 In coupling of -C(O)-acyl groups, it is sometimes desirable to keep the hydroxyl group in a protected form (e.g., benzyl ether).

[0110] In various embodiments, the coupling of poly(ethylene glycol) with a second amine group can be carried out stepwise. For example, a short PEG chain (or a single ethylene glycol unit) is first coupled to the central skeleton, and then etherification is performed to obtain a longer PEG chain. An example of this is shown in Reaction Equation 1 below. JPEG2026528703000027.jpg105170 Synthesis of propanediaminomonomethoxydodecaethylene glycol

[0111] Here, the so-called "Boc" protecting group is used to protect the primary amine of the diamine. Those skilled in the art will understand that Boc is a useful group for protecting the primary amine in other methods of this disclosure. They will also understand that other protecting groups can be used to protect the primary amine.

[0112] Similarly, the benzyl (Bn) group can be used to protect the hydroxyl group. Removal of the benzyl group to liberate the hydroxyl group of the PEG reagent can be carried out using any suitable reagent. For example, the benzyl group can be removed by hydrogenation in the presence of a palladium catalyst, and the PEG chain can be extended by repeating a similar etherification process. While the benzyl group is used in the example of reaction formula 1, those skilled in the art will be able to find other suitable alcohol protecting groups.

[0113] The extension of poly(ethylene glycol) is R 1 Although shown in Scheme 1 as being performed before coupling with the -C(O)-acyl group, in other embodiments, acylation can be performed while the hydroxyl protecting group is still present, and deprotection and extension of the alcohol can be performed after acylation.

[0114] After the reaction in reaction formula 1, before removing the protecting group of the skeletal terminal amine, the second amine group is R 1 It can be acylated with a -C(O)-acyl group. An example of this is shown in reaction formula 2. This can be done, for example, by reaction with a suitable acid chloride. For example, in the various embodiments described herein, R 1 The coupling between the -C(O)-acyl group and the secondary amine group is R 1The reaction is carried out using C(O)-halides. Those skilled in the art can determine appropriate reaction conditions, such as 20-30°C in N-methyl-2-pyrrolidinone (NMP). Acid chlorides can be prepared separately by dissolving the corresponding acid in tetrahydrofuran (THF), adding an excess amount of triethylamine (TEA) as a base, and then adding isobutyl chloroformate (IBCF). Treatment with oxalyl chloride is another method to make acid chlorides suitable for acylation. JPEG2026528703000028.jpg128170

[0115] With the PEG and acyl group bonded to the secondary amine, the primary amine can be deprotected using an appropriate deprotection method. Therefore, in various embodiments, the bonding of the sugar to the primary amine group involves deprotecting the primary amine group and bonding the sugar in the form of a sugar acid or its lactone. An example of deprotection of a Boc-protected amino group is shown in Example 2 below. Subsequently, the carbohydrate can be bonded to the central skeleton via the primary amine. This example is shown in reaction formula 4. In this method, any suitable sugar, such as lactobionolactone, is bonded in N2 in dichloromethane. 3 -Fatty acid propanediamino-mPEG-12 is reacted to produce the final product N 3 - Fatty acid propanediamino-mPEG-12-N 1 - Lactobionate can be produced. JPEG2026528703000029.jpg79170

[0116] In various embodiments of this disclosure, the synthesis methods described herein, for example, the methods shown in the various reaction schemes above, can be modified in any suitable way. For example, the "skeleton" 1,3-diaminopropane (propane-1,3-diamine) can be replaced with various agents including ethylenediamine, putrescine (butane-1,4-diamine), cadaverine (pentane-1,5-diamine), hexamethylenediamine (hexane-1,6-diamine), etc.

[0117] In various embodiments, the fatty acid residue has a carbon chain length in the range of approximately C8 to approximately C22, for example, approximately C10 to approximately 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, linoleidic acid, and α-linolenic acid.

[0118] In various embodiments, when the lipid group is oleic acid, the purity of the oleic acid should be in the range of 65% to 88%, according to the current European Pharmacopoeia (EP) definition. If higher purity oleic acid is required, further purification may be necessary.

[0119] The solvent for the PEG-lipid binding reaction in the disclosed method can be selected by those skilled in the art. Polar solvents, such as polar aprotic solvents, may be suitable in many embodiments. In some embodiments, the solvent is one or more of the following: N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), pyridine, tetrahydrofuran (THF), dichloromethane (DCM), chloroform, 1,2-dichloroethane, ethyl acetate, isopropanol, methanol, etc.

[0120] The disclosed method can be used to prepare a variety of novel PEG-saccharide-lipid conjugates. For example, it can be used to prepare N3-lipid propanediamino-mPEG-12-N1-lacbionate in a high-purity PEG form containing a lipophilic carrier group.

[0121] While monodisperse PEG is highly useful for polymer characterization and profiling, the preparation process of pure oligomeric PEG is time-consuming and labor-intensive. For economic reasons, USP (United States Pharmacopeia) grade polyethylene glycol with a PDI of 1.1 or less is often used for scale-up and commercial production. Because USP grade materials generally have sufficiently low polydispersity, they offer many of the same advantages as materials produced from monodisperse PEG products. The weight-average and number-average molecular weights of polyethylene glycol can be measured using mass spectrometry, which can also be used to measure polydispersity.

[0122] The hemolytic activity of polyoxyethylene polymers is thought to be due to the tendency for peroxide formation during the synthesis process of radical reactions. However, it is important to emphasize that hemolysis is only one form of cytotoxicity of polyoxyethylene polymers.

[0123] Notably, the synthesis methods described herein can provide polymer conjugates of this disclosure with minimal peroxide formation. Peroxide formation can be significantly reduced by using total synthesis in the production of the polymer, or by using stepwise covalent bonding of PEG and lipids rather than free radical-mediated "one-pot" random polymerization.

[0124] This disclosure provides a method for synthesizing PEG-glycolipid conjugates that offers several advantages, including simplified synthesis, high product yield, and reduced starting material costs. Furthermore, the synthesis method described herein can be applied to the synthesis of a wide range of PEG-glycolipid conjugates.

[0125] In many cases, it is difficult to precisely control the molecular weight distribution in free radical polymerization, and it is usually within 50% of the target PEG molecular weight. A narrower distribution can be achieved by size exclusion chromatography, and it is usually within 10% of the target PEG molecular weight. However, for small PEG chains with a molecular weight of 2000 or less, achieving a single distribution of purified PEG is extremely difficult.

[0126] Unlike free radical polymerization used in the production of polysorbates and cremophor, this disclosure allows for a clear definition of the composition or structure of the PEG-saccharide-lipid conjugate, which can include all of the various functional linker groups described herein. Where appropriate, USP-grade polyethylene glycol or its monomethyl ether with a narrow molecular weight distribution, i.e., several oligomers or within ±10% of the average PEG number-average molecular weight, can be used. By using the synthesis methods described herein, a clearly defined conjugate structure can be ensured. The level of impurities in the clearly defined mPEG product, particularly peroxides, can be minimized. Preferably, the level of hydroperoxides in the conjugate of this disclosure, as measured by the FOX2 assay (see Wasylaschuk WR, et al (2007). “Evaluation of hydroperoxides in common pharmaceutical excipients.” J.Pharm Sci. 96(1):106-16, which is thus incorporated herein by reference in its entirety), is less than or equal to 100 nmol / g, for example, less than or equal to 50 nmol / g, or less than or equal to 30 nmol / g.

[0127] For clarity, the molecular weight (MW) range of commercially available polyethylene glycol oligomers varies considerably depending on quality and supplier. For example, the number-average molecular weight of USP-grade polyethylene glycol monomethyl ether is 95.0% to 105.0% of the nominal label value if the nominal label value is less than 1000 g / mol (e.g., 750 ±), and 90.0% to 110.0% of the nominal label value if the nominal label value is less than 2000 g / mol. In the examples of this disclosure, only USP-grade monomethyl polyethylene glycol was used for the synthesis of PEG-saccharide-lipid conjugates. In this case, the distribution range of mPEG was within the range of ±5% (Mw ≤ 1000) to ±10% (max. 2000) of the USP standard or target number-average molecular weight (Mw). Overall, a PDI of less than 1.1 for mPEG is desirable.

[0128] The importance of purity in the PEG-sugar-lipid conjugates disclosed in this invention goes beyond mere quality control, fundamentally ensuring patient safety. Reactive impurities in commercially available pharmaceutical polymer excipients can cause instability in pharmaceuticals, potentially leading to reduced product performance, decreased potency, and / or the formation of potentially toxic degradation products. For example, commercially available polysorbates are chemically diverse mixtures, and while the expected structure of polyoxyethylene(20) sorbitan is present, monolaurate and polyoxyethylene(80) sorbitan monooleate account for only about 20% of the total volume of some commercially available polysorbates. The composition of polysorbates can also vary between vendors, and lot-to-lot variability may be due to differences in radical synthesis methods or raw materials. Polysorbate 80 (PS80) and Cremofor (Cr-EL) are major PEG-lipid polymers approved for clinical use. According to the FDA database "Approved Drug Ingredient Search," the "maximum daily intake" for intravenous products is 27,668 mg for Cr-EL and 4,739 mg for PS80, which corresponds to approximately 395 mg / kg for Cr-EL and approximately 68 mg / kg for PS80 in a typical human weighing 70 kg. In many cases, ethanol is used as a co-solvent with PS80 or Cr-EL (see rxlist.com for a description of the composition of "paclitaxel" and "Taxotere").

[0129] It has been reported that intravenous administration of 3% Cr-EL (5% glucose solution, 6.3 mL / kg) or 3% PS80 (5% glucose solution, 6.3 mL / kg) over 30 minutes to miniature pigs caused transient skin erythema, itching, and anxiety. Other studies have also shown pseudo-allergic reactions to these two additives. These pseudo-allergic reactions are thought to be mainly caused by high concentrations of impurities in the mixture of Cr-EL and PS80. These impurities cannot be completely removed and are thought to be due to radical synthesis.

[0130] Unlike complex mixtures such as Cr-EL and PS80, the PEG-saccharide-lipid conjugates disclosed herein allow for easy control of lot-to-lot variability. For example, in various embodiments of the PEG-saccharide-lipid conjugates disclosed herein, fatty acid-related impurities can be limited to 5% by weight or less. On the other hand, as defined in the polymer monographs of the European Pharmacopoeia or the United States Pharmacopoeia, the limit for fatty acid-related impurities is a maximum of 40% for PS80 and a maximum of 25% for Cr-EL.

[0131] The following describes the toxicological and pharmacological safety evaluations of the specific PEG-sugar-lipid conjugates included in this disclosure. For example, no pseudoallergic reactions were observed up to 200 mg / kg with intravenous administration in miniature pigs, and no pseudoallergic reactions were observed up to 2000 mg / kg with oral administration in dogs.

[0132] The chemical stability of polysorbates and the PEG-saccharide-lipid conjugates described herein is a key difference between these two polymeric materials. The ester bonds of polysorbate 80 (PS80), made from pure oleic acid (i.e., 98%), are even more sensitive and prone to degradation. Compared to the amide bonds in the various PEG-saccharide-lipid conjugates of this disclosure, PS80 may be more sensitive to degradation. For example, one study showed that the concentration of PS80 rapidly decreased to levels below 0.05% (v / v) of plasma volume. Within 15 minutes after bolus injection in mice, only 66% of the initial concentration of PS80 recovered. In direct comparison, the recovery rate of (complete) DOPS-12 in mouse plasma was approximately 98%. The cause of the pseudo-allergy is unknown, but is thought to be mainly due to high levels of contaminants in the PS80 mixture that cannot be completely removed, or to the inherent auto-oxidation of polysorbate 80, which produces reactive hydroperoxides and alkylperoxides.

[0133] Therefore, replacing polysorbate and cremofol with the PEG-sugar-lipid conjugate of this disclosure significantly improves stability, reduces immunogenicity, extends shelf life, and can meet important unmet needs in the fields of chemotherapeutic agents and biocompatible formulations.

[0134] In various embodiments, the formulations of the present disclosure can be provided without ethanol (e.g., with an ethanol content of 0.1% by weight or less). This is particularly useful in parenteral formulations based on PEG-saccharide-lipid conjugates. The absence of alcohol further prevents potential alcohol poisoning and significantly reduces the amount of excipients compared to parenteral formulations based on Cr-EL or PS80.

[0135] Those skilled in the art can provide suitable parenteral formulations comprising the conjugate of the present disclosure. For example, in a 5% by weight aqueous solution of the PEG-saccharide-lipid conjugate, the concentration of the drug can be as high as 1% by weight in some embodiments. Formulations for parenteral administration can be formulated, for example, by dissolving an appropriate amount of sodium chloride (e.g., 9% by weight) in purified water. If necessary, pH adjustment can be made using, for example, sodium hydroxide and / or hydrochloric acid, or a suitable buffer solution.

[0136] The conjugates of this disclosure can also be used in solid dosage forms. For example, in one formulation, a PEG-saccharide-lipid conjugate is added to a stainless steel container equipped with propeller-type mixing blades, and an appropriate amount of ethanol is added to the container and mixed. The drug substance is filled into the container and mixed at a constant rate at a temperature of 40-50°C. Mixing is continued until the drug is visually completely dispersed and a homogeneous solution is obtained. The ethanol is removed by vacuum at a temperature of 35-45°C. The waxy mixture solidifies upon cooling. This substance can then be encapsulated or tableted. An example of a formulation is shown below. JPEG2026528703000030.jpg38170

[0137] Another aspect of this disclosure is the conjugate described herein, which is used as a pharmaceutical excipient or in a pharmaceutical product.

[0138] Another aspect of this disclosure is a therapeutic composition comprising a conjugate and a therapeutic agent as described herein.

[0139] Another aspect of this disclosure is a composition for use in the treatment of an object having a condition, the composition comprising a conjugate and a therapeutic agent as described herein.

[0140] Another aspect of the present disclosure is a method for treating a subject having a certain condition, the method comprising administering a composition of the present disclosure to the subject. In some embodiments described herein, the therapeutic agent is suitable for treating the condition.

[0141] Another aspect of this disclosure provides a composition comprising a conjugate described herein and a therapeutic agent for use as a pharmaceutical.

[0142] Another aspect of this disclosure is the use of the conjugates described herein to enhance the bioavailability of therapeutic agents.

[0143] Another aspect of this disclosure is the use of the conjugate described herein to increase the solubility of a therapeutic agent in an aqueous system.

[0144] Another aspect of this disclosure is the use of the conjugates described herein as pharmaceutical excipients or as therapeutic agents.

[0145] Various therapeutic agents can be suitably used in the compositions, methods, and applications of this disclosure. However, those skilled in the art will understand from this disclosure that the compositions, methods, and applications of this disclosure are particularly advantageous for therapeutic agents that are poorly soluble or insoluble in water. For example, in various embodiments, the therapeutic agent has a concentration of 5 mg / mL or less, e.g., 2 mg / mL or less, in deionized water at 37°C. In various embodiments, the therapeutic agent has a concentration of 1 mg / mL or less, e.g., 0.5 mg / mL or less, or 0.2 mg / mL or less, in deionized water at 37°C. In various embodiments, the therapeutic agent has a solubility in deionized water of 0.1 mg / mL or less, e.g., 0.05 mg / mL or less, or 0.02 mg / mL or less, in deionized water at 37°C. In various embodiments, the therapeutic agent has a solubility in phosphate-buffered saline at pH 7.4 of 5 mg / mL or less, e.g., 2 mg / mL or less, in 37°C. In various embodiments, the therapeutic agent has a solubility in phosphate-buffered saline at pH 7.4 of 1 mg / mL or less at 37°C, for example, 0.5 mg / mL or less, or 0.2 mg / mL or less. In various embodiments, the therapeutic agent has water solubility in phosphate-buffered saline at pH 7.4 of 37°C of 0.1 mg / mL or less, for example, 0.05 mg / mL or less, or 0.02 mg / mL or less.

[0146] Similarly, the compositions, methods, and uses of this disclosure are particularly advantageous with respect to lipophilic therapeutic agents. For example, in various embodiments of the compositions, methods, and uses of this disclosure, the therapeutic agent has a logD7.4 value of at least 2, e.g., at least 2.25, at least 2.5, or at least 2.75. In various embodiments, the therapeutic agent has a logD7.4 value of at least 3, e.g., at least 3.25, at least 3.5, or at least 3.75. In various embodiments, the therapeutic agent has a logD7.4 value of at least 4, e.g., at least 4.25, at least 4.5, or at least 4.75. The logD7.4 value is measured using the flask shaking method described below. First, two solutions are prepared: one of n-octanol saturated with water and another of pH 7.4 phosphate-buffered saline (PBS) saturated with n-octanol. 490 μL of pH 7.4 PBS (n-octanol saturated) is added to the wells of a 96-well plate. Next, 20 μL of 50 μM stock of the test compound dissolved in a suitable n-octanol and / or water-miscible organic solvent is added to the well. Then, 490 μL of water-saturated n-octanol is added to the well. The plate is covered and shaken at 37°C for 24 hours. The relative amounts of the test compound in the n-octanol phase and the aqueous phase are measured and quantified using HPLC. The logD7.4 value is calculated as logD7.4 = log((OR / AR)), where (OR / AR) is the ratio of the relative amounts of the compound in the octanol phase and the aqueous phase (which can be obtained from the response of a suitable HPLC detector without calculating the absolute amount). In this analysis, the distribution of the stock solvent of the test compound is ignored. In other embodiments, the therapeutic agent has a logP value of any of the above values, measured as described above using deionized water instead of PBS.

[0147] For ionized therapeutics, logP (i.e., measured using water as the aqueous phase) is approximately the same as logD at logD 7.4 or other pH values ​​(i.e., using buffer as the aqueous phase), but this may not be the case for many other therapeutics, especially ionized therapeutics. The logD value of such therapeutics varies with pH and depends, for example, on the various ionization states (including ionized, partially ionized, and non-ionized species) of the therapeutic at a given pH. Various pharmaceutical compositions of this disclosure can have a variety of pH values, such as in the range of 3 to 9. Therefore, it may be desirable to ensure the solubility of the desired formulation at a desired pH. Furthermore, the use of conjugates of this disclosure is non-ionic and suitable for use at a variety of pH values. Those skilled in the art can provide pharmaceutical compositions of this disclosure having a variety of pH values, such as in the range of 3 to 4.5, 4 to 5.5, 5 to 6.5, 6 to 7.5, 7 to 8.5, or 8 to 9. Those skilled in the art will use appropriate buffers and pH adjusters as needed.

[0148] Furthermore, the conjugates of this disclosure may be desirable to use in combination with therapeutic agents that are moderately water-soluble at one pH value but not highly water-soluble at other pH values. For example, in various embodiments of the compositions, methods, and uses of this disclosure, the therapeutic agent has a logDX value of at least 2, e.g., at least 2.25, at least 2.5, or at least 2.75. In various embodiments, the therapeutic agent has a logDX value of at least 3, e.g., at least 3.25, at least 3.5, or at least 3.75. In various embodiments, the therapeutic agent has a logDX value of at least 4, e.g., at least 4.25, at least 4.5, or at least 4.75. In various embodiments, the DX value is a D8 value, a D8.5 value, or a D9 value. The logDX value is measured using the shaking flask method described above. Similarly, in various embodiments, the therapeutic agent is 5 mg / mL or less, e.g., 2 mg / mL or less, in a buffer at pHX at 37°C. In various embodiments, the therapeutic agent is 1 mg / mL or less, for example 0.5 mg / mL or less, or 0.2 mg / mL or less, in a pHX buffer at 37°C. In various embodiments, the therapeutic agent is 0.1 mg / mL or less, for example 0.05 mg / mL or less, or 0.02 mg / mL or less, in a pHX buffer at 37°C. In such various embodiments, X is 3, or 3.5, or 4, or 4.5. In such various embodiments, X is 5, or 5.5, or 6, or 6.5, or 7. In such various embodiments, X is 8, or 8.5, or 9. Solubility and logDX values ​​are determined using 0.1 M citrate / sodium citrate buffered saline for pH up to 5.8, 0.1 M phosphate buffered saline for pH between 5.8 and 8.0, and bicine buffered saline for pH above 8.0.

[0149] In various embodiments, the therapeutic agent is selected from apixaban, atorvastatin, cabazitaxel, celecoxib, docetaxel, dolutegravir, edaravone, etomidate, everolimus, midazolam, paclitaxel, (oral) propofol, rivaroxaban, tacrolimus, tenofovir, alafenamide, and ticagrelor.

[0150] The amounts of conjugate and therapeutic agents in this disclosure vary depending on the specific dosage form and the desired specific dose. Those skilled in the art can select specific amounts based on this disclosure and the identification of the desired therapeutic agent.

[0151] In various embodiments, the conjugates of this disclosure are present in amounts exceeding their critical micelle concentration. For example, in some embodiments, the conjugates are present in aqueous solution in amounts exceeding their critical micelle concentration or less than 0.1 mmol. While not bound by theory, the conjugates of this disclosure are thought to act partially by forming micelles with therapeutic agents.

[0152] In various embodiments, the weight ratio of the conjugate to the therapeutic agent is in the range of 500:1 to 1:2, for example, 200:1 to 1:2, 100:1 to 1:2, 50:1 to 1:2, or 20:1 to 1:2. In various embodiments, the weight ratio of the conjugate to the therapeutic agent is in the range of 500:1 to 1:1, for example, 200:1 to 1:1, 100:1 to 1:1, 50:1 to 1:1, 20:1 to 1:1, 10:1 to 1:1, or 5:1 to 1:1. In various embodiments, the weight ratio of the conjugate to the therapeutic agent is in the range of 500:1 to 2:1, for example, 200:1 to 2:1, 100:1 to 2:1, 50:1 to 2:1, 20:1 to 2:1, 10:1 to 2:1, or 5:1 to 2:1. In various embodiments, the weight ratio of the conjugate to the therapeutic agent is in the range of 500:1 to 4:1, for example, 200:1 to 4:1, 100:1 to 4:1, 50:1 to 4:1, 20:1 to 4:1, or 10:1 to 4:1.

[0153] The therapeutic agent can be present in the composition in various amounts, depending on the type of therapeutic agent and the specific form of the composition. For example, in various embodiments, the therapeutic agent is present in the composition in an amount of at least 0.1% by weight, for example, at least 0.2% by weight. In various embodiments, the therapeutic agent is present in the composition in an amount of at least 0.5% by weight, for example, at least 1% by weight. In various embodiments, the therapeutic agent is present in the composition in an amount of at least 2% by weight, for example, at least 5% by weight. In various embodiments, the therapeutic agent is present in the composition in an amount of at least 10% by weight, for example, at least 20% by weight.

[0154] In various embodiments, the therapeutic agent is present in the composition in an amount of 0.1 to 10% by weight, for example, 0.2 to 10% by weight, or 0.1 to 5% by weight, or 0.2 to 5% by weight, or 0.1 to 2% by weight, or 0.2 to 2% by weight. In various embodiments, the therapeutic agent is present in the composition in an amount of 0.5 to 20% by weight, for example, 1 to 20% by weight, or 0.5 to 10% by weight, or 0.5 to 10% by weight, or 0.5 to 5% by weight, or 1 to 5% by weight. In various embodiments, the therapeutic agent is present in the composition in an amount ranging from 2 to 30% by weight, for example, 5 to 30% by weight, or 2 to 20% by weight, or 5 to 20% by weight, or 2 to 10% by weight, or 5 to 15% by weight. In various embodiments, the therapeutic agent is present in the composition in an amount ranging from 10 to 50% by weight, for example, 20 to 50% by weight, or 10 to 30% by weight, or 20 to 40% by weight, or 10 to 20% by weight, or 20 to 30% by weight.

[0155] The conjugates of the present disclosure can be present in a composition in varying amounts. In various embodiments, the conjugates of the present disclosure are present in an amount of at least 1% by weight, for example, at least 2% by weight. In various embodiments, the conjugates of the present disclosure are present in an amount of at least 5% by weight, for example, at least 10% by weight. In various embodiments, the conjugates of the present disclosure are present in an amount of at least 15% by weight, for example, at least 20% by weight. In various embodiments, the conjugates of the present disclosure are present in an amount of at least 25% by weight, for example, at least 30% by weight.

[0156] The conjugate is present in a range of weight percent, for example, 2–25% by weight, or 1–15% by weight, or 2–15% by weight, or 1–10% by weight, or 2–10% by weight, or 1–5% by weight, or 2–5% by weight. In various embodiments, the conjugate of the Disclosure is present in a range of weight percent, for example, 10–35% by weight, or 5–25% by weight, or 10–25% by weight, or 5–15% by weight, or 10–20% by weight. In various embodiments, the conjugate of the Disclosure is present in a range of weight percent, for example, 20–50% by weight, 15–40% by weight, 20–40% by weight, 15–30% by weight, or 20–35% by weight. In various embodiments, the conjugate of the present disclosure is present in the composition in an amount ranging from 20 to 60% by weight, for example, 25 to 60% by weight, 20 to 50% by weight, 25 to 50% by weight, 20 to 40% by weight, or 25 to 45% by weight.

[0157] Of course, those skilled in the art can use the above relative mass ratios to determine various appropriate amounts of the conjugate for a given amount of therapeutic agent.

[0158] The compositions described herein can be provided in various types of dosage forms. For example, in various embodiments, the compositions of the Disclosure are in the form of aqueous solutions or suspensions. Such aqueous solutions or suspensions can be provided, for example, for oral administration, topical administration, intranasal administration, or parenteral administration. In other embodiments, the compositions of the Disclosure are in the form of concentrates for dilution into aqueous solutions or suspensions. In other embodiments, the compositions of the Disclosure are in the form of creams or gels for topical administration or ophthalmic use, for example. In other embodiments, the compositions of the Disclosure are in the form of solid dosage forms, such as tablets, capsules, or granules. Such solid dosage forms may be useful for oral or intraoral administration. Various other types of dosage forms are generally known to those skilled in the art.

[0159] The following examples are intended to further illustrate the disclosures and should not be interpreted as limiting their scope. example

[0160] Chemicals and Reagents: Lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, lactobionic acid, bile acids, glucuronic acid, methoxypolyethylene glycol or polyethylene glycol (PEG), and other chemicals or reagents were obtained from Sigma-Aldrich (St. Louis, Missouri, USA), Alfa Aesar (Ward Hill, Massachusetts, USA), ThermoFisherScientific (Rockford, Illinois, USA), and other commercial suppliers. All PEG-sugar-lipid conjugates used in this study were manufactured in-house by LipoSeuticals Inc. (Monmouth Junction, New Jersey, USA).

[0161] Example 1. Preparation of tert-butylcarbamate (Boc) protected amino groups

[0162] A highly yielding and effective catalyst-free, room-temperature synthesis method has been previously reported (Weiszhar Z., et al (2012). EurJ. Harm Sci. 45(4):492-8), and was used with some modifications. Di-t-butyl dicarbonate was added in a 1:1 molar ratio to a methanol solution of the starting compound. The resulting mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was removed under vacuum, the residue was dissolved in ethyl acetate, washed once with saturated ammonium chloride aqueous solution, dried over sodium sulfate, and concentrated to obtain the target product (>90%). An example of this reaction is shown in reaction equation 5, where R is the main structure of the central skeleton. This method chemically selectively produces Nt-Boc derivatives without generating large amounts of by-products such as isocyanates and urea. JPEG2026528703000031.jpg43170

[0163] Example 2. Deprotection of Boc-protected amino groups

[0164] Effective reagents for the deprotection of tert-butylcarbamates or tert-butyl esters include phosphoric acid and trifluoroacetic acid. These reactions are very simple and yield high yields. CH2C of Boc-carbamate (10% of crude product) l2 Equal volumes of trifluoroacetic acid were added to the solution. The resulting solution was stirred overnight at room temperature, then the solvent was evaporated, and the residue was collected as CH2C. l2 After redissolving in a solution and washing with saturated NaHCO3, the solution was dried over MgSO4. The solvent was evaporated, and the solution was used in the next step without purification.

[0165] Example 3. Preparation of Boc-1-animohexamethyleneamine

[0166] Transfer 20 mol of hexamethylenediamine to a 30-liter round-bottom flask equipped with a mechanical stirrer. Add 15 L of solvent mixture containing methylene chloride / methanol (1 / 4, v / v, 10 L total) to the flask and place the reaction flask in an ice bath to maintain the solution temperature at 0–10°C. Slowly add 5 mol of Boc₂O in 1.0 L of methylene chloride. Once the addition is complete, continue the reaction mixture for another 2 hours with vigorous stirring. Monitor the consumption of Boc₂O by TLC. Remove unreacted hexamethylenediamine by washing with sodium bicarbonate solution (10% NaHCO₃ in water). Collect the organic layer and dry it over sodium sulfate for 1–2 hours. The resulting crude product is stored refrigerated (4–8°C) (yield 85–105%). The resulting compound (chemical structure 6) is stable in the refrigerator for at least one week. JPEG2026528703000032.jpg29170

[0167] Example 4. Preparation of cholic acid chloride

[0168] 150 g of cholic acid was transferred to a 5-liter round-bottom flask and dissolved in 500 mL of methylene chloride. The reaction flask was placed in an ice bath and the temperature was maintained at 0-10°C. 55 g of oxalyl chloride was slowly added to the reaction flask using a funnel. The reaction was continued for 2 hours with constant stirring. The solvent was removed under vacuum, and unreacted oxalyl chloride was further removed under vacuum by co-evaporation with 500 mL of hexane to obtain a yellow solid (chemical structure 7, 150-165 g, yield 85-100%). The obtained product was used in the next step without further purification. JPEG2026528703000033.jpg42170

[0169] Example 5: Preparation of Boe-protected 1,3-propanediamine

[0170] Crude product was obtained in a yield of 85-105% following the same procedure as in Example 3 (Chemical Structure 8). JPEG2026528703000034.jpg25170

[0171] Preparation of mesylated polyethylene glycol monomethoxyl ether

[0172] 100 g of polyethylene glycol monomethoxyl ether (mPEG)-550 was transferred to a 5-liter round-bottom flask equipped with a mechanical stirrer and placed in an ice bath. 500 mL of THF and 24 g of triethylamine were added. The reaction mixture was cooled to 0-10°C, and 24 g of mesylchloride was added through a funnel, maintaining the mixture at 0-10°C. The reaction was continued with stirring for a certain period of time and maintained at 0-10°C for 1 hour. The mixture was washed twice with 300 mL of 0.5N HCl. The organic layer was collected and dried on 10 g of sodium sulfate for 1 hour. The salt was removed by filtration, and the solvent was removed under vacuum to obtain a yellowish liquid (chemical structure 9: 100-110 g, 90-110% yield). JPEG2026528703000035.jpg30170

[0173] Preparation of Boc-aminopropylamine-mPEG

[0174] The formation of the CN bond was carried out by N-alkylation of the amine in the central skeleton by the activated hydroxyl group of PEG. In a 1-liter round-bottom flask equipped with a mechanical stirrer and a heated mantle, 135 g of Boc-aminopropyleneamine from Example 5 was mesylated, and 114 g of mPEG from Example 6 was dissolved in 200 ml of a mixture of THF and water (1 / 1, v / v). The reaction mixture was stirred under reflux and nitrogen purging for 2-4 hours. The solvent was removed under vacuum, and 500 ml of CH2Cl2 was added to the residue. The solution was washed with 50 ml of water and 50 ml of 2N hydrochloric acid. The organic phase was collected and dried over Na2SO4, and the solvent was removed to obtain Boc-aminopropanamine-mPEG (chemical structure 10). The crude product was not further purified and proceeded to the next step. JPEG2026528703000036.jpg31170

[0175] Preparation of aminopropanamine-mPEG-oleate

[0176] The crude product (90 g) from Example 7 was dissolved in methylene chloride (800 mL) in a round-bottom flask (2 L) equipped with a mechanical stirrer. In a separate container, oleoyl chloride (100 g) was dissolved in methylene chloride (200 mL) and slowly added to Boc-aminopropaneamino-mPEG using a funnel. After the addition was complete, the reaction was continued for 2 hours with constant stirring at room temperature. Completion of the reaction was confirmed by the complete disappearance of oleoyl chloride by TLC. The reaction mixture was washed three times with 300 mL of 0.5N NaOH, the methylene chloride layer was recovered and dried on sodium sulfate (100 g) for about 2 hours. The salt was removed by filtration, and the solution was removed under vacuum (chemical structure 11, yield 70-75%). JPEG2026528703000037.jpg40170

[0177] Example 10. Preparation of 1,3-propanediamine-lactobionate-mPEGoleate (DOPS-12)

[0178] Following the procedure of Example 2, the protecting group was removed from the Boc-aminopropanamine-mPEG-oleate product of Example 8, and the N1-amino group was liberated. The resulting product (200 g) was dissolved in 400 mL of CH2Cl2 (DCM) and transferred to a 1 L round-bottom flask equipped with a mechanical stirrer. Triethylamine (24 g) was added to the flask, and the mixture was cooled to 0°C and 10°C with stirring in an ice bath for a set period of time. Pre-dried. Lactobionic acid (81 g) was added. The reaction was completed in 2 hours with stirring at room temperature for a set period of time. The completion of the reaction was tracked by checking the peak profile using HPLC. The final product was washed with diluted HCl (0.1 N) or NaOH (0.1 N) to neutral pH (7), then extracted with methylene chloride (DCM), and the water washing and DCM extraction procedure was repeated until the desired purity was obtained by HPLC chromatography. The DCM layer was collected and dried over sodium sulfate (100 g) for about 2 hours. The salt was removed by filtration, and the solution was removed under vacuum. The product was further freeze-dried to obtain a yellowish, waxy substance (chemical structure 2: yield 70-80%).

[0179] Using the intermediate from Example 5, chloropropanediamino-mPEG-lactivionate conjugate (chemical structure 5) was prepared according to the procedures of Examples 7, 8, and 9.

[0180] Examples 3-10 are suitable for producing PEG-sugar-lipid conjugates with any type of available lipid, including but not limited to fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, and bile acids, or their analogues such as cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, chenodeoxycholic acid, and lithocholic acid. As described above, in various preferred embodiments, the mPEG group contains 8 to 45 subunits.

[0181] One feature or aspect of the embodiment has been demonstrated to be widely present in methods for producing polymers, including but not limited to the following PEG-saccharide-lipid conjugates, as of the filing date of this patent application. JPEG2026528703000038.jpg233170JPEG2026528703000039.jpg83170 Here, n is as described in any of the embodiments above.

[0182] Example 11: Chromatographic profile of PEG-glycolipid conjugate

[0183] Fatty acid-based FA-propanediamino-mPEG(12)-lactobionic acid conjugates were prepared according to the synthesis method described herein. Reverse-phase isocratic HPLC was used for the analysis of PEG-saccharide-lipid conjugates and related compounds. The chromatography conditions are shown in Table 3. JPEG2026528703000040.jpg60170

[0184] The purity of these fatty acids and related analogues can be monitored in a similar manner. Each of the polymers was dissolved in pure methanol at a concentration of approximately 5 mg / mL and injected into the column in 10 μL portions. The resulting chromatograms are shown in Figure 1. Figure 2 shows the chromatogram of a large batch of DOPS-12 (DOPS-F02) prepared according to Example 10. Similarly, Figure 3 shows the linoleoylpropanediamino-mPEG-lactobionate conjugate and its isoforms prepared in the same manner as DOPS-12.

[0185] The relative retention time (RRT) of individual peaks for each fatty acid-based PEG-sugar-lipid conjugate against DOPS-12 (as RT reference) is calculated using the following formula: JPEG2026528703000041.jpg14170 Here, the RRT of DOPS-12 is 1.00. The retention times of individual fatty acids are in minutes. Comparisons must be made using the same chromatogram or the same sequence run. Representative RRTs are shown in Table 4, and specific analogues are defined according to the differences from DOPS-12 (e.g., differences in fatty acid acyl groups, differences in sugars in the case of gluconic acid, etc.). JPEG2026528703000042.jpg76170

[0186] In some embodiments, the HPLC profiles of the PEG-saccharide-lipid conjugates prepared according to the present invention can show relative retention times consistent with those in Table 4, using the assay procedure described in Example 11.

[0187] Example 12: Screening test for hemolytic capacity

[0188] The test substances were prepared in three separate lines of pH 7.4 PBS (phosphate-buffered saline) / 2.5% glucose buffer at concentrations of 100, 10, and 1 g / L (corresponding to 10, 1.0, and 0.1%, respectively). 2% RBCs (red blood cells) collected from two human donors were suspended in these cells. Various concentrations of the test substances were added to 2 mL of this cell suspension, and the cells were incubated at 20±2°C for approximately 60 minutes while shaking in a benchtop tube shaker. After lysing of the red blood cells, intact cells were removed by centrifugation, and the hemoglobin released into the solution was measured. The degree of hemolysis was calculated according to the following formula. Hemolysis rate (%)=100xEH / EK EH represents the optical density at 540 nm of the supernatant of the reaction mixture between the test substance and cells, while EK represents the optical density at the same wavelength of the supernatant of completely hemolyzed red blood cells (10% saponin was used as a positive control). The results (n=3) are summarized in Table 5, expressed in hemolysis rate (%). JPEG2026528703000043.jpg86170

[0189] In Table 5, SolutolHS15 = polyethylene glycol 12-hydroxystearate (FDA-approved intravenous additive), TPGS = d-α-tocopherol polyethylene glycol 1000 succinate (FDA-approved oral additive). CDPS-12 = coloylpropanediamino-mPEG(12)-lactobionate, DOPS-12 = oleoylpropanediamino-mPEG(12)-lactobionate, DOPS-H12 = oleoylhexanediamino-mPEG(12)-lactobionate, OPS-12 = oleoylputressindiamino-mPEG(12)-lactobionate, DSPS-12 = stearoylpropanediamino-mPEG(12)-lactobionate. DCPS-12 = Cholesteryl(oxyethoxy)acetyldiaminopropane-mPEG(12)-lactobionate; DMPS-12 = MyristoylpropanediaminomPEG-(12)-lactobionate; TOPS-12 = Oleoylbis(3-aminopropyl)amine-mPEG(12)-lactobionate

[0190] Generally, in μM-level samples, values ​​exceeding 2% are considered hemolysis. While a 10% concentration of the test substance was relatively high in such experiments, if hemolysis exceeds 5% for demonstration purposes, the results should indicate relatively high hemolytic activity.

[0191] The results demonstrated that, at high concentrations of 10%, DOPS-12 (Figure 4A), DMPS-12, and DSPS-12 were the safest excipients among the two parenteral excipients approved by regulatory authorities (polysorbate 80 and solutol H15), compared to other excipients containing polysorbate 80 and solutol H15.

[0192] Within the same lipid group, polymers containing triamine (TOPS-12) or diaminohexane (DOPS-H12) exhibited high hemolytic activity and were therefore unsuitable for parenteral use (Figure 4B). Within the same central skeleton, increased hydrophobicity or steric size of lipid groups such as cholesterol (DCPS-12) may also contribute to the increased hemolytic activity.

[0193] As one of the features or aspects of an embodiment of the present disclosure, since the distance between the two terminal diamines in these PEG-saccharide-fatty acid conjugates is short (4 or fewer carbon atoms), they are suitable for parenteral administration, and longer-chain (more than 4 carbon atoms) PEG-saccharide-lipid conjugates may be suitable for oral administration. Furthermore, bulky lipid groups such as cholesterol may not be suitable for intravenous administration even when using short-chain diamines.

[0194] Example 13 Long-Term Storage Stability

[0195] The stability of the product is another important factor in clinical applications. Bulk samples collected from the pilot batch of DOPS-12 were evaluated in a formal stability test. 500 - 600 grams of DOPS-12 samples were packaged at a weight-to-volume ratio of 0.6 - 1.1 (kg / L) in packaging that simulated the commercial packaging form. The constituent material of the polyethylene container simulated the commercial packaging form. Three sets of DOPS-12 were packaged in this way and tested by the HPLC method described in Example 11. No significant changes were observed in related substances, impurities, or physical properties even after storage at 40°C / 75% RH (relative humidity) for 6 months and at 25°C / 60% RH for 36 months (Figure 5).

[0196] Example 14 Toxicokinetic (TK) Profile of DOPS-12 in Yucatan Miniature Pigs

[0197] Due to the tendency for polymer accumulation in the body, and the lack of prior knowledge and published references, intravenous administration studies in large animals have been a major challenge. The TK study was part of a 28-day toxicity study conducted in Yucatan miniature pigs using repeated intravenous administration, based on a GLP study protocol approved by the Institutional Animal Care Committee (IACUC). DOPS-12 (also known as DOPS-12) solution was administered to male and female Yucatan miniature pigs (S&S Arms, Ramona, California) aged 7-8 months and weighing 27-33 kg at a fixed dose of 2 mL / kg for 28 days against a target dose of 200 mg / kg. Actual doses were 193 mg / kg to 207 mg / kg (n=6) via 90-minute infusion. Here, we use the TK 36 hours after the last dose on day 28 as an example.

[0198] As shown in Fig. 6, liquid chromatography / tandem mass spectrometry (LC-MS-MS) was used for the assay of TK plasma samples, and TK data were analyzed using the non-compartmental pharmacokinetic method of the WinNonlin program (version 5.3, Pharsight, Mountain View, CA) under the assumption of linear PK (constant infusion NCA model 202). The analyzed parameters included the maximum plasma concentration (Cmax), the time to the maximum plasma concentration (Tmax), the area under the plasma concentration curve from time 0 to 36 hours (AUC0-36hr), the area under the plasma concentration curve from time 0 to infinity (AUC0-inf), the half-life (t1 / 2), and the total body clearance (CL). To determine the residual DOPS-12 after 36 hours, the concentration at the last TK time point was also included. The average Cmax value after the final intravenous administration was 2842.6 ± 332.7 μg / mL in the male dosing group and 2768.0 ± 257.3 μg / mL in the female dosing group. In the male dosing group, the average t1 / 2 after the final dose was 33.6 hours (29.9 - 36 hours), the average t1 / 2 was 38.7 hours (31.4 - 51.9 hours), and the average CL was 0.0017 mL / hr·kg. In the female dosing group, the average t1 / 2 was 32.7 hours (31 - 34.2 hours), and the average CL was 0.005 mL / hr·kg. The average AUC(0 - 36 hours) was 62050.5 ± 4670.4 hour μg / mL in the dosed male animals. The average AUC(0 - 36 hours) was 56909. Embodiment 954 ± 3495.4 hour μg / mL in female animals after the final dose. The toxicokinetic parameters of DOPS-12 in minipigs injected with 200 mg / kg over 90 minutes after the last intravenous administration were summarized in Table 6 and Fig. 7. The slow disappearance indicates a long half-life (t1 / 2) due to the slow clearance rate. Despite the accumulation of the polymer due to the slow clearance, DOPS-12 was well tolerated by the minipigs. This indicates that it is suitable for parenteral administration. JPEG2026528703000044.jpg170170

[0199] Example 15 Oral Toxicity of DOPS-12 in Young Beagle Dogs

[0200] This study was conducted based on a GLP study protocol approved by the Institutional Animal Care Committee (IACUC). Animals were 11–13 weeks old and randomly divided into four groups of 3–5 animals of each sex. The dosage was selected after the initial dose from 2000 mg / kg and 1000 mg / kg. Both doses were well tolerated, but considering sample availability, 1000 mg / kg was selected for the follow-up study. The control drug (sterile water for injection) or the DOPS-12 (or DOPS-F-2) formulation (DOPS-12 dissolved in sterile water) was administered orally once daily for 90 consecutive days at doses of 5, 3, 4, and 5 mL / kg, and 600, 800, and 1000 mg / kg, respectively.

[0201] In dogs, no abnormalities were observed in body weight or food intake during the administration and recovery periods (Figures 8A and 8B). All dogs grew normally throughout the study period, and no significant adverse reactions were observed in the puppies studied.

[0202] Example 16: DOPS-12 oral TK in young Beagle dogs

[0203] Following the general procedure of Example 14, blood samples were collected from animals in the DOPS-12 group before administration and at 0.5, 2, 4, 12, 24, and 36 hours after administration (selectively at the time of the final administration on day 90). Actual in vivo exposure to DOPS-12 was nearly identical between males and females based on mean AUC values ​​(Figures 9A and 9B), with dose exposures of 10,500, 10,600, and 18,400 h·ng / mL (females), 12,100, 12,900, and 12,700. On day 1, male dose exposures corresponding to 600, 800, and 1,000 mg / kg were h·ng / mL. On day 90, the dose exposures corresponding to 19,600, 19,700, and 23,900 h·ng / mL in females and 600, 800, and 1,000 mg / kg in males were 17,700, 22,000, and 23,200 h·ng / mL, respectively. Therefore, the difference in DOPS-12 exposure between the female and male groups was considered insignificant. Dose accumulation was observed, and the mean AUC value increased, but the range of AUC was narrow. On day 90, the dose exposure increased slightly from 600 mg / kg to 800 or 1000 mg / kg, which is thought to be mainly due to the dose accumulation effect.

[0204] DOPS-12 did not show significant adverse events in a 90-day repeated-dose study. On the other hand, in one-third of the animals that received polysorbate 80 orally at a dose of 10 mg / kg, mild and transient clinical signs of hypersensitivity reactions such as erythema, edema, and scratching were observed approximately 20 to 60 minutes after administration.

[0205] For safety assessments of novel molecules, it is always preferable to use non-rodent animal models. This is because, when considering all species, the agreement rate between animal toxicity and human toxicity is approximately 71%, and it has been shown that non-rodent models alone can predict 63% of events, while rodent models can predict 43%. It should be noted that the animal model data presented here has far greater probative power than rodent data and therefore cannot be directly compared with rodent data from previous studies.

[0206] Example 17: Oral bioavailability of DOPS-12 in young Beagle dogs

[0207] This study was conducted in accordance with a research protocol approved by the Institutional Animal Care Committee (IACUC). Animals were administered DOPS-12 intravenously by short-duration infusion at doses of 3 mg / kg or 0.2 mL / kg of saline solution. Blood samples were collected before administration, and at 5, 15, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours after administration. After administration, the concentration of DOPS-12 in canine plasma was measured using LC-MS / MS. Relevant PK parameters were calculated using a non-compartmental analysis model with PhoenixWinNonlin8.2 (Certara, Princeton, New Jersey). After a single intravenous administration of DOPS-12 at a concentration of 3 mg / kg (Figure 10), the AUC0-24 and AUC0-∞ of DOPS-12 in female canine plasma were 90600. In male dogs, AUC0-24 was 133,000 h·ng / mL and AUC0-∞ was 135,000 h·ng / mL. Cmax was 27,200 ng / mL and CL was 32.9 mL / h / kg in female dogs. In male dogs, Cmax was 43,300 ng / mL and CL was 22.3 mL / h / kg. The half-life (t1 / 2) was approximately the same for both female and male dogs, at 3.72 hours for females and 3.97 hours for males. The absolute oral utilization rate (Fabs) can be estimated using the following formula. Based on the dose-exposure ratio (Example 15), the bioavailability of DOPS-12 is 0.03% on day 1 and 0.05% on day 90 in male dogs, and 0.06% on day 1 and 0.05% on day 90 in female dogs. The low bioavailability of polymers as dissolution accelerators is particularly beneficial in clinical applications.

[0208] Example 18: Experiment on improving solubility

[0209] To verify the effect of improving solubility, the amount of polymer required to solubilize hydrophobic solutes was measured. The solubility of 1% propofol was measured at various concentrations and with different polymers, and the results were directly compared with those shown in Table 7 below for various polymers and concentrations. The determination was made based on whether a clear solution was obtained. JPEG2026528703000046.jpg82170

[0210] In some embodiments, the conjugates of the present disclosure have one or both of the following features: The oligomer purity of the PEG-sugar-lipid conjugate is greater than 85%, or the nominal value indicated on the polymer label is between 85.0% and 115.0%. The individual related analogues or impurities are less than 5%.

[0211] Example 19: Toxicity estimation of polymer structures

[0212] The hemolytic activity of surfactants has been studied in relation to their physicochemical parameters and descriptors, such as critical micelle concentration (CMC), hydrophilic-lipophilic balance (HLB), and surfactant partition coefficient (LogP, or logD7.4). Studies have shown that increasing hydrophobic chain length promotes membrane-surfactant bonding, accompanied by an increase in the partition coefficient. This destabilizes the membrane, allowing it to be broken down at minimum surfactant concentrations. On the other hand, increasing the volume of hydrophilic groups due to improved length or flexibility of the hydrophilic groups promotes the conical shape of the monomer and the curvature of the membrane produced by the surfactant. As a result, the surfactant has a greater destabilizing effect, enhancing its hemolytic properties. In the case of certain polyoxyethylene ethers, hemolytic activity increases with hydrophilic chain length. However, due to the complexity of polymer properties, there is no effective method for making predictions. The results showed no correlation between hemolytic droplets and HLB or LogP values ​​(Table 8) compared to experimental results, indicating that LogP or HLB are not effective or reliable methods for estimation or prediction. Therefore, PEG-sugar-lipid conjugates suitable for clinical application need to be obtained through experimental testing or research, rather than through prediction or estimation. JPEG2026528703000047.jpg91170

[0213] The example conjugates prepared from mPEG (12 subunits) have HLB values ​​in the range of 13 to 15, calculated using the well-known Griffin method. The HLB value increases with increasing PEG chain length; for example, with 45 ethylene glycol subunits, the HLB is approximately 17.3. In this specification, it is preferable that the HLB value measured by the Griffin method is in the range of 13 to 18, for example, 14.5 to 15.5 or 15 to 17.5.

[0214] Each PEG-sugar-lipid conjugate possesses unique properties that affect safety and solubility. Surprisingly, even with only a few methylene groups differing between two terminal amines having the same composition and carrier, conjugates with short diamines in the central skeleton are known to have lower biological activity than other conjugates. For example, comparing DOPS-12 (a conjugate with 1,3-diaminopropane) and DOPS-H12 (a conjugate with hexamethylenediamine), the conjugate with the short diamine exhibits lower biological activity than the other conjugates. Polymer structures with short diamines have been shown to have lower hemolytic activity compared to materials with triamines (TOPS-12), long-chain diamines (DOPS-H12), or bulkier lipid moieties (DCPS-12).

[0215] Example 20 Purification of sugar-lipid conjugates

[0216] Even after most impurities have been removed by the "work-up" at the end of synthesis, residual solvents often pose a safety concern. Because polymers are highly soluble in both organic solvents and water, a washing process was developed to remove residual solvents that are harmful to the polymer. First, the polymer was redissolved in USP-grade pure ethanol in a 1:1 weight ratio and vacuumed at 35-40°C. The alcohol-washed polymer was then redissolved in USP-grade or higher pure water in a 1:3 weight ratio. The polymer solution was transferred to a suitable drying tray and stored overnight in a freezer at -45°C.

[0217] The shelves of the dryer were cooled to approximately -50°C, and the product was placed on trays maintained at -45°C or lower for at least 8 hours. The vacuum was set to 50 - 100 millitorr, the shelves were set to -30 to -35°C, and maintained at -32 ± 3°C for at least 55 - 65 hours. When the system pressure reached below -50 millitorr, the chamber pressure was reduced and the shelves were heated to 22 - 25°C. The product temperature was maintained at 22 ± 3°C until it exceeded 20°C for at least 6 hours, and then the chamber was evacuated to a partial vacuum. The chamber was returned to atmospheric pressure and the trays were removed. Figure 11 shows a sample of a freeze-dried polymer (DOPS-12) that is solid and has a good appearance. Only a trace amount of alcohol (<0.5%) was detected, and all other solvents were almost completely removed. It is either not detected (USP Class II residual solvents) or less than 0.5% (USP Class III solvents).

[0218] Alternatively, the polymer can also be dried using a spray drying process. For example, a 10% - 20% concentrate of DOPS-12 in ethanol is fed into a dryer set with the following parameters. Spray dryer: 5L / hour Blower: 40Hz Inlet temperature: 79°C (76 - 82°C) Outlet temperature: 30°C (25°C - 35°C) Flow rate: 10 - 15 gm / min (or 600g - 900g / hour) Deblock piston setting: 300 Spray pressure: 0.2Mpa Needle pressure: 0.3Mpa Cooling water setting: 10°C Nitrogen generator setting: As required.

[0219] In various embodiments, in the formulation step, for example, a drying step using a freeze dryer or a spray dryer can be used. The active pharmaceutical ingredient (API) is dissolved with a conjugate in a solvent such as water, alcohol, acetone, etc., and then appropriately dried using a freeze dryer (when using water as the solvent) or a spray dryer.

[0220] In various embodiments of this disclosure, it may be desirable to control the quality of the starting materials to a specific level. One of the three main components of PEG-sugar-lipid conjugates is a naturally occurring fatty acid, such as oleic acid. While manufacturers certify an oleic acid content in the high 80s, a purification process to remove other saturated and unsaturated fatty acids may be desirable. The second component is a sugar acid, such as lactobionic acid, which is also a naturally occurring oxidation product of lactose. Therefore, certain monosaccharides, such as galactose and glucose, may coexist with lactose, and oxidation may produce small amounts of other sugar acids, such as galacturonic acid and glucuronic acid. Furthermore, monomethoxypolyethylene glycol ether is a mixture of polyethylene chains, typically in the range of 5-10% of the target molecular weight, based on USP limits. Therefore, a series of specifications, such as purity assays by HPLC as shown in Example 11, are desirable to control the quality of the polymer.

[0221] Example 21: Active systemic anaphylaxis test in mice

[0222] This study aimed to investigate whether intravenous administration of PEG-glycolipid conjugates had an effect in inducing or preventing anaphylactic reactions. Mouse models of systemic anaphylaxis are important tools for elucidating the pathogenesis of anaphylaxis and for identifying and characterizing potential treatments for anaphylaxis. In these models, hypothermia is a major quantitative indicator of anaphylaxis.

[0223] This study was conducted according to a research protocol approved by the Institutional Animal Care Committee (IACUC). Six animals (G#) were sensitized by intraperitoneal administration of saline (G1), positive control ovalbumin [OVA] 100 μg / animal (G2), the test substance, and DOPS-12 350 mg / kg (G3), or 500 mg / kg (G4) of DOPS-12 body weight. Pertussis toxin and aluminum potassium sulfate adjuvants were used for sensitization of groups G1, G2, and G3. After a 21-day rest period, animals were administered intravenously with OVA 500 μg / animal (G1 and G2 groups) and the test substance 350 mg / kg (G3 and G4 groups). Clinical symptoms and mortality were observed twice daily on sensitization days. On the day of the challenge, rectal temperature was measured before treatment and at 5, 15, and 30 minutes after treatment or until death. Clinical signs were observed at 5, 10, 15, 20, 25, and 30 minutes after the challenge or until death.

[0224] Ataxia, recumbency, mild tremors, mild lacrimation (clear discharge), respiratory distress, and mild piloerection were observed. All animals died 10–25 minutes after exposure. All mice in group G2 developed anaphylactic symptoms and experienced a rapid decrease in body temperature. After exposure, no clinical signs, death, or changes in rectal temperature were observed in groups G1, G3, and G4. There was no effect on weight gain, and no abnormalities were observed on macroscopic autopsy. The validity of the experiment was confirmed by a positive reaction using ovalbumin in positive control mice, which induced signs of anaphylaxis and hypothermia leading to death. No reaction was observed in the groups administered the medium and the test substance. From these results, it was concluded that the test substance DOPS-12 did not show the potential to produce IgE (re-antigenic) antibodies in the mouse model of active systemic anaphylaxis under the test conditions used.

[0225] Example 22: Passive systemic cutaneous anaphylaxis test in rats

[0226] This study was conducted in accordance with a research protocol approved by the Institutional Animal Research Committee (IACUC). This study focused on passive systemic anaphylaxis (PSA) and aimed to identify the potential clinical applications of PEG-sugar-lipid conjugates and to elucidate their characteristics by evaluating the presence of IgE (re-antigenic) antibodies as a key quantitative indicator of anaphylaxis.

[0227] A group of four animals received three sensitization injections: a medium control (saline, G1), a positive control (ovalbumin (OVA) + aluminum potassium sulfate dodecahydrate (ALH) [OVA+ALH] - 100 mg OVA + 12 mg ALH / rat, G2), and the test substance (DOPS-12 - 10 mg / rat [200 μL / rat, 50 mg / mL test substance preparation], G3). On days 1, 3, and 5, each group received the medium control and positive control via the intraperitoneal route, and the test substance via the intravenous route. On day 10, all sensitized animals were euthanized using isoflurane anesthesia, blood was collected, serum was separated and pooled, and stored at 2-8°C for 4 days for use in the challenge. Passive sensitization was performed on five untreated animals / groups (G1a, G2a, G3a) by intradermal injection (0.1 mL / site at two locations) of serum from donor animals (G1, G2, G3, respectively) (serum diluted 1:2 (50%) and 1:4 (25%) with physiological saline, as well as undiluted serum). Approximately 24 hours later, the intradermal-sensitized animals were intravenously administered 0.6 mL of solvent control or positive control (10 mg / mL OVA) or test substance (50 mg / mL) + 0.4 mL of Evans blue (1% w / v in physiological saline). Approximately 30 minutes after administration, the animals were euthanized using isoflurane anesthetic, the skin was excised and inverted, and the diameter of the blue spots was measured, recorded, and photographed.

[0228] In animals administered DOPS-12, no clinical signs of toxicity or death were observed, and there were no effects on weight gain or abnormalities on macroscopic autopsy. Passive cutaneous anaphylactic reactions (PCA) (mean ± SD) were measured by the diameter (mm) of the blue spots shown in Table 9. JPEG2026528703000048.jpg74170

[0229] The validity of the experiment was confirmed by a positive reaction using ovalbumin as a positive control. Ovalbumin produced blue spots with diameters of 1.68 mm, 7.35 mm, and 12.18 mm, corresponding to 25% serum, 50% serum, and undiluted serum, compared to the solvent administration group. No reaction was observed in the test substance administration group. Based on these results, it can be concluded that the test substance DOPS-12 did not exhibit the ability to produce IgE (re-antigenic) antibodies in a rat passive cutaneous anaphylaxis model under the test conditions.

[0230] Example 23: Improvement of DOPS-12 solubility

[0231] Water-soluble formulations based on PEG-sugar-lipid conjugates are useful for improving the bioavailability (BA) of drugs in both oncology and non-oncology fields, particularly those with low BA due to gastrointestinal metabolism. While tablet size is limited to orally disintegrating, sublingual, or buccal tablets, typically less than 500 mg, this can be achieved using polymers such as DOPS-12. Typical weight ratios of the polymer to the active ingredient (API) for forming a stable solution after dissolution in water are summarized in Table 10. JPEG2026528703000049.jpg118170

[0232] Table 10 shows only a few examples where the weight ratio of PEG-glycosyl conjugate to oncological compound is approximately 200 (e.g., approximately 50) to approximately 1 in the case of drug delivery, and similarly, where the weight ratio of PEG-glycosyllipid conjugate to non-oncological compound is approximately 200 to approximately 1 in the case of compound delivery.

[0233] Example 24: Measurement of critical micelle concentration of DOPS-12

[0234] The test apparatus used for the critical micelle concentration (CMC) test was a surface tension meter model DY-700 (Kyowa Interface Science Co., Ltd., Tokyo, Japan). Deionized water (50 mL) was placed in the test container, and the corresponding DOPS-12 solution was added to an automatic burette, controlling the amount added. Next, DOPS-12 solution (0.6 mg / mL) was added to the test solution in a controlled volume. After each addition, the test solution was stirred for 30 seconds and allowed to stand for 60 seconds before measuring the surface tension. This process was repeated until the titration was complete.

[0235] The results of the CMC test are shown numerically and graphically in Figure 12. To calculate the CMC, two lines were fitted to the plot and the intersection of the two lines was found (Figure 3). The line represents the R of the fitting. 2 The values ​​were fitted to be 0.999 or greater. The data points used for fitting and the actual fitting lines are shown in the figure. The CMC was determined to be 12.67 mg / L, or approximately 0.01 mmol. To optimize solubility, the amount of conjugates present in the aqueous solution that exceeds the critical micelle concentration is preferably less than 0.1 mmol, for example, 0.005 to 0.01 or 0.02 to 0.05.

[0236] Example 25: PEG distribution in DOPS-12

[0237] LC-MS was used to determine the PEG distribution profile in DOPS-12. The analytical parameters were as follows: JPEG2026528703000050.jpg113170

[0238] As shown in Figure 13, the distribution of PEG was within a narrow range, for example, within the target molar mass (average = 1221 g / mol), as described throughout this specification.

[0239] These examples illustrate the toxicity and pharmacological profiles of short-diamine-centered fatty acid-based PEG-sugar conjugates, which may enable the development of novel therapies and potent medicines, particularly for parenteral administration.

[0240] In the various embodiments described herein, PEG-sugar-lipid conjugates centered on shorter diamines (e.g., 2-4 carbon atoms) and fatty acids are generally considered safer in parenteral administration, based on the results of both in vitro and in vivo studies described herein. Furthermore, the same polymers exhibited very low bioavailability suitable for oral administration.

[0241] In the various embodiments described herein, the individual lipid-related impurities and monosaccharide impurities (e.g., glucuronic acid) are preferably less than 5% by weight, and most preferably less than 2%. High amounts of lipid-related impurities can form self-emulsifying systems, potentially reducing the solubility of the solute. High monosaccharide content reduces the surface area, which can also reduce the solubility of the solute or decrease the stability of the solution.

[0242] In various embodiments described elsewhere in this specification, the concentration of the PEG-saccharide-lipid conjugate in an aqueous system (e.g., parenteral formulations or other liquid formulations, creams or gels) is at least the critical micelle concentration (CMC). In some embodiments, the CMC is in the range of 0.01 to 0.1 mM, for example, 0.01 to 0.015 mM or 0.02 to 0.05 mM.

[0243] In various embodiments, this disclosure relates to methods for preparing and safely using compounds having the following molecular structures as water-soluble enhancers or compound carriers. JPEG2026528703000051.jpg36170 Here, the lipid is selected from the group consisting of C6-C18 alkyl fatty acids, cholic acid, bile acids and their analogues. m(PEG)n is a polyethylene glycol monomethoxy ether in the range of 6 to 45 ethylene glycol units (i.e., n units).

[0244] The current disclosure describes novel PEG-sugar-lipid conjugate systems in various embodiments. Appropriate polymer structure and molecular purity can directly impact the safety and biocompatibility in drug and other molecular delivery. Therapeutic agents may be solubilized or encapsulated in such conjugates to form solids, semi-solids, solutions, or microsuspensions.

[0245] Generally, in various embodiments, the disclosure provides a conjugate comprising a diamine skeleton, a polymer (PEG) chain, lactobionic acid (a sugar), and a lipid or similar group attached to the skeleton. In some embodiments, a spacer group or linker group, including an amino acid, may be included between the skeleton and the PEG chain, carbohydrate, or lipophilic group. Furthermore, the ends of the PEG chain may be charged or polar groups.

[0246] The polymers of the present invention are effective in preparing compositions of active drugs such as tumor treatments, and can reduce therapeutic side effects and toxicity. The permeability-enhancing properties of PEG-saccharide conjugates may improve the in vivo target delivery of drugs and enhance the oral bioavailability of various drugs.

[0247] One embodiment of the present disclosure is a compound represented by the following formula or a method for producing such a compound. JPEG2026528703000052.jpg39170

[0248] To reduce immunogenicity, shorter diamine skeletons (m*<2) are desirable. However, for bulk carriers such as steroid acids, ethylenediamines are not very desirable due to their low synthesis yield. Since the order of the bond positions on the skeleton of each carrier is not restricted, they are chemically as interchangeable as possible.

[0249] Another embodiment of the present disclosure is a method for producing a compound, the conjugate described herein, by a method comprising the following (interchangeable) steps: a. Select a central backbone that has at least three sites available for connection between the three carriers and the central backbone; b. Choosing PEG as the initial carrier; c. Selecting lipids as the second carrier; d. Selecting sugars as a third carrier; and e. Selecting a linker for alkylation coupling reactions, including N-alkylation or O-alkylation, esterification, etherification, or amidation between the carrier and the central skeleton.

[0250] The process may further include an amidation step. f. Protecting a hydroxyl group or an amino group. g. Connecting the first carrier to the central backbone; h. Connecting the second carrier to the central backbone; i. Removing hydroxyl or amino protecting groups; and j. Attaching the third carrier to the central protecting group.

[0251] In various embodiments, only polymers with shorter diamine centers containing fatty acid lipid groups are suitable for parenteral applications due to their low hemolytic activity.

[0252] In various embodiments, the PEG component of the conjugate is PEG having 5 to 45 subunits. The PEG chain may consist of, for example, about 6 to 45 subunits. More preferably, the PEG chain consists of about 8 to 45 subunits.

[0253] In various embodiments, the PEG is a branched PEG having two or more subchains, each chain having 5 to 23 PEG subunits.

[0254] In various embodiments, the conjugate is a compound represented by formulas 1 to 12 of the general structure.

[0255] In various embodiments, the lipid group is selected from steroid acids, including cholesterol, cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, chenodeoxycholic acid, and lithocholic acid.

[0256] In various embodiments, the sugar components are selected from amino sugars, steviol glycosides, sucrose, gluconic acid, glucaric acid, glucuronic acid, and galacturonic acid, but are not limited to these; sucralose, lactitol, maltitol, isomalt, maltotriitol, maltotetraitol, mogroside, glycyrrhizin, inulin, and osradine, but are not limited to these monosaccharides and disaccharides and their analogues or derivatives.

[0257] In various embodiments, the PEG chain is substantially monodisperse and is particularly suitable for intravenous administration of pharmaceuticals. A substantially monodisperse PEG chain may contain several oligomers of different chain lengths (e.g., not only n=12, but also different chains such as n=11, n=13, etc.). The preferred number of oligomers is 1 to 10, but in many embodiments, the number of oligomers is 3 to 10.

[0258] In various embodiments, the PEG chain has a narrow molecular weight distribution, and HPLC analysis by HPLC peak area normalization yields PEG-saccharide-lipid conjugates with a purity of 85% to 115%.

[0259] In various embodiments, the PEG chain is a monomethoxypolyethylene glycol ether having an average molecular weight of 95.0% to 105.0% of the nominal value of the label when the nominal value of the label is less than 1000, and a monomethoxypolyethylene glycol ether having an average molecular weight of 90.0% to 110.0% of the nominal value of the label when the nominal value of the label is between 1000 and 2000.

[0260] While preferred embodiments of the present invention have been described, those skilled in the art should understand that other further changes and modifications are possible without departing from the spirit of the invention, and that all such changes and modifications fall within the scope of the present invention.

[0261] Various aspects and embodiments of this disclosure are provided by the following claims, which can be combined in any number and any combination that is not logically or technically inconsistent. Embodiment 1. Lipid / PEG / sugar conjugate having a structural formula JPEG2026528703000053.jpg26170 Here m has an average value in the range of 2 to 10. S is a monosaccharide, disaccharide, or trisaccharide group, and each sugar unit is a sugar, sugar alcohol, amino sugar, or sugar acid. L is -C(O)-R 1 And here R 1 These are alkanyl or alkenyl groups and / or steroidacyl groups having an average number of carbon atoms of 6 to 22.

[0262] P is -(CH2-CH2-O)nR 2 Here, n has a numerical mean in the range of 5 to 50 (e.g., 8 to 45), and R 2These are hydrogen and / or alkanes, with a number-average number of carbon atoms ranging from 0 to 4. Embodiment 2. A conjugate of Embodiment 1, wherein the average value of m is in the range of 2 to 8, for example, 2 to 6, 2 to 5, or 2 to 4. Embodiment 3. A conjugate according to Embodiment 1, wherein the average value of m is 3. Embodiment 4. A conjugate of Embodiment 1, wherein the average number of m is 2 or the average number of m is 4. Embodiment 5. A conjugate of Embodiment 1, wherein the average value of m is in the range of 5 to 10, for example, 5 to 8 or 8 to 10. Embodiment 6. A conjugate according to any of Embodiments 1 to 5, wherein S is a disaccharide group. Embodiment 7. A conjugate according to any of Embodiments 1 to 5, wherein S is a monosaccharide group. Embodiment 8. A conjugate according to any of Embodiments 1 to 5, wherein S is a trisaccharide group. Embodiment 9. A conjugate according to any of Embodiments 1 to 8, wherein the sugar unit S is individually selected from hexoses and pentoses and their sugar alcohols, sugar acids and amino sugar analogs. Embodiment 10. A conjugate according to any of Embodiments 1 to 9, wherein the sugar unit of S is individually selected from hexoses and sugar alcohols, sugar acids, and their amino sugar analogs. Embodiment 11. A conjugate according to any of Embodiments 1 to 10, wherein the sugar unit of S directly bonded to the nitrogen of the diamine central skeleton is derived from a sugar acid and bonded as an amide. Embodiment 12. In the conjugate of Embodiment 11, all sugar units of S that are not directly bonded to the nitrogen of the diamine are sugars. Embodiment 13. A conjugate according to any of Embodiments 1 to 12, wherein S is a structural formula JPEG2026528703000054.jpg21170 Here, -(Cx1 H 2x1 O x1 -1)-CO- is, x1 A sugar acyl residue derived from a sugar acid where is 4 or 5, (C x2 H 2x2 -1O x2 -1)- is, x2 It is a sugar residue derived from a sugar where 5 or 6 is present, or its open-chain version. Embodiment 14. The conjugate of Embodiment 13, x1 The value is 5, x2 Those whose value is 6. Embodiment 15. A conjugate according to any of Embodiments 1 to 14, wherein S has the following structure. JPEG2026528703000055.jpg34170 or its open-chain version. Embodiment 16. A conjugate according to any of Embodiments 1 to 15, wherein S is lactobionyl or gluconyl, for example, lactobionyl. Embodiment 17. A conjugate according to any of Embodiments 1 to 15, wherein S is a residue of gluconolactone, or neuraminic acid, or a residue of another disaccharide or trisaccharide, which is modified by oxidation or the like. Examples include sucrose, lactose, maltose, trehalose, turanose, cellobiose raffinose, melegitose, and maltotriose. Embodiment 18. A compound of any of Embodiments 1 to 17, wherein L is (or) -C(O)-R 1 Including, here, R 1 This is a compound of alkanyl and / or alkenyl groups having an average number of carbon atoms in the range of 6 to 22. Embodiment 19. A conjugate according to any of Embodiments 1 to 18, wherein R 1 The average number of carbon atoms is in the range of 6 to 20, or 6 to 18. Embodiment 20. A conjugate according to any of Embodiments 1 to 18, wherein R 1A conjugate having an average number of carbon atoms in the range of 10 to 22, for example, 10 to 20 or 10 to 18. Embodiment 21. A conjugate according to any of Embodiments 1 to 18, wherein R 1 A conjugate having an average number of carbon atoms in the range of 12 to 22, for example, 12 to 20 or 12 to 18. Embodiment 22. A conjugate according to any of Embodiments 1 to 18, wherein R 1 A conjugate having an average number of carbon atoms in the range of 14 to 22, for example, 14 to 20 or 14 to 18. Embodiment 23. A combination of any of Embodiments 1 to 22, wherein R 1 A compound with an average of 18 or fewer carbon atoms. Embodiment 24. A combination of any of Embodiments 1 to 23, wherein R 1 A combination having an average unsaturated number in the range of 0 to 3, for example, 0 to 2. Embodiment 25. A conjugate according to any of Embodiments 1 to 24, wherein R 1 A conjugate in which is a linear alkyl group or alkenyl group. Embodiment 26. A conjugate of any of the embodiments 1 to 25, where R 1 A conjugate derived from one or more of the following: 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. A conjugate according to any of Embodiments 1 to 26, wherein L is -C(O)-R 1 And -C(O)-R 1 A conjugate having at least 80 mol% of a single chemical identity, e.g., at least 85 mol%. Embodiment 28. A conjugate according to any of Embodiments 1 to 26, wherein L is -C(O)-R 1 And -C(O)-R 1 A conjugate having at least 90 mol% single chemical identity, e.g., at least 95 mol%. Embodiment 29. A conjugate according to Embodiment 27 or Embodiment 28, wherein the single chemical identity is cis-CH3(CH2)7CH=CH(CH2)7C(O)-. Embodiment 30. A conjugate according to Embodiment 27 or Embodiment 28, wherein the single chemical identity is cis, cis-CH3(CH2)4CH=CHCH2CH=CH(CH2)7C(O)-. Embodiment 31. A conjugate according to Embodiment 27 or Embodiment 28, wherein the single chemical identity is cis-CH3(CH2)3CH=CH(CH2)7C(O)-. Embodiment 32. A conjugate of Embodiment 27 or Embodiment 28, wherein a single chemical identity is selected from n-hexanoyl, n-octanoyl, n-decanoyl, n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl, n-octadecanoyl, n-eicosayl, and n-docosayl. Embodiment 33. A conjugate of Embodiment 27 or Embodiment 28, wherein a single chemical identity is selected from the following: cis-CH3(CH2)5CH=CH(CH2)7C(O)-, cis, cis-CH3CH2CH=CHCH2CH=CHCH2CH=CH(CH2)7C(O)-,

[0263] cis, cis, cis-CH3(CH2)4CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)3C(O)- and cis-CH3(CH2)7CH=CH(CH2)11C(O)-. Embodiment 34. A conjugate according to any of Embodiments 1 to 26, wherein L contains (or is a steroidacyl group) a steroidacyl group (e.g., a bile acyl group). Embodiment 35. A conjugate according to any of embodiments 1 to 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. A conjugate according to any of Embodiments 1 to 35, wherein "n" has a numerical average value in the range of 5 to 45, for example, 5 to 40, 5 to 30, 5 to 20, 5 to 15, or 5 to 10. Embodiment 37. A conjugate according to any of Embodiments 1 to 35, wherein n has a numerical mean in the range of 8 to 50, for example, 8 to 45, 8 to 40, 8 to 30, 8 to 20, 8 to 15, 8 to 12, or 8 to 10. Embodiment 38. A conjugate according to any of Embodiments 1 to 35, wherein n has a numerical mean in the range of 10 to 50, for example, 10 to 45, or 10 to 40, or 10 to 30, or 10 to 20, or 10 to 15. Embodiment 39. A conjugate according to any of Embodiments 1 to 35, wherein n is a numerical mean in the range of 9 to 14, for example, 9 to 13, 10 to 14, 10.5 to 13.5, 11 to 13, 11.5 to 12.5, 11.8 to 12.2, 10.2 to 13.8, 10.8 to 13.2, or 11.4 to 12.6. Embodiment 40. A conjugate according to any of the embodiments 1 to 35, wherein n has a numerical mean in the range of 18 to 28, for example, 20 to 26, or 22 to 24, or 22.5 to 23.5, or 22.8 to 23.2. Embodiment 41. A conjugate according to any of Embodiments 1 to 35, wherein the average value of n is in the range of 25 to 40. Embodiment 42. A conjugate according to any of Embodiments 1 to 35, wherein n has a numerical mean in the range of 40 to 50, for example, 42 to 48, or 44 to 46, or 44.5 to 45.5, or 44.8 to 45.2. Embodiment 43. A conjugate according to any of Embodiments 1 to 42, wherein R 2 The average number of carbon atoms is at least 0.95, for example, at least 0.99 or at least 1. Embodiment 44. A conjugate according to any of Embodiments 1 to 42, wherein R 2 A conjugate whose average carbon number is in the range of 0.9–1.1, 0.95–1.05, or 0.98–1.02. Embodiment 45. A conjugate according to any of Embodiments 1 to 42, wherein R 2 A substance whose core is C1-C4. Alkanyl, e.g., methyl or ethyl. Embodiment 46. A conjugate according to any of Embodiments 1 to 42, wherein R 2 Those that are methyl. Embodiment 47. A composite of any of Embodiments 1 to 42, wherein R 2 The average number of carbon atoms is in the range of 0 to 3, for example, 0 to 2. Embodiment 48. A conjugate of any of the embodiments 1 to 42, where R 2 The average number of carbon atoms is in the range of 0 to 0.94, for example, 0 to 0.75, or 0 to 0.5, or 0 to 0.1, or 0 to 0.05. Embodiment 49. A conjugate according to any of Embodiments 1 to 35, wherein the -P group is a methylated PEG residue having a number average molecular weight in the range of 300 to 2200 g / mol. Embodiment 50. A conjugate according to any of Embodiments 1 to 35, wherein the -P group is a methylated PEG residue having a number average molecular weight in the range of 300 to 1200 g / mol, for example, 300 to 600 g / mol. Embodiment 51. A conjugate according to any of Embodiments 1 to 35, wherein the -P group is a methylated PEG residue having a number average molecular weight in the range of 500 to 2200 g / mol, for example, 500 to 1200 g / mol, or 500 to 900 g / mol. Embodiment 52. A conjugate according to any of Embodiments 1 to 35, wherein the -P group is a methylated PEG residue having a number average molecular weight in the range of 700 to 2200 g / mol, for example, 700 to 1200 g / mol, or 700 to 1100 g / mol. Embodiment 53. A conjugate according to any of Embodiments 1 to 35, wherein the -P group is a methylated PEG residue having a number-average molecular weight in the range of 475 to 525 g / mol. Embodiment 54. A conjugate according to any of Embodiments 1 to 35, wherein the -P group is a methylated PEG residue having a number average molecular weight in the range of 525 to 575 g / mol. Embodiment 55. A conjugate according to any of Embodiments 1 to 35, wherein the -P group is a methylated PEG residue having a number average molecular weight in the range of 710 to 790 g / mol. Embodiment 56. A conjugate according to any of Embodiments 1 to 35, wherein the -P group is a methylated PEG residue having a number-average molecular weight in the range of 900 to 1100 g / mol, for example, 950 to 1050 g / mol. Embodiment 57. A conjugate according to any of Embodiments 1 to 35, wherein the -P group is a methylated PEG residue having a number-average molecular weight in the range of 1800 to 2200 g / mol, for example, 1900 to 2100 g / mol. Embodiment 58. A conjugate according to any of Embodiments 1 to 57, wherein the polyvariance index of P is 1.1 or less, for example, 1.07 or less. Embodiment 59. A conjugate according to any of Embodiments 1 to 57, wherein the polyvariance index of P is 1.06 or less, for example, 1.05 or less. Embodiment 60. A conjugate of any of the above non-consistent embodiments, m is 3. The structural formula for S is as follows: JPEG2026528703000056.jpg18170

[0264] Here, -(C x1 H 2x1 Ox1 -1)-CO- is, x1 A sugar acyl residue derived from a sugar acid where is 4 or 5, (C x2 H 2x2 -1O x2 -1)- is, x2 It is a sugar residue derived from a sugar where 5 or 6 is present, or its open-chain version.

[0265] -C(O)-R 1 This is at least 80 mol%, for example, at least 85 mol%, of cis-CH3(CH2)7CH=CH(CH2)7C(O)-. R 2 It is methyl; The weighted mean of n is in the range of 11.5 to 12.5, for example, 11.8 to 12.2. The polyvariance index of P is 1.1 or less, for example, 1.07 or less. Embodiment 61. A conjugate of an embodiment not inconsistent with the above embodiments, m is 3. The structural formula for S is as follows: JPEG2026528703000057.jpg14170 Here, -(C x1 H 2x1 O x1 -1)-CO- is, x1 A sugar acyl residue derived from a sugar acid where is 4 or 5, (C x2 H 2x2 -1O x2 -1)- is, x2 It is a sugar residue derived from a sugar where 5 or 6 is present, or its open-chain version. -C(O)-R 1 This is at least 80 mol%, for example, at least 85 mol%, of cis-CH3(CH2)7CH=CH(CH2)7C(O)-. These are methylated PEG residues that are within the molar range and have a polydispersity index of 1.1 or less, for example, 1.07 or less. Embodiment 62. A conjugate of Embodiment 60 or Embodiment 61, x1 The value is 5, x2 Those whose value is 6. Embodiment 63. A conjugate according to any of Embodiments 60 to 62, wherein S has the following structure. JPEG2026528703000058.jpg34170 or its open-chain version. Embodiment 64. A conjugate according to any of Embodiments 60 to 63, wherein S is lactobionyl. Embodiment 65. A conjugate according to any of Embodiments 60 to 64, wherein -C(O)-R 1 A conjugate in which at least 90 mol%, for example at least 95 mol%, of cis-CH3(CH2)7CH=CH(CH2)7C(O)- is present. Embodiment 66. A conjugate according to any of Embodiments 60 to 65, wherein the polyvariance index of P is 1.06 or less, for example, 1.05 or less. Embodiment 67. A conjugate of any non-contradictory embodiment described above, having the structural formula of chemical structure 1: JPEG2026528703000059.jpg33170 Here, m(PEG)n is a methylated PEG residue.

[0266] Embodiment 68. The conjugate of Embodiment 67, wherein the aliphatic acyl residue -C(O)-R 1 A substance derived from one or more of the following: lauric acid, myristic acid, palmitic acid, linoleic acid, oleic acid, and stearic acid.

[0267] Embodiment 69. A conjugate of any of the above non-consistent embodiments, wherein the conjugate is oleoyldiaminopropane-monomethoxypolyethylene-glycol-ether-lacbionate (DOPS) and is represented by chemical structure 2: JPEG2026528703000060.jpg37170 Here, m(PEG)n is a methylated PEG residue, and n is any desired value as described above. Embodiment 70. A conjugate of any of the above non-consistent embodiments, wherein the conjugate is stearylpropanediamino-monomethoxypolyethylene-glycol-ether-lacbionate and is represented by chemical structure 3: JPEG2026528703000061.jpg46170 Here, m(PEG)n is a methylated PEG residue, and n is any desired value as described above. Embodiment 71. A conjugate of any non-constrained embodiment described above, wherein the conjugate is represented by chemical structure 4: JPEG2026528703000062.jpg39170 Here, m(PEG)n is a methylated PEG residue, n is any desired value as described above, and m is in the range of 2 to 6, for example, 3. Embodiment 72. A conjugate of a non-consistent embodiment, wherein the conjugate is chloroylpropanediamino-mPEG-lacbionate (CDPS) and is represented by chemical structure 5: JPEG2026528703000063.jpg42170 Here, m(PEG)n is a methylated PEG residue, and n is any desired value as described above. Embodiment 73. A conjugate according to any of Embodiments 70 to 72, wherein the numerical mean of n is in the range of 9.2 to 13.8, for example, 10.2 to 13.2, or 11 to 13, or 11.4 to 13.6, or 11.5 to 12.5, or 11.8 to 12.2. Embodiment 74. A combination of any of the above non-consistent embodiments having any of the following structures: JPEG2026528703000064.jpg196170JPEG2026528703000065.jpg203170 Embodiment 75. A conjugate according to any of Embodiments 1 to 74, wherein -P is provided from a PH poly(ethylene glycol) source (e.g., mPEG) having a number average molecular weight in the range of 95.0 to 105.0% of the nominal labeled value when the nominal labeled value is less than 1000 g / mol, and from a PH poly(ethylene glycol) source (e.g., mPEG) having a number average molecular weight in the range of 90.0 to 110.0% of the nominal labeled value when the nominal labeled value is in the range of 1000 to 2000 g / mol. Embodiment 76. A conjugate according to any of Embodiments 1 to 75, having a purity of at least 85% by weight when measured by HPLC. Embodiment 77. A conjugate according to any of Embodiments 1 to 76, having a purity of at least 90% by weight when measured by HPLC. Embodiment 78. A conjugate according to Embodiment 76, which is used for oral administration. Embodiment 79. A conjugate according to Embodiment 77, which is used in parenteral administration. Embodiment 80. A conjugate of any of Embodiments 1 to 79, wherein R 1 A conjugate in which the -C(O)- group is an aliphatic acyl group having a single chemical identity in at least 65 mol%, for example, at least 80 mol%, or at least 85 mol%, or at least 90%, or at least 95 mol%. Embodiment 81. A conjugate of Embodiment 80, wherein a single chemical identity is oleoyl, myristoyl, palmitoyl, stearoyl, or linoleyl. Embodiment 82. A conjugate according to any of Embodiments 1 to 81, wherein R 1 -C(O) is an aliphatic acyl, and the conjugate, when analyzed by HPLC, is similar to the peak profile and relative retention time (RRT) shown in Figures 1, 2, or 3 below: JPEG2026528703000066.jpg76170 Embodiment 83.1 A conjugate of any of Embodiments 1 to 82 having an HLB value in the range of 13 to 18, for example, in the range of 13 to 15. Embodiment 84. A useful solubility or bioavailability enhancer for the safe delivery of hydrophobic or lipophilic compounds, formula: JPEG2026528703000067.jpg28170 Here: It is selected from the group consisting of fatty acids such as lauric acid, myristic acid, linoleic acid, palmitic acid, oleic acid, elaidic acid, and steroid acids. m(PEG)n is a polyethylene glycol polymer. n is in the range of 8 to 45 ethylene glycol subunits. m* = CH2 1-6 Embodiment 85. The polymer of Embodiment 84 or any of the non-inconsistent embodiments described above has one or more of the following properties or specifications: a. If the label's nominal value is less than 1000, the mPEG is in the range of 95.0% to 105.0% of the label's nominal value. If the label's nominal value is between 1000 and 2000, the mPEG is in the range of 90.0% to 110.0% of the label's nominal value. b. When used for oral applications, the purity of the polymer conjugate is between 85% and 115.0% as determined by HPLC analysis. c. The purity of the polymer conjugate is 90% to 110.0% when used for parenteral administration, as determined by HPLC analysis. d. If oleic acid is used, its purity must be 65% or higher. e. Each related analogue or impurity is less than 5%, f. The fatty acid-based polymer has a peak profile similar to that of Figure 1, 2, or 3 and has the following relative retention time (RRT): JPEG2026528703000068.jpg69170 Embodiment 86. Embodiment 86 is the polymer conjugate of Embodiment 84 or Embodiment 85 or any of the above non-inconsistent embodiments, wherein the synthesis method for preparing the polymer includes the following steps. (1) Activated monomethoxypolyethylene glycol ether is coupled to the unprotected amino group of the central skeleton. (2) Lipids or disaccharides are attached to the backbone to form a PEG-saccharide-lipid conjugate in which the purity of the conjugate by HPLC assay is in the range of 85% to 115%. Embodiment 87. The polymer conjugate according to Embodiment 84 or Embodiment 85, or any of the above non-inconsistent embodiments, wherein the synthesis method for preparing the polymer includes the following steps. (1) A short chain is synthesized consisting of an ethylene glycol group as the central skeleton and an ethylene glycol-protected hydroxyl group on an amino group. (2) The PEG chain is extended by repeating short ethylene glycol chain reactions. (3) Lipids or disaccharides are attached to the backbone to form PEG-saccharide-lipids having high-purity PEG oligomers. Here, the order of the coupling steps or coupling parts is interchangeable. Embodiment 88. The polymer conjugate of any of Embodiments 84 to 87, or any of the above non-inconsistent embodiments, wherein the m* in the backbone is 0 or 1, thereby forming a PEG-sugar-lipid conjugate having no or low hemolytic activity, suitable for parenteral and oral administration, having the following structure. JPEG2026528703000069.jpg31170 Here m * If the value is 1, the skeleton is propane. m * If it is zero, the skeleton is ethylene. A fatty acid selected from the group consisting of lauric acid, myristic acid, linoleic acid, palmitic acid, oleic acid, or stearic acid, but not limited to these. n is in the range of 8 to 45. Embodiment 89. The polymer conjugate of any of Embodiments 84 to 88, or any of the non-inconsistent embodiments described above, wherein, when used for parenteral administration, the distance between the two terminal amines is less than 4 carbon atoms. Embodiment 90. The polymer conjugate of any of Embodiments 84 to 88, or any of the non-consistent embodiments described above, wherein the m* in the backbone is greater than 1, thereby forming a PEG-saccharide-lipid conjugate more suitable for oral administration or other applications. Embodiment 91. The polymer conjugate of any of Embodiments 84 to 90, or any of the non-inconsistent embodiments described above, wherein the PEG-saccharide-lipid conjugate is solid (low moisture) or semi-solid (high moisture) and is stable for at least 36 months under room temperature storage conditions. Embodiment 92. The polymer conjugate according to any of Embodiments 84 to 91 or any of the above non-inconsistent embodiments, wherein the average molecular weight of the monomethoxypolyethylene glycol ether is 95.0% to 105.0% of the nominal value of the label if the nominal value of the label is less than 1000, and 90.0% to 110.0% of the nominal value of the label if the nominal value of the label is 1000 to 2000. Embodiment 93. The polymer conjugate according to any of Embodiments 84 to 92, or any of the non-consistent embodiments described above, wherein the amount of monosaccharide-related impurities in the polymer is less than 5%. Embodiment 94. The polymer conjugate of any of Embodiments 84 to 93, or any of the non-consistent embodiments described above, wherein the total amount of fatty acid-related impurities in the polymer is less than 10%, and the individual fatty acid-related impurities are less than 5%. Embodiment 95. The polymer conjugate described in any of Embodiments 84-89 and 92-94, or any of the above non-inconsistent embodiments, wherein the purity of the polymer is at least (≧) 90% for use in parenteral compositions. Embodiment 96. The polymer according to any of Embodiments 84-89 and 92-94, or any of the above non-inconsistent embodiments, wherein the polymer is purified or dried by lyophilization when used for parenteral administration. Embodiment 97. The polymer conjugate described in any of Embodiments 84-89 and 90-94, or any of the above non-inconsistent embodiments, wherein the purity of the polymer is (≧) 85% and is used in a pharmaceutical oral composition. Embodiment 98. The polymer conjugate of any of Embodiments 84 to 97, or any of the above non-inconsistent embodiments, wherein the weight ratio of the PEG-sugar conjugate to the oncological compound is about 200 to about 1 for drug delivery. Embodiment 99. The polymer conjugate of any of Embodiments 84 to 97, or any of the above non-inconsistent embodiments, wherein the weight ratio of the PEG-saccharide-lipid conjugate to the non-oncological compound for compound delivery is about 200 to about 1. Embodiment 100. A polymer conjugate of any of Embodiments 84 to 99, or any of the non-consistent embodiments described above, wherein the PEG-saccharide-lipid conjugate has a structure selected from the following: JPEG2026528703000070.jpg148170JPEG2026528703000071.jpg217170 Here, n is in the range of 8 to 45. Embodiment 101. A method for manufacturing a conjugate according to any of Embodiments 1 to 100. Poly(ethylene) glycol, sugars and R 1 A process involving the bonding of a -C(O)-acyl group to a diamine skeleton. Embodiment 102. The process of Embodiment 101, wherein the method comprises a monoprotected diamine having a protected primary amine group and an unprotected secondary amine group; poly(ethylene glycol) and R 1 The -C(O)-acyl group is coupled to the second amine group, then the protected first amine group is deprotected, and a sugar is coupled to the newly unprotected first amine group. Embodiment 103. The process of Embodiment 101 or Embodiment 102, performed in substantially the absence of a free radical initiator. Embodiment 104. A process in any of Embodiments 101 to 103, wherein the coupling of poly(ethylene glycol) is R 1 This can be done before coupling the -C(O)-acyl group. Embodiment 105. In any of the processes of Embodiments 101 to 104, the coupling of poly(ethylene glycol) with a second amine group can be carried out in a stepwise manner, for example, by first coupling a short PEG chain to the central skeleton and then performing etherification to obtain a longer PEG chain. Embodiment 106. A process according to any of Embodiments 101 to 105, wherein R 1 The coupling between the -C(O)-acyl group and the second amine group is R 1 This is carried out using -C(O)-halides. Embodiment 107. A process according to any of Embodiments 101 to 105, wherein the step of coupling a sugar to a first amine group includes the step of deprotecting the first amine group and coupling the sugar in the form of a sugar acid or its lactone. Embodiment 108. A conjugate according to any of Embodiments 1 to 100 for use as a pharmaceutical excipient or for use in a pharmaceutical product. Embodiment 109. A therapeutic composition comprising a conjugate and a therapeutic agent of any of Embodiments 1 to 100. Embodiment 110. A composition for use in the treatment of a subject having a condition, comprising a conjugate of any of Embodiments 1 to 100 and a therapeutic agent suitable for the treatment of the condition. Embodiment 111. A method for treating a subject having a condition, comprising administering the composition of Embodiment 110 to the subject, wherein the administration is, for example, oral, intranasal, topical, or parenteral. Embodiment 112. A composition for use as a pharmaceutical, comprising a conjugate and a therapeutic agent as described in any of Embodiments 1 to 100. Embodiment 113. A method for preparing the composition of Embodiment 112, comprising preparing a liquid containing the therapeutic agent and the conjugate in a solvent (e.g., water or an organic solvent), and freeze-drying or spray-drying the liquid to obtain a solid material containing the therapeutic agent and the conjugate. Embodiment 114. A conjugate according to any of Embodiments 1 to 100 is used to enhance the bioavailability of the therapeutic agent. Embodiment 115. Use of a conjugate according to any of Embodiments 1 to 100 to enhance the solubility of a therapeutic agent in an aqueous system. Embodiment 116. Using the conjugate described in any of Embodiments 1 to 100 as a pharmaceutical excipient or therapeutic agent. Embodiment 117. A composition, method, or use according to any of Embodiments 109-116, wherein the water solubility of the therapeutic agent in deionized water is 5 mg / mL or less, for example, 2 mg / mL or less at 37°C. Embodiment 118. A composition, method, or use according to any of Embodiments 109-116, wherein the therapeutic agent has a solubility in deionized water of 1 mg / mL or less, for example, 0.5 mg / mL or less, or 0.2 mg / mL or less, at 37°C. Embodiment 119. A composition, method, or use according to any of Embodiments 109-116, wherein the therapeutic agent has a water solubility of 0.1 mg / mL or less, for example, 0.05 mg / mL or less, or 0.02 mg / mL or less in deionized water at 37°C. Embodiment 120. A composition, method, or use according to any of Embodiments 109-116, wherein the therapeutic agent has a water solubility of 5 mg / mL or less in pH 7.4 phosphate-buffered saline, for example, 2 mg / mL or less at 37°C. Embodiment 121. A composition, method, or use according to any of Embodiments 109 to 116, wherein the therapeutic agent has a water solubility of 1 mg / mL or less, for example, 0.5 mg / mL or less, or 0.2 mg / mL or less, in phosphate-buffered saline at pH 7.4 at 37°C. Embodiment 122. A composition, method, or use according to any of Embodiments 109 to 116, wherein the therapeutic agent has a water solubility of 0.1 mg / mL or less, for example, 0.05 mg / mL or less, or 0.02 mg / mL or less, in phosphate-buffered saline at pH 7.4 at 37°C. Embodiment 124. A composition, method, or use according to any of Embodiments 109 to 116, wherein the therapeutic agent has a logD7.4 value (or logP value) of at least 2, for example, at least 2.25, at least 2.5, or at least 2.75. Embodiment 125. A composition, method, or use according to any of Embodiments 109 to 116, wherein the therapeutic agent has a logD7.4 value (or logP value) of at least 3, for example, at least 3.25, at least 3.5, or at least 3.75. Embodiment 126. A composition, method, or use according to any of Embodiments 109 to 116, wherein the therapeutic agent has a logD7.4 value (or logP value) of at least 4, for example, at least 4.25, at least 4.5, or at least 4.75. Embodiment 127. A composition, method, or use according to any of Embodiments 109 to 116, wherein the therapeutic agent has a logDX value of at least 2, for example, at least 2.25, at least 2.5, or at least 2.75. Embodiment 128. A composition, method, or use according to any of Embodiments 109 to 116, wherein the therapeutic agent has a logDX value of at least 3, for example, at least 3.25, at least 3.5, or at least 3.75. Embodiment 129. A composition, method, or use according to any of Embodiments 109 to 116, wherein the logDX value of the therapeutic agent is at least 4, for example, at least 4.25, at least 4.5, or at least 4.75. Embodiment 130. A composition, method, or use according to any of Embodiments 109-116, wherein the therapeutic agent has water solubility of 5 mg / mL or less in a pHX buffer, for example, 2 mg / mL or less at 37°C. Embodiment 131. A composition, method, or use according to any of Embodiments 109 to 116, wherein the therapeutic agent has a water solubility of 1 mg / mL or less, for example, 0.5 mg / mL or less, or 0.2 mg / mL or less, in a pHX buffer at 37°C. Embodiment 132. A composition, method, or use according to any of Embodiments 109 to 116, wherein the therapeutic agent has a water solubility of 0.1 mg / mL or less, for example, 0.05 mg / mL or less, or 0.02 mg / mL or less, in a pHX buffer at 37°C. Embodiment 133. A composition, method, or use according to any of Embodiments 127 to 132, wherein X is 3, 3.5, 4, or 4.5. Embodiment 134. A composition, method, or use according to any of Embodiments 127 to 132, wherein X is 5, or 5.5, or 6, or 6.5, or 7. Embodiment 135. A composition, method, or use according to any of Embodiments 127 to 132, wherein X is 8, 8.5, or 9. Embodiment 136. A composition, method, or use according to any of Embodiments 127 to 135, wherein the pH is in the range of 3 to 9, for example, 3 to 4.5, or 4 to 5.5, or 5 to 6.5, or 6 to 7.5, or 7 to 8.5, or 8 to 9. Embodiment 137. A composition, method, or use of any of Embodiments 109 to 136, wherein the therapeutic agent is selected from apixaban, atorvastatin, cabazitaxel, celecoxib, docetaxel, dolutegravir, edaravone, etomidate, everolimus, midazolam, paclitaxel, propofol (oral), rivaroxaban, tacrolimus, tenofovir alafenamide, and ticagrelor. Embodiment 138. A composition, method, or use according to any of Embodiments 109 to 137, wherein the conjugate is present in an amount exceeding its critical micelle concentration. Embodiment 139. A composition, method, or use of Embodiments 109 to 137, wherein the conjugate is present in an aqueous solution in an amount exceeding its critical micelle concentration or in an amount less than 0.1 mmol. Embodiment 140. A composition, method, or use according to any of Embodiments 109 to 139, wherein the weight ratio of the conjugate to the therapeutic agent of the Disclosure is in the range of 500:1 to 1:2, for example, 200:1 to 1:2, or 100:1 to 1:2, or 50:1 to 1:2, or 20:1 to 1:2. Embodiment 141. A composition, method, or use according to any of Embodiments 109 to 139, wherein the weight ratio of the conjugate to the therapeutic agent of the Disclosure is in the range of 500:1 to 1:1, for example, 200:1 to 1:1, or 100:1 to 1:1, or 50:1 to 1:1, or 20:1 to 1:1, or 10:1 to 1:1, or 5:1 to 1:1. Embodiment 142. A composition, method, or use according to any of Embodiments 109 to 139, wherein the weight ratio of the conjugate to the therapeutic agent of the Disclosure is in the range of 500:1 to 2:1, for example, 200:1 to 2:1, or 100:1 to 2:1, or 50:1 to 2:1, or 20:1 to 2:1, or 10:1 to 2:1, or 5:1 to 2:1. Embodiment 143. A composition, method, or use according to any of Embodiments 109 to 139, wherein the weight ratio of the conjugate to the therapeutic agent of the Disclosure is in the range of 500:1 to 4:1, for example, 200:1 to 4:1, or 100:1 to 4:1, or 50:1 to 4:1, or 20:1 to 4:1, or 10:1 to 4:1. Embodiment 144. A composition, method, or use according to any of Embodiments 109 to 143, wherein the therapeutic agent is present in the composition in an amount of at least 0.1% by weight, for example, at least 0.2% by weight. Embodiment 145. A composition, method, or use according to any of Embodiments 109-143, wherein the therapeutic agent is present in the composition in an amount of at least 0.5 wt%, for example, 1 wt%. Embodiment 146. A composition, method, or use according to any of Embodiments 109 to 143, wherein the therapeutic agent is present in the composition in an amount of at least 2% by weight, for example, at least 5% by weight. Embodiment 147. A composition, method, or use according to any of Embodiments 109-143, wherein the therapeutic agent is present in the composition in an amount of at least 10 wt%, for example, at least 20 wt%. Embodiment 148. A composition, method, or use according to any of Embodiments 109 to 143, wherein the therapeutic agent is present in the composition in an amount ranging from 0.1 to 10 wt%, for example, 0.2 to 10 wt%, or 0.1 to 5 wt%, or 0.2 to 5 wt%, or 0.1 to 2 wt%, or 0.2 to 2 wt%. Embodiment 149. A composition, method, or use according to any of Embodiments 109 to 143, wherein the therapeutic agent is present in the composition in an amount ranging from 0.5 to 20 wt%, for example, 1 to 20 wt%, or 0.5 to 10 wt%, or 0.5 to 10 wt%, or 0.5 to 5 wt%, or 1 to 5 wt%. Embodiment 150. A composition, method, or use according to any of Embodiments 109 to 143, wherein the therapeutic agent is present in the composition in an amount ranging from 2 to 30 wt%, for example, 5 to 30 wt%, or 2 to 20 wt%, or 5 to 20 wt%, or 2 to 10 wt%, or 5 to 15 wt%. Embodiment 151. A composition, method, or use according to any of Embodiments 109 to 143, wherein the therapeutic agent is present in the composition in an amount ranging from 10 to 50 wt%, for example, 20 to 50 wt%, or 10 to 30 wt%, or 20 to 40 wt%, or 10 to 20 wt%, or 20 to 30 wt%. Embodiment 152. A composition, method, or use according to any of Embodiments 109-151, wherein the conjugate is present in an amount of at least 1 wt%, for example, at least 2 wt%. Embodiment 153. A composition, method, or use according to any of Embodiments 109-151, wherein the conjugate is present in an amount of at least 5 wt%, for example, at least 10 wt%. Embodiment 154. In any of the compositions, methods, or uses of Embodiments 109 to 151, the conjugate is present in an amount of at least 15% by weight, for example, at least 20% by weight. In various embodiments, the conjugate of the Disclosure is present in an amount of at least 25% by weight, for example, at least 30% by weight. Embodiment 155. A composition, method, or use of any of Embodiments 109-151, wherein the conjugate is present in the composition in an amount ranging from 1-25 wt%, for example, 2-25 wt%, or 1-15 wt%, or 2-15 wt%, or 1-10 wt%, or 2-10 wt%, or 1-5 wt%, or 2-5 wt%. Embodiment 156. A composition, method, or use according to any of Embodiments 109 to 151, wherein the conjugate is present in the composition in an amount ranging from 5 to 35 wt%, for example, 10 to 35 wt%, or 5 to 25 wt%, or 10 to 25 wt%, or 5 to 15 wt%, or 10 to 20 wt%. Embodiment 158. A composition, method, or use according to any of Embodiments 109 to 151, wherein the conjugate is present in the composition in an amount ranging from 15 to 50 wt%, for example, 20 to 50 wt%, or 15 to 40 wt%, or 20 to 40 wt%, or 15 to 30 wt%, or 20 to 35 wt%. Embodiment 159. A composition, method, or use according to any of Embodiments 109-151, wherein the conjugate is present in the composition in an amount ranging from 20-60 wt%, for example, 25-60 wt%, or 20-50 wt%, or 25-50 wt%, or 20-40 wt%, or 25-45 wt%. Embodiment 160. A composition, method, or use according to any of Embodiments 109-158, wherein the composition is in the form of an aqueous solution or suspension. Embodiment 161. A composition, method, or use according to any of Embodiments 109 to 158, wherein the composition is in the form of a concentrate for dilution in an aqueous solution or suspension. Embodiment 162. A composition, method, or use according to any of Embodiments 109-158, wherein the composition is, for example, in the form of a cream or gel for topical administration. Embodiment 163. A composition, method, or use according to any of Embodiments 109-158, wherein the composition is in the form of a solid dosage form, such as a tablet, capsule, or granule.

Claims

1. Lipid / PEG / sugar conjugate having the following structural formula: Here m has a numerical mean in the range of 2 to 10; S is a monosaccharide, disaccharide, or trisaccharide group, and each sugar unit is a sugar, sugar alcohol, amino sugar, or sugar acid; L is -C(O)-R １ And R １ is an alkanyl or alkenyl group with an average number of carbon atoms in the range of 6 to 22, and / or a steroidacyl group; P is - (CH ２ -CH ２ -O)nR ２ Therefore, n is a number whose mean value is in the range of 5 to 50 (for example, 8 to 45), and R ２ These are hydrogen and / or alkanyl atoms, with a number-average of 0 to 4 carbon atoms.

2. A conjugate according to claim 1, wherein the average numerical value of m is in the range of 2 to 4.

3. A conjugate according to claim 1, wherein the average numerical value of m is in the range of 5 to 10.

4. A conjugate according to claim 1, wherein S is a disaccharide group.

5. The conjugate according to claim 1, wherein the sugar unit of S directly bonded to the nitrogen of the diamine central skeleton originates from a sugar acid and is bonded as an amide bond.

6. In the conjugate according to claim 1, S has the following structural formula: Here, -(C ｘ１ H ２ｘ１ O ｘ１ -1)-CO- is a sugar acyl residue derived from a sugar acid, ｘ１ is 4 or 5. Also, (C ｘ２ H ２ｘ２ -1O ｘ２ -1)- is a sugar residue derived from a sugar, ｘ２ is 5 or 6. Alternatively, it is the open-chain form of this.

7. The conjugate according to claim 1, wherein S has the following structure: or its open-chain version.

8. A conjugate according to claim 1, wherein S is lactobionyl or gluconyl.

9. The conjugate according to claim 1, R １ Conjugates have an average carbon number of 6 to 20.

10. The conjugate according to claim 1, R １ The average number of carbon atoms in a conjugate is in the range of 12 to 18.

11. The conjugate according to claim 1, R １ A conjugate in which the group is a linear alkyl group or alkenyl group.

12. The conjugate according to claim 1, wherein L is -C(O)-R １ And -C(O)-R １ A conjugate having at least 85 mol% single chemical identity.

13. A conjugate according to claim 1, wherein L comprises (or is a steroidacyl group) a steroidacyl group (for example, a bile acyl group).

14. A conjugate according to claim 1, wherein the average value of n is in the range of 8 to 45.

15. A conjugate according to claim 1, wherein the average value of n is in the range of 9 to 13.

16. The conjugate according to claim 1, R ２ A conjugate in which the methyl group is present.

17. A conjugate according to claim 1, wherein the polyvariance index of P is 1.1 or less.

18. The conjugate according to claim 1, m is 3, The structural formula for S is as follows: Here, -(C ｘ１ H ２ｘ１ O ｘ１－１ )-CO- is, ｘ１ It is a sugar acyl residue derived from a sugar acid where is 4 or 5, (C ｘ２ H ２ｘ２ -1O ｘ２－１ )-teeth, ｘ２ A sugar residue derived from a sugar where 5 or 6 is present, or its open-chain version thereof. -C(O)-R １ is Sys-CH ３ (CH ２ ) ７ CH = CH (CH ２ ) ７ It is at least 80 mol% of C(O)-, for example, at least 85 mol%, R ２ is methyl; The weighted mean of n is in the range of 11.5 to 12.5, for example, 11.8 to 12.

2. The polyvariance index of P is 1.1 or less, for example, 1.07 or less.

19. A conjugate according to claim 1, wherein the conjugate is oleoyldiaminopropane-monomethoxypolyethylene-glycol-ether-lacbionate (DOPS) represented by chemical structure 2. Here, m(PEG)n is a methylated PEG residue, and n is in the range of 9 to 13.

20. A conjugate according to claim 1, having any of the following structures:

21. A conjugate according to claim 1, wherein the conjugate has a purity of at least 90% by weight as measured by HPLC.

22. A method for producing a conjugate according to any one of claims 1 to 21, comprising poly(ethylene) glycol, sugars and R １ A manufacturing method comprising bonding a -C(O)-acyl group to a diamine skeleton.

23. In the conjugate of claim 1, R １ -C(O) is a fatty acid acyl, and in HPLC analysis, it is a conjugate similar to the peak profile in Figures 1, 2, or 3, and has the following relative retention time (RRT).

24. The manufacturing method according to claim 22 comprises providing a monoprotected diamine having a protected first amine group and an unprotected second amine group, and comprising poly(ethylene glycol) and R １ A method for producing a product comprising coupling a -C(O)-acyl group to a second amine group, deprotecting the protected first amine group, and coupling a carbohydrate to the newly unprotected first amine group.

25. A conjugate according to any one of claims 1 to 22, which is used as a pharmaceutical additive or as a pharmaceutical.

26. A therapeutic composition comprising a conjugate according to any one of claims 1 to 21 and a therapeutic agent.

27. A composition for use in the treatment of a subject having some disease, the composition comprising a conjugate according to any one of claims 1 to 21 and a therapeutic agent suitable for the treatment of the disease.

28. A method for preparing the composition according to claim 27, comprising preparing a therapeutic agent and a conjugate in a solvent (e.g., water or an organic solvent), and freeze-drying or spray-drying the liquid to provide a solid material comprising the therapeutic agent and the conjugate.

29. A method for treating a subject having a disease, the method comprising administering the composition according to claim 27 to the subject, for example, by oral, nasal, topical, or parenteral administration.

30. A composition for use as a pharmaceutical product, comprising a conjugate according to any one of claims 1 to 22 and a therapeutic agent.

31. Use of a polyconjugate according to any one of claims 1 to 22 to enhance the bioavailability of a therapeutic agent.

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

33. Use of the conjugate according to any one of claims 1 to 21 as a pharmaceutical excipient or therapeutic agent.

34. The composition according to claim 27, wherein the therapeutic agent has a water solubility of 0.2 mg / mL or less in an aqueous buffer solution with a pH of 7.4 at 37°C.

35. The composition according to claim 27, wherein the therapeutic agent is a composition having a water solubility of 0.2 mg / mL or less at 37°C in a buffer solution having a pH in the range of 3 to 9.

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