Amphiphilic carbohydrate compound

Abstract

To provide an optimized amphiphilic carbohydrate compound for encapsulating a hydrophobic drug based on the study on the effect of acetylation on the self-assembly of an amphiphilic chitosan derivative and the encapsulation of the drug.SOLUTION: The present invention relates to acetylated amphiphilic carbohydrates compounds with average molecular weights from 1 to 50kDa based on glycol chitosans, wherein the level of acetylation can be varied. The compound can be formulated with a hydrophobic compound, such as a drug. The degree of acetylation of the carbohydrate compound is optimized to maximize solubilization of the drug. The compounds are formulated with drugs and are useful in therapy.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to acetylated amphiphilic carbohydrate compounds and their formulation with hydrophobic drugs. [Background technology]

[0002] Amphiphilic carbohydrate compounds are useful for the formulation of drugs, especially hydrophobic drugs. For example, Patent Document 1 discloses carbohydrate polymers having hydrophobic and hydrophilic pendant groups suitable for solubilizing compounds with hydrophobic properties. The carbohydrate polymers have the following general formula:

[0003] [ka] may have

[0004] In this formula, X can be any linear or branched, substituted or unsubstituted, or cyclic form of alkyl, alkenyl, aryl, amine, amide, alcohol, or acyl group. Preferably, the X group is a fatty acid derivative, such as palmitic acid. Smaller groups, such as acetamide, are not specifically disclosed. The value of m is 0.01% to 10.00%.

[0005] Various studies have been conducted on the acetylation of chitosan and its derivatives. However, the effect of acetylation on the self-assembly and drug encapsulation of chitosan amphiphile derivatives has not been extensively studied. Acetyl groups on chitosan are hydrophobic, and therefore, it can be expected that the higher the degree of acetylation, the more hydrophobic the acetylated chitosan will be. Because hydrophobicity promotes self-assembly and drug encapsulation, chitosan amphiphiles with higher hydrophobicity (higher degree of acetylation) are expected to self-assemble more easily and encapsulate higher levels of hydrophobic compounds (Non-Patent Document 1). Increasing the hydrophobicity of other polymers also increases their ability to self-assemble, encapsulate hydrophobic compounds, and deliver them via the oral route (Non-Patent Document 2). However, the relationship between hydrophobicity (measured by aqueous solubility) and the acetylation level of chitosan is complex. As such, it is not possible to predict that the acetylation level on chitosan amphiphiles will have a positive impact on the encapsulation efficiency of hydrophobic drugs.

[0006] In light of the above, if one wishes to prepare amphiphilic, self-assembling chitosan derivatives for use as pharmaceutical or other product excipients, it is important to appreciate the relationship between acetyl derivatization of chitosan and the resulting hydrophobicity (reduced water solubility) of the chitosan derivatives.

[0007] The water solubility of chitosan increases with increasing levels of deacetylation (from 34% to 64%), and at about half deacetylation (50% acetyl groups), chitosan becomes water soluble due to the reduced crystallinity provided by the acetyl groups (Non-Patent Documents 3 and 4). Further studies have shown that N-acetylchitosan with acetylation levels of 42-82% is water soluble (Non-Patent Document 5).

[0008] Other studies have shown that chitosan (0.5% w / w) becomes more soluble in dilute acetic acid as the deacetylation level increases from 9 to 55% (Non-Patent Document 4). Thus, there is literature evidence suggesting that chitosan is most water-soluble at 50% acetylation (Non-Patent Document 3), and that chitosan's hydrophobicity increases as the deacetylation level decreases below 50%. However, the effect of deacetylation on chitosan's water solubility above 70% is unclear, with no clear trend. For example, for chitosan with acetylation levels of 14%, 50%, or no detectable acetylation (fully deacetylated), fully deacetylated chitosan begins to precipitate at pH 5.8, 14% acetylated chitosan begins to precipitate at pH 6.0, and 50% acetylated chitosan begins to precipitate at pH 7.4; all were studied at 1 mg / mL (Non-Patent Document 6). This suggests that at neutral pH (pH = 7.0), fully deacetylated chitosan and 14% acetylated chitosan are insoluble, while partially deacetylated chitosan is soluble. Additionally, 72% deacetylated chitosan has been reported to be insoluble in water (Non-Patent Document 3). When chitosan is further derivatized, the relationship between the acetylation level of chitosan and its water solubility is unclear. Chitosan (2 mg / mL) with a sugar level of 5% acetylated sugars is insoluble in water when the acetylation level ranges from 5 to 29% and when the acetylation level is 68%, while chitosan with a sugar level of 5% and an acetylation level of 49% sugars is water soluble (Non-Patent Document 7).

[0009] In addition, N-acetyl-glycol chitosan with acetylation ranging from 73 to 92% has been shown to be water-soluble (Non-Patent Document 8).

[0010] As is evident from the above, the existing literature lacks clear direction as to where the optimal acetylation level lies for preparing hydrophobic chitosan amphiphilic derivatives with good ability to encapsulate hydrophobic compounds. [Primary Technology Documents] [Chartered documents]

[0011]

Patent Document 1

Non-licensed literature

[0012] [Non-licensed document 1] Qu et al., "Carbohydrate-based micelle clusters which enhance hydrophobic drug bioavailability by up to 1 order of magnitude", Biomacromolecules 2006,7,3452-3459 [Non-licensed document 2] Le et al., "Polymer hydrophobicity has a positive effect on the oral absorption of cyclosporine A from poly(ethylenimine) based nanomedicines", Pharmaceutical Nanotechnology, 2013, 1, 15-25 [Non-licensed document 3] Lu et al., "Preparation of water-soluble chitosan",Journal of Applied Polymer Science 2004,91,(6),3497-3503

Non-licensed Document 4

Non-licensed Document 5

[0013] The present invention is based on the study of the effect of acetylation on the self-assembly of amphiphilic chitosan derivatives and thus on drug encapsulation. Optimized amphiphilic carbohydrate compounds for encapsulating hydrophobic drugs are provided. [Means for solving the problem]

[0014] In a first aspect, the present invention provides an amphiphilic carbohydrate compound having an average molecular weight of 1 to 50 kDa and represented by the following formula (I):

[0015] [ka] During the ceremony, the level of units A is from 0.5% to 30 mole %; the level of units D is from 1% to 95.5 mole %; the level of units H is from 1% to 95.5 mole %; the level of units Q is from 3% to 97.5 mole %; the level of units T is from 0% to 94.5 mole %; R 1 , R 2 , R 3 , R 4 , and R 10 are independently hydrogen or a sugar substituent selected from alkyl, alkenyl, alkynyl, aryl, acyl groups, any linear, branched, or cyclic form, glucose, galactose, fructose, and muramic acid, or an oligopolyoxaC1-C3 alkylene unit, optionally substituted with an amine, amide, or alcohol; R 5 is a hydrophobic, substituted or unsubstituted, linear, branched or cyclic C 4-30 Alkyl group, C 4-30 Alkenyl group, C 4-30 Alkynyl group, C 4-30 Aryl group, amine group, C 4-30 Amide group, C 4-30 Alcohol group, or C 3-30 is an acyl group; R6 , R 7 , and R 8 are independently any alkyl, alkenyl, alkynyl, aryl, or acyl group in any linear, branched, or cyclic form; R 9 may or may not be present, and if present, is a substituted or unsubstituted alkyl group, a substituted or unsubstituted amine group, or a substituted or unsubstituted amide group; R 11 is a substituted or unsubstituted alkyl group, a substituted or unsubstituted ether group, a substituted or unsubstituted alkene group, or hydrogen; R 12 is a substituted or unsubstituted alkyl group, a substituted or unsubstituted ether group, or a substituted or unsubstituted alkene group; R 13 is a substituted or unsubstituted alkyl group, a substituted or unsubstituted ether group, a substituted or unsubstituted alkene group, or hydrogen. amphiphilic carbohydrate compounds, or a salt thereof.

[0016] According to a second aspect of the present invention, there is provided a pharmaceutical composition comprising an amphipathic carbohydrate compound according to the first aspect of the present invention, a hydrophobic drug, and one or more pharmaceutically acceptable excipients.

[0017] According to a third aspect of the present invention there is provided a composition comprising an amphipathic carbohydrate compound according to the first aspect of the present invention and a hydrophobic drug for use in therapy.

[0018] According to a fourth aspect of the present invention there is provided a method of forming an amphiphilic carbohydrate compound according to the first aspect of the present invention, the method comprising: Depolymerization of carbohydrate compounds; Increasing, decreasing, or maintaining the level of acetylation; reacting the carbohydrate with a compound to add a hydrophobic side chain; and reacting a carbohydrate with a compound to generate a quaternary ammonium group; Includes:

[0019] Also provided is an agrochemical composition comprising an amphiphilic carbohydrate compound according to the first aspect of the invention, an agrochemical agent, and one or more agrochemically acceptable excipients.

[0020] Also provided is a method of controlling fungal contamination using an agrochemical composition according to the fifth aspect of the invention.

[0021] Increasing the degree of acetylation of amphiphilic carbohydrate compounds such as quaternary ammonium palmitoyl glycol chitosan (GCPQ) is expected to enable stronger hydrophobic interactions with hydrophobic molecules, thus enabling better encapsulation of hydrophobic drugs. However, the present inventors unexpectedly observed the opposite effect. The present invention reveals that controlling the degree of acetylation (the level of unit A in the above formula) in combination with an appropriate degree of hydrophobicity (unit H in the above formula) is an effective way to increase the solubilization of hydrophobic compounds. [Brief explanation of the drawings]

[0022] [Figure 1] FIG. 1 shows the level of acetylation (DA) obtained with various equivalents of acetic anhydride. [Figure 2] FIG. 1 shows the solubilization level of cyclosporin A as a function of acetylation level, palmitoylation level, and quaternization level, respectively. [Figure 3] FIG. 1 shows observed levels of cyclosporin A solubilization versus those predicted by a mathematical model. [Figure 4] FIG. 1 shows predicted levels of solubilization of cyclosporin A as a function of acetylation, palmitoylation, and quaternization levels, respectively, in theoretical polymers. DETAILED DESCRIPTION OF THE INVENTION

[0023] As mentioned above, the present invention describes an amphiphilic carbohydrate compound or a salt thereof having an average molecular weight of 1 to 50 kDa, represented by the following formula (I), which is reproduced below for ease of reference:

[0024] [ka] In this formula: * is used to represent a continuous polymer chain; the level of units A (acetylated units) is between 0.5% and 30 mole %; the level of units D (deacetylated units) is from 1% to 95.5 mole %; the level of units H (hydrophobizing units) is from 1% to 95.5 mole %; the level of units Q (quaternary amine units) is from 3% to 97.5 mole %; The level of units T (tertiary amine units) is from 0% to 94.5 mole %.

[0025] All percentages refer to mole %.

[0026] It should be understood that A+D+H+Q+T equals 100%. It should also be understood that A, D, H, Q, and T can be in any arrangement in the amphiphilic carbohydrate compound. Thus, the arrangement can be completely random or in the form of a block copolymer such as ADHQADHQ.

[0027] The present invention provides a method for maximizing compound solubilization through varying acetylation levels of the polymer.

[0028] In one preferred embodiment of the invention, the unit T is absent. Whether or not the unit T is present, the following preferred ranges apply.

[0029] In preferred embodiments of the present invention, A is in the range of 0.5% to 26 mol%, preferably in the range of 0.5% to 20 mol%, preferably in the range of 0.5% to 15 mol%, more preferably in the range of 0.5% to 10 mol%, even more preferably in the range of 0.5% to 5 mol%, or 0.5 to 4 mol%, or 0.5 to 3 mol%.

[0030] In alternative preferred embodiments, A is in the range of 2 to 20 mol%, preferably in the range of 2 to 15 mol%, more preferably in the range of 2 to 10 mol%, even more preferably in the range of 2 to 5 mol%, or in the range of 2 to 4 mol%.

[0031] In alternative preferred embodiments, A is in the range of 1 to 20 mol%, preferably in the range of 1 to 15 mol%, more preferably in the range of 1 to 10 mol%, even more preferably in the range of 1 to 5 mol%, or in the range of 2 to 5 mol%.

[0032] In preferred embodiments of the invention, D is in the range of 2% to 94.5 mol%, preferably in the range of 10% to 94.5 mol%, more preferably in the range of 10% to 90 mol%, typically in the range of 20 to 80 mol%, or in the range of 50% to 75 mol%, more preferably in the range of 55% to 75 mol%, even more preferably in the range of 65% to 75 mol%.

[0033] In preferred embodiments of the present invention, H is in the range of 2% to 94.5 mol%, preferably in the range of 2% to 90 mol%, more preferably in the range of 5% to 80 mol%. In further preferred embodiments, H is in the range of 5% to 70 mol%, for example, 5% to 60 mol%, or 5% to 50 mol%. In alternative embodiments, H is in the range of 10% to 30 mol%, more preferably, 10 to 20 mol%, or 20 to 30 mol%.

[0034] In preferred embodiments of the invention, Q is present in the range of 1% to 90 mol%, preferably 2% to 50 mol%, such as 5% to 30 mol%, 5% to 20 mol%, 5 to 15 mol%, or 5 to 10 mol%.

[0035] In preferred embodiments of the invention, T is in the range of 0% to 20 mol%, more preferably in the range of 0% to 10 mol%, even more preferably in the range of 0% to 5 mol%. In some embodiments, T is present in the range of 0.5% to 20 mol%, or 1% to 20 mol%, such as in the range of 1 to 10 mol%, or 1 to 5 mol%.

[0036] Any of the preferred ranges for A, D, H, Q, and T can be combined.

[0037] In a preferred embodiment, the following ranges exist: A is in the range of 2 to 30 mole %; H is in the range of 14 to 24 mol %; Q is in the range of 6 to 14 mole percent.

[0038] In further preferred embodiments, the following ranges exist: A is in the range of 2 to 11 mole %; H is in the range of 10 to 24 mol %; Q is in the range of 6 to 14 mole percent.

[0039] The amphipathic carbohydrate may be accompanied by a salt, for example, the salt may include a chloride, iodide, acetate, or glucuronide salt.

[0040] The molecular weight of the amphiphilic carbohydrate compound is in the range of 1 to 50 kDa, and is preferably measured using gel permeation chromatography-multi-angle light scattering detector (GPC-MALLS).

[0041] Amphiphilic carbohydrate compounds can self-assemble into nanoparticles in aqueous media.

[0042] R 1 , R 2 , R 3 , R 4 , and R 10 are independently hydrogen or a sugar substituent selected from any linear, branched, or cyclic alkyl, alkenyl, alkynyl, aryl, acyl group, glucose, galactose, fructose, and muramic acid, or an oligopolyoxa C1-C3 alkylene unit, optionally substituted with an amine, amide, or alcohol. Preferably, these groups are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted ether, or substituted or unsubstituted alkene.

[0043] Typically, R 1 , R 2 , R 3 , R 4 , and R 10 Conveniently, R may be a C1-C4 linear alkyl group. 1 , R 2 , R 3 , R 4 , and R 10 are all -CH 2- CH 2- It may also be OH.

[0044] Typically, R 1 , R 2 , R 3 , R 4 , and R 10 may be a C1-C4 linear glycol-based group.

[0045] Typically, R 1 , R 2 , R 3 , R 4 , and R 10 is any of the following sugar substituents: glucose, galactose, fructose, and muramic acid.

[0046] R 1 , R 2 , R 3 , R 4 , and R 10 may be an oligopolyoxa C1-C3 alkylene unit such as an ethylene glycol oligomer.

[0047] R 1 , R 2 , R 3 , R 4 , and R 10 may all be CH2OCH2CH2OH or CH2CH2OH.

[0048] R 1 , R 2 , R 3 , R 4 , and R 10 may all be H.

[0049] Typically, R 5 is a hydrophobic, substituted or unsubstituted, linear, branched or cyclic C 4-30 Alkyl group, C 4-30 Alkenyl group, C 4-30 Alkynyl group, C 4-30 Aryl group, amine group, C 4-30 Amide group, C 4-30 Alcohol group, or C 3-30 It is an acyl group.

[0050] R 5 The group is preferably C 4-30 Alkyl groups such as alkyl groups, C 4-30 Alkenyl groups such as alkenyl groups, C 4-30 Alkynyl groups such as alkynyl groups, C 5-20 two or more C groups such as aryl groups, sterols (e.g., cholesterol), 4- Polycyclic hydrophobic groups with C8 ring structures, two or more C 4- Polycyclic hydrophobic groups having a C8 heteroatom ring structure, polyoxa C such as polyoxabutylene polymers 1-R is selected from a C4 alkylene group, or a substituted or unsubstituted group that is a hydrophobic polymer substituent such as a poly(lactic acid) group, a poly(lactide-co-glycolide) group, or a poly(glycolic acid) group. 5 The group may be a straight chain, branched or cyclic group.

[0051] R 5 Preferred examples of groups include groups of the formula CH3(CH2) n -CO- or CH3(CH2) n - or alkenoic acid CH3(CH2) p -CH=CH-(CH2) q -CO-, where n is from 4 to 30, more preferably from 6 to 20, and p and q may be the same or different and are from 4 to 16, more preferably from 4 to 14. A particularly preferred class of R 5 The substituents are attached to the chitosan monomer units through amide groups (containing pendant NH in the formula), e.g., of the formula CH3(CH2) n The amide groups are represented by CO-, where n is from 2 to 28. Examples of amide groups are formed by the attachment of carboxylic acids to the amine groups of chitosan. Preferred examples are fatty acid derivatives CH3(CH2) such as those based on capric acid (n=8), lauric acid (n=10), myristic acid (n=12), palmitic acid (n=14), stearic acid (n=16), or arachidic acid (n=18). n It is COOH.

[0052] R 6 , R 7 , and R 8 R is independently any alkyl group, alkenyl group, alkynyl group, aryl group, or acyl group in any linear, branched, or cyclic form. 6 , R 7 , and R 8 is preferably independently C 1-10 R is selected from substituted or unsubstituted alkyl groups such as alkyl groups. 6 , R 7 , and / or R 8may be linear or branched. Preferably, R 6 , R 7 , and R 8 is independently selected from a methyl group, an ethyl group, or a propyl group.

[0053] Conveniently, R 6 , R 7 , and R 8 forms a quaternary ammonium group which is hydrophilic.

[0054] Hydrophilic groups are groups that are fully hydrated by water and bind water at the molecular level. Additional non-ionic hydrophilic groups are R 6 , R 7 , and R 8 is equal to CHO-Y (where Y is a hydrophilic substituent), 6 R 7 R 8 In that case, both hydrophilic substituents on the carbohydrate polymer can be mono- and oligohydroxy C 1- C6 alkyl, mono and oligohydroxy substituted C 2- C6 acyl, optionally with one or more of the hydroxy groups substituted on an alkoxy or alkylene group 1- C2 alkoxyalkyl, oligo- or poly-(oxaC 1- C alkylene), preferably polyethylene glycol containing up to 120 ethylene oxide units (i.e., molecular weight 5000), and optionally hydroxy-substituted C 1- C4 alkyl (oligo or polyoxa C 1- C alkylene), preferably oligo- or polyglycerol ethers; 6 R 7 R 8 The substituents for are attached via ether bonds to the saccharide units of the polysaccharide. The acyl groups may contain alkyl, alkenyl, or alkynyl groups.

[0055] R 1、 R 2、 R 3、 R4 , and R 10 The surface may also be hydrophilic.

[0056] R 9 The group R may or may not be present in the general formula. 9 may or may not be present and, if present, is a substituted or unsubstituted alkyl group, a substituted or unsubstituted amine group, or a substituted or unsubstituted amide group.

[0057] If not present, provide a quaternary ammonium functional group directly attached to the monomer unit of the chitosan backbone. 9 If a group is present, it may be, for example, -(CH2) n- As represented by the formula: 1-10 alkyl group, etc.), where n is preferably 1 to 4. R 9 N + R 6 R 7 R 8 A preferred example of the substituent is a betaine (-OOC-CH2-N) on the amine substituent of the b unit. + -(CH3)3) to form -NH-CO-CH2-N + R 6 R 7 R 8 by providing an amide group such as in

[0058] R 11 is a substituted or unsubstituted alkyl group, a substituted or unsubstituted ether group, a substituted or unsubstituted alkene group, or hydrogen. 11 is hydrogen, and C 1-10 R is selected from substituted or unsubstituted alkyl groups such as alkyl groups. 11 may be linear or branched. Preferably, R 11 is selected from a methyl group, an ethyl group, or a propyl group, or is an OH-substituted alkyl group, preferably of the formula CH2CH2OH.

[0059] R12 is a substituted or unsubstituted alkyl group, a substituted or unsubstituted ether group, or a substituted or unsubstituted alkene group. 12 is C 1-10 R is selected from substituted or unsubstituted alkyl groups such as alkyl groups. 12 may be linear or branched. Preferably, R 12 is selected from a methyl group, an ethyl group, or a propyl group, or is an OH-substituted alkyl group, preferably of the formula CH2CH2OH.

[0060] Typically, R 12 is C 1-10 R is an alkyl group. 12 may be linear or branched. Preferably, R 12 is selected from a methyl group, an ethyl group, or a propyl group.

[0061] R 13 is a substituted or unsubstituted alkyl group, a substituted or unsubstituted ether group, a substituted or unsubstituted alkene group, or hydrogen. 13 is hydrogen, and C 1-10 R is selected from substituted or unsubstituted alkyl groups such as alkyl groups. 13 may be linear or branched. Preferably, R 13 is selected from methyl, ethyl, or propyl groups, or is an OH-substituted alkyl group, preferably of formula CH2CH2OH. Most preferably, R 13 is hydrogen.

[0062] The total number of A+D+H+Q+T monomer units may be about 10 to 100. Preferably, the total number of A+D+H+Q+T monomer units may be less than about 200.

[0063] The amphiphilic carbohydrate compounds may also have additional targeting groups such as peptides, antibodies, and other ligands, e.g., folate and transferrin ligands, that may enable the polymer to target endogenous receptors and thus target its drug payload to such endogenous receptors at the site of pathology.

[0064] In a preferred embodiment of the present invention, the amphiphilic carbohydrate compound is the partially deacetylated form of N-palmitoyl, N-monomethyl, N,N-dimethyl, N,N,N-trimethyl-6-O-glycol chitosan (GCPQ), which is known to be an amorphous compound (Non-Patent Document 9) and therefore is not subject to the increase in crystallinity observed when acetylated chitosan is converted to deacetylated chitosan. As indicated, some of the substituents described herein may be unsubstituted or substituted with one or more additional substituents, as is well known to those skilled in the art. Examples of common substituents include halo; hydroxyl; ether (e.g., C 1-7 alkoxy, etc.); formyl; acyl (e.g., C 1-7 Alkyl acyl, C 5-20 aryl acyls, etc.); acyl halides; carboxy; esters; acyloxy; amides; acylamidos; thioamides; tetrazolyls; amino; nitro; nitroso; azides; cyano; isocyano; cyanates; isocyanates; thiocyano; isothiocyano; sulfhydryls; thioethers (e.g., C 1-7 Alkylthio, etc.); Sulfonic acid; Sulfonate; Sulfone; Sulfonyloxy; Sulfinyloxy; Sulfamino; Sulfonamino; Sulfinamino; Sulfamyl; Sulfonamide; C 1-7 Alkyl (e.g., unsubstituted C 1-7 Alkyl 、 C 1-7 Haloalkyl 、 C 1-7 Hydroxyalkyl 、 C 1-7 Carboxyalkyl 、 C 1-7 Aminoalkyl 、 C5-20 Aryl-C 1-7 alkyl, etc.);C 3-20 Heterocyclyl; and C 5-20 Aryl (e.g., C 5-20 Carboaryl, C 5-20 Heteroaryl, C 1-7 Alkyl-C 5-20 Aryl, and C 5-20 haloaryl and the like).

[0065] The term "ring structure" as used herein refers to a closed ring of 3 to 10 covalently bonded atoms, even more preferably 3 to 8 covalently bonded atoms, and even more preferably 5 to 6 covalently bonded atoms. The ring may be alicyclic or aromatic. The term "alicyclic" as used herein refers to a ring that is not an aromatic ring.

[0066] The term "carbocycle" as used herein pertains to a ring in which all of the ring atoms are carbon atoms.

[0067] The term "carboaromatic ring" as used herein refers to an aromatic ring in which all of the ring atoms are carbon atoms.

[0068] As used herein, the term "heterocycle" refers to a ring in which at least one of the ring atoms is a polyvalent ring heteroatom, such as nitrogen, phosphorus, silicon, oxygen, or sulfur, but more commonly nitrogen, oxygen, or sulfur, etc. Preferably, the heterocycle has 1 to 4 heteroatoms.

[0069] The above rings may also be part of a "polycyclic group."

[0070] Preferred compounds of the present invention have the following formula (II):

[0071] [ka] During the ceremony, the level of acetylated units A is from 0.5% to 30 mole %; the level of deacetylated units D is from 1% to 95.5 mole %; the level of hydrophobizing units H is from 1% to 95.5 mole %; the level of quaternary amine units Q is from 3% to 97.5 mole %; The other groups are as defined above, with the preferred percentages above applying.

[0072] Further preferred compounds of the present invention have the following formula (III):

[0073] [ka] During the ceremony, Units a and g together correspond to unit D in claim 1; Units b and d together correspond to unit H in claim 1; The unit c corresponds to the unit Q in claim 1; The unit e corresponds to the unit T in claim 1; Unit f corresponds to unit A in claim 1; The ratio of the units a+b+c+d+e+f+g is 1; and The corresponding levels of A, D, H, Q, and T are within the ranges set forth in claim 1; or a salt thereof.

[0074] In one embodiment of the present invention, there is provided a method of forming an amphiphilic carbohydrate compound of general formula (I), the method comprising: depolymerizing the carbohydrate polymer to form a depolymerized carbohydrate; reacting the depolymerized carbohydrate with various equivalents of a first reactive compound to increase, decrease, or maintain the level of acetylation present; reacting the depolymerized carbohydrate with a second reactive compound to form hydrophobic side groups on the carbohydrate backbone, thus forming a hydrophobically substituted depolymerized carbohydrate; and adding a third reactive compound to a carbohydrate compound having a greater, lesser, or the same level of acetylation to quaternize the amine groups, thereby forming an amphiphilic carbohydrate compound; Includes:

[0075] The carbohydrate polymer may be selected from glycol chitosan.

[0076] The carbohydrate polymer may be depolymerized using any of the following acids, bases, or enzymes.

[0077] The acid used to depolymerize the carbohydrate polymer may be selected from any of the following: HCl, HSO, HNO, or HF.

[0078] The carbohydrate polymer may be depolymerized for several days, for example, 48 hours, and then isolated and subjected to further depolymerization depending on the average molecular weight of the solubilized carbohydrate polymer required.

[0079] The average molecular weight of the carbohydrate polymer to be depolymerized is about 2 to 100 kDa, preferably about 5-50 kDa or 5-30 kDa.

[0080] The first reactive compound is typically acetic anhydride, which is used in various equivalent amounts to increase, decrease, or maintain the level of acetylation. Typically, the degraded glycol chitosan is fully acetylated in a first reaction step and then partially deacetylated in a second reaction step to obtain the desired level of acetylation.

[0081] The second reactive compound that forms the hydrophobic side group on the depolymerized carbohydrate polymer may be selected from any of the following: any type of fatty acid derivative, such as stearic acid, oleic acid, palmitic acid, etc.; organic halides such as alkyl, alkenyl, alkynyl, cyclic or non-aromatic halides, acyl chlorides, anhydrides, N-hydroxysuccinimide, and other activated acyl compounds that can be attacked on the Cl carbon by a compound capable of nucleophilic attack. Nucleophilic attack means that the compound attacks an atom with low electron density. The acyl group may also have an alkyl, alkenyl, or alkynyl group.

[0082] Preferably, the second reactive compound that increases, decreases, or maintains the acetylation level on the depolymerized glycol chitosan can be selected from any of the following: hexadecyl bromide, dodecyl bromide, myristate N-hydroxysuccinimide.

[0083] Preferably, the fatty acid derivative may be palmitic acid N-hydroxysuccinimide; palmitic acid benzotriazole carbonate; palmitaldehyde; palmitoyl chloride; and palmitic acid p-nitrophenyl carbonate.

[0084] The third reactive compound may be an organic halide, where the organic group may be selected from any alkyl group, alkenyl group, alkynyl group, aryl group, amine group, amide group, alcohol group, or acyl group, in any linear or branched, substituted or unsubstituted, or cyclic form.

[0085] Typically, the third reactive compound is any of the following alkyl, alkenyl, alkynyl, aryl, amine, amide, alcohol, or acyl groups in any linear or branched, substituted or unsubstituted, or cyclic form: C-C 30 ;C1-C 12 ;C1-C6; or C1:.

[0086] Typically, the organic group of the organic halide may be a short-chain linear alkyl group.

[0087] The organic group of the organic halide may be CH3.

[0088] In one aspect of the present invention, a pharmaceutical composition is provided comprising the above-described amphipathic carbohydrate compound, a hydrophobic drug, and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, 0.1 M or preferably 0.05 M phosphate buffer, or 0.9% saline. In addition, such pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, and emulsions.

[0089] Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions, or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's solution, or fixed oils. Preservatives and other additives, such as antibacterial agents, antioxidants, chelating agents, and inert gases, may also be present. Typically, the ratio of carbohydrate polymer to pharmaceutically acceptable carrier ranges from 0.05 wt.% to 10 wt.%.

[0090] A hydrophobic drug is one that is poorly soluble in an aqueous medium such as water. A poorly soluble drug means that 1 gram of the drug requires more than 10,000 ml of solvent (water) to be solubilized. Alternatively, this means that the solubility in water is less than 0.1 mg mL. -1 means less than the prescribed dose of a drug.

[0091] Hydrophobic drugs are typically encapsulated by amphiphilic carbohydrate compounds. The hydrophobic drug may be an analgesic, antibiotic, anticoagulant, antidepressant, anticarcinogen, antitumor, anti-inflammatory, antihistamine, antiemetic, antianxiety, anticonvulsant, antipsychotic, antiviral, antidiabetic, sedative, antihypertensive, or cardiovascular drug.

[0092] Hydrophobic drugs may act as diuretics or antidiuretics, chronotropes, inotropes, decongestants, bronchodilators, anticholinergics, antithrombotic agents, antibacterial agents, or antifungal agents.

[0093] The hydrophobic drug is preferably a steroid. Preferred drugs include prednisolone, estradiol, testosterone, drugs with polycyclic structures and lacking polar groups, such as paclitaxel, and drugs such as etoposide.

[0094] The hydrophobic drug is preferably a macrolide immunosuppressant. Macrolide drugs are highly valuable as antibacterial agents, particularly as antibacterial and antifungal agents, and as immunomodulators. In this latter category, they are particularly useful in the treatment of autoimmune disorders, which may include rheumatoid arthritis, psoriasis, Crohn's disease, nephrotic syndrome, or dry eye syndrome of autoimmune origin.

[0095] Preferred macrolide drugs include rapamycin (also known as sirolimus), cyclosporin A, tacrolimus, and everolimus, with the drug being preferably cyclosporin A (CSA), rapamycin, or tacrolimus. CSA is a potent immunosuppressant that has shown potential use in ophthalmology for the treatment of various ocular disorders, including corneal transplant rejection and keratoconjunctivitis sicca and uveitis. As discussed further above, due to its poor water solubility, CSA is currently formulated as an ophthalmic emulsion (Restasis®). Tacrolimus (TAC) is an immunosuppressant used to treat allergic conjunctivitis and atopic dermatitis. Rapamycin (RAP) is an immunosuppressant used, for example, to prevent transplant rejection or coat coronary artery stents.

[0096] The compositions of the present invention can be used to treat schizophrenia, obesity, pain, and sleep disorders, psychiatric disorders, neurodegenerative conditions, brain tumors, or infectious diseases.

[0097] The compositions of the present invention can be used to treat ocular conditions such as dry eye syndrome (DES) (also known as keratoconjunctivitis sicca (KCS)), vernal keratoconjunctivitis (VKC), eczema, atopic keratoconjunctivitis (AKC), Sjogren's syndrome, post-operative refractive surgery, corneal transplant, or contact lens intolerance.

[0098] In one embodiment of the present invention, the compound cyclosporin A was solubilized at concentrations from 0.18 to 1.57 mg / mL by varying the acetylation level while maintaining other parameters of the polymer used for solubilization.

[0099] In one embodiment of the present invention, the compound tacrolimus was solubilized at concentrations from 0.07 to 1.58 mg / mL by varying the acetylation level while maintaining other parameters of the polymer used for solubilization.

[0100] In one embodiment of the present invention, the compound rapamycin was solubilized at concentrations from 0.01 to 1.34 mg / mL by varying the acetylation level while maintaining other parameters of the polymer used for solubilization.

[0101] In the compositions of the present invention, the drug is preferably present at a concentration of less than 2% w / v, preferably in the range of 0.001 to 1% w / v.

[0102] When concentrations are expressed as % w / v, this means the amount of solids (g) contained in 100 mL of the composition.

[0103] Typically, the ratio of amphiphilic carbohydrate compound to drug may be 10 wt.%:5000 wt.%.

[0104] Typically, the ratio of amphipathic carbohydrate compound to drug to pharmaceutically acceptable carrier may be about 1-20 mg:1 mg-10 mg:1 g.

[0105] The pharmaceutical composition may be in any of the following forms: tablet, suppository, liquid capsule, powder form, or a form suitable for pulmonary or nasal delivery.

[0106] When tablets are used for oral administration, carriers typically used include typical lubricants such as sucrose, lactose, mannitol, maltitol, dextran, cornstarch, magnesium stearate, etc., preservatives such as parabens and sorbic acid, antioxidants such as ascorbic acid, α-tocopherol, cysteine, disintegrants, or binders. When administered orally as capsules, effective diluents include lactose and dry cornstarch. Liquids for oral use include syrups, suspensions, solutions, and emulsions, which may contain typical inert diluents used in this field, such as water, and may additionally contain sweeteners or flavoring agents. Suppositories can be prepared by combining the compounds of the present invention with suitable non-irritating excipients, such as those that are solid at room temperature but liquid at intestinal temperature and melt in the rectum to release the active ingredient, such as cocoa butter and polyethylene glycol.

[0107] The pharmaceutical compositions may be formulated for any route of administration, for example oral, parenteral, intranasal, inhaled or topical, and are particularly suitable for topical ocular administration.

[0108] The dosage can be determined based on the age, body weight, administration time, administration method, drug combination, clinical condition or the severity of the actual condition of the patient undergoing treatment, and other factors. Although the daily dose may vary depending on the condition and body weight of the patient, the type or active ingredient, and the administration route, in the case of oral administration, the daily dose may be about 0.1 mg to 2 g / person / day, preferably 0.5 to 100 mg / person / day.

[0109] In one embodiment of the present invention, there is provided an agricultural composition comprising an amphiphilic carbohydrate compound according to the first aspect of the invention and an agricultural chemical agent together with an agriculturally acceptable excipient.

[0110] Agriculturally acceptable carriers can be solid, liquid, or both. Solid carriers are essentially: silica, silica gel, silicates, talc, kaolin, montmorillonite, attapulgite, pumice, sepiolite, bentonite, limestone, lime, chalk, red earth, ochre, clay, dolomite, diatomaceous earth, calcite, calcium sulfate, magnesium sulfate, magnesium oxide, mineral earths such as sand, crushed plastic, fertilizers such as ammonium sulfate, ammonium phosphate, ammonium nitrate, urea, and ground plant materials such as grain flour, bark flour, wood flour, and nut flour, cellulose powder, or other solid carriers.

[0111] In the context of the present invention, an agricultural chemical agent is a chemical suitable for use for agricultural purposes and may typically be an insecticide, herbicide, fungicide, or nematicide. In the context of the present invention, the agricultural chemical agent is preferably a fungicide.

[0112] The invention is illustrated by the following non-limiting examples.

[0113] Example material Rapamycin (RAP) was purchased from Cambridge Biosciences (Cambridge, UK). Tacrolimus (TAC) was purchased from Generon Ltd. (Slough, UK). All polymers were supplied by Nanomerics Ltd.

[0114] method dGC acetylation Degraded glycol chitosan (dGC, MW 11.4 kDa) was dissolved in 10% v / v acetic acid to a concentration of 16.7 mg / mL, and multiple molar equivalents (2, 4, 8, 10, 15, or 20) of acetic anhydride were added. The solution was shaken at room temperature for 5 hours, the pH was adjusted to 8-9 with powdered NaOH, dialyzed (against water, molecular weight cutoff of the dialysis bag - MWCO = 3.5 kDa) for 24 hours, and lyophilized. The resulting product was then treated with 0.1 M KOH (30 mL / g dGC), centrifuged (8000 g, 10 min, 4 °C), washed twice with methanol (10 mL / g dGC), dissolved in water (6 mL / g dGC), and lyophilized.

[0115] dGC deacetylation Degraded glycol chitosan (dGC, MW 11.4 kDa) was added to a boiling solution of 45% w / v NaOH, and the reaction was allowed to proceed under nitrogen for 1 h, after which the pH was adjusted to 7 with HCl. The solution was then dialyzed (HO, MWCO = 3.5 kDa, 24 h) and lyophilized.

[0116] Palmitoylation of dGC Palmitoylation was carried out as previously described with minor modifications. Briefly, dGC was dissolved in 3.7% v / v triethylamine / DMSO to a concentration of 30 mg / mL. To this solution, 0.25 molar equivalents of palmitic acid N-hydroxysuccinimide relative to the molar concentration of free amine (degree of deacetylation determined by NMR) were added, and the reaction was allowed to proceed for 16 hours protected from light. The product was precipitated and washed with acetone.

[0117] pGC quaternization Quaternization was carried out as previously described. Briefly, pGC, NaOH, and NaI were dissolved in NMP to concentrations of 15.1, 16.3, and 18.6 mg / mL, respectively. The solutions were combined in a 7:2:1 ratio, followed by a 15-minute nitrogen purge after the addition of the NaI solution. MeI was added (1.5 mL / g pGC), and the reaction proceeded under a nitrogen atmosphere at 37°C for 2 hours with magnetic stirring. GCPQ was precipitated by addition to 6 vol of methyl tert-butyl ether (MTBE), washed three times with 1 vol of MTBE, dialyzed (HO, MWCO = 3.5 kDa, 24 hours), ion-exchanged against IRA-410, and finally lyophilized. The resulting N-palmitoyl-N-acetyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycol chitosan (AGCPQ) was recovered as a lyophilized powder.

[0118] Determining the level of polymer modification The degree of acetylation (DA) was determined by H NMR by comparing the integral of the acetyl peak at 2.02–2.10 ppm (1.5 protons per half acetyl group) with the sugar / glycol peak at 3.44–4.40 ppm (nominally 9 protons per GC unit). Similarly, palmitoylation (DP) and quaternization (DQ) were determined by comparing the peaks at 0.85–1.00 ppm (3 protons per terminal methyl) and 0.35–3.43 ppm (4.5 protons per half quaternary amine). These ranges are representative and are more clearly defined by the associated peaks and troughs (Figure 1).

[0119] Encapsulation of Cyclosporin A (CsA) GCPQ (7.5 mg) was dispersed in glycerol (3.1% w / v, 1 mL) with shaking for >2 hours. This dispersion was then used to rehydrate 2 mg of cyclosporine, which had previously been dissolved in methanol, aliquoted, and dried under nitrogen. The resulting solution was shaken for >2 hours, sonicated at an amplitude of 5 for 3 minutes, and refrigerated overnight. The supernatant was then collected, and the cyclosporine concentration was determined by HPLC.

[0120] Tacrolimus Encapsulation TAC powder was dissolved in absolute ethanol (2 mg / mL, 1.5 mL). The polymer was dispersed in a 50:50% v / v ethanol:methanol mixture (10 mg / mL, 1 mL). Both preparations were mixed, and 0.4 mL of methanol was added to each mixture to ensure complete dissolution of all components. The organic solvent was then removed under vacuum until a thin, dry film was formed. The dried film was rehydrated with 1.5 mL of distilled water and vigorously mixed for 30 minutes to disperse the film in the solvent. The formulation was adjusted to pH 4.0-5.0 using a calibrated pH meter with 1.0 M NaOH and then subjected to a simulated sterile filtration step using a 0.22 μm PES sterile filter. All formulations were then analyzed for drug content using RP-HPLC (parameters in Table 1).

[0121] [Table 1] Encapsulation of rapamycin RAP powder was dissolved in absolute ethanol (5 mg / mL, 0.4 mL). The polymer was dispersed in a 50:50% v / v water:methanol mixture (7.5 mg / mL, 0.5 mL). Both preparations were combined, and 0.4 mL of methanol was added to each mixture to ensure complete dissolution of all components. All preparations were combined and placed in a Savant Vacuum Evaporator at 45°C and spun under vacuum for 5 hours until a thin, dry film formed. The dried film was rehydrated with 1 mL of distilled water and vigorously mixed for 30 minutes to disperse the film in the solvent. The mixture was then sonicated for 3 minutes in an ice bath at 30% of its maximum power using an MSE Soniprep 150 sonicator. The formulation was adjusted to pH 4.0-5.0 using a calibrated pH meter with 1.0 M NaOH and then subjected to a simulated sterile filtration step using a 0.22 μm PES sterilizing filter. All formulations were then analyzed for drug content using RP-HPLC (parameters in Table 2).

[0122] [Table 2] Results and Discussion dGC acetylation The level of acetylation can be tightly controlled in the range tested (2–20 molar equivalents of acetic anhydride (AcO)), providing a degree of acetylation (DA) of 5.5–16.4%, where DA = 0.0059 * AcO + 0.0449 R 2 A linear correlation of =0.9976 resulted, highlighting the precision with which DA can be controlled (Table 3).

[0123] [Table 3] Encapsulation of Cyclosporine (CsA) The target DP and DQ were the same for all AGCPQ polymers, but these parameters changed as the degree of acetylation was varied (Table 4). The concentration of CsA [CsA] was plotted against the DA, DP, and DQ of the polymers tested, and showed a negative correlation with DA and no significant correlation with other polymer properties (Table 5). Thus, DA was shown to have a significant effect on encapsulation.

[0124] [Table 4]

[0125] [Table 5] Mathematical Model Although DA has the most significant effect on encapsulation, DP and DQ were incorporated into the model to refine its predictive power. Using the sum of the products of each polymer variable and coefficient and a constant, each polymer provided a predicted value [CsA], and the coefficients were varied to minimize the error between the predicted and observed values. The coefficients for DA, DP, and DQ were -2.21, 0.44, and -8.07, respectively, resulting in an R for the model. 2 was 1, suggesting that [CsA] increases with increasing DP and decreasing DA and DQ.

[0126]

number

[0127] [Table 6] Encapsulation of rapamycin (RAP) The concentration of rapamycin [RAP] was plotted against the DA, DP, and DQ of the polymers being tested (Table 7).

[0128] [Table 7] conclusion The hypothesis of this study was that increasing the degree of acetylation of GCPQ would allow stronger hydrophobic interactions with hydrophobic molecules and therefore increase encapsulation, but the opposite was observed.

[0129] Unexpectedly, it was found that acetylation levels of 2 to 27% in N-palmitoyl, N-monomethyl, N,N-dimethyl, N,N,N-trimethyl-6-O-glycol chitosan produced the best molecules for encapsulating hydrophobic compounds, and that increasing the acetylation level to 37.6% significantly reduced drug encapsulation.

[0130] Although DP and DQ also varied among the polymers tested, there was no clear trend between encapsulation and properties, so these parameters can be confidently ruled out as a likely explanation for the observed results. The only clear trend was the negative correlation between DA and encapsulation, for which one explanation is that the acetyl groups on the polymer contribute little to hydrophobic interactions but serve to sterically hinder the polymer folding necessary for efficient encapsulation of small hydrophobic compounds.

[0131] Previous studies have shown that DP and DQ affect the encapsulation of hydrophobic compounds in polymer nanoassemblies. This is the first time that DA has been systematically varied to study its effect on hydrophobic compound encapsulation. Controlling DA has been shown to be an effective means of increasing the encapsulation of hydrophobic compounds. Increased encapsulation of hydrophobic compounds means that higher levels of compounds can be loaded into these nanoassemblies, making drug delivery more efficient.

[0132] The same conclusion was found for tacrolimus and rapamycin, where the level of drug encapsulated in polymer nanoparticles increased with decreasing levels of polymer acetylation.

[0133] [Form 1] An amphiphilic carbohydrate compound having an average molecular weight of 1 to 50 kDa and represented by the following formula (I): [ka] During the ceremony, the level of units A is from 0.5% to 30 mole %; the level of units D is from 1% to 95.5 mole %; the level of units H is from 1% to 95.5 mole %; the level of units Q is from 3% to 97.5 mole %; the level of units T is from 0% to 94.5 mole %; R 1 , R 2 , R 3 , R 4 , and R 10 are independently hydrogen or an alkyl group, alkenyl group, alkynyl group, aryl group, acyl group, any linear, branched or cyclic form, a sugar substituent selected from glucose, galactose, fructose, and muramic acid, or an oligopolyoxaC1-C3 alkylene unit, optionally substituted with an amine, amide, or alcohol; R 5 is a hydrophobic, substituted or unsubstituted, linear, branched or cyclic C 4-30 Alkyl group, C 4-30 Alkenyl group, C 4-30 Alkynyl group, C 4-30 Aryl group, amine group, C 4-30 Amide group, C 4-30 Alcohol group, or C 3-30 is an acyl group, R 6 , R 7 , and R 8are independently any alkyl, alkenyl, alkynyl, aryl, or acyl group in any linear, branched, or cyclic form; R 9 is may or may not be present and, if present, is a substituted or unsubstituted alkyl group, a substituted or unsubstituted amine group, or a substituted or unsubstituted amide group; R 11 is a substituted or unsubstituted alkyl group, a substituted or unsubstituted ether group, a substituted or unsubstituted alkene group, or hydrogen, and further R 12 is a substituted or unsubstituted alkyl group, a substituted or unsubstituted ether group, or a substituted or unsubstituted alkene group, R 13 is a substituted or unsubstituted alkyl group, a substituted or unsubstituted ether group, a substituted or unsubstituted alkene group, or hydrogen; or a salt thereof. [Form 2] The following formula [ka] and During the ceremony, the level of acetylation units A is between 0.5% and 30%; the level of deacetylated units D is between 1% and 95.5%; the level of hydrophobizing units H is between 1% and 95.5%; the level of quaternary amine units Q is from 3% to 97.5%; R 1 , R 2 , R 3 , and R 4 are independently alkyl groups, alkenyl groups, alkynyl groups, aryl groups, acyl groups, sugar substituents selected from glucose, galactose, fructose, and muramic acid, in any linear, branched, or cyclic form, or oligopolyoxaC1-C3 alkylene units, optionally substituted with an amine, amide, or alcohol; R5 is a hydrophobic, substituted or unsubstituted, linear, branched or cyclic C 4-30 Alkyl group, C 4-30 Alkenyl group, C 4-30 Alkynyl group, C 4-30 Aryl group, amine group, C 4-30 Amide group, C 4-30 Alcohol group, or C 3-30 an acyl group, and R 6 , R 7 , and R 8 are independently any alkyl, alkenyl, alkynyl, aryl, or acyl group in any linear, branched, or cyclic form; or a salt thereof, 10. The amphiphilic carbohydrate compound according to claim 1, wherein all % are given as mole %. [Form 3] The following formula [ka] and During the ceremony, The units a and g correspond to the unit D described in embodiment 1, Units b and d correspond to unit H according to embodiment 1; The unit c corresponds to the unit Q according to embodiment 1; The unit e corresponds to the unit T described in form 1, The unit f corresponds to the unit A described in embodiment 1, The ratio of the units a+b+c+d+e+f+g is 1, and furthermore, the corresponding levels of A, D, H, Q, and T are within the ranges described in embodiment 1; or a salt thereof. [Form 4] 3. An amphiphilic carbohydrate compound according to any one of the preceding embodiments, wherein the units A, D, H, Q, and T, if present, are in any configuration in the polymer. [Form 5] 5. An amphiphilic carbohydrate compound according to any one of forms 1 to 4, wherein the level of acetylated units A is in the range of 0.5 to 26 mol % or 0.5 to 20 mol %, preferably 0.5 to 15 mol %, 0.5 to 10 mol %, or 0.5 to 5 mol %. [Form 6] 6. An amphiphilic carbohydrate compound according to any one of forms 1 to 5, wherein the level of hydrophobizing units H is in the range of 2 to 94.5 mol%, preferably 2 to 90 mol%, 5 to 80 mol%, 5 to 70 mol%, 5 to 50 mol%, or 10 to 30 mol%. [Form 7] 7. The amphiphilic carbohydrate compound according to any one of the preceding embodiments, wherein the level of quaternary amine units Q is in the range of 1 to 90 mol%, preferably 2 to 50 mol%, 5 to 30 mol%, 5 to 20 mol%, 5 to 15 mol%, or 5 to 10 mol%. [Form 8] 8. The amphiphilic carbohydrate compound of any one of forms 1 to 7, wherein A is in the range of 2 to 30 mol%, H is in the range of 14 to 24 mol%, and Q is in the range of 6 to 14 mol%, preferably A is in the range of 2 to 11 mol%, H is in the range of 10 to 24 mol%, and Q is in the range of 5 to 10 mol%. [Form 9] 9. An amphiphilic carbohydrate compound according to any one of forms 1 to 8, which is N-palmitoyl, N-monomethyl, N,N-dimethyl, N,N,N-trimethyl-6-O-glycol chitosan (GCPQ) in partially acetylated form. [Form 10] 10. A pharmaceutical composition comprising an amphipathic carbohydrate compound according to any one of Forms 1 to 9, a hydrophobic drug, and one or more pharmaceutically acceptable excipients. [Form 11] 11. The pharmaceutical composition of form 10, wherein the drug is an analgesic, antibiotic, anticoagulant, antidepressant, anticarcinogen, antitumor, anti-inflammatory, antihistamine, antiemetic, anxiolytic, anticonvulsant, antipsychotic, antiviral, antidiabetic, sedative, antihypertensive, or cardiovascular drug. [Form 12] 12. The pharmaceutical composition of claim 11, wherein the drug is a macrolide immunosuppressant, preferably, the drug is cyclosporin A, tacrolimus, or rapamycin. [Form 13] 13. The pharmaceutical composition of any one of Forms 10 to 12, wherein the concentration of the drug is from 0.01% to 0.2% w / v. [Form 14] A composition comprising a hydrophobic drug and an amphiphilic carbohydrate compound according to any one of Forms 1 to 9 for use in therapy. [Form 15] 15. Composition according to form 14 for use in the treatment of an autoimmune disorder, preferably for use in the treatment of rheumatoid arthritis, psoriasis, Crohn's disease, nephrotic syndrome, dry eye syndrome (DES) (also known as keratoconjunctivitis sicca (KCS)), vernal keratoconjunctivitis (VKC), eczema, atopic keratoconjunctivitis (AKC), Sjogren's syndrome, post-operative refractive surgery, corneal transplant, or contact lens intolerance. [Form 16] 16. The composition according to form 14 or 15, for use in therapy by intraocular administration. [Form 17] 16. The composition of form 14 or 15 for use in therapy by oral administration. [Form 18] A method of treatment comprising administering a compound of any one of Forms 1 to 9 or a pharmaceutical composition of any one of Forms 10 to 13 to a human or animal subject in need thereof. [Form 19] 19. The method of embodiment 18, wherein said treatment is treatment of an autoimmune disorder, preferably said treatment is treatment of rheumatoid arthritis, psoriasis, Crohn's disease, nephrotic syndrome, dry eye syndrome (DES) (also known as keratoconjunctivitis sicca (KCS)), vernal keratoconjunctivitis (VKC), eczema, atopic keratoconjunctivitis (AKC), Sjogren's syndrome, post-operative refractive surgery, corneal transplant, or contact lens intolerance. [Form 20] Depolymerization of carbohydrate compounds, Increasing, decreasing, or maintaining the level of acetylation; reacting the carbohydrate with a compound to add a hydrophobic side chain; and reacting the carbohydrate with a compound to quaternize the amine; 10. A method for forming an amphiphilic carbohydrate compound according to any one of aspects 1 to 9, comprising: [Form 21] 10. Use of a composition comprising a hydrophobic drug and an amphiphilic carbohydrate compound according to any one of Forms 1 to 9 in the manufacture of a medicament for use in therapy, preferably for the treatment of an autoimmune disorder, preferably for the treatment of rheumatoid arthritis, psoriasis, Crohn's disease, nephrotic syndrome, dry eye syndrome (DES) (also known as keratoconjunctivitis sicca (KCS)), vernal keratoconjunctivitis (VKC), eczema, atopic keratoconjunctivitis (AKC), Sjogren's syndrome, post-operative refractive surgery, corneal transplant, or contact lens intolerance.

Claims

1. An amphiphilic carbohydrate compound having an average molecular weight of 1 to 50 kDa and represented by the following formula (I): 【Chemistry 9】 During the ceremony, the level of units A is from 0.5 to 30 mole %; the level of units D is from 1 to 95.5 mole %; the level of units H is from 1 to 95.5 mole %; the level of units Q is from 3 to 97.5 mole %; the level of units T is from 0 to 94.5 mole %; R １ , R ２ , R ３ , R ４ , and R １０ are independently hydrogen or a sugar substituent selected from alkyl groups, alkenyl groups, alkynyl groups, aryl groups, acyl groups, glucose, galactose, fructose, and muramic acid in any linear, branched, or cyclic form, or oligopolyoxa C １ -C ３ alkylene units, optionally substituted with amines, amides, or alcohols; R ５ is a hydrophobic, substituted or unsubstituted, linear, branched or cyclic C ４－３０ Alkyl group, C ４－３０ Alkenyl group, C ４－３０ Alkynyl group, C ４－３０ Aryl group, amine group, C ４－３０ Amide group, C ４－３０ Alcohol group, or C ３－３０ is an acyl group, R ６ , R ７ , and R ８ are independently any alkyl, alkenyl, alkynyl, aryl, or acyl group in any linear, branched, or cyclic form; R ９ is may or may not be present and, if present, is a substituted or unsubstituted alkyl group, a substituted or unsubstituted amine group, or a substituted or unsubstituted amide group; R １１ is a substituted or unsubstituted alkyl group, a substituted or unsubstituted ether group, a substituted or unsubstituted alkene group, or hydrogen, and further R １２ is a substituted or unsubstituted alkyl group, a substituted or unsubstituted ether group, or a substituted or unsubstituted alkene group, R １３ is a substituted or unsubstituted alkyl group, a substituted or unsubstituted ether group, a substituted or unsubstituted alkene group, or hydrogen, or an amphiphilic carbohydrate compound or a salt thereof.

2. The amphiphilic carbohydrate compound or salt thereof of claim 1, wherein the proportion of units A+D+H+Q+T is equal to 100%, and further, the level of units A is controlled in combination with the level of units H so as to increase the solubilization of the hydrophobic drug to be encapsulated by the amphiphilic carbohydrate compound.

3. The following formula 【Chemistry 10】 and During the ceremony, the level of acetylation units A is between 0.5 and 30%; the level of deacetylation units D is from 1 to 95.5%; the level of hydrophobizing units H is from 1 to 95.5%; the level of quaternary amine units Q is from 3 to 97.5%; R １ , R ２ , R ３ , and R ４ are independently selected from alkyl groups, alkenyl groups, alkynyl groups, aryl groups, acyl groups, any linear, branched, or cyclic form, sugar substituents selected from glucose, galactose, fructose, and muramic acid, or oligopolyoxa C １ -C ３ alkylene units, optionally substituted with amines, amides, or alcohols; R ５ is a hydrophobic, substituted or unsubstituted, linear, branched or cyclic C ４－３０ Alkyl group, C ４－３０ Alkenyl group, C ４－３０ Alkynyl group, C ４－３０ Aryl group, amine group, C ４－３０ Amide group, C ４－３０ Alcohol group, or C ３－３０ an acyl group, and R ６ , R ７ , and R ８ are independently any alkyl, alkenyl, alkynyl, aryl, or acyl group in any linear, branched, or cyclic form; 3. The amphiphilic carbohydrate compound or salt thereof according to claim 1 or 2, wherein all percentages are given as mole percentages.

4. The following formula 【Chemistry 11】 and During the ceremony, The units a and g correspond to the unit D according to claim 1, The units b and d correspond to the unit H according to claim 1, The unit c corresponds to the unit Q according to claim 1, The unit e corresponds to the unit T in claim 1, The unit f corresponds to the unit A in claim 1, The ratio of the units a+b+c+d+e+f+g is 1, and further 2. The amphipathic carbohydrate compound or salt thereof of claim 1, wherein the corresponding levels of A, D, H, Q, and T are within the ranges set forth in claim 1.

5. 3. The amphiphilic carbohydrate compound or salt thereof of claim 1 or 2, wherein the units A, D, H, Q, and T (if present) are in any configuration in the polymer.

6. 6. The amphiphilic carbohydrate compound or salt thereof according to any one of claims 1 to 5, wherein the level of acetylated units A is in the range of 0.5 to 26 mol % or 0.5 to 20 mol %.

7. 6. The amphiphilic carbohydrate compound or salt thereof according to any one of claims 1 to 5, wherein the level of acetylated units A is in the range of 0.5 to 15 mol%, 0.5 to 10 mol%, or 0.5 to 5 mol%.

8. 8. An amphiphilic carbohydrate compound or salt thereof according to any one of claims 1 to 7, wherein the level of hydrophobizing units H is in the range of 2 to 94.5 mole %.

9. 8. The amphiphilic carbohydrate compound or salt thereof according to any one of claims 1 to 7, wherein the level of hydrophobizing units H is in the range of 2 to 90 mol%, 5 to 80 mol%, 5 to 70 mol%, 5 to 50 mol%, or 10 to 30 mol%.

10. 10. An amphiphilic carbohydrate compound or salt thereof according to any one of claims 1 to 9, wherein the level of quaternary amine units Q is in the range of 1 to 90 mole %.

11. 10. The amphiphilic carbohydrate compound or salt thereof according to any one of claims 1 to 9, wherein the level of quaternary amine units Q is in the range of 2 to 50 mol%, 5 to 30 mol%, 5 to 20 mol%, 5 to 15 mol%, or 5 to 10 mol%.

12. 12. An amphiphilic carbohydrate compound or salt thereof according to any one of claims 1 to 11, wherein A is in the range of 2 to 30 mol%, H is in the range of 14 to 24 mol%, and Q is in the range of 6 to 14 mol%.

13. 12. An amphiphilic carbohydrate compound or salt thereof according to any one of claims 1 to 11, wherein A is in the range of 2 to 11 mol%, H is in the range of 10 to 24 mol%, and Q is in the range of 5 to 10 mol%.

14. 14. The amphiphilic carbohydrate compound or salt thereof according to any one of claims 1 to 13, which is N-palmitoyl, N-monomethyl, N,N-dimethyl, N,N,N-trimethyl-6-O-glycol chitosan (GCPQ) in partially acetylated form.

15. A pharmaceutical composition comprising an amphipathic carbohydrate compound or a salt thereof according to any one of claims 1 to 14, a hydrophobic drug, and one or more pharmaceutically acceptable excipients.

16. 16. The pharmaceutical composition of claim 15, wherein the drug is an analgesic, antibiotic, anticoagulant, antidepressant, anticarcinogen, antitumor, anti-inflammatory, antihistamine, antiemetic, antianxiety, anticonvulsant, antipsychotic, antiviral, antidiabetic, sedative, antihypertensive, or cardiovascular drug.

17. 17. The pharmaceutical composition of claim 16, wherein the drug is a macrolide immunosuppressant.

18. 17. The pharmaceutical composition of claim 16, wherein the drug is cyclosporin A, tacrolimus, or rapamycin.

19. 19. A pharmaceutical composition according to any one of claims 15 to 18, wherein the concentration of the drug is from 0.01 to 0.2% w / v.

20. 15. A composition for use in therapy comprising a hydrophobic drug and an amphipathic carbohydrate compound or salt thereof according to any one of claims 1 to 14.

21. 21. The composition of claim 20 for use in treating an autoimmune disorder.

22. 21. The composition of claim 20 for use in treating rheumatoid arthritis, psoriasis, Crohn's disease, nephrotic syndrome, dry eye syndrome (DES) (also known as keratoconjunctivitis sicca (KCS)), vernal keratoconjunctivitis (VKC), eczema, atopic keratoconjunctivitis (AKC), Sjogren's syndrome, post-operative refractive surgery, corneal transplant, or contact lens intolerance.

23. 23. A composition according to any one of claims 20 to 22 for use in therapy by intraocular administration.

24. 23. A composition according to any one of claims 20 to 22 for use in therapy by oral administration.

25. 20. A compound according to any one of claims 1 to 14 or a salt thereof or a pharmaceutical composition according to any one of claims 15 to 19, for administration to a human or animal subject in need of treatment.

26. 26. The compound or salt thereof or pharmaceutical composition of claim 25, wherein the treatment is treatment of an autoimmune disorder.

27. 26. The compound or salt thereof or pharmaceutical composition according to claim 25, wherein the treatment is treatment of rheumatoid arthritis, psoriasis, Crohn's disease, nephrotic syndrome, dry eye syndrome (DES) (also known as keratoconjunctivitis sicca (KCS)), vernal keratoconjunctivitis (VKC), eczema, atopic keratoconjunctivitis (AKC), Sjogren's syndrome, post-operative refractive surgery, corneal transplant, or contact lens intolerance.

28. Depolymerization of carbohydrate compounds, Increasing, decreasing, or maintaining the level of acetylation; reacting the carbohydrate with a compound to add a hydrophobic side chain; and reacting the carbohydrate with a compound to quaternize the amine; 15. A method for forming an amphiphilic carbohydrate compound or a salt thereof according to any one of claims 1 to 14, comprising:

29. 15. Use of a composition comprising a hydrophobic drug and an amphipathic carbohydrate compound or salt thereof according to any one of claims 1 to 14 in the manufacture of a drug for use in therapy.

30. 30. The use according to claim 29, wherein the treatment is treatment of an autoimmune disorder.

31. 31. The use of claim 30, wherein the treatment is treatment of rheumatoid arthritis, psoriasis, Crohn's disease, nephrotic syndrome, dry eye syndrome (DES) (also known as keratoconjunctivitis sicca (KCS)), vernal keratoconjunctivitis (VKC), eczema, atopic keratoconjunctivitis (AKC), Sjogren's syndrome, post-operative refractive surgery, corneal transplant, or contact lens intolerance.

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