amphiphilic carbohydrate compounds

Abstract

The present invention relates to acetylated amphiphilic carbohydrate compounds based on glycol chitosan, with an average molecular weight of 1 to 50 kDa, and the level of acetylation can be varied. These compounds can be formulated with hydrophobic compounds, such as drugs. The degree of acetylation of the carbohydrate compound is optimized to maximize drug solubilization. These compounds are useful in therapeutic formulations with drugs.

Description

[Technical Field]

[0001] This invention relates to acetylated amphiphilic carbohydrate compounds and formulations thereof with hydrophobic drugs. [Background technology]

[0002] Amphiphilic carbohydrate compounds are useful in the formulation of drugs, particularly hydrophobic drugs. Patent Document 1 discloses a carbohydrate polymer having hydrophobic and hydrophilic pendant groups suitable for solubilizing compounds having hydrophobic properties, for example. This carbohydrate polymer has the following general formula

[0003] [ka] It may have.

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

[0005] Numerous studies have been conducted on the acetylation of chitosan and its derivatives. However, the effects of acetylation on the self-assembly and drug encapsulation of chitosan amphiphilic derivatives have 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. Since hydrophobicity promotes self-assembly and drug encapsulation, it is expected that highly hydrophobic (higher degree of acetylation) chitosan amphiphilic materials will self-assemble more easily and encapsulate higher levels of hydrophobic compounds (Non-Patent Literature 1). Increased hydrophobicity of other polymers also increases their ability to self-assemble, encapsulate hydrophobic compounds, and deliver them via the oral route (Non-Patent Literature 2). However, the relationship between hydrophobicity (measured by water solubility) and the acetylation level of chitosan is complex. As such, it is not possible to predict that the acetylation level on chitosan amphiphilic materials will have a positive effect on the encapsulation efficiency of hydrophobic drugs.

[0006] Based on the above, when preparing amphiphilic and self-assembling chitosan derivatives for use as pharmaceuticals or excipients in other products, it is important to correctly understand the relationship between the acetylation of chitosan and the resulting hydrophobicity (decreased water solubility) of the chitosan derivative.

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

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

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

[0010] As is clear from the above, existing literature lacks clear guidance on the optimal acetylation level for preparing hydrophobic chitosan amphiphilic derivatives that have good ability to encapsulate hydrophobic compounds. [Advanced Technology Documents] [Chartered documents]

[0011]

Patent Document 1

Non-licensed literature

[0012]

Non-licensed literature 1

Non-licensed Document 4

Non-licensed Document 5

[0013] The present invention is based on research on the self-assembly of amphiphilic chitosan derivatives and, thus, the effect of acetylation on the encapsulation of drugs. An optimized amphiphilic carbohydrate compound for encapsulating hydrophobic drugs is provided.

Means for Solving the Problems

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

[0015]

Chemical formula

[0016] A second aspect of the present invention provides a pharmaceutical composition comprising an amphiphilic carbohydrate compound according to the first aspect of the present invention, a hydrophobic drug, and one or more pharmaceutically acceptable excipients.

[0017] A third aspect of the present invention provides a composition for therapeutic use comprising an amphiphilic carbohydrate compound according to the first aspect of the present invention and a hydrophobic drug.

[0018] According to a fourth aspect of the present invention, a method for forming an amphiphilic carbohydrate compound according to a first aspect of the present invention is provided, and this method is Depolymerization of carbohydrate compounds; To increase, decrease, or maintain the level of acetylation; Reacting a carbohydrate with a compound for adding a hydrophobic side chain; and Reacting a compound that produces a quaternary ammonium group with a carbohydrate; Includes.

[0019] Furthermore, an agricultural chemical composition comprising an amphiphilic carbohydrate compound, an agricultural chemical agent, and one or more agriculturally acceptable excipients according to a first aspect of the present invention is also provided.

[0020] Furthermore, a method for controlling fungal contamination using an agricultural chemical composition according to a fifth aspect of the present invention is also provided.

[0021] It is expected that increasing the degree of acetylation of amphiphilic carbohydrate compounds such as quaternary ammonium palmitoyl glycol chitosan (GCPQ) will enable stronger hydrophobic interactions with hydrophobic molecules, and therefore, better encapsulation of hydrophobic drugs. However, the inventors unexpectedly observed the opposite effect. This 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 method for increasing the solubilization of hydrophobic compounds. [Brief explanation of the drawing]

[0022] [Figure 1] This figure shows the levels of acetylation (DA) obtained using various equivalent amounts of acetic anhydride. [Figure 2] This figure shows the solubilization level of cyclosporine A as a function of the acetylation level, palmitoylation level, and quaternization level, respectively. [Figure 3] This figure shows the observed solubilization levels of cyclosporine A compared to the predicted values ​​from a mathematical model. [Figure 4] This figure shows the predicted solubilization level of cyclosporine A as a function of the acetylation level, palmitoylation level, and quaternization level, respectively, in a theoretical polymer. [Modes for carrying out the invention]

[0023] As described above, the present invention describes amphiphilic carbohydrate compounds or salts thereof with an average molecular weight of 1 to 50 kDa represented by the following formula (I), which are reproduced below for ease of reference.

[0024] [ka] In this formula: * is used to represent a continuous polymer chain; The level of unit A (acetylation unit) ranges from 0.5% to 30 mol%; The level of unit D (deacetylation unit) ranges from 1% to 95.5 mol%; The level of the unit H (hydrophobic unit) ranges from 1% to 95.5 mol%; The level of unit Q (quaternary amine unit) ranges from 3% to 97.5 mol%; The level of unit T (tertiary amine unit) ranges from 0% to 94.5 mol%.

[0025] All percentages refer to mole percentages.

[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 take on any configuration in amphiphilic carbohydrate compounds. Therefore, their configuration may be completely random, or they may be in the form of block copolymers such as ADHQADHQ.

[0027] This invention provides a method for maximizing the solubilization of a compound by changing the acetylation level of a polymer.

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

[0029] In a preferred embodiment 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 an alternative preferred embodiment, A is in the range of 2 to 20 mol%, preferably 2 to 15 mol%, more preferably 2 to 10 mol%, even more preferably 2 to 5 mol%, or 2 to 4 mol%.

[0031] In an alternative preferred embodiment, 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 a preferred embodiment of the present 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%, and even more preferably in the range of 65% to 75 mol%.

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

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

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

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

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

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

[0039] Amphiphilic carbohydrates may be accompanied by salts. For example, the salts may include chlorides, iodides, acetates, or glucuronide salts.

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

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

[0042] R 1 , R 2 , R 3 , R 4 , and R 10 These are independently hydrogen, or alkyl, alkenyl, alkynyl, aryl, acyl groups, sugar substituents selected from glucose, galactose, fructose, and muramic acid in any linear, branched, or cyclic form, or oligopolyoxa C1-C3 alkylene units, which are optionally substituted with amines, amides, or alcohols. Preferably, these groups are independently selected from hydrogen, substituted or unsubstituted alkyl groups, substituted or unsubstituted ether groups, or substituted or unsubstituted alkene groups.

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

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

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

[0046] R 1 , R 2 , R 3 , R 4 , and R 10 This may also 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 All of the above may be CH2OCH2CH2OH or CH2CH2OH.

[0048] R 1 , R 2 , R 3 , R 4 , and R 10 All of them may be H.

[0049] Typically, R 5 is hydrophobic of , substituted or unsubstituted, linear, branched or cyclic forms of C 4-30 Alkyl 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 base is preferably C 4-30 Alkyl alkyl groups, C 4-30 Alkenyl groups such as alkenyl groups, C 4-30 Alkynyl groups such as alkynyl groups, C 5-20 Aryl groups such as aryl groups, sterols (e.g., cholesterol), and two or more C groups. 4- A polycyclic hydrophobic group having a C8 ring structure, two or more C 4- Polycyclic hydrophobic groups having a C8 heteroatomic ring structure, polyoxa C, etc. 1-It is selected from a substituent or an unsubstituted group which is a C4 alkylene group, or a hydrophobic polymer substituent such as a poly(lactic acid) group, a poly(lactide-co-glycolide) group, or a poly(glycolic acid) group. R 5 The group is a linear, branched, or cyclic group.

[0051] R 5 Preferred examples of the group include those represented by the formula CH3(CH2) n -CO-, or CH3(CH2) n -, or an alkene acid CH3(CH2) p -CH=CH-(CH2) q -CO-, where n is from 4 to 30, more preferably from 6 to 20, 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 substituent is bonded to the chitosan monomer unit via an amide group (including pendant NH in the formula), for example, represented by the formula CH3(CH2) n CO-, where n is from 2 to 28. Examples of the amide group are formed by the bonding of a carboxylic acid to the amine group of chitosan. Preferred examples are fatty acid derivatives 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), etc., which are CH3(CH2) n COOH.

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

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

[0054] Hydrophilic groups are those that are fully hydrated by water and bond with water at the molecular level. Further nonionic hydrophilic groups are R 6 , R 7 , and R 8 Assuming that is equal to CH2O-Y (where Y is a hydrophilic substituent), NR 6 R 7 R 8 It can be replaced by... In that case, both hydrophilic substituents on the carbohydrate polymer are mono and oligohydroxy C 1- C6 alkyl, mono, and oligohydroxy substituted C6 alkyl, mono, and oligohydroxy substituted C6 2- C6 acyl, C6 in which one or more hydroxyl groups are optionally substituted on an alkoxy or alkylene group. 1- C2 alkoxyalkyl, oligo or poly-(oxaC) 1- C2 alkylene), preferably polyethylene glycol containing up to 120 ethylene oxide units (i.e., molecular weight of 5000), and optionally hydroxysubstituted C 1- C4 alkyl (oligo or polyoxa C 1- C3 alkylene), preferably selected from oligo or polyglycerol ether; where NR 6 R 7 R 8 The substituents are attached to the polysaccharide unit via ether bonds. The acyl group may contain an alkyl group, an alkenyl group, or an alkynyl group.

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

[0056] R 9 The base may or may not exist in the general formula. 9 These may or may not be present, and if present, they are substituted or unsubstituted alkyl groups, substituted or unsubstituted amine groups, or substituted or unsubstituted amide groups.

[0057] If not present, a quaternary ammonium functional group directly bonded to the monomer unit of the chitosan skeleton is provided. 9 If a group exists, for example, -(CH2) n- As represented by, an unsubstituted or substituted alkyl group (e.g., C 1-10 It may also be an alkyl group, where n is preferably 1 to 4. 9 N + R 6 R 7 R 8 A preferred example of a substituent is a b-unit amine substituent with betaine (-OOC-CH2-N + -(CH3)3) is bonded to -NH-CO-CH2-N + R 6 R 7 R 8 It is provided by giving amide groups such as those in the above.

[0058] R 11 is a substituted or unsubstituted alkyl group, a substituted or unsubstituted ether group, a substituted or unsubstituted alkene group, or hydrogen. Preferably, R 11 is hydrogen, and C 1-10 Selected from substituted or unsubstituted alkyl groups. 11 It may be linear or branched. Preferably, R 11 This is an alkyl group selected from a methyl group, an ethyl group, or a propyl group, or 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. Preferably, R 12 C 1-10 Selected from substituted or unsubstituted alkyl groups. 12 It may be linear or branched. Preferably, R 12 This is an alkyl group selected from a methyl group, an ethyl group, or a propyl group, or an OH-substituted alkyl group, preferably of the formula CH2CH2OH.

[0060] Typically, R 12 C 1-10 It is an alkyl group. 12 It may be linear or branched. Preferably, R 12 The group 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. Preferably, R 13 is hydrogen, and C 1-10 Selected from substituted or unsubstituted alkyl groups. 13 It may be linear or branched. Preferably, R 13 is selected from a methyl group, an ethyl group, or a propyl group, or an OH-substituted alkyl group, preferably of the formula CH2CH2OH. Most preferably, R 13 It is hydrogen.

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

[0063] Amphiphilic carbohydrate compounds may also have further targeting groups, such as peptides, antibodies, and other ligands, e.g., folic acid and transferrin ligands, which can enable the polymer to target endogenous receptors and thus allow its drug payload to target such endogenous receptors at pathological sites.

[0064] In preferred embodiments of the present invention, the amphiphilic carbohydrate compound is a partially deacetylated form of N-palmitoyl,N-monomethyl,N,N-dimethyl,N,N,N-trimethyl-6-O-glycol chitosan (GCPQ). This is known to be an amorphous compound (Non-Patent Literature 9) and is therefore not bound by the increase in crystallinity observed when acetylated chitosan is converted to deacetylated chitosan. As shown herein, 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.); Formil; Acyl (e.g., C 1-7 Alkylacyl, C 5-20 Aryl acyls, etc.); acyl halides; carboxyl; esters; acyloxy; amides; acylamides; thioamides; tetrazolyl; amino; nitro; nitroso; azide; cyano; isocyanos; cyanates; isocyanates; thiocyano; isothiocyano; sulfhydryl; thioethers (e.g., C 1-7 Alkylthio etc.); sulfonic acid; sulfonate; sulfone; sulfonyloxy; sulfinyloxy; sulfamino; sulfonamino; sulfinamino; sulfamyl; sulfonamide; C 1-7 Alkyl (for example, unsubstituted C) 1-7 Alkyl 、 C 1-7 Haloalkyl 、 C 1-7 Hydroxyalkyl 、 C 1-7 Carboxyalkyl 、 C 1-7 aminoalkyl、 C 5-20 Aryl-C 1-7 Contains alkyl groups, etc.); C 3-20 Heterocycline; and C 5-20 Aryl (for example, C 5-20 Carboaryl, C 5-20 Heteroaryl, C 1-7 Alkyl-C 5-20 Aryl, and C 5-20 Examples include groups such as haloaryl compounds.

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

[0066] As used herein, the term "carbocyclic ring" refers to a ring in which all of the ring atoms are carbon atoms.

[0067] As used herein, the term "carbon aromatic ring" refers to an aromatic ring in which all ring atoms are carbon atoms.

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

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

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

[0071] [ka] During the ceremony, The level of acetylated unit A ranges from 0.5% to 30 mol%; The level of deacetylation unit D ranges from 1% to 95.5 mol%; The level of hydrophobic units H ranges from 1% to 95.5 mol%; The level of quaternary amine unit Q ranges from 3% to 97.5 mol%; The other groups are as previously defined, and the preferred percentages mentioned above apply.

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

[0073] [ka] During the ceremony, Units a and g both correspond to unit D as described in claim 1; Units b and d both correspond to unit H as described in claim 1; The unit c corresponds to the unit Q described in claim 1; The unit e corresponds to the unit T described in claim 1; Unit f corresponds to unit A as described in claim 1; The ratio of units a+b+c+d+e+f+g is 1; furthermore, The corresponding levels of A, D, H, Q, and T are within the range described in claim 1; Or its salt.

[0074] One embodiment of the present invention provides a method for forming an amphiphilic carbohydrate compound of general formula (I), the method being: A step of depolymerizing a carbohydrate polymer to form a depolymerized carbohydrate; A step of reacting a depolymerized carbohydrate with a first reactive compound in varying equivalent amounts to increase, decrease, or maintain the existing acetylation level; The steps of reacting a depolymerized carbohydrate with a second reactive compound to form hydrophobic side groups on the carbohydrate skeleton, thereby forming a hydrophobically substituted depolymerized carbohydrate; and A step of adding a third reactive compound to a carbohydrate compound having more, less, or the same level of acetylation to quaternize the amine group, 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 among HCl, H2SO, HNO3, or HF.

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

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

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

[0081] The second reactive compound that forms a 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, and alkynyl compounds, cyclic or non-aromatic halides, acyl chlorides, anhydrides, N-hydroxysuccinimide, and other activated acyl compounds that can be attacked on the Cl carbon by compounds capable of nucleophilic attack; nucleophilic attack means that a compound attacks an atom with a low electron density. The acyl group may also have an alkyl group, an alkenyl group, or an alkynyl group.

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

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

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

[0085] Typically, the third reactive compound is any linear or branched, substituted or unsubstituted, or cyclic alkyl, alkenyl, alkynyl, aryl, amine, amide, alcohol, or acyl group: C1-C 30 ;C1-C 12 ;C1-C6; or C1: may also be used.

[0086] Typically, the organic group of an 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-mentioned amphiphilic carbohydrate compound, a hydrophobic drug, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier is well known to those skilled in the art and includes, but is not limited to, 0.1 M, or preferably 0.05 M, phosphate buffer or 0.9% physiological saline. In addition, such a pharmaceutically acceptable carrier may be an aqueous solution or a non-aqueous solution, a suspension, or an emulsion.

[0089] Examples of non-aqueous solvents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcohol / aqueous solutions, emulsions, or suspensions, and include physiological saline and buffering media. Parenteral solvents include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, Ringer's lactate solution, or fixing oils. Preservatives and other additives, such as antimicrobial 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] Hydrophobic drugs are drugs that are poorly soluble in aqueous media 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 could mean a drug with a solubility of 0.1 mg / mL in water. -1 It means less than a certain amount of drugs.

[0091] Hydrophobic drugs are typically encapsulated by amphiphilic carbohydrate compounds. Hydrophobic drugs may include analgesics, antibiotics, anticoagulants, antidepressants, anticarcinogens, antitumor substances, anti-inflammatory drugs, antihistamines, antiemetics, anxiolytics, anticonvulsants, antipsychotics, antivirals, antidiabetics, sedatives, antihypertensives, or cardiovascular drugs.

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

[0093] Hydrophobic drugs are preferably steroids. Preferred drugs include prednisolone, estradiol, testosterone, drugs having a polycyclic structure and lacking polar groups such as paclitaxel, and drugs such as etoposide.

[0094] Hydrophobic drugs are preferably macrolide immunosuppressants. Macrolide drugs are highly valuable as antimicrobial agents, particularly as antibacterial and antifungal agents, and as immunomodulators. In the latter category, they are particularly useful in the treatment of autoimmune disorders. Such autoimmune disorders may include rheumatoid arthritis, psoriasis, Crohn's disease, nephrotic syndrome, or autoimmune dry eye syndrome.

[0095] Preferred macrolide drugs include rapamycin (also known as sirolimus), cyclosporine A, tacrolimus, and everolimus, with cyclosporine A (CSA), rapamycin, or tacrolimus being preferred. CSA is a potent immunosuppressant that has shown potential applications in ophthalmology for the treatment of various eye disorders, including corneal transplant rejection and keratoconjunctivitis sicca and uveitis. As discussed further previously, due to its poor water solubility, CSA is currently formulated as an eye 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 to cover coronary stents.

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

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

[0098] In one embodiment of the present invention, the compound cyclosporine A was solubilized at concentrations ranging 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 ranging 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 ranging 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 composition of the present invention, the drug is preferably present at a concentration of less than 2% w / v, and preferably in the range of 0.001 to 1% w / v.

[0102] When the concentration is expressed in %w / v, this means the amount (g) of solid contained in 100mL of the composition.

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

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

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

[0106] When tablets are used for oral administration, typical carriers include typical lubricants such as sucrose, lactose, mannitol, maltitol, dextran, corn starch, and magnesium stearate; preservatives such as parabens and sorbin; antioxidants such as ascorbic acid; α-tocopherols, cysteine, disintegrants, or binders. When administered orally as capsules, effective diluents include lactose and dry corn starch. 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 also contain sweeteners or flavorings. Suppositories can be prepared by mixing the compound of the present invention with a suitable non-irritating excipient, such as one that is solid at room temperature but becomes liquid at intestinal temperature and melts in the rectum to release active ingredients such as cocoa butter and polyethylene glycol.

[0107] The pharmaceutical composition may be formulated for any route of administration, such as oral, parenteral, nasal, inhalation, or topical administration, and is particularly suitable for topical intraocular administration.

[0108] The dosage can be determined by age, weight, time of administration, method of administration, combination of drugs, clinical status or the severity of the actual condition of the patient being treated, and other factors. The daily dose may vary depending on the patient's condition and weight, type or active ingredient, and route of administration, but for oral use, 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, an agricultural composition is provided comprising an amphiphilic carbohydrate compound according to a first aspect of the present invention, an agricultural chemical agent, and an agriculturally acceptable excipient.

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

[0111] In relation to the present invention, the agricultural chemical agent is a chemical substance suitable for use in agriculture, and is typically an insecticide, herbicide, fungicide, or nematicide. In the present invention, the agricultural chemical agent is preferably a fungicide.

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

[0113] Examples 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 Decomposed glycol chitosan (dGC, MW11.4kDa) was dissolved in 10% v / v acetic acid to a concentration of 16.7 mg / mL, and several molar equivalents (2, 4, 8, 10, 15, or 20) of acetic anhydride were added. This solution was vibrated at room temperature for 5 hours, the pH was adjusted to 8-9 with powdered NaOH, dialyzed for 24 hours (molecular weight cutoff of the dialysis bag -MWCO- = 3.5kDa relative to water), 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] Deacetylation of dGC Decomposed glycol chitosan (dGC, MW11.4kDa) was added to a boiling solution of 45% w / v NaOH, and the reaction was allowed to proceed under nitrogen for 1 hour. After that, the pH was adjusted to 7 with HCl. Next, the solution was dialyzed (H2O, MWCO=3.5kDa, 24 hours) and freeze-dried.

[0116] Palmitoylation of dGC Palmitoylation was carried out as described above, with some 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 N-hydroxysuccinimide palmitate were added relative to the molar concentration of the free amine (the degree of deacetylation determined by NMR), and the reaction was allowed to proceed under protection from light for 16 hours. The product was precipitated and washed with acetone.

[0117] Classification of pGC into four levels As previously described, quaternization was performed. Briefly, pGC, NaOH, and NaI were dissolved in NMP to concentrations of 15.1, 16.3, and 18.6 mg / mL, respectively. These solutions were combined sequentially in a ratio of 7:2:1, and after adding the NaI solution, the mixture was purged with nitrogen for 15 minutes. MeI was added (1.5 mL / g pGC), and the reaction was carried out under a nitrogen atmosphere at 37°C for 2 hours with magnetic stirring. GCPQ was precipitated by adding it to 6 vol of methyl tert-butyl ether (MTBE), washed three times with 1 vol of MTBE, dialyzed (H2O, MWCO = 3.5 kDa, 24 hours), ion-exchanged with 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 freeze-dried powder.

[0118] Determination of polymer modification level The degree of acetylation (DA) was determined by 1H 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 (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 group) and 0.35–3.43 ppm (4.5 protons per half quaternary amine). These ranges are representative and can be more clearly defined by the relevant peaks and troughs (Figure 1).

[0119] Encapsulation of cyclosporine A (CsA) GCPQ (7.5 mg) was dispersed in glycerol (3.1% w / v, 1 mL) while being vibrated for >2 hours. Next, this dispersion was used to rehydrate 2 mg of cyclosporine, which had been previously dissolved in methanol, aliquot, and dried under nitrogen. The resulting solution was vibrated 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] Encapsulation of tacrolimus TAC powder was dissolved in anhydrous 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 dry film was rehydrated with 1.5 mL of distilled water and mixed vigorously for 30 minutes to disperse the film in the solvent. The formulation was adjusted to pH 4.0–5.0 using 1.0 M NaOH on a calibrated pH meter, 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] Rapamycin encapsulation RAP powder was dissolved in anhydrous 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 mixed together, and 0.4 mL of methanol was added to each mixture to ensure complete dissolution of all components. All preparations were mixed together and placed in a Savant Vacuum Evaporator at 45°C and spun under vacuum for 5 hours until a thin, dry film formed. The dry film was rehydrated with 1 mL of distilled water and mixed vigorously for 30 minutes to disperse the film in the solvent. The mixture was then sonicated in an ice bath for 3 minutes at 30% of its maximum output using an MSE Soniprep 150 sonicator. The formulation was adjusted to pH 4.0–5.0 using 1.0 M NaOH in a calibrated pH meter, and then subjected to a simulated sterile filtration step using a 0.22 μm PES sterile filter. Next, all formulations were 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 precisely controlled within the tested range (2 to 20 molar equivalents of acetic anhydride (Ac2O)), providing a degree of acetylation (DA) of 5.5 to 16.4%, where DA = 0.0059 * Ac2O + 0.0449R 2 A linear correlation of 0.9976 was obtained as a result, highlighting the accuracy 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 varied (Table 4). When the concentration of CsA [CsA] was plotted against DA, DP, and DQ of the polymers being tested, it showed a negative correlation with DA and no significant correlation with other polymer properties (Table 5). Therefore, it was shown that DA has a significant effect on encapsulation.

[0124] [Table 4]

[0125] [Table 5] Mathematical model While DA has the most significant impact on encapsulation, DP and DQ were incorporated into the model to refine their predictive power. Using the sum of the products of each polymer variable and coefficient, as well as a constant, each polymer provides 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 are -2.21, 0.44, and -8.07, respectively, and the R of the model 2 The value was 1, suggesting that [CsA] increases as DP increases and DA and DQ decrease.

[0126]

number

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

[0128] [Table 7] conclusion The hypothesis of this study was that increasing the degree of acetylation of GCPQ would enable stronger hydrophobic interactions with hydrophobic molecules, and therefore increase encapsulation; however, 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, while increasing the acetylation level to 37.6% significantly reduced drug encapsulation.

[0130] Although DP and DQ also changed in the tested polymers, these parameters can be reliably excluded as strong explanations for the observations, as there was no clear trend between encapsulation and properties. The only clear trend was the negative correlation between DA and encapsulation, one explanation for which is that acetyl groups on the polymer contribute little to hydrophobic interactions but help sterically hinder the polymer folding necessary for the efficient encapsulation of small hydrophobic compounds.

[0131] Previous studies have shown that DP and DQ influence the encapsulation of hydrophobic compounds in polymer nanoassemblies. This application is the first example in which systematically altered DA has been studied for 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, leading to more efficient drug delivery.

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

Claims

1. An amphiphilic carbohydrate compound having an average molecular weight of 1 to 50 kDa, represented by the following formula (I): 【Transformation 6】 During the ceremony, The level of unit A ranges from 0.5 to 30 mol%, The level of unit D ranges from 1 to 95.5 mol%, The level of unit H is from 5 to 50 mol%, The level of unit Q ranges from 3 to 97.5 mol%, The level of unit T ranges from 0 to 94.5 mol%, The proportion of units A + D + H + Q + T is equal to 100%, and furthermore, the level of unit A is controlled in combination with the level of unit H so as to increase the solubilization of the hydrophobic drug that will be encapsulated by the amphiphilic carbohydrate compound. R １ , R ２ , R ３ , R ４ , and R １０ This can be any hydrogen, or any linear, branched, or cyclic alkyl, alkenyl, alkynyl, aryl, or acyl group, sugar substituent selected from glucose, galactose, fructose, and muramic acid, or oligopolyoxa C １ -C ３ It is an alkylene unit, optionally substituted with an amine, amide, or alcohol. R ５ is CH ３ (CH ２ ) ｎ -CO-, or CH ３ (CH ２ ) ｎ -, or CH ３ (CH ２ ) ｐ -CH=CH-(CH ２ ) ｑ -CO-, where n is from 4 to 30, and p and q are the same or different and are from 4 to 16, R ６ , R ７ , and R ８ This is independently any alkyl group, alkenyl group, alkynyl group, aryl group, or acyl group in any linear, branched, or cyclic form. R ９ These may or may not be present, and if present, they are substituted or unsubstituted alkyl groups, substituted or unsubstituted amine groups, or substituted or unsubstituted amide groups. R １１ is a substituted or unsubstituted alkyl group, a substituted or unsubstituted ether group, or a substituted or unsubstituted alkene group, or hydrogen, and further, R １２ This is a substituted or unsubstituted alkyl group, a substituted or unsubstituted ether group, or a substituted or unsubstituted alkene group. R １３ amphiphilic carbohydrate compounds or salts thereof, wherein is a substituted or unsubstituted alkyl group, a substituted or unsubstituted ether group, a substituted or unsubstituted alkene group, or hydrogen.

2. The following formula 【Transformation 7】 It has, During the ceremony, The level of acetylated unit A ranges from 0.5 to 30%. The level of deacetylation unit D ranges from 1 to 95.5%. The level of hydrophobic units H is between 5 and 50%. The level of quaternary amine unit Q ranges from 3 to 97.5%. R １ , R ２ , R ３ , and R ４ This independently includes any linear, branched, or cyclic alkyl, alkenyl, alkynyl, aryl, acyl group, sugar substituent selected from glucose, galactose, fructose, and muramic acid, or oligopolyoxa C. １ -C ３ It is an alkylene unit, optionally substituted with an amine, amide, or alcohol. R ５ CH ３ (CH ２ ) ｎ -CO-, or CH ３ (CH ２ ) ｎ -, or CH ３ (CH ２ ) ｐ -CH=CH-(CH ２ ) ｑ -CO-, where n is from 4 to 30, p and q are the same or different, from 4 to 16, and further, R ６ , R ７ , and R ８ This is independently any alkyl group, alkenyl group, alkynyl group, aryl group, or acyl group in any linear, branched, or cyclic form. Herein, all percentages are given as mole percentages, the amphiphilic carbohydrate compound or salt thereof according to claim 1.

3. The following formula 【Transformation 8】 It has, During the ceremony, Units a and g correspond to unit D as described in claim 1, Units b and d correspond to unit H as described in claim 1, Unit c corresponds to unit Q as described in claim 1, The unit e corresponds to the unit T described in claim 1, Unit f corresponds to unit A as described in claim 1, The ratio of units a + b + c + d + e + f + g is 1, and furthermore, The amphiphilic carbohydrate compound or salt thereof according to claim 1, wherein the corresponding levels of A, D, H, Q, and T are within the range described in claim 1.

4. The amphiphilic carbohydrate compound or salt thereof according to claim 1 or 2, wherein the units A, D, H, Q, and T (if present) are in any arrangement in the polymer.

5. The amphiphilic carbohydrate compound or salt thereof according to any one of claims 1 to 4, wherein the level of acetylation unit A is in the range of 0.5 to 26 mol% or 0.5 to 20 mol%.

6. The amphiphilic carbohydrate compound or salt thereof according to any one of claims 1 to 4, wherein the level of acetylation unit A is in the range of 0.5 to 15 mol%, 0.5 to 10 mol%, or 0.5 to 5 mol%.

7. The amphiphilic carbohydrate compound or salt thereof according to any one of claims 1 to 6, wherein the level of hydrophobic unit H is in the range of 10 to 30 mol%.

8. The amphiphilic carbohydrate compound or salt thereof according to any one of claims 1 to 7, wherein the level of the quaternary amine unit Q is in the range of 1 to 90 mol%.

9. The amphiphilic carbohydrate compound or salt thereof according to any one of claims 1 to 8, wherein the level of quaternary amine unit 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%.

10. An amphiphilic carbohydrate compound or salt thereof according to any one of claims 1 to 9, 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%.

11. An amphiphilic carbohydrate compound or salt thereof according to any one of claims 1 to 10, 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%.

12. The amphiphilic carbohydrate compound or salt thereof according to any one of claims 1 to 11, which is a partially acetylated form of N-palmitoyl, N-monomethyl, N,N-dimethyl, N,N,N-trimethyl-6-O-glycol chitosan (GCPQ).

13. A pharmaceutical composition comprising an amphiphilic carbohydrate compound or a salt thereof according to any one of claims 1 to 12, a hydrophobic drug, and one or more pharmaceutically acceptable excipients.

14. The pharmaceutical composition according to claim 13, wherein the drug is an analgesic, antibiotic, anticoagulant, antidepressant, anticarcinogen, antitumor, anti-inflammatory drug, antihistamine, antiemetic, anxiolytic, anticonvulsant, antipsychotic, antiviral, antidiabetic, sedative, antihypertensive, or cardiovascular therapeutic agent.

15. The pharmaceutical composition according to claim 14, wherein the drug is a macrolide immunosuppressant.

16. The pharmaceutical composition according to claim 14, wherein the drug is cyclosporine A, tacrolimus, or rapamycin.

17. The pharmaceutical composition according to any one of claims 13 to 16, wherein the concentration of the drug is 0.01 to 0.2% w / v.

18. A composition comprising a hydrophobic drug for therapeutic use and an amphiphilic carbohydrate compound or a salt thereof according to any one of claims 1 to 12.

19. The composition according to claim 18 for use in the treatment of autoimmune disorders.

20. The composition according to claim 18 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), Sjögren's syndrome, postoperative refractive surgery, corneal transplantation, or contact lens intolerance.

21. A composition according to any one of claims 18 to 20 for use in treatment by intraocular administration.

22. A composition according to any one of claims 18 to 20 for use in treatment by oral administration.

23. A compound or salt thereof according to any one of claims 1 to 12, or a pharmaceutical composition according to any one of claims 13 to 17, administered to a human or animal subject in need of treatment.

24. The aforementioned treatment is the treatment of an autoimmune disorder, the compound or salt thereof or pharmaceutical composition according to claim 23.

25. The compound or salt thereof or pharmaceutical composition according to claim 23, wherein the treatment is 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), Sjögren's syndrome, postoperative refractive surgery, corneal transplantation, or contact lens intolerance.

26. Depolymerization of carbohydrate compounds, To increase, decrease, or maintain the level of acetylation. Reacting a carbohydrate with a compound for adding a hydrophobic side chain, and The reaction of a compound for quaternizing an amine with a carbohydrate. A method for forming an amphiphilic carbohydrate compound or a salt thereof according to any one of claims 1 to 12, comprising:

27. Use of a composition comprising a hydrophobic drug and an amphiphilic carbohydrate compound or a salt thereof according to any one of claims 1 to 12 in the manufacture of a drug for therapeutic use.

28. The use according to claim 27, wherein the treatment is the treatment of an autoimmune disorder.

29. The use according to claim 28, wherein the treatment is 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), Sjögren's syndrome, postoperative refractive surgery, corneal transplantation, or contact lens intolerance.

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