Compositions, their use in therapy and methods thereof

Abstract

The present invention relates to a method of treating lymphedema comprising administering to a patient in need thereof an effective amount of a composition. The composition consists essentially of a cyclodextrin or a pharmaceutically acceptable salt, solvate, or prodrug thereof. The present invention also relates to a composition consisting essentially of a cyclodextrin.

Description

TECHNICAL FIELD

[0001] The present invention relates generally to compositions and their use in therapy. The present invention also relates to methods of treatment thereof. BACKGROUND

[0002] Lymphedema, also known as lymphoedema and lymphatic edema, is a condition of localized swelling caused by damage to the lymphatic system. The lymphatic system is a critical part of the body's immune system and returns interstitial fluid to the blood. Generally, swelling occurs in the arms, hands, legs, breasts, or torso. Lymphedema is most commonly a complication of cancer treatment, parasitic infection, trauma, but it can also be observed in some genetic diseases. Because the lymphatic system has been compromised, tissues with lymphedema are at high risk for infection, fibrosis, and malignant transformation.

[0003] Lymphedema can be further divided into primary (genetic) lymphedema and secondary lymphedema (caused by cancer, infection, etc.). Primary lymphedema is a rare genetic disease caused by developmental problems with the lymphatic vessels in the body. Specific causes of primary lymphedema include Milroy disease (congenital lymphedema), Meige disease (early onset lymphedema), and late onset lymphedema (late onset lymphedema).

[0004] Secondary lymphedema is a debilitating chronic inflammatory disease caused by poor lymphatic drainage resulting from cancer treatment (surgery and / or radiation therapy), injury, trauma, or infection. Examples of such causes include surgery, radiation therapy for cancer, cancer, and infection. Lymphedema can also be caused by blockages in the lymphatic system. Blockages prevent lymph fluid from draining well, and the buildup of fluid leads to swelling.

[0005] Swelling caused by lymphedema ranges from a slight, almost imperceptible change in the size of an arm or leg to an extreme change that makes the limb difficult to use. Lymphedema caused by cancer treatment can occur months or years after treatment.

[0006] There is currently no cure for lymphedema. In particular, there is currently no drug suitable for treating lymphedema. Physical therapies such as compression therapy, good skin care, exercise, and manual lymphatic drainage are generally recommended to improve treatment outcomes.

[0007] It would be desirable to overcome or ameliorate at least one of the above problems. SUMMARY

[0008] The present invention is based on the premise that cancer-associated lymphedema patients also exhibit symptoms of inflammation and fibrosis at later stages of the disease. This is caused by dying adipocytes that are unable to store excess lipids that accumulate in the tissue due to impaired lymphatic clearance. Based on these findings, the inventors hypothesized that clearance of lipids from the body would reverse lymphedema and associated tissue changes, such as fibrosis and adipocyte death. It was found that intradermal injection of cyclodextrin was effective in reducing lymphedema in an animal model of lymphedema. In particular, treatment with cyclodextrin significantly reduced lipid accumulation in the tissue, thereby reducing tissue swelling and restoring lymphatic drainage.

[0009] The present invention provides a method of treating lymphedema, comprising administering to a patient in need thereof an effective amount of a composition comprising cyclodextrin or a pharmaceutically acceptable salt, solvate, or prodrug thereof;

[0010] wherein the internal cavity of the cyclodextrin is unoccupied.

[0011] The present invention also provides a composition for use in treating lymphedema in a patient in need thereof, the composition comprising cyclodextrin or a pharmaceutically acceptable salt, solvate, or prodrug thereof;

[0012] wherein the internal cavity of the cyclodextrin is unoccupied.

[0013] The present invention also provides use of a composition in the manufacture of a medicament for treating lymphedema, the composition comprising cyclodextrin or a pharmaceutically acceptable salt, solvate, or prodrug thereof;

[0014] wherein the internal cavity of the cyclodextrin is unoccupied.

[0015] In some embodiments, the composition to be administered can improve or reduce tissue edema, lymphatic function, lipid accumulation, tissue cholesterol, fibrosis, inflammation, or a combination thereof.

[0016] In some embodiments, the composition will be administered every other day.

[0017] In some embodiments, the composition will be administered at least 2 doses over at least 4 days.

[0018] In some embodiments, the composition will be administered at a dose of about 0.5 g / kg to about 10 g / kg.

[0019] In some embodiments, the composition will be administered to a patient in need thereof having a lymphedema severity of stage 2 or less.

[0020] The present invention also provides a composition comprising cyclodextrin;

[0021] wherein the internal cavity of the cyclodextrin is unoccupied.

[0022] In some embodiments, the cyclodextrin is present in the composition in a weight ratio of about 0.1% w / w to about 50% w / w.

[0023] In some embodiments, the cyclodextrin is derivatized with an alkyl, alkenyl, alkynyl, alkoxy, hydroalkyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, alkyl acyl, alkenyl acyl, alkynyl acyl, aryl, or alkyl aryl.

[0024] In some embodiments, the cyclodextrin is derivatized with a methyl, ethyl, propyl, hydro methyl, hydro ethyl, hydro propyl, fluorine, chlorine, bromine, benzyl, or phenyl.

[0025] In some embodiments, the cyclodextrin is derivatized 1 to 24 times.

[0026] In some embodiments, the cyclodextrin is a β-cyclodextrin selected from methyl-β- cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, or a combination thereof.

[0027] In some embodiments, the cyclodextrin has an internal cavity with a diameter of about to about

[0028] In some embodiments, the internal cavity of the cyclodextrin is unoccupied or occupied by an inert molecule.

[0029] In some embodiments, the composition further comprises an excipient selected from a stabilizer, a solubilizer, an emulsifier, a surfactant, a water-soluble polymer, a pH adjuster, a filler, a binder, a pigment, a disintegrant, an antioxidant, a preservative, an emollient, a silicone, a penetration enhancer, a lubricant, and a fragrance.

[0030] In some embodiments, the excipient is selected from microcrystalline cellulose; metal salts of acids such as aluminum stearate, calcium stearate, magnesium stearate, sodium stearate, and zinc stearate; fatty acids, hydrocarbons, and fatty alcohols such as stearic acid, palmitic acid, liquid paraffin, stearyl alcohol, and palmitoleyl alcohol; fatty acid esters such as (mono and di) glyceryl stearate, glyceryl triester, glyceryl (palmitostearate), sorbitan monostearate, sucrose monostearate, sucrose monopalmitate, and sodium stearyl fumarate; alkyl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; polymers such as polyethylene glycol, polyoxyethylene glycol, and polytetrafluoroethylene, and inorganic materials such as talc and dicalcium phosphate, and sodium carboxymethyl starch.

[0031] In some embodiments, the composition is an intradermal composition.

[0032] In some embodiments, the intradermal composition comprises an aqueous medium.

[0033] In some embodiments, the intradermal composition comprises a saline solution.

[0034] In some embodiments, the aqueous medium is selected from 0.9% NaCl saline solution, 0.9% KCl saline solution, Ringer's lactate solution, Acetated Ringer's solution, intravenous dextrose solution, 5% dextrose in normal saline solution (D5NS), 10% dextrose in normal saline solution (D10NS), 5% dextrose in half normal saline solution (D5HNS), 10% dextrose in half normal saline solution (D10HNS), phosphate buffered saline (PBS), TRIS buffered saline (TBS), Hank's balanced salt solution (HBSS), Earle's balanced salt solution (EBSS), standard citrate saline (SSC), HEPES buffered saline (HBS), Gey's balanced salt solution (GBSS).

[0035] In some embodiments, the aqueous medium is in a weight ratio of about 0.1% w / w to about 50% w / w to the composition.

[0036] In some embodiments, the intradermal composition includes an excipient selected from sodium carboxymethylcellulose, microcrystalline cellulose, cresol, methyl paraben, and propyl paraben.

[0037] In some embodiments, the excipient is in a weight ratio of about 0.1% w / w to about 50% w / w to the intradermal composition.

[0038] In some embodiments, the composition is a topical composition.

[0039] In some embodiments, the topical composition is a topical cream or a topical gel.

[0040] In some embodiments, the topical composition further includes an excipient selected from a carrier, an emulsifier, and / or a thickening agent.

[0041] In some embodiments, the carrier is selected from mineral oil, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetostearyl alcohol, 2-octyldodecanol, benzalkonium chloride, and water.

[0042] In some embodiments, the topical composition further comprises an excipient selected from acacia, acetic acid, acetone, acetyl tri-butyl citrate, agar, alcohol, alginic acid, almond oil, alpha-tocopherol, aluminum monostearate, aluminum stearate, aluminum oxide, ascorbic acid, ascorbyl palmitate, bentonite, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, benzyl benzoate, boric acid, bronopol, butylated hydroxyanisole, butylated hydroxytoluene, butylene glycol, butyl paraben, calcium acetate, calcium alginate, calcium chloride, calcium hydroxide, calcium lactate, carbomer, carboxymethylcellulose sodium, carrageenan, castor oil, microcrystalline cellulose, ceresin, cetearyl alcohol, cetrimide, cetyl alcohol, chlorocresol, chloroxylenol, cholesteryl chloride, citric acid, colloidal silicon dioxide, cresol, cross-linked polyplarone, cyclomethicone, denatonium benzoate, dibutyl phthalate, diethanolamine, dimethicone, dimethyl phthalate, dimethylacetamide, edetate disodium, docusate sodium, ethyl acetate, ethyl lactate, ethyl oleate, ethylene-vinyl acetate, ethyl paraben, gelatin, glycerin, glyceryl monooleate, glyceryl monostearate, tetraethylene glycol, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, imidurea, isopropyl alcohol, isopropyl myristate, isopropyl palmitate, kaolin, lactic acid, lanolin, lecithin, linoleic acid, silicates, malic acid, mannitol, methyl cellulose, methyl paraben, monothioglycerol, myristic acid, myristyl alcohol, oleic acid, oleyl alcohol, palmitic acid, paraffin, petrolatum, phenoxyethanol, poloxamer, polycarbophil, polyethylene glycol, poly(methyl acrylate), polyoxyl glycerol, polyvinyl alcohol, povidone, propylene glycol, propyl paraben, pyrrolidone, sodium hyaluronate, sodium lactate, sodium lauryl sulfate, sorbitan esters, sorbitol, starch, tricaprylin, triethanolamine, xanthan gum, or xylitol.

[0043] In some embodiments, the weight ratio of the excipient to the topical composition is about 0.1% w / w to about 50% w / w.

[0044] In some embodiments, the composition is applied in a transdermal patch.

[0045] In some embodiments, the composition is applied as a layer within a transdermal patch or on the surface of a transdermal patch. BRIEF DESCRIPTION OF DRAWINGS

[0046] Embodiments of the present application will now be described, by way of non-limiting examples only, with reference to the accompanying drawings in which:

[0047] Figure 1 Images of the footpads of female wild-type (WT) or apoE- / - mice after receiving a subcutaneous injection of cyclodextrin or saline are shown;

[0048] Figure 2Microscopic images of female WT or apoE- / - mice after receiving a subcutaneous injection of cyclodextrin or saline are shown;

[0049] Figure 3 Relative fluorescence in the lymph nodes of each female WT or apoE- / - mouse after receiving a subcutaneous injection of cyclodextrin or saline is shown;

[0050] Figure 4 Relative fluorescence in the lymph nodes of each mouse under different dosing regimens is shown;

[0051] Figure 5 The structure of cyclodextrin is shown;

[0052] Figure 6 Total cholesterol concentrations analyzed in the forepaw plantar of wild type, apoE- / - mice and treated apoE- / - mice are shown;

[0053] Figure 7 shows staining images of the dorsal skin of treated and untreated mice;

[0054] Figure 8A Lymphatic function assessment of treated and untreated mice is shown; and

[0055] Figure 8B Footpad tissue swelling of treated and untreated mice is shown. DETAILED DESCRIPTION

[0056] It is a premise of the present invention that if lipid is removed from the organism, lymphedema and the associated tissue changes, such as fibrosis and adipocyte depletion, can be reversed. Without wishing to be bound by theory, the inventors believe that cyclodextrin, due to its truncated cone shape, is able to solubilize and extract lipids from cells. To this end, it was found that treating an organism with lymphedema-like conditions with cyclodextrin significantly reduces lipid accumulation in the tissue, thereby reducing tissue swelling and restoring lymphatic drainage.

[0057] This is advantageous because current treatment of lymphedema is limited to garments or microsurgery. There is no drug treatment. In this regard, the composition can be formulated as a drug to treat lymphedema.

[0058] Furthermore, cyclodextrin will help clear proteins and lipids, thus reducing inflammation and fibrosis. For this reason, cyclodextrin is also expected to improve the efficiency of current microsurgical procedures aimed at restoring lymphatic transport, including lymph-venous anastomosis and lymph node transplantation. Cyclodextrin is also non-toxic, thus facilitating the approval of ethical and clinical trials.

[0059] Thus, the present invention provides a composition consisting essentially of cyclodextrin.

[0060] As used herein, "cyclodextrin" refers to a family of cyclic oligosaccharides consisting of a macrocycle of glucose subunits linked by a-1,4-glucosidic bonds. Cyclodextrins consist of 5 or more a-D-glucopyranoside units linked in 1->4 positions as in amylose (starch fragments). The largest cyclodextrin found contains 32 1,4-anhydro-a-D-glucopyranoside units. More commonly, cyclodextrins contain some number of glucose monomers, ranging from 6 to 8 units, that make up a ring, forming a conical shape. Cyclodextrins with 6 glucose subunits are also known as a (alpha)-cyclodextrin, cyclodextrins with 7 glucose subunits are known as b (beta)-cyclodextrin, and cyclodextrins with 8 glucose subunits are known as g (gamma)-cyclodextrin. Cyclodextrins have a ring-like shape with a larger opening and a smaller opening of the ring exposing the secondary and primary hydroxyl groups, respectively, to the solvent. Due to this arrangement, the interior of the ring is not hydrophobic, but is much less hydrophilic than the aqueous environment, thus able to accommodate other hydrophobic molecules. Conversely, the exterior is sufficiently hydrophilic to render the cyclodextrin (or its complex) water-soluble. They are not soluble in typical organic solvents.

[0061] In some embodiments, the cyclodextrin is selected from a group consisting of a- cyclodextrin, b-cyclodextrin, g-cyclodextrin, or a combination thereof.

[0062] As used herein, cyclodextrin also includes derivatives thereof. Derivatization is a technique used in chemistry that transforms a compound into a product (the derivative of the reaction) with a similar chemical structure, called a derivative. Typically, a specific functional group of the compound is involved in the derivatization reaction, and the product is transformed into a derivative that deviates from the reactivity, solubility, boiling point, melting point, state of aggregation, or chemical composition. The hydroxyl groups on the cyclodextrin can be chemically modified, which can also change its host-guest behavior. For example, transformations such as O-methylation and acetylation can be used. Hydroxypropylated derivatives can also be formed using propylene oxide. Primary alcohols can also be p-toluenesulfonylated.

[0063] In some embodiments, the cyclodextrin is optionally derivatized. The optional derivative can be selected from an alkyl, alkenyl, alkynyl, alkoxy, hydroalkyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, alkylacyl, alkenylacyl, alkynylacyl, aryl, or alkylaryl. The optional derivative can be selected from a methyl, ethyl, propyl, hydro-methyl, hydro-ethyl, hydro-propyl, fluorine, chlorine, bromine, benzyl, or phenyl. Other types of derivatized cyclodextrins are shown in Table 1 below:

[0064] Table 1 a-Cyclodextrin Derivatives

[0065]

[0066] While Table 1 shows derivatives of a-cyclodextrin, the skilled artisan will appreciate that similar derivatization can be performed on b-cyclodextrin and g-cyclodextrin.

[0067] In other embodiments, the derivatized cyclodextrin is randomly substituted. Randomly substituted cyclodextrin derivatives are modified at different positions, which can be characterized by the degree of substitution.

[0068] The degree of derivatization can be adjusted. For example, the cyclodextrin can be fully methylated or partially methylated. In the case of a-cyclodextrin, there are six secondary hydroxyl groups exposed relative to the truncated cone-shaped compound Figure 5 ). To this end, the a-cyclodextrin can be partially methylated, i.e., 1, 2, 3, 4, or 5 of the secondary hydroxyl groups are methylated. Methylation can also occur at the primary hydroxyl groups.

[0069] In some embodiments, the cyclodextrin is about 5% derivatized. In other embodiments, the cyclodextrin is about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% derivatized.

[0070] In some embodiments, the cyclodextrin is subjected to 1 to 24 derivatization reactions. In other embodiments, the cyclodextrin is subjected to 1 to 22, 1 to 20, 1 to 18, 1 to 16, 1 to 14, 1 to 12, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 derivatizations.

[0071] As used herein, cyclodextrin does not include cyclodextrin conjugates. A conjugate refers to a compound formed by the linkage of two or more compounds. Thus, a cyclodextrin conjugate refers to a compound formed by the linkage of a cyclodextrin to another compound. For example, the other compound can be an active agent, a fluorescent group, or a polymer.

[0072] In some embodiments, the cyclodextrin is methyl-β-cyclodextrin. In other embodiments, the cyclodextrin is 2-hydroxypropyl-β-cyclodextrin. In other embodiments, the cyclodextrin is 3-hydroxypropyl-β-cyclodextrin. In other embodiments, the cyclodextrin is dimethyl-β-cyclodextrin. In other embodiments, the cyclodextrin is trimethyl-β-cyclodextrin. In other embodiments, the cyclodextrin is sulfobutyl ether-β-cyclodextrin. In other embodiments, the cyclodextrin is carboxymethyl-β-cyclodextrin. In other embodiments, the cyclodextrin is a β-cyclodextrin selected from methyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, or a combination thereof.

[0073] In some embodiments, the composition comprises cyclodextrin. In other embodiments, the composition consists essentially of cyclodextrin. In this regard, cyclodextrin is the only active agent in the composition. In some embodiments, cyclodextrin is administered as the only active ingredient in the composition for treating lymphedema. Thus, in some embodiments, cyclodextrin is not used as an excipient in the composition. However, this does not exclude the presence of excipients in the composition that do not exert an active pharmaceutical effect.

[0074] In some embodiments, the cyclodextrin in the composition is provided in an uncomplexed or unoccupied state; that is, the internal cavity of the cyclodextrin is unoccupied. As used herein, "complex" refers to the inclusion of a guest molecule within the cavity or space of the truncated conical cyclodextrin. By doing so, the cyclodextrin is able to more easily exert its role in complexing with lipids. The present inventors have found that the compositions disclosed herein are particularly advantageous. It has also been found that the presence of certain excipients is particularly advantageous in maintaining the uncomplexed state of the cyclodextrin prior to use.

[0075] Thus, the present invention provides a composition comprising cyclodextrin, wherein the internal cavity of the cyclodextrin is unoccupied.

[0076] In some embodiments, the composition consists essentially of cyclodextrin, wherein the internal cavity of the cyclodextrin is unoccupied.

[0077] In some embodiments, the internal cavity of the cyclodextrin has a diameter of about to about In other embodiments, the diameter is about to about about to about about to about about to about about to about about to about about to about about to about about to about about to about about to about about to about about to about about to about about to about about from about about from about about from about about from about or about from about

[0078] In some embodiments, the cyclodextrin in the composition is complexed with an inert molecule. The complexation energy or interaction energy of this cyclodextrin-molecule complex is preferably lower than the complexation energy of the final cyclodextrin-lipid complex. Thus, the complexation of the lipid with the cyclodextrin is still favorable. It was found that by complexing an inert molecule with the cyclodextrin, the stability of the composition can be improved. It should be noted that in this case, the cyclodextrin-molecule complex is not used in the sense of a host-guest complex, as the cyclodextrin is not used as a delivery platform / delivery agent to carry an active drug. Thus, the use of cyclodextrin (and any form thereof) as a delivery platform is excluded. The inert molecule can be, for example, an excipient that can be found in the composition. The inert molecule can act as a "guard" for the cyclodextrin cavity, making it available to form a host-guest complex with the lipid when needed.

[0079] As used herein, "complexation energy" or "interaction energy" refers to the energy (ΔΕ AB ) between molecules A and B. AB It can be determined as the difference between the energy of the dimer (Ε A + Ε B ).

[0080] Thus, in some embodiments, the composition comprises cyclodextrin, wherein the internal cavity of the cyclodextrin is unoccupied or occupied by an inert molecule.

[0081] In some embodiments, the composition consists essentially of cyclodextrin, wherein the internal cavity of the cyclodextrin is unoccupied or occupied by an inert molecule.

[0082] The composition can also include excipients. Excipients or additives can be added to improve solubility of the cyclodextrin, promote stability or process the composition. Such additives and excipients include stabilizers, solubilizers, emulsifiers, surfactants, water-soluble polymers, pH adjusters, fillers, binders, pigments, disintegrants, antioxidants, preservatives (parabens, benzoic acid and benzoate esters), emollients (polyols such as sorbitol; natural oils such as castor oil, jojoba oil; waxes, synthetic organic polymers, petrolatum), silicones, penetration enhancers, lubricants, and fragrances. Other additives can also help the cyclodextrin penetrate the skin, or at least the epidermal layer of the skin. Examples of these ingredients are microcrystalline cellulose; metal salts of acids such as aluminum stearate, calcium stearate, magnesium stearate, sodium stearate, and zinc stearate; fatty acids, hydrocarbons, and fatty alcohols such as stearic acid, palmitic acid, liquid paraffin, stearyl alcohol, and palmitoleic alcohol; fatty acid esters such as (mono and di)glyceryl stearate, triglycerides, glyceryl (palmitostearate) ester, sorbitan monostearate, sucrose monostearate, sucrose monopalmitate, and sodium stearyl fumarate; alkyl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; polymers such as polyethylene glycol, polyoxyethylene glycol, and polytetrafluoroethylene, and inorganic materials such as talc and dicalcium phosphate, and sodium carboxymethyl starch.

[0083] Other excipients can be selected from carbomer (gelling agent), purified water (solvent), potassium sorbate (preservative), propylene glycol (penetration enhancer). Other examples of excipients in topical formulations can be found in Chang et al., The AAPS Journal, 15:41-52 (2013), which is hereby incorporated by reference in its entirety. In some embodiments, the excipients can be selected from acrylates copolymer, carbomer 940, docusate sodium, edetate disodium, glycerin, poloxamer 182, propylene glycol, purified water, silicon dioxide, sodium hydroxide. In another variation, the excipients can include carbomer, disodium edetate, hydroxypropyl methylcellulose, laureth-4, sodium hydroxide, water. Other examples of topical formulations can be found in Raphael et al., Therapeutic Delivery, February 06, 2:197-216 (2015), which is hereby incorporated by reference in its entirety.

[0084] In some embodiments, the cyclodextrin is present in a weight ratio to the composition of about 0.1% w / w to about 50% w / w. In other embodiments, the weight ratio is about 0.1% w / w to about 45% w / w, about 0.5% w / w to about 45% w / w, about 1% w / w to about 45% w / w, about 1% w / w to about 40% w / w, about 1% w / w to about 35% w / w, about 1% w / w to about 30% w / w, about 1% w / w to about 25% w / w, or about 1% w / w to about 20% w / w. The weight ratio of cyclodextrin to the composition can depend, for example, on the type of dosage form in which the cyclodextrin is present.

[0085] The cyclodextrin can be administered to the subject as a pharmaceutically acceptable salt thereof. Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulfuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, maleic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulfonic, toluenesulfonic, benzenesulfonic, salicylic, sulfanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic, and valeric acids.

[0086] Base salts include, but are not limited to, salts of pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, ammonium, and alkylammonium. Specifically, the present application includes within its scope cationic salts, for example, sodium or potassium salts, or alkyl esters (e.g., methyl, ethyl) of the phosphoric acid group.

[0087] Basic nitrogenous groups can be quaternized with lower alkyl halides, such as methyl, ethyl, propyl, butyl chloride, bromides, iodides; dialkyl sulfates, such as dimethyl, diethyl, and dibutyl sulfate; and other agents.

[0088] In some embodiments, the composition includes a saline solution. In other embodiments, the saline solution is a 0.9% saline solution. The salt can be NaCl or KCl. Other saline solutions can also be used, such as lactated Ringer's solution, acetic Ringer's solution, intravenous dextrose solution, 5% dextrose in normal saline solution (D5NS), 10% dextrose in normal saline solution (D10NS), 5% dextrose in half-normal saline solution (D5HNS), 10% dextrose in half-normal saline solution (D10HNS), phosphate-buffered saline (PBS), TRIS-buffered saline (TBS), Hank's balanced salt solution (HBSS), Earle's balanced salt solution (EBSS), standard saline citrate (SSC), HEPES-buffered saline (HBS), and Gey's balanced salt solution (GBSS).

[0089] In some embodiments, the aqueous medium is in a weight ratio to the composition of about 0.1% w / w to about 50% w / w. In other embodiments, the weight ratio is about 0.1% w / w to about 45% w / w, about 0.5% w / w to about 45% w / w, about 1% w / w to about 45% w / w, about 1% w / w to about 40% w / w, about 1% w / w to about 35% w / w, about 1% w / w to about 30% w / w, about 1% w / w to about 25% w / w, or about 1% w / w to about 20% w / w.

[0090] It is understood that any compound that is a prodrug of a cyclodextrin is also within the scope and spirit of the present application. Thus, cyclodextrins can be administered to a subject in the form of a pharmaceutically acceptable prodrug. The term "prodrug" is used in its broadest sense and encompasses derivatives that are converted in vivo to the compounds of the application. Such derivatives would readily occur to those skilled in the art. Further texts that generally describe prodrugs (and their preparation) include: Design of Prodrugs, 1985, H. Bundgaard (Elsevier); The Practice of Medicinal Chemistry, 1996, Camille G. Wermuth et al., Chapter 31 (Academic Press); and A Textbook of Drug Design and Development, 1991, Bundgaard et al., Chapter 5 (Harwood Academic Publishers). For example, a hydroxyl group on a cyclodextrin can be derivatized with a protecting group to form a methoxymethyl ether, a tetrahydropyranyl ether, a t-butyl ether, an allyl ether, a benzyl ether, a t-butyldimethylsilyl ether, a t-butyldiphenylsilyl ether, an acetate, a pivaloate, a benzoate, an acetal, or a benzylidene acetal.

[0091] The cyclodextrin can be in crystalline form, either as the free compound or as a solvate (e.g., hydrate), both of which are within the scope of the present application. Methods of solvating are generally known in the art.

[0092] As previously described, the composition is suitable for treating lymphedema. In other embodiments, the composition is suitable as a prophylactic for lymphedema.

[0093] The composition is administered to a patient in a therapeutically effective amount. As used herein, a therapeutically effective amount means at least partially achieving the intended effect, or delaying the onset of lymphedema, or inhibiting or arresting the progression of lymphedema, or preventing or reversing the onset or progression of lymphedema.

[0094] As used herein, the term "effective amount" relates to the amount of cyclodextrin that, when administered according to the desired dosage regimen, provides the desired therapeutic activity. The amount can be administered in intervals of several minutes, hours, days, weeks, months or years, or continuously over any of these intervals. Appropriate dosages can range from about 0.1 mg per kg body weight to 100 g per kg body weight, for example in the range of 1 mg to 50 g per kg body weight. In one embodiment, the dosage can range from 1 mg to 20 g per kg body weight per dose. In another embodiment, the dosage can range from 1 mg to 10 g per kg body weight per dose. In yet another embodiment, the dosage can range from 1 mg to 50 g per kg body weight per dose, such as up to 5 g per kg body weight per dose.

[0095] In some embodiments, the dosage is in the range of 0.5 g to 10 g per kg body weight, 0.5 g to 9 g per kg body weight, 0.5 g to 8 g per kg body weight, 0.5 g to 7 g per kg body weight, 0.5 g to 6 g per kg body weight, 0.5 g to 5 g per kg body weight, 0.5 g to 4 g per kg body weight, or 0.5 g to 3 g per kg body weight. In some embodiments, the composition will be administered at a dosage of about 0.5 g / kg body weight to about 10 g / kg body weight.

[0096] In some embodiments, the composition will be administered every other day.

[0097] In some embodiments, the composition is provided to a subject in need thereof in 2 to 10 doses every other day. In other embodiments, the composition is provided in 2, 4, 5, 6, 7, 8, 9, or 10 doses every other day.

[0098] In some embodiments, the composition will be administered at least 2 doses over at least 4 days. For example, the composition can be administered on days 1 and 3 of treatment, with a single dose administered on each of the treatment days.

[0099] Preferred unit dose compositions or combinations are those compositions or combinations containing a daily dose, or unit, of the active ingredient, or an appropriate fraction thereof, as described above.

[0100] Other suitable dosages and administration regimens can be determined by the attending physician, and can depend on the severity of the illness and the general state of the patient to be treated, as well as on the patient's age, health and weight.

[0101] The compositions of the present application can be administered in a single dose, or in a series of doses. Preferably, the compositions are presented as a pharmaceutical composition. The formulation of these compositions is well known to those skilled in the art. The compositions can comprise any suitable carrier, diluent or excipient. This includes all conventional solvents, dispersion media, fillers, solid carriers, coatings, antifungal and antibacterial agents, skin penetration agents, surfactants, isotonic and absorption agents and the like.

[0102] The carrier must be pharmaceutically "acceptable" in the sense of being compatible with the other ingredients of the composition and not injurious to the patient. The compositions can conveniently be presented in unit dosage form and can be prepared by any methods well known in the art of pharmacy. These methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the preparations are obtained by uniformly and intimately bringing into association the active ingredient with a liquid carrier or a finely divided solid carrier or both. The product is then shaped if necessary.

[0103] The compositions can be suitable for parenteral administration. Parenteral routes are any route other than through the gastrointestinal tract (i.e. administration other than via the gastrointestinal tract). For example, the compositions can be suitable for subcutaneous delivery (application under the skin). Subcutaneous injection is the injection of a bolus into the subcutaneous tissue, the layer of skin just below the dermis and epidermis, collectively known as the skin. Alternatively, the compositions can be suitable for transdermal delivery (application on the skin), or intradermal delivery (application in the skin).

[0104] In other embodiments, the compositions can be suitable for transdermal delivery. Transdermal is a route of administration that delivers an active ingredient through the skin for systemic distribution.

[0105] In some embodiments, the compositions are applied in a transdermal patch. Transdermal is a route of administration that delivers a cyclodextrin through the skin. Cyclodextrins can be administered in the form of a patch. A patch can be an adhesive patch placed on the skin to deliver a specific dose of a drug through the skin and selectively into the bloodstream. One advantage of the transdermal route of drug administration compared to other types of drug delivery such as oral, topical, intravenous, intramuscular, etc. is that the patch can control the release of the drug into the patient typically through a porous membrane that covers a reservoir of the drug or through a thin layer of the drug embedded in an adhesive that melts at body temperature. Further, since the patch can be applied directly on the skin surface where lymphedema is observed, the treatment can be visually tracked.

[0106] In some embodiments, the compositions are used as a layer within a transdermal patch. In other embodiments, the compositions are applied on the surface of a transdermal patch.

[0107] For example, a transdermal patch can include a backing layer such as aluminum foil, polyethylene terephthalate, polyethylene, or nonwoven cloth. The composition can be applied as a layer on the backing layer. There can also be an adhesive layer for contact with the patient’s skin. The composition layer and adhesive layer can be in any form and configuration as long as the composition can be delivered to the patient via the skin. Alternatively, the composition and adhesive can be inseparably mixed together to form a single layer. The adhesive can be an acrylic-based adhesive or a silicone-based adhesive.

[0108] In some embodiments, the weight ratio of cyclodextrin in the transdermal patch is about 0.1% w / w to about 50% w / w. In other embodiments, the weight ratio is about 0.1% w / w to about 45% w / w, about 0.5% w / w to about 45% w / w, about 1% w / w to about 45% w / w, about 1% w / w to about 40% w / w, about 1% w / w to about 35% w / w, about 1% w / w to about 30% w / w, about 1% w / w to about 25% w / w, or about 1% w / w to about 20% w / w.

[0109] The compositions of the present application can be administered to a patient using any known administration technique. For example, the composition can be administered continuously (allowing careful regulation of the amount of fluid over a long period of time), intermittently (giving shorter term doses at set intervals), or directly (providing a single dose or bolus). For example, the composition will be administered in a dose of up to 20 g / m 2 of body surface area.

[0110] Injectables for such use can be prepared in conventional forms, either as liquid solutions or suspensions, or solid forms suitable for reconstitution as solutions or suspensions, or as emulsions, prior to injection. The carrier can include, for example, water, saline (e.g., normal saline (NS), phosphate-buffered saline (PBS), balanced salt solution (BSS)), Ringer’s lactate, dextrose, glycerol, ethanol, and the like; if desired, small amounts of auxiliary substances, such as wetting or emulsifying agents, buffers, and the like can be added. For example, the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of a desired particle size in the case of dispersion, and by the use of surfactants.

[0111] In some embodiments, the composition is an intradermal composition. The intradermal composition is suitable for intradermal injection into a patient in need thereof. Intradermal injection is the injection or superficial injection of a substance into the dermis, which lies between the epidermis and the hypodermis. Studies have found that the intradermal route is associated with a faster systemic absorption of cyclodextrin compared to subcutaneous injection, and therefore a faster response time for treating lymphedema. As a result, the body’s response to the composition is easier to see because it is closer to the surface.

[0112] In some embodiments, the intradermal composition comprises an aqueous medium. As used herein, the term "aqueous medium" refers to an aqueous solvent or solvent system primarily composed of water. These solvents can be polar or nonpolar, and / or can be protonal or aprotic. A solvent system refers to a combination of solvents that results in a final single phase. Both "solvent" and "solvent system" can include, but are not limited to, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, dioxane, chloroform, diethyl ether, dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide, nitromethane, propylene carbonate, formic acid, butanol, isopropanol, propanol, ethanol, methanol, acetic acid, ethylene glycol, diethylene glycol, or water. Aqueous solvents or solvent systems can also include dissolved ions, salts, and molecules such as amino acids, proteins, carbohydrates, and phospholipids. This salt can be, but is not limited to, sodium chloride, potassium chloride, ammonium acetate, magnesium acetate, magnesium chloride, magnesium sulfate, potassium acetate, potassium chloride, sodium acetate, sodium citrate, zinc chloride, sodium HEPES, calcium chloride, ferric nitrate, sodium bicarbonate, potassium phosphate, and sodium phosphate. Therefore, biological fluids, physiological solutions, and culture media also fall within this definition.

[0113] In some embodiments, the weight ratio of cyclodextrin to the intradermal composition is from about 0.1% w / w to about 50% w / w. In other embodiments, the weight ratio is from about 0.1% w / w to about 45% w / w, from about 0.5% w / w to about 45% w / w, from about 1% w / w to about 45% w / w, from about 1% w / w to about 40% w / w, from about 1% w / w to about 35% w / w, from about 1% w / w to about 30% w / w, from about 1% w / w to about 25% w / w, or from about 1% w / w to about 20% w / w.

[0114] In some embodiments, the intradermal composition includes excipients. Excipients can help improve the solubility and / or stability of cyclodextrin in the composition. For example, excipients such as sodium carboxymethyl cellulose, microcrystalline cellulose, cresol, methylparaben, and / or propylparaben can be used.

[0115] In some embodiments, the excipient is expressed in a weight ratio of about 0.1% w / w to about 50% w / w to the intradermal composition. In other embodiments, the weight ratio is expressed in the following proportions: about 0.1% w / w to about 45% w / w, about 0.5% w / w to about 45% w / w, about 1% w / w to about 45% w / w, about 1% w / w to about 40% w / w, about 1% w / w to about 35% w / w, about 1% w / w to about 30% w / w, about 1% w / w to about 25% w / w, or about 1% w / w to about 20% w / w.

[0116] The compositions of the present application can be suitable for parenteral administration, including aqueous and non-aqueous isotonic sterile injection solutions, which can contain antioxidants, buffers, bactericides and solutes that render the composition or combination isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that can include suspending agents and thickening agents. The compounds, compositions or combinations can be presented in unit-dose or multi-dose sealed containers, for example, ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.

[0117] Those skilled in the art will appreciate that other means can also be used to inject and / or administer the compositions. These other means can include, for example, medical delivery devices. These devices and methods can include, for example, biodegradable polymeric delivery members that are inserted into the body of a subject for long-term delivery of a drug.

[0118] Other modes of administration are also possible, including topical administration. Topical administration refers to application to a specific location on or in the body. In most applications, topical administration refers to application to the surface of the body, such as the skin or mucosa, via a large number of classes including creams, foams, gels, lotions, and ointments to treat a disease. For example, a solution or suspension of the compositions of the present application can be formulated into a film-like patch that is applied directly to the surface of the skin of a subject. Alternatively, the composition can be a cream or gel that is applied to the surface of the skin of a subject. Topical application typically involves administration of cyclodextrin in an amount between 0.1 mg and 100 g.

[0119] It is believed that subcutaneous injection can reflect topical application, as both routes of administration target the same layer of the skin, such as the dermis.

[0120] In some embodiments, the composition is a topical composition. A topical drug is a drug that can be used on or in a specific location of the body. Most commonly, topical administration refers to application to the surface of the body, such as the skin or mucosa, via a large number of classes including creams, foams, gels, lotions, and ointments to treat a disease. Many topical drugs are transdermal, that is, they are applied directly to the skin. Topical drugs can also be inhaled, such as asthma drugs, or applied to tissue surfaces other than the skin, such as eye drops applied to the conjunctiva, or ear drops applied to the ear, or drugs applied to the surface of the teeth.

[0121] In some embodiments, the cyclodextrin is present in the topical composition in a weight ratio of about 0.1% w / w to about 50% w / w. In other embodiments, the weight ratio is about 0.1% w / w to about 45% w / w, about 0.5% w / w to about 45% w / w, about 1% w / w to about 45% w / w, about 1% w / w to about 40% w / w, about 1% w / w to about 35% w / w, about 1% w / w to about 30% w / w, about 1% w / w to about 25% w / w, or about 1% w / w to about 20% w / w.

[0122] In some embodiments, the topical composition includes an excipient. The excipient can help improve the solubility and / or stability of the cyclodextrin in the composition. For example, the excipient can be an emulsifying agent and / or a thickening agent. For example, the excipient can also be acacia, acetic acid, acetone, acetyl trihydroxy citronellin, agar, alcohol, alginic acid, almond oil, alpha-tocopherol, aluminum monostearate, aluminum stearate, aluminum oxide, ascorbic acid, ascorbyl palmitate, bentonite, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, benzyl benzoate, boric acid, bronopol, butylated hydroxyanisole, butylated hydroxytoluene, butylene glycol, butyl paraben, calcium acetate, calcium alginate, calcium chloride, calcium hydroxide, calcium lactate, carbomer, carboxymethylcellulose sodium, carrageenan, castor oil, microcrystalline cellulose, ceresin, cetearyl alcohol, cetrimide, cetyl alcohol, chlorocresol, chloroxylenol, cholestrol, citric acid, colloidal silicon dioxide, cresol, cross-linked polyplarone, cyclomethicone, denatonium benzoate, dibutyl phthalate, diethanolamine, dimethicone, dimethyl phthalate, dimethylacetamide, edetate disodium, docusate sodium, ethyl acetate, ethyl lactate, ethyl oleate, ethylene-vinyl acetate, ethyl paraben, gelatin, glycerin, glyceryl monooleate, glyceryl monostearate, tetraethylene glycol, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, imidurea, isopropyl alcohol, isopropyl myristate, isopropyl palmitate, kaolin, lactic acid, lanolin, lecithin, linoleic acid, silicates, malic acid, mannitol, methyl cellulose, methyl paraben, monothioglycerol, myristic acid, myristyl alcohol, oleic acid, oleyl alcohol, palmitic acid, paraffin, petrolatum, phenoxyethanol, poloxamer, polycarbophil, polyethylene glycol, poly(methyl acrylate), polyoxyl esters, polyvinyl alcohol, povidone, propylene glycol, propyl paraben, pyrrolidone, sodium hyaluronate, sodium lactate, sodium lauryl sulfate, sorbitan esters, sorbitol, starch, tricaprylin, triethanolamine, xanthan gum, or xylitol.

[0123] In some embodiments, the weight ratio of excipient to topical composition is about 0.1% w / w to about 50% w / w. In other embodiments, the weight ratio is about 0.1% w / w to about 45% w / w, about 0.5% w / w to about 45% w / w, about 1% w / w to about 45% w / w, about 1% w / w to about 40% w / w, about 1% w / w to about 35% w / w, about 1% w / w to about 30% w / w, about 1% w / w to about 25% w / w, or about 1% w / w to about 20% w / w.

[0124] Compositions of the present application that can be suitable for topical administration to the skin can include the compounds dissolved or suspended in any suitable carrier or base and can take the form of lotions, gels, creams, pastes, ointments and the like. Suitable carriers include mineral oil, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Transdermal patches can also be used to administer the compositions of the present application.

[0125] The present application provides a method of treating lymphedema, comprising administering to a patient in need thereof an effective amount of a composition comprising a cyclodextrin or a pharmaceutically acceptable salt, solvate, or prodrug thereof;

[0126] wherein the internal cavity of the cyclodextrin is unoccupied.

[0127] In some embodiments, the method of treating lymphedema, comprises administering to a patient in need thereof an effective amount of a composition consisting essentially of a cyclodextrin or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0128] In some embodiments, the method of treating lymphedema, comprises administering to a patient in need thereof an effective amount of a composition consisting essentially of a cyclodextrin or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the internal cavity of the cyclodextrin is unoccupied.

[0129] The term "treatment" as used herein can refer to (1) preventing or delaying the onset of one or more symptoms of a disorder; (2) inhibiting the development of a disorder or one or more symptoms of a disorder; (3) relieving a disorder, i.e., causing regression of a disorder or at least one or more symptoms of a disorder; and / or (4) causing a decrease in severity of one or more symptoms of a disorder.

[0130] The term "administering" refers to contacting a subject with an inhibitor referred to herein, or applying, injecting, infusing, or providing a subject with an inhibitor referred to herein.

[0131] The present disclosure also provides a composition for treating lymphedema in a patient in need thereof, the composition comprising a cyclodextrin or a pharmaceutically acceptable salt, solvate, or prodrug thereof;

[0132] wherein the internal cavity of the cyclodextrin is unoccupied.

[0133] In some embodiments, the composition is for treating lymphedema in a patient in need thereof, the composition consisting essentially of a cyclodextrin or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0134] In some embodiments, the composition is for treating lymphedema in a patient in need thereof, the composition consisting essentially of a cyclodextrin or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the internal cavity of the cyclodextrin is unoccupied.

[0135] The present disclosure also provides a use of a composition in the manufacture of a medicament for treating lymphedema, the composition comprising a cyclodextrin or a pharmaceutically acceptable salt, solvate, or prodrug thereof;

[0136] wherein the internal cavity of the cyclodextrin is unoccupied.

[0137] In some embodiments, the use of the composition is for the manufacture of a medicament for treating lymphedema, the composition consisting essentially of a cyclodextrin or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0138] In some embodiments, the use of the composition is for the manufacture of a medicament for treating lymphedema, the composition consisting essentially of a cyclodextrin or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the internal cavity of the cyclodextrin is unoccupied.

[0139] In some embodiments, the lymphedema is primary lymphedema. In other embodiments, the lymphedema is secondary lymphedema. In other embodiments, the lymphedema is selected from primary lymphedema or secondary lymphedema.

[0140] In some embodiments, the composition to be administered can improve or reduce tissue edema, lymphatic function, lipid accumulation, tissue cholesterol, fibrosis, inflammation, or a combination thereof.

[0141] A method of classifying primary and secondary lymphedema is as follows:

[0142]

[0143]

[0144] The staging system helps to determine the severity of lymphedema. With the help of medical imaging devices such as MRI or CT, a physician can determine the stage and can take therapeutic or medical intervention measures.

[0145] Lymphedema and chronic edema have devastating physical and psychosocial effects on patients and their families. The additional weight of the swollen limb affects gait and mobility, and causes pain in the surrounding joints and muscles. There are often difficulties with dressing and shoe wear, which lead to body image and social problems. Many find it difficult to maintain their current job or find alternative options, which can lead to or exacerbate a sedentary lifestyle. Other complications include malignant transformation and recurrent skin infections.

[0146] In some embodiments, the composition will be administered to a patient in need thereof having a lymphedema severity of stage 2 or below. In other embodiments, the composition will be administered to a patient in need thereof having a lymphedema severity of stage 1 or below.

[0147] Example

[0148] Methodology

[0149] To assess the effect of cyclodextrin on secondary lymphedema, an animal model of lymphatic dysfunction that mimics the pathophysiology of human lymphedema, such as adipose tissue remodeling, lipid accumulation, inflammation, and fibrosis, is used. This mouse model can be apoE lipoprotein E deficient mice. It has been shown that mice exhibit impaired lymphatic transport of skin, tissue swelling, lipid accumulation, and inflammation in tissues. It is believed that this lymphatic dysfunction leads to adipose tissue expansion followed by involution and fibrosis, which is also observed in human secondary lymphedema. To demonstrate this, female apoE- / -mice are injected subcutaneously with 2 g / kg body weight of cyclodextrin (saline) or vehicle alone (saline) for a total of 2, 4, or 8 doses every other day. Mice are euthanized, tissue swelling is observed macroscopically, and lymphatic transport is detected by tracking FITC dextran transport from the footpads to draining lymph nodes. Histological examination of skin tissue for lipid content (Oil Red O staining) is also performed.

[0150] Results and Analysis

[0151] The effect of a total of 4 doses of cyclodextrin on tissue edema, lipid accumulation, and lymphatic transport in apoE- / -mice is tested ( Figure 1 , Figure 2 and Figure 3 ). The results show that 4 doses of cyclodextrin significantly improve tissue edema in the footpads ( Figure 1 ), and reduce lipid accumulation by reducing Oil Red O staining in the tissue of mice treated with cyclodextrin ( Figure 2 ). In addition, cyclodextrin is shown to completely restore lymphatic transport in apoE- / -mice ( Figure 3 ), thereby improving tissue swelling.

[0152] Figure 1 Images of the paws of female wild-type (WT) or apoE- / - mice harvested at 17 weeks of age after receiving four subcutaneous injections of cyclodextrin (CD; 2 g / kg body weight) or saline (control group, NT) every other day, on a high-fat diet. Gross observation of paw swelling (arrow head: swollen area). ApoE- / - mice treated with cyclodextrin (apoE CD) showed reduced paw swelling compared to untreated apoE- / - mice (apoENT).

[0153] Figure 2 Microscopic images are shown of female WT or apoE- / - mice at 17 weeks of age after receiving four subcutaneous injections of cyclodextrin (CD; 2 g / kg body weight) or saline (control group, NT) every other day for a total of four times. Neutral lipid staining of paw skin sections was performed using Oil Red O (red staining) to determine lipid accumulation in the tissue. Untreated apoE- / - mice (apoE NT) showed lipid accumulation in the skin compared to untreated wild-type mice (WT NT). Conversely, apoE- / - mice treated with cyclodextrin (apoE CD) showed reduced lipid accumulation compared to untreated apoE- / - mice.

[0154] Figure 3 The relative fluorescence in lymph nodes of female WT or apoE- / - mice after receiving four subcutaneous injections of cyclodextrin (CD; 2 g / kg body weight) or saline (control group, NT) every other day is shown. Mice on a high-fat diet were harvested at 17 weeks of age. Lymphatic drainage was assessed by measuring the transport of fluorescent dextran from the paw (injection site) to the draining lymph nodes.

[0155] Next, the effect of cyclodextrin on lymphatic function was tested. This improvement was observed in apoE- / - mice treated with 2, 4, or 8 doses every other day. Two doses improved lymphatic function, but to a lesser extent than four doses. Eight doses did not further enhance lymphatic function in apoE- / - mice compared to four doses, as four doses had already completely restored lymphatic function in these mice. Figure 4 ).

[0156] Figure 4 Relative fluorescence in lymph nodes of mice under different dosing regimens is shown. Seventeen-week-old female wild-type (WT) or apoE- / - mice were subcutaneously administered 2, 4, or 8 doses of cyclodextrin (2 g / kg body weight) every other day (SCD: 2 doses; UCD: 4 doses (standard treatment); and LCD: 8 doses). Untreated (NT) treated WT and apoE mice received 4 doses of saline. Lymphatic transport was assessed as follows.Figure 3 Two doses of cyclodextrin were sufficient to improve lymphatic function in apoE- / - mice, but four doses of cyclodextrin completely restored lymphatic function. Long-term treatment did not further improve lymphatic function in apoE- / - mice.

[0157] It was thus demonstrated that subcutaneous treatment with cyclodextrin formulations reduces lipid accumulation in lymphedema skin and tissue edema. In addition, it also restores lymphatic transport. Since lipid accumulation initiates adipose tissue remodeling and subsequent inflammation and fibrosis in human lymphedema, it is believed that cyclodextrin compositions can be used to treat lymphedema.

[0158] Treatment of apoE- / - mice, an animal model that recapitulates the pathophysiology of lymphedema, with cyclodextrin reduced tissue cholesterol, but did not affect plasma cholesterol levels, indicating that cyclodextrin has the efficacy to remove cholesterol from the skin. Figure 6 ).

[0159] Figure 6 Total cholesterol concentrations analyzed in the forepaw plantar of wild type (n=4), apoE- / - mice (n=4), 4 doses treated apoE- / - mice (n=2) and 8 doses treated apoE- / - mice (n=5) at 17 weeks of age are shown. *p<0.05. Total cholesterol levels in the forepaw plantar of apoE- / - mice decreased with increasing doses of cyclodextrin. Cyclodextrin was administered subcutaneously every other day.

[0160] It was evaluated whether the formulation could reverse some of the tissue changes associated with lymphedema, including fibrosis and inflammation. apoE- / - mice treated with cyclodextrin, particularly the 8-dose regimen, reduced fibrosis Figure 7A ) and inflammation Figure 7B ), which can be illustrated by a reduction in collagen deposition and macrophage infiltration in adipose tissue. These data suggest that lymphedema can be improved by cyclodextrin treatment.

[0161] Figure 7A Masson's trichrome staining of the dorsal skin of wild type, untreated apoE- / - mice, 4-dose treated mice and 8-dose treated mice at 17 weeks of age is shown. Collagen is stained blue, muscle and cytoplasm are stained red, and nuclei are stained black.

[0162] Figure 7BImmunofluorescence staining of dorsal skin of 17-week-old wild-type, untreated apoE- / - mice and cyclodextrin-treated apoE- / - mice is shown. CD68 is a pan-macrophage marker, perilipin was used to identify adipocytes, and DAPI stains the nuclei. With increasing doses of cyclodextrin, the extent of macrophage accumulation and the crown-like structures (white boxes) decreased as shown by CD68 staining.

[0163] The efficacy of 8 doses of cyclodextrin treatment was tested in the context of lymphatic dysfunction and more severe disease. The test was performed on 42-week-old mice, rather than 17-week-old mice. At 8 doses, it was observed that cyclodextrin did not improve lymphatic function and did not improve tissue changes such as tissue swelling.

[0164] Figure 8A Lymphatic function of 42-week-old WT, untreated apoE- / - and cyclodextrin 8-dose treated apoE- / - was assessed by quantifying the amount of FITC-dextran from the plantar to the draining lymph node is shown.

[0165] Figure 8B Visual inspection of plantar tissue swelling of 42-week-old WT, untreated apoE- / - and cyclodextrin 8-dose treated apoE- / - is shown.

[0166] In summary, these data further support the potential therapeutic effect of cyclodextrin on lymphedema by reducing tissue cholesterol and subsequent adipose tissue remodeling, fibrosis and inflammation.

[0167] It is understood that many further modifications and permutations can be made to the described embodiments. Accordingly, the described aspects are intended to embrace all such alterations, modifications, and variations that fall within the spirit and scope of the appended claims.

[0168] In this specification and the following claims, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integer or step.

[0169] In this specification and the following claims, unless the context otherwise requires, the phrase "consisting essentially of" and variations such as "consistses essentially of" will be understood to indicate that the listed elements are fundamental, i.e., essential, elements of the invention. This phrase allows for the presence of other non-listed elements that do not substantially affect the features of the invention, but excludes other unspecified elements that would affect the fundamental and novel features of the defined method.

[0170] References to any prior publications (or information obtained from them) or any known matters in this specification are not, and should not be construed as, an admission or endorsement or, in any way, an implication that such prior publications (or information obtained from them) or known matters constitute part of the general knowledge in the field of effort covered by this specification.

Claims

1. Use of a composition in the manufacture of a medicament for treating lymphedema, the composition comprising a pharmaceutically active component consisting of a cyclodextrin or a pharmaceutically acceptable salt thereof or a hydrate thereof; wherein the internal cavity of the cyclodextrin is unoccupied; wherein the weight ratio of cyclodextrin to the composition is 0.1% w / w to 50% w / w.

2. The use of claim 1, wherein the composition to be administered improves or reduces tissue edema, lymphatic function, lipid accumulation, tissue cholesterol, fibrosis, inflammation, or a combination thereof.

3. The use of claim 1 or 2, wherein the composition is to be administered on alternate days.

4. The use of claim 1 or 2, wherein the composition is to be administered at least 2 doses over at least 4 days.

5. The use of claim 1 or 2, wherein the composition is to be administered at a dose of 0.5 g / kg to 10 g / kg.

6. The use of claim 1 or 2, wherein the composition is to be administered to a patient in need thereof having a lymphedema severity of stage 2 or below.

7. The use of claim 1 or 2, wherein the cyclodextrin is derivatized with an alkyl, alkenyl, alkynyl, alkoxy, hydroalkyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, alkyl acyl, alkenyl acyl, alkynyl acyl, aryl, or alkyl aryl.

8. The use of claim 1 or 2, wherein the cyclodextrin is derivatized with a methyl, ethyl, propyl, hydro methyl, hydro ethyl, hydro propyl, fluorine, chlorine, bromine, benzyl, or phenyl.

9. The use of claim 1 or 2, wherein the cyclodextrin is derivatized 1 to 24 times.

10. The use of claim 1 or 2, wherein the cyclodextrin is a β-cyclodextrin selected from methyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, or a combination thereof.

11. The use according to claim 1 or 2, wherein the diameter of the internal cavity of the cyclodextrin is to 12. The use of claim 1 or 2, wherein the internal cavity of the cyclodextrin is unoccupied or occupied by an inert molecule.

13. The use of claim 1 or 2, the composition further comprising an excipient selected from a stabilizer, a solubilizer, a surfactant, a water-soluble polymer, a pH adjuster, a filler, a binder, a pigment, a disintegrant, an antioxidant, a preservative, an emollient, a silicone, a penetration enhancer, a lubricant, and a fragrance.

14. The use of claim 13, wherein the excipient is selected from microcrystalline cellulose, a metal salt of an acid, a fatty acid, a hydrocarbon, a fatty alcohol, a fatty acid ester, an alkyl sulfate, a polymer, and an inorganic material.

15. The use of claim 13, wherein the excipient is selected from microcrystalline cellulose, aluminum stearate, calcium stearate, magnesium stearate, sodium stearate, zinc stearate, stearic acid, palmitic acid, liquid paraffin, stearyl alcohol, palmitoyl alcohol, glycerol monostearate, glycerol distearate, glycerol triester, glycerol palmitostearate, sorbitan monostearate, sucrose monostearate, sucrose monopalmitate, sodium stearyl fumarate, sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol, polyoxyethylene glycol, polytetrafluoroethylene, talc, calcium hydrogen phosphate, and sodium carboxymethyl starch.

16. The use of claim 1 or 2, wherein the composition is an intradermal composition.

17. The use of claim 16, wherein the intradermal composition comprises an aqueous medium.

18. The use of claim 17, wherein the aqueous medium is selected from the group consisting of 0.9% NaCl saline solution, 0.9% KCl saline solution, lactated Ringer's solution, acetic Ringer's solution, intravenous dextrose solution, 5% dextrose in normal saline solution (D5NS), 10% dextrose in normal saline solution (D10NS), 5% dextrose in half normal saline solution (D5HNS), 10% dextrose in half normal saline solution (D10HNS), phosphate buffered saline (PBS), TRIS buffered saline (TBS), Hank's balanced salt solution (HBSS), Earle's balanced salt solution (EBSS), standard citrate saline (SSC), HEPES buffered saline (HBS), and Gey's balanced salt solution (GBSS).

19. The use of claim 17 or 18, wherein the weight ratio of the aqueous medium to the composition is from 0.1% w / w to 50% w / w.

20. The use of claim 16, wherein the intradermal composition comprises an excipient selected from the group consisting of sodium carboxymethylcellulose, microcrystalline cellulose, cresol, methyl paraben, and propyl paraben.

21. The use of claim 20, wherein the weight ratio of the excipient to the intradermal composition is from 0.1% w / w to 50% w / w.

22. The use of claim 1 or 2, wherein the composition is a topical composition selected from the group consisting of a topical cream and a topical gel.

23. The use of claim 22, wherein the topical composition further comprises an excipient selected from the group consisting of a carrier, an emulsifier, and / or a thickening agent.

24. The use of claim 22, wherein the topical composition further comprises an excipient selected from acacia, acetic acid, acetone, acetyl triethyl citrate, agar, alcohol, alginic acid, almond oil, alpha-tocopherol, aluminum monostearate, aluminum stearate, aluminum oxide, ascorbic acid, ascorbyl palmitate, bentonite, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, benzyl benzoate, boric acid, bronopol, butylated hydroxyanisole, butylated hydroxytoluene, butylene glycol, butyl paraben, calcium acetate, calcium alginate, calcium chloride, calcium hydroxide, calcium lactate, carbomer, carboxymethylcellulose sodium, carrageenan, castor oil, microcrystalline cellulose, ceresin, cetearyl alcohol, cetrimide, cetyl alcohol, chlorocresol, chloroxylenol, cholesteryl chloride, citric acid, colloidal silicon dioxide, cresol, cross-linked polyplarone, cyclomethicone, denatonium benzoate, dibutyl phthalate, diethanolamine, dimethicone, dimethyl phthalate, dimethylacetamide, edetate disodium, docusate sodium, ethyl acetate, ethyl lactate, ethyl oleate, ethylene-vinyl acetate, ethyl paraben, gelatin, glycerin, glyceryl monooleate, glyceryl monostearate, tetraethylene glycol, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, imidurea, isopropyl alcohol, isopropyl myristate, isopropyl palmitate, kaolin, lactic acid, lanolin, lecithin, linoleic acid, silicates, malic acid, mannitol, methyl cellulose, methyl paraben, monothioglycerol, myristic acid, myristyl alcohol, oleic acid, oleyl alcohol, palmitic acid, paraffin, petrolatum, phenoxyethanol, poloxamer, polycarbophil, polyethylene glycol, poly(methyl acrylate), polyoxyl, polyvinyl alcohol, povidone, propylene glycol, propyl paraben, pyrrolidone, sodium hyaluronate, sodium lactate, sodium lauryl sulfate, sorbitan esters, sorbitol, starch, tricaprylin, triethanolamine, xanthan gum, or xylitol.

25. The use of claim 23, wherein the excipient is in a weight ratio of 0.1% w / w to 50% w / w to the topical composition.

26. The use of claim 1 or 2, wherein the composition is applied to a transdermal patch.

27. The use of claim 26, wherein the composition is applied as a layer within the transdermal patch or on the surface of the transdermal patch.

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