Classifications

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  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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  • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
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  • A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
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  • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
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  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
  • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
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  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
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  • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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  • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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Definitions

• Diabetes is a metabolic disease characterized by the inability of the pancreas to secrete a level of insulin adequate to maintain a normal level of systemic glucose.
• pancreas to secrete a level of insulin adequate to maintain a normal level of systemic glucose.
• a method of treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a composition comprising an ionic liquid.
• the disease or disorder is diabetes. In some embodiments, the disease or disorder is Type 1 diabetes. In some embodiments, the disease or disorder is Type 2 diabetes. In some embodiments, the disease or disorder is non-alcoholic steatohepatitis.
• a method of treating obesity, preventing weight gain, or reducing weight in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a composition comprising an ionic liquid.
• the composition is administered via subcutaneous, intravenous, or oral administration. In some embodiments, the composition is administered via oral administration. In some embodiments, the composition is administered as a liquid-filled capsule. In some embodiments, the composition is administered in a single dose. In some embodiments, the composition is administered in multiple doses. In some embodiments, the composition is administered to a mucus membrane.
• the composition comprises the ionic liquid at a concentration of at least 0.1% weight per volume. In some embodiments, the composition comprises the ionic liquid at a concentration of at least 0.05M. In some embodiments, the ionic liquid comprises a catiomanion ratio of from about 4: 1 to about 1 :4.
• the ionic liquid is represented by Formula (I): wherein:
• R 1 , R 2 , R 3 , R 4 , and R 5 are independently selected from hydrogen, halo, cyano, nitro, amino, C 1-6 alkoxy, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl; and R 6 is selected from C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl.
• At least two of R 1 , R 2 , R 3 , R 4 , and R 5 are hydrogen. In some embodiments, at least three of R 1 , R 2 , R 3 , R 4 , and R 5 are hydrogen. In some embodiments, R 1 , R 2 , R 3 , R 4 , and R 5 are hydrogen.
• R 6 is selected from C 1-6 alkyl and C 2-6 alkenyl. In some embodiments, R 6 is C 1-6 alkyl. In some embodiments, R 6 is Cialkyl. In some embodiments, R 6 is C 1-6 alkenyl. In some embodiments, R 6 is Cialkenyl.
• the ionic liquid is represented by Formula (II): wherein:
• R is selected from C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl.
• R is C 1-6 alkyl. In some embodiments, R is Cialkyl. In some embodiments, R is Cgalkyl.
• the ionic liquid is represented by Formula (III):
• the ionic liquid comprises a cholinium cation and an anion selected from cinnamate, hydrocinnamate, malonate, citronellate, and glutarate.
• the anion is selected from cinnamate, hydrocinnamate, and citronellate.
• the composition further comprises one or more additional agents.
• the one or more additional agents are selected from a nucleic acid, a small molecule, and a polypeptide.
• the one or more additional agents comprise a nucleic acid.
• the one or more additional agents comprise a small molecule.
• the one or more additional agents comprise a polypeptide.
• the one or more additional agents are selected from a glucagon-like peptide (GLP-1), a glucagon-like peptide derivative, and a glucagon-like peptide mimetic.
• the one or more additional agents are selected from liraglutide, exenatide, and semaglutide.
• the one or more additional agents comprise liraglutide.
• the one or more additional agents are selected from insulin and pramlintide.
• the composition further comprises a pharmaceutically acceptable excipient.
• composition comprising an ionic liquid, wherein the ionic liquid comprises choline and hydrocinnamic acid in a 1 :2 molar ratio.
• composition comprising an ionic liquid, wherein the ionic liquid comprises choline and cinnamic acid in a 1 : 1 molar ratio.
• composition comprising an ionic liquid, wherein the ionic liquid comprises choline and glutaric acid in a 1 : 1 molar ratio.
• composition comprising an ionic liquid, wherein the ionic liquid comprises choline and malonic acid in a 1 : 1 molar ratio.
• composition comprising an ionic liquid, wherein the ionic liquid comprises choline and octenoic acid in a 1 : 1 molar ratio.
• composition comprising an ionic liquid, wherein the ionic liquid comprises choline and octenoic acid in a 1 :2 molar ratio.
• composition comprising an ionic liquid, wherein the ionic liquid comprises choline and citronellic acid in a 1 : 1 molar ratio.
• composition comprising an ionic liquid, wherein the ionic liquid comprises choline and citronellic acid in a 1 :2 molar ratio.
• the composition further comprises one or more additional agents.
• the one or more additional agents are selected from a nucleic acid, a small molecule, and a polypeptide.
• the one or more additional agents comprise a nucleic acid.
• the one or more additional agents comprise a small molecule.
• the one or more additional agents comprise a polypeptide.
• the one or more additional agents are selected from a glucagon-like peptide (GLP-1), a glucagon-like peptide derivative, and a glucagon-like peptide mimetic.
• the one or more additional agents are selected from liraglutide, exenatide, and semaglutide.
• the one or more additional agents comprise liraglutide.
• the one or more additional agents are selected from insulin and pramlintide.
• composition comprising a composition described herein and a pharmaceutically acceptable excipient
• FIG. 3 shows the amino acid sequence of Liraglutide.
• FIG. 6 shows various ionic liquids which are not liquid at room temperature.
• FIG. 7 shows the change in blood glucose levels over time following intrajejunal administration of choline-citronellic acid to non-diabetic rats.
• FIG. 9 shows the change in blood glucose levels over time following administration of citronellic acid to non-diabetic rats.
• FIG. 11 shows the change in blood glucose levels over time following oral administration of choline-citronellic acid to diabetic rats.
• FIG. 12 shows the change in plasma insulin levels over time following intrajejunal, subcutaneous, and oral administration of choline-citronellic acid to diabetic rats.
• FIG. 13 shows the change in blood glucose levels and glucose levels in the urine over time following intrajejunal administration of choline-citronellic acid to non-diabetic rats.
• FIG. 14 shows the change in serum liraglutide levels over time following intrajejunal administration of choline-hydrocinnamic acid and liraglutide to non-diabetic rats.
• FIG. 17 shows Semaglutide in Choline-Cinnamic Acid 1 : 1 delivered to the stomach in 0, 00 or 000 gelatin capsules coated with Evonik EPO coating or 0 HPMC capsules.
• a 3- to 8-membered heteroalkyl has a chain length of 3 to 8 atoms. Connection to the rest of the molecule may be through either a heteroatom or a carbon in the heteroalkyl, heteroalkenyl or heteroalkynyl chain. Unless stated otherwise specifically in the specification, a heteroalkyl, heteroalkenyl, or heteroalkynyl group is optionally substituted by one or more substituents such as those substituents described herein.
• the term "ionic liquids” as used herein refers to organic salts or mixtures of organic salts which exist in a liquid state. Ionic liquids have been shown to be useful in a variety of fields, including in industrial processing, catalysis, pharmaceuticals, and electrochemistry.
• the properties of an ionic liquid are determined by the ionic interactions between the anion and the cation. In some embodiments, the properties of an ionic liquid are determined by the hydrogen bonding interactions between the anion and cation. The relative contribution of ionic and hydrogen bonding interactions to the properties of the ionic liquid may vary depending on the nature of the ions.
• the composition comprises the ionic liquid at a concentration of at least 0.7M. In some embodiments, the composition comprises the ionic liquid at a concentration of at least 0.8M. In some embodiments, the composition comprises the ionic liquid at a concentration of at least 0.9M. In some embodiments, the composition comprises the ionic liquid at a concentration of at least 1.0M.
• the ionic liquid comprises a catiomanion ratio of from about 4: 1 to about 1 :4. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 4.4: 1. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 4.3: 1. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 4.2: 1. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 4.1 : 1. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 4.0: 1.
• the ionic liquid comprises a catiomanion ratio of about 1.8: 1. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 1.7: 1. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 1.6: 1. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 1.5: 1. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 1.4: 1. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 1.3: 1. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 1.2:1.
• the ionic liquid comprises a catiomanion ratio of about 1 : 1.6. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 1 : 1.7. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 1 : 1.8. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 1 : 1.9. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 1 :2. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 1 :2.1. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 1 :2.2.
• the ionic liquid comprises a catiomanion ratio of about 1 :2.3. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 1 :2.4. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 1 :2.5. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 1 :2.6. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 1 :2.7. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 1 :2.8. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 1 :2.9.
• the ionic liquid comprises a catiomanion ratio of about 1 :3.0. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 1 :3.1. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 1 :3.2. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 1 :3.3. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 1 :3.4. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 1 :3.5. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 1 :3.6.
• the ionic liquid comprises a catiomanion ratio of about 1 : 1.5. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 1 : 1.6. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 1 : 1.7. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 1 : 1.8. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 1 : 1.9. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 1 :2. In some embodiments, the ionic liquid comprises a catiomanion ratio of about 1 :2.1.
• the ionic liquid comprises any one of the cations listed in Table 1. In some embodiments, the ionic liquid comprises any one or more of the cations listed in Table 1. In some embodiments, the ionic liquid comprises any one of the anions listed in Table 1. In some embodiments, the ionic liquid comprises any one or more of the anions listed in Table 1. In some embodiments, the ionic liquid comprises any one of the catiomanion ratio listed in Table 1. In some embodiments, the composition as provided herein comprises any one of the ionic liquids listed in Table 1. In some embodiments, the composition as provided herein comprises any one or more of the ionic liquids listed in Table 1.
• the one or more drugs may be designed with the intent of treating a local tissue, e.g., the mucosal membrane of the intestine, treating a distant tissue, e.g., the liver, or entering systemic circulation.
• a composition as described herein can further comprise a pharmaceutically acceptable excipient.
• suitable excipients include, for example, water, saline, glycerol, ethanol, or the like, and combinations thereof.
• the composition can contain minor amounts of additional excipients such as emulsifying agents, surfactants, pH buffering agents, and the like, which enhance the effectiveness of the one or more drugs.
• formulation may require excipients sugars (such as lactose), starches (such as corn starch), cellulose, cellulose derivatives (such as sodium carboxymethyl cellulose), gelatin, and other compatible substances.
• excipients sugars such as lactose
• starches such as corn starch
• cellulose such as sodium carboxymethyl cellulose
• gelatin such as gelatin
• a composition comprising an ionic liquid described herein further comprises one or more additional agents.
• the one or more additional agents are selected from a nucleic acid, a small molecule, and a polypeptide.
• the one or more additional agents comprise a nucleic acid.
• the one or more additional agents comprise a small molecule.
• the one or more additional agents comprise a polypeptide.
• the polypeptide comprises an Antibody.
• the Antibody comprises any one selected from Fragment Antigen-binding (Fab, F(ab’)2), single chain variable fragment (scFv), and Nanobodies.
• the one or more additional agents are selected from a glucagon-like peptide (GLP-1), a glucagon-like peptide derivative, and a glucagon-like peptide mimetic.
• the one or more additional agents are selected from liraglutide, exenatide, and semaglutide.
• the one or more additional agents comprise liraglutide.
• Metabolic disorders include but are not limited to obesity, diabetes, fatty liver disease, or non-alcoholic fatty liver disease.
• described herein is a method of treatment of diabetes comprising orally administering an oral formulation of insulin in combination with an ionic liquid.
• described herein is a method of treatment of diabetes comprising orally administering an oral formulation of insulin and pramlintide in combination with an ionic liquid.
• described herein is a method of treatment of diabetes comprising orally administering an oral formulation of liraglutide or exenatide in an ionic liquid.
• ionic liquids are able to safely carry active compounds across the mucus membranes encountered during oral administration.
• ionic liquids when administered together with one or more drugs, solubilize the one or more drugs and result in enhanced delivery into systemic circulation. Accordingly, they are particularly suitable as delivery vehicles to and/or across mucus membranes.
• a method of delivery of one or more drugs comprising administering the one or more drugs in combination with an ionic liquid to a mucus membrane, e.g., a nasal, oral, or vaginal membrane.
• a method of delivery of one or more drugs comprising administering the one or more drugs at the dose of 0.01 mg/kg, 0.02 mg/kg, 0.03 mg/kg, 0.04 mg/kg, 0.05 mg/kg, 0.06 mg/kg, 0.07 mg/kg, 0.08 mg/kg, 0.09 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 3.0 mg/kg, 4.0 mg/kg, 5.0 mg/kg, 6.0 mg/kg, 7.0 mg/kg, 8.0 mg/kg, 9.0 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 150 mg/kg, 200 mg/kg,
• GLP-1 Glucagon-Like Peptide- 1
• FIG. 1 The amino acid sequence of GLP-1 is shown in FIG. 1.
• GLP-1 is an incretin derived from the transcription product of the proglucagon gene that contributes to glucose homeostasis. Because natural GLP-1 has an extremely short half-life, making its use as a therapeutic challenging, modified versions of GLP-1 with greater stability have been developed. Such modifications can be performed either by varying the sequence of the peptide or by conjugating another entity to the peptide. A common modification includes attachment of a lipid tail.
• GLP-1 mimetics are currently being used in the treatment of Type 2 diabetes, with recent clinical trials demonstrating that these treatments improve glucose homeostasis. They also help in achieving weight loss.
• a method of treatment of diabetes comprising orally administering an oral formulation of a GLP-1 polypeptide or mimetic/analog thereof in combination with ionic liquid.
• compositions provided herein can be used to treat obesity by delivering a composition comprising an ionic liquid and a GLP-1 analog.
• compositions provided herein can be used to treat obesity by dual action of the ionic liquid and the GLP-1 analog.
• Certain ionic liquids reduce fat absorption across the intestinal mucosa.
• the net result of the composition on reduced body weight may arise from a combination of reduced fat absorption, reduced food uptake, and increased delivery of a GLP-1 analog.
• ionic liquids comprising choline as a cation and various anions were synthesized.
• 2, 1, 0.5, or 0.33 equivalents of choline bicarbonate 80 wt% solution
• a co-solvent such as ethanol
• choline-tartaric acid (1:1) is a solid
• choline-decanoic acid (1:1) is a waxy solid.
• Various nonliquid compositions are shown in FIG. 6. Ionic liquids that exist in a liquid form at room temperature are particularly suitable for the pharmaceutical applications described herein.
• Example 5 Effect on Blood Glucose Levels Following Choline-Citronellic Acid Administration
• the blood glucose level dropped in a dose-dependent manner.
• the glucose level dropped by about 70% from baseline. This scale of reduction in blood glucose level would likely be efficacious in the treatment of diabetes.
• Example 6 Effect on Blood Glucose Levels Following Choline-Octanoic Acid and Choline- Octenoic Acid Administration
• Example 8 Reduction in Blood Glucose Levels Following Oral and Subcutaneous Choline- Citronellic Acid Administration
• Example 9 Reduction in Blood Glucose Levels Following Oral Choline-Citronellic Acid Administration in a Rat Model of Type 1 Diabetes
• Example 10 Induced Insulation Secretion Following Choline-Citronellic Acid Administration in a Rat Model of Type 1 Diabetes
• Example 11 Increased Glucose Excretion in Urine Following Choline-Citronellic Acid Administration
• choline-citronellic acid reduced the ability of the kidneys to reabsorb glucose, enhancing the amount of glucose removal from the body and helping to reduce blood glucose levels.
• liraglutide When delivered as a choline-hydrocinnamic acid formulation, liraglutide was delivered into blood circulation with surprisingly high serum concentration. Oral delivery of liraglutide is known to be difficult. For example, Buckley and coworkers demonstrated only minute absorption of liraglutide even in the presence of well-known permeation enhancers (Sci. Transl. Med. 2018, 10, eaar7047). The blood concentrations of liraglutide reported herein are approximately 4,400-fold greater than those reported in the literature.
• Example 13 Delivery of Liraglutide With Various Choline-Based Ionic Liquids
• the amount of liraglutide delivered depended on the composition of the ionic liquid. Choline-citronellic acid yielded a modest but significant absorption to yield a peak concentration of 4.5 ng/mL. Choline-linoleic acid improved the concentration by about 10-fold to 44 ng/mL.
• Choline-malonic acid further improved the absorption to yield a blood liraglutide concentration of 365 ng/mL.
• choline-hydrocinnamic acid yielded a blood liraglutide concentration of greater than 2000 ng/mL, a 500-fold improvement over choline-citronellic acid.
• Example 14 Lira-C-Cinnamic l:l/dogs - delivery of Liraglutide With Choline-Cinnamic Acid 1:1 to the stomach or duodenum
• Example 15 Exenatide-C-Cinnamic l:l/dogs - delivery of Exenatide With Choline-Cinnamic Acid 1:1 to the stomach
• Example 16 Semaglutide-C-Cinnamic 1:1 capsules/dogs - delivery of Semaglutide With Choline-Cinnamic Acid 1:1 to the stomach in gelatin and HPMC capsules
• Example 17 Semaglutide-C-Cinnamic l:l/dogs - delivery of Semaglutide With Choline- Cinnamic Acid 1:1 to the stomach
• Example 18 mixture of Liraglutide/Exenatide - co-delivery of Liraglutide and Exenatide With Choline-Cinnamic Acid 1:1
• Sections of organs (heart, lungs, liver, kidneys, and spleen) and all GI tract sections (stomach, duodenum, jejunum, ileum and colon) were stained with H&E and an expert pathologist read the results, concluding that there was no significant difference found in their histological examination of IL or saline (placebo) dosed animals’ organs and GI tract tissues (FIG. 20). Blood cell counts were not statistically significantly different between the IL-dosed and placebo groups for either dose level, nor were plasma indicators of organ toxicity (FIG. 21).
• Example 20 Delivery of drugs formulated with Choline-Cinnamic Acid in various cation:anion ratios to the stomach or duodenum
• Control groups include intravenous (IV) and subcutaneous (SC) dosing.
• IV intravenous
• SC subcutaneous
• Example 21 Delivery of drugs formulated with various ionic liquids to the stomach or duodenum
• Choline-Hydrocinnamic acid Choline-Glutaric acid, Choline-Malonic acid, Choline-Octenoic acid, or Choline-Citronellic acid is formulated at any of the ratio as described in paragraphs [0085] or [0087], Dogs are recovered and plasma is collected over a 12h period.
• Control groups include intravenous (IV) and subcutaneous (SC) dosing.
• IV intravenous
• SC subcutaneous
• the same dose of the unformulated drug for example,.
• Liraglutide, Exenatide, or Semaglutide is also administered to the stomach endoscopically.

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