Synergistic permeability enhancer for the inner layer of gastrointestinal synthetic epithelium

Abstract

This disclosure relates to a "synthetic endothelial lining" or "GSEL," a synthetic lining of the gastrointestinal (GI) tubule, which can modulate the absorption of drugs, nutrients, and other substances in the GI tubule, and to synergistic combinations of permeabilis enhancers that aid such absorption. GSEL is a transient lining on the inner surface of the lumen of the GI tubule, which maintains close contact between its activator (e.g., drug, nutrient, or other substance) and the GI mucosa, thereby enabling the activator to be absorbed over a longer period.

Description

[Technical Field]

[0001] Cross-reference of related applications This patent application claims priority to U.S. Provisional Patent Application No. 63 / 541,237 filed September 28, 2023, U.S. Provisional Patent Application No. 63 / 623,109 filed January 19, 2024, and U.S. Provisional Patent Application No. 63 / 673,614 filed July 19, 2024. The contents of these applications are incorporated herein by reference in their entirety.

[0002] The present invention relates to a synthetic inner lining for gastrointestinal (GI) tubules that can regulate the absorption of drugs, nutrients, and other substances in the GI tubule, and a synergistic combination of permeabilis enhancers that assist such absorption. [Background technology]

[0003] The gastrointestinal (GI) tract in humans, vertebrates, and other animals functions as a highly versatile organ system with multiple functions. The primary function of the GI tract is the absorption of substances, such as nutrients, from food. Because oral administration of drugs is convenient compared to other methods such as injection or inhalation, absorption of substances in the GI tract is widely used for the administration of pharmaceuticals. Multiple diverse forms of oral drug administration are available, including both immediate-release and sustained-release formulations.

[0004] However, because the epithelial layer acts as a barrier to certain types of substances, many drugs cannot be administered orally. Various physical and chemical properties of certain drugs prevent them from passing through the epithelium inside the GI duct. Drugs, especially biologics, may be too large to be transported through the epithelium. Other properties that affect transport include electric charge and hydrophobicity.

[0005] This disclosure provides gastrointestinal synthetic lining of epithelium (GSEL) in combination with a synergistic combination of permeabilis enhancers that are particularly effective in promoting drug absorption in the gastrointestinal tract. The synergistic combination of permeabilis enhancers disclosed herein for use with gastrointestinal synthetic lining of epithelium results in higher levels of drug absorption compared to the individual permeabilis enhancers. [Overview of the Initiative]

[0006] This disclosure relates to a synthetic lining formed in situ within the gastrointestinal tract, such as the small intestine, wherein the synthetic lining is used in combination with a drug and a permeabilis enhancer, the enhancer synergistically increasing the absorption of the drug through the intestinal tissue. The synthetic lining itself is called the gastrointestinal synthetic epithelial lining (GSEL).

[0007] This specification discloses orally administered compositions for forming polymers in situ in a subject to facilitate drug permeation, the compositions comprising a polymer precursor, an oxygen source, and a combination of a permeation enhancer comprising at least one of ammonium salts, carbonates, or bicarbonates, and at least one of bile salts or bile acids. In some embodiments, the compositions further comprise one or more agents. In some embodiments, the one or more agents comprise one or more active pharmaceutical ingredients. In some embodiments, the ammonium salt, carbonate, or bicarbonate is an ammonium salt. In some embodiments, the ammonium salt, carbonate, or bicarbonate is a carbonate. In some embodiments, the ammonium salt, carbonate, or bicarbonate is a bicarbonate. In some embodiments, the bile salt or bile acid is a bile salt. In some embodiments, the bile salt or bile acid is a bile acid. In some embodiments, the ammonium salt is ammonium carbonate (NHCO), ammonium sulfate (NHSO), ammonium citrate (NHCA), ammonium phosphate (NHPO), diammonium phosphate (DAP), monoammonium phosphate (MAP), ammonium bicarbonate (NHHCO), or ammonium chloride (NHCl). In some embodiments, the ammonium salt is ammonium carbonate. In some embodiments, the ammonium salt is ammonium bicarbonate. In some embodiments, the carbonate is sodium carbonate or potassium carbonate. In some embodiments, the bicarbonate is sodium bicarbonate or potassium bicarbonate.In some embodiments, bile salts or bile acids are bile acids, and bile acids include cholic acid (CHA), glycocholic acid (GCA), deoxycholic acid (DCA), glycochenodeoxycholic acid (GCDCA), glycodeoxycholic acid (GDCA), taurodeoxycholic acid (TDCA), taurocholic acid (TCA), bovine bile (OX), chenodeoxycholic acid (CDCA), taurochenodeoxycholic acid (TCDCA), litcholic acid (LCA), glycolicotocholic acid (GLC), glycohyocholic acid (GHC), and taurolic acid. These are bile acids (TLC), ursodeoxycholic acid (UDCA), tauroursodeoxycholic acid (TUDCA), glycoursodeoxycholic acid (GUDCA), 12-monoketocholic acid (12-MKC), 7-monoketocholic acid (7-MKC), 7,12-diketocholic acid (7,12-DKC), 3,7,12-tricketocholic acid (3,7,12-TKC), 12-monoketodeoxycholic acid (12-MKDC), or 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS). In some embodiments, the bile salt or bile acid is a bile acid, and the bile acid is a glycocholic acid. In some embodiments, the ammonium salt, carbonate, or bicarbonate is an ammonium salt, the ammonium salt is ammonium carbonate, the bile salt or bile acid is bile acid, and the bile acid is glycocholic acid.In some embodiments, bile salts or bile acids are bile salts, and bile salts are salts of cholic acid, glycocholic acid, deoxycholic acid, glycochenodeoxykrylic acid, glycodeoxycholic acid, taurodeoxycholic acid, taurocholic acid, bovine bile, chenodeoxycholic acid, taurochenodeoxycholic acid, litcholic acid, glycolicotocholic acid, glycohyocholic acid, ta These are salts of urolithocholic acid, ursodeoxycholic acid, tauroursodeoxycholic acid, glycoursodeoxycholic acid, 12-monoketocholic acid, 7-monoketocholic acid, 7,12-diketocholic acid, 3,7,12-triketocholic acid, 12-monoketodeoxycholic acid, or salts of 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate. In some embodiments, the bile salt or bile acid is a bile salt, and the bile salt is a salt of glycocholic acid. In some embodiments, the ammonium salt, carbonate, or bicarbonate is an ammonium salt, and the ammonium salt is ammonium carbonate, and the bile salt or bile acid is a bile salt, and the bile salt is a salt of glycocholic acid. In some embodiments, an ammonium salt, carbonate, or bicarbonate is an ammonium salt, an ammonium salt is ammonium bicarbonate, a bile salt or bile acid is a bile salt, and a bile salt is a salt of glycocholic acid.In some embodiments, the bile salt or bile acid is a bile salt, and the bile salt is sodium cholate, sodium glycocholate, sodium deoxycholate, sodium glycochenodeoxycholate, sodium glycodeoxycholate, sodium taurodeoxycholate, sodium taurocholate, sodium bovine bile sodium salt, sodium chenodeoxycholate, sodium taurochenodeoxycholate, sodium lithocholate, sodium glycococholate, sodium glycohyocholate, sodium taurolitocholate, sodium ursodeoxycholate, sodium tauroursodeoxycholate, sodium glycoursodeoxycholate, sodium 12-monoketocholate, sodium 7-monoketocholate, sodium 7,12-diketocholate, sodium 3,7,12-triketocholate, sodium 12-monoketodeoxycholate, or sodium 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate. In some embodiments, the bile salt or bile acid is a bile salt, and the bile salt is sodium glycocholate. In some embodiments, the ammonium salt, carbonate, or bicarbonate is an ammonium salt, and the ammonium salt is ammonium carbonate; the bile salt or bile acid is a bile salt, and the bile salt is sodium glycocholate. In some embodiments, the ammonium salt, carbonate, or bicarbonate is an ammonium salt, and the ammonium salt is ammonium bicarbonate; the bile salt or bile acid is a bile salt, and the bile salt is sodium glycocholate.

[0008] In some embodiments, the composition further includes a buffer.

[0009] In some embodiments, the polymer precursor comprises one or both of a monomer and an oligomer precursor of the polymer. In some embodiments, the polymer precursor is selected from Table 1 or Table 2, or a combination thereof. In some embodiments, the monomer is dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, levodopa ethyl ester, or a combination thereof. In some embodiments, the monomer is dopamine. In some embodiments, the oligomer precursor of the polymer is an oligomer of dopamine, an oligomer of levodopa, an oligomer of norepinephrine, an oligomer of methyldopa, an oligomer of levodopa methyl ester, an oligomer of levodopa ethyl ester, or an oligomer of any combination of dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, or levodopa ethyl ester. In some embodiments, the oligomer precursor of the polymer is a dopamine oligomer. In some embodiments, the monomer is dopamine, and the oligomeric precursor of the polymer is an oligomer of dopamine. In some embodiments, the oxygen source is a substrate of the endogenous catalyst. In some embodiments, the oxygen source is urea peroxide or hydrogen peroxide.

[0010] In some embodiments, the composition is an oral dosage form. In some embodiments, the oral dosage form is a solution, gel, tablet, powder, or capsule. In some embodiments, the oral dosage form comprises one or more solutions, gels, tablets, powders, or capsules. In some embodiments, the oral dosage form includes an enteric-coated dosage form.

[0011] In some embodiments, the drug is a polymer having a molecular weight of about 1 kD to about 160 kD. In some embodiments, the polymer is a polypeptide or polynucleotide. In some embodiments, the polymer is a polypeptide. In some embodiments, the molecular weight of the polypeptide is about 1 kD to about 10 kD. In some embodiments, the polypeptide contains about 8 to about 80 amino acids. In some embodiments, the polypeptide comprises insulin, GLP-1 receptor agonists, liraglutide, desmopressin, octreotide, analgesic peptides, diferikephalin, H-20, antibiotics, cyclosporine, vancomycin, lactase, beta-galactosidase, exenatide, teriparatide, nafarelin, buserelin, captopril, daptomycin, antibodies, caplacizumab, ozoralizumab, brolucizumab, ranibizumab, bevacizumab, trastuzumab, rituximab, adalimumab, enzymes, lipase, protease, phenylalanine hydroxylase, carbamoyl phosphate synthetase I, glucose oxidase, or L-asparaginase. In some embodiments, the polypeptide comprises semaglutide. In some embodiments, the polypeptide comprises tylzepatide. In some embodiments, the polymer is a polynucleotide. In some embodiments, the molecular weight of the polynucleotide is about 5 kD to about 1500 kD. In some embodiments, the polynucleotide is single-stranded. In some embodiments, the polynucleotide is double-stranded. In some embodiments, the polynucleotide is single-stranded and contains about 10 to about 5000 bases. In some embodiments, the polynucleotide is single-stranded and contains about 10 to about 1000 bases. In some embodiments, the polynucleotide is single-stranded and contains about 10 to about 30 bases. In some embodiments, the polynucleotide is double-stranded and contains about 5 to about 2500 base pairs. In some embodiments, the polynucleotide is double-stranded and contains about 5 to about 500 base pairs. In some embodiments, the polynucleotide is double-stranded and contains about 5 to about 15 base pairs.In some embodiments, the polynucleotides include antisense oligonucleotides, mipomersen, patisirane, exondys, siRNA, or inflammatory bowel disease (IBD) targeted siRNA. In some embodiments, the drug is a small molecule having a molecular weight of 1 kD or less.

[0012] This specification discloses a method for forming a polymer coating within the gastrointestinal tract of a subject, the method comprising administering to the subject one of the compositions disclosed herein. In some embodiments, the polymer coating is formed in the small intestine of the subject. In some embodiments, the polymer coating is formed in the duodenum of the subject.

[0013] This specification discloses a method for forming a polymer coating within the gastrointestinal tract of a subject, the method comprising orally administering to the subject a combination of a polymer precursor, an oxygen source, and a permeabilis enhancer comprising at least one of an ammonium salt, a carbonate, or a bicarbonate, and at least one of a bile salt or a bile acid, wherein the polymer precursor and oxygen source come into contact with a catalyst inherent in the subject, and the catalyst polymerizes the polymer precursor. In some embodiments, the polymer coating is formed in the small intestine of the subject. In some embodiments, the polymer coating is formed in the duodenum of the subject. In some embodiments, the method further comprises administering one or more agents to the subject. In some embodiments, the combination of the polymer precursor, oxygen source, and permeabilis enhancer is administered as a single composition. In some embodiments, the combination of the polymer precursor, oxygen source, and permeabilis enhancer, and one or more agents are administered as a single composition. In some embodiments, one or more agents are administered in a composition separate from the administration of the combination of the polymer precursor, oxygen source, and permeabilis enhancer. In some embodiments, the agents are active pharmaceutical ingredients.

[0014] This specification discloses orally administered compositions for forming polymers in situ in a subject to facilitate drug permeation, the compositions comprising a polymer precursor, an oxygen source, and a combination of permeation enhancers, including a first permeation enhancer and a second permeation enhancer, wherein the combination of the first and second permeation enhancers increases drug permeation compared to the sum of the permeation of the individual drugs by each enhancer. In some embodiments, the first permeation enhancer is an ammonium salt. In some embodiments, the first permeation enhancer is a carbonate. In some embodiments, the first permeation enhancer is a bicarbonate. In some embodiments, the second permeation enhancer is a bile salt. In some embodiments, the second permeation enhancer is a bile acid. In some embodiments, the composition further comprises a drug. In some embodiments, the drug is an active pharmaceutical ingredient. In some embodiments, the drug comprises semaglutide. In some embodiments, the drug comprises tilzepatide. In some embodiments, the composition further comprises one or more additional drugs. [Brief explanation of the drawing]

[0015] [Figure 1A] A schematic diagram of the GSEL formulation mechanism and GSEL delivery mechanism is shown. [Figure 1B] A schematic diagram of the GSEL formulation mechanism and GSEL delivery mechanism is shown. [Figure 1C] A schematic diagram of a 96-well plate screen is shown. [Figure 1D]This table shows the average permeability percentage of the active pharmaceutical ingredient (API) semaglutide. Each data point represents the average permeability of the individual formulation. Short horizontal bars represent the average value. The data is normalized to the permeability of GSEL_40 and sorted by average permeability. The x-axis is displayed as an abbreviation of the excipient and its concentration in mg / ml (for example, CHA_80 represents 80 mg / ml of CHA, and CHA represents sodium cholate). All formulations contained GSEL_40 (9.8 mg / mL dopamine HCl, 25 mg / mL PDA nanoparticles, 0.67 mg / mL hydrogen peroxide, 2.2 mg / mL tris HCl, and 4.3 mg / mL Tris base). Table E1 of Example 1 provides a list of abbreviations used for the excipients. [Figure 1E] This shows the average permeability percentage of the active pharmaceutical ingredient (API) tilzepatide. Pm = (amount permeated through tissue) divided by (amount initially placed in the upper chamber) multiplied by 100. CV represents the coefficient of variation and is defined as (standard deviation) divided by (mean) multiplied by 100. Each data point represents the average permeability of the individual formulation. Short horizontal bars represent the mean. The data is sorted according to average permeability. The x-axis is labeled with excipient abbreviations and concentrations in mg / ml (e.g., CHA_80 indicates 80 mg / ml of CHA, and CHA indicates sodium cholate). All formulations contained GSEL_40 (9.8 mg / mL dopamine HCl, 25 mg / mL PDA nanoparticles, 0.67 mg / mL hydrogen peroxide, 2.2 mg / mL Tris HCl, 4.3 mg / mL Tris base; values ​​may vary by plus or minus 5%; pH 8.5). Table E1 of Example 1 provides a list of abbreviations used in the excipients, and Table E2 lists the %Pm values. [Figure 1F]This section summarizes the values ​​determined for each GSEL-single excipient combination. The transported active pharmaceutical ingredient (API) is semaglutide. Fifth-order GSEL (FC GSEL) measures the fifth-order change in permeability of each formulation including the excipient and normalizes it to the permeability of GSEL alone. Data are sorted by mean permeability. The numerical values ​​indicate the excipient concentration (e.g., GSEL-GCA_40-40 indicates 40 mg / ml GSEL and 40 mg / ml sodium glycocholate). Pm = (amount permeated through tissue) divided by (amount initially placed in the upper chamber) multiplied by 100. CV represents the coefficient of variation and is defined as (standard deviation) divided by (mean) multiplied by 100. [Figure 1G] This section summarizes the values ​​determined for each GSEL-single excipient combination. The transported active pharmaceutical ingredient (API) is tilzepatide. FC GSEL (Focused GSEL) measures the multiplier change in permeability of each formulation including the excipient and normalizes it by the permeability of the GSEL alone. The data are sorted by mean permeability. The values ​​indicate the excipient concentration. Pm = (amount permeated through tissue) divided by (amount initially placed in the upper chamber) multiplied by 100. CV represents the coefficient of variation and is defined as (standard deviation) divided by (mean) multiplied by 100. [Figure 1H] This graph shows the mean multiplier change in permeability of the gastrointestinal synthetic inner epithelium (GSEL), clustered by excipient class. The transported active pharmaceutical ingredient (API) is semaglutide. Multiplier change GSEL (FC GSEL) measures the multiplier change in permeability for each formulation containing the excipient and normalizes it to the permeability of GSEL only. Each data point represents the mean permeability of the individual formulation. Short horizontal bars represent the mean value. The data is sorted by the mean permeability of the class. The values ​​indicate the excipient concentration (mg / ml). [Figure 1I]Shown is the average fold change in permeability of the gastrointestinal synthetic epithelial inner layer (GSEL), clustered by excipient class. The active pharmaceutical ingredient (API) to be transported is tirzepatide. The fold change GSEL (FC GSEL) is determined by measuring the fold change in permeability of each formulation containing an excipient, and normalizing it to the permeability of GSEL alone. Each data point represents the average permeability of an individual formulation. Short horizontal bars represent the mean value. The data are sorted by the average permeability of the class. The values indicate the excipient concentration (mg / ml). [Figure 1J] Shown is the effect of excipient concentration on the average percent permeability of the active pharmaceutical ingredient (API) tirzepatide. Each data point represents the average permeability of an individual formulation. Short horizontal bars represent the mean value. The data are normalized to the permeability of GSEL_40 and sorted according to average permeability. The x-axis is displayed with excipient abbreviations and concentrations in mg / ml (for example, CHA_80 indicates 80 mg / ml CHA, and CHA indicates sodium cholate). All formulations contained GSEL_40 (9.8 mg / mL dopamine HCl, 25 mg / mL PDA nanoparticles, 0.67 mg / mL hydrogen peroxide, 2.2 mg / mL Tris HCl, 4.3 mg / mL Tris base). [Figure 1K] Shown is the effect of excipient concentration on the average percent permeability of the active pharmaceutical ingredient (API) tirzepatide. Each data point represents the average permeability of an individual formulation. Short horizontal bars represent the mean value. The data are normalized to the permeability of GSEL_40 and sorted according to average permeability. The x-axis is displayed with excipient abbreviations and concentrations in mg / ml (for example, CHA_80 indicates 80 mg / ml CHA, and CHA indicates sodium cholate). All formulations contained GSEL_40 (9.8 mg / mL dopamine HCl, 25 mg / mL PDA nanoparticles, 0.67 mg / mL hydrogen peroxide, 2.2 mg / mL Tris HCl, 4.3 mg / mL Tris base). [Figure 2A]Shown is the average fold change in permeability of the gastrointestinal synthetic epithelial inner layer (GSEL) for each combination of excipients. The active pharmaceutical ingredient (API) to be transported is tirzepatide. Percent Pm = (amount permeated through the tissue) divided by (the amount initially placed in the upper chamber) multiplied by 100. CV stands for coefficient of variation, defined as (standard deviation) divided by (mean value) multiplied by 100. Each data point represents the average permeability of an individual formulation. Short horizontal bars represent the mean value. Data are ordered by the average permeability of the class. The numerical values on the x-axis (e.g., 20, 40, 80) indicate the excipient concentration (mg / ml). [Figure 2B] Shown is the average fold change in permeability of the gastrointestinal synthetic epithelial inner layer (GSEL) for each combination of excipients. The active pharmaceutical ingredient (API) to be transported is tirzepatide. Percent Pm = (amount permeated through the tissue) divided by (the amount initially placed in the upper chamber) multiplied by 100. CV stands for coefficient of variation, defined as (standard deviation) divided by (mean value) multiplied by 100. Each data point represents the average permeability of an individual formulation. Short horizontal bars represent the mean value. Data are ordered by the average permeability of the class. The numerical values on the x-axis (e.g., 20, 40, 80) indicate the excipient concentration (mg / ml). [Figure 2C] Shown is the average fold change in permeability of the gastrointestinal synthetic epithelial inner layer (GSEL) for each excipient. The active pharmaceutical ingredient (API) to be transported is tirzepatide. Percent Pm = (amount permeated through the tissue) divided by (the amount initially placed in the upper chamber) multiplied by 100. CV stands for coefficient of variation, defined as (standard deviation) divided by (mean value) multiplied by 100. Each data point represents the average permeability of an individual formulation. Short horizontal bars represent the mean value. Data are ordered by the average permeability of the class. The numerical values on the x-axis (e.g., 20, 40, 80) indicate the excipient concentration (mg / ml). [Figure 2D]This graph shows the mean magnification change in gastrointestinal synthetic inner epithelial layer (GSEL) permeability for single excipients and combinations of excipients. The transported active pharmaceutical ingredient (API) is tilzepatide. Percent Pm = (amount permeated through tissue) divided by (amount initially placed in the upper chamber) multiplied by 100. CV represents the coefficient of variation and is defined as (standard deviation) divided by (mean) multiplied by 100. Each data point represents the mean permeability of the individual formulation. Short horizontal bars represent the mean. The data is sorted by mean permeability of the class. The numbers on the x-axis (e.g., 20, 40, 80) represent the excipient concentration (mg / ml). [Figure 3A] This graph shows the calculated permeation (Pm) of the transported active pharmaceutical ingredient (API) (semaglutide) using GSELs with bile salts (CHA = sodium cholate, GCA = sodium glycocholate) and various concentrations of ammonium carbonate (NHCO), as well as GSELs using ammonium carbonate alone, ammonium carbonate without GSELs, and GSELs without permeation enhancers. Each data point represents the average permeation of the individual formulation. Short horizontal bars represent the average value. The data is sorted by average permeation. The numbers on the x-axis (e.g., 20, 40, 80) represent the excipient concentration (mg / ml). [Figure 3B] This graph shows the calculated permeation (Pm) of the transported active pharmaceutical ingredient (API) (semaglutide) using GSELs with bile salts (CHA = sodium cholate, GCA = sodium glycocholate) and various concentrations of ammonium carbonate (NHCO), as well as GSELs using ammonium carbonate alone, ammonium carbonate without GSELs, and GSELs without permeation enhancers. Each data point represents the average permeation of the individual formulation. Short horizontal bars represent the average value. The data is sorted by average permeation. The numbers on the x-axis (e.g., 20, 40, 80) represent the excipient concentration (mg / ml). [Figure 3C] We presented the results of a screening of 50 combinations of bile salts with other excipients, demonstrating a synergistic effect on semaglutide permeability (n=4-8). [Figure 3D]The results of the permeability test are shown. In the test, GSEL was combined with the bile salt CHA and different ammonium salts in Franz cells. GSEL contained 6.25 mg of PDA nanoparticles and 2.45 mg of DA-HCl, with a DA-HCl:H2O2 ratio of 14.6:1 and a partition volume of 4 μL / mm2. The ammonium salt was tested at 40 mg / mL (mass 10 mg) of GSEL concentration, with n=7 to 24. Semaglutide was quantified using ELISA. [Figure 3E] The results of the permeability test are shown. In the test, GSEL was combined with the bile salt CHA and SNAC or other benzene ring excipients. Each GSEL contained 6.25 mg of PDA nanoparticles and 2.45 mg of DA-HCl, with a DA-HCl:H2O2 ratio of 14.6:1 and a dispensing volume of 4 μL / mm2. The benzene ring excipient was tested at 40 mg / mL (10 mg by mass), with n=7 to 24. Semaglutide was quantified using ELISA. [Figure 4] This shows the average permeability percentage (Pm) of the active pharmaceutical ingredient (API) (semaglutide). The data is sorted by total mass of CHA (sodium cholate) and / or NHCO (ammonium carbonate). The values ​​on the x-axis (e.g., 20, 40, 80) represent the excipient concentration (mg / ml). [Figure 5] This shows the mean permeability percentage (Pm) of tilzepatide transported through porcine duodenal tissue 20 hours after delivery of GSEL as a suspension. The values ​​on the x-axis (e.g., 20, 40, 80) represent the excipient concentration (mg / ml). [Figure 6A] The FD4 permeability on Franz cells is shown over time, with GSEL and GSEL_CHA-20 showing a statistically significant difference at 22 hours (**P=0.029, Mann-Whitney t-test, 95% confidence level, n=7). [Figure 6B] This table shows the percentage of FITC-dextran-40K (FD40) that permeated GSEL 20 hours after GSEL delivery. The values ​​on the X axis represent the excipient concentration (mg / ml). The table summarizes the percentage of FITC-dextran-40K (FD40) that permeated 6 and 20 hours after GSEL delivery. [Figure 7A] The amounts (μg) of FITC-dextran-4K (FD4) permeated over time after GSEL delivery are shown, with and without the use of various ratios of permeation accelerators (PE). (The permeation accelerators are 1:1 combinations of 40 mg / ml sodium glycocholate (GCA) and ammonium carbonate (NHCO), i.e., GCA-NHCO_40-40). The values ​​represent the excipient concentration (mg / ml). [Figure 7B] This shows the amount (μg) of FITC-dextran-4K (FD4) permeated over time after delivery of various GSEL formulations. The values ​​represent the excipient concentration (mg / ml). [Figure 7C] The table below summarizes the amount (μg) of FITC-dextran-4K (FD4) permeated over time after delivery of various GSEL formulations. The values ​​represent the excipient concentration (mg / ml). [Figure 8] This shows the average permeability percentage (Pm) of the active pharmaceutical ingredient (API) (semaglutide). Porcine colon tissue is used as a barrier. [Figure 9] This shows the average permeability percentage of semaglutide in the Franz Cell experiment, which compared bile salts alone and in combination with other excipients as permeability enhancers. [Figure 10A] This shows the average permeability percentage of semaglutide at 20 hours in the Franz Cell test, comparing the combination of sodium glycocholate (GCA) and ammonium carbonate (NHCO) as permeability enhancers with the combination of sodium glycocholate (GCA) and sodium carbonate (NaCO). [Figure 10B] Figure 10B shows the amount of semaglutide (μg) at 7 hours in the Franz Cell test, comparing the combination of sodium glycocholate (GCA) and ammonium carbonate (NHCO) as permeation enhancers with the combination of sodium glycocholate (GCA) and sodium carbonate (NaCO). Figure 10B is a magnified view of the initial time of the graph shown in Figure 10C. [Figure 10C]Figure 10B shows the amount of semaglutide (μg) permeated after 20 hours in the Franz Cell test, comparing the combination of sodium glycocholate (GCA) and ammonium carbonate (NHCO) as permeation enhancers with the combination of sodium glycocholate (GCA) and sodium carbonate (NaCO). Figure 10B is a magnified view of the initial time of the graph shown in Figure 10C. [Figure 10D] This shows the average permeability percentage of semaglutide permeated over 20 hours in the Franz Cell test, comparing the combination of sodium glycocholate (GCA) and ammonium carbonate (NHCO) as permeation enhancers with the combination of sodium glycocholate (GCA) and sodium carbonate (NaCO). [Figure 11A] This shows the average permeability percentage of semaglutide in a comparison of various ammonium carbonate (NHCO) salts combined with sodium cholate (CHA) as a permeability enhancer. [Figure 11B] The measured average permeability percentage of semaglutide after 20 hours is shown in a comparison of various ammonium carbonate (NHCO) salts combined with sodium cholate (CHA) as a permeability enhancer. [Figure 12A] This shows the average permeability percentage of semaglutide in a comparison of the bile salts taurocholic acid (TCA) and taurochenodeoxycholic acid (TCDCA) as permeability enhancers. [Figure 12B] The measured mean permeability percentage of semaglutide after 20 hours in a comparison of bile salts as permeability enhancers is shown. [Figure 13A] This shows the average permeability percentage of semaglutide that permeated duodenal tissue after 20 hours, in comparisons of GCA and NHCO, or GCA, NHCO, and GSEL, as permeability enhancers. [Figure 13B] The measured mean permeability percentage of semaglutide that permeated duodenal tissue after 20 hours is shown in comparisons of GCA and NHCO, or GCA, NHCO, and GSEL, as permeability enhancers. [Figure 14]This study demonstrates that the surface coverage rate by GSEL does not significantly increase after 30 minutes of incubation. Each GSEL consists of 10 mg of PDA nanoparticles and 3.92 mg of DA-HCl, with a DA-HCl:H2O2 weight ratio of 14.6:1 and a dispensing volume of 1.966 μL / mm2. n=4. [Figure 15] A schematic diagram of the Franz Cell experiment, which tests co-administration versus co-formulation, is shown. [Figure 16] The percentage of FITC-dextran-4K capture of the dye (FITC-dextran-4K) on duodenal tissue with or without GSEL and / or CHA (as a permeabilis enhancer) is shown, and the formulation is administered as a liquid (e.g., suspension) compared to a solid formulation. Using one-way ANOVA, P<0.0001. Confidence interval: 95%, n=4-8. [Figure 17] This shows the percentage of dye (FITC-dextran-4K) permeated through duodenal tissue when administered as a liquid (e.g., suspension) compared to a solid formulation. * indicates p<0.05. [Figure 18A] A schematic diagram of a co-localization assay is shown, in which the capture of FITC-dextran pigment is evaluated by measuring the pigment in the supernatant after GSELs have formed on the tissue surface. [Figure 18B] The percentage of pigment (FITC-dextran 4K, FITC-dextran 10K, or FITC-dextran 40K) captured on porcine duodenal tissue in the presence of GSEL, or GSEL and a permeabilizing agent (CHA) is shown. Values ​​were compared using two-way ANOVA followed by Dunnett's multiple comparison test. **** indicates p<0.0001. The table summarizes the percentage of FITC-dextran 4K, FITC-dextran 10K, or FITC-dextran 40K captured on tissue in the presence of GSEL, or GSEL and a permeabilizing agent (CHA). Formulations were delivered as liquids (e.g., suspensions). [Figure 19A] A schematic diagram of a permeability test in Franz cells is shown, in which receptor chamber fluid is collected to measure the FITC-dextran dye that has permeated the tissue. [Figure 19B] The table shows the percentage of dye (FITC-dextran 4K, FITC-dextran 10K, or FITC-dextran 40K) that permeated the porcine duodenum in the presence of GSEL, or GSEL and a permeation enhancer (CHA). Values ​​were compared using two-way ANOVA followed by Sidac's multiple comparison test. **** indicates p<0.0001, and *** indicates p<0.0002. The formulations were delivered as liquids (e.g., suspensions). The table summarizes the percentage of FITC-dextran 4K, FITC-dextran 10K, or FITC-dextran 40K that permeated the tissue in the presence of GSEL, or GSEL and a permeation enhancer (CHA). The formulations were delivered as liquids (e.g., suspensions). [Figure 20A] The results of bile salt screening using the GSEL platform in Franz cells are presented. GSELs contained 6.25 mg of PDA nanoparticles and 2.45 mg of DA-HCl, with a DA-HCl:H2O2 ratio of 14.6:1 and a dispensing volume of 4 μL / mm2. CHA was tested at 40 mg / mL (10 mg mass), n=4-8, and semaglutide was quantified using ELISA. The formulations were delivered as liquids (e.g., suspensions). [Figure 20B] The results of the permeability test are shown. In the test, GSEL was combined with the bile salt CHA at increasing concentrations. Each GSEL contained 6.25 mg of PDA nanoparticles and 2.45 mg of DA-HCl, with a DA-HCl:H2O2 ratio of 14.6:1 and a dispensing volume of 4 μL / mm2. CHA was tested in the range of 40–160 mg / mL (mass 10–40 mg), with n=7–24. Semaglutide was quantified using ELISA. The formulation was delivered as a liquid (e.g., suspension). [Figure 21] The settings for dynamic colocalization studies performed on porcine jejunal tissue (6 inches long) at a 17.92° angle for FD4 or semaglutide, with and without GSEL, and at different GSEL concentrations, are described. The suspension was dispensed at 3 mL / min, and the flow-through was collected to analyze the amount of non-colocalized FD4 or semaglutide. [Figure 22A]The results of the Franz cell permeability test are shown. In the test, GSEL was combined with the bile salt CHA and different ammonium salts in Franz cells. Each GSEL contained 6.25 mg of PDA nanoparticles and 2.45 mg of DA-HCl, with a DA-HCl:H2O2 ratio of 14.6:1 and a dispensing volume of 4 μL / mm2. The ammonium salt was tested at 40 mg / mL (10 mg by mass) of GSEL concentration, with n=7 to 24. Semaglutide was quantified using ELISA. [Figure 22B] The results of the Franz cell permeability test are shown. In the test, GSEL was combined with the bile salt CHA and SNAC or other benzene ring excipients. Each GSEL contained 6.25 mg of PDA nanoparticles and 2.45 mg of DA-HCl, with a DA-HCl:H2O2 ratio of 14.6:1 and a dispensing volume of 4 μL / mm2. The benzene ring excipient was tested at 40 mg / mL (10 mg by mass), with n=7 to 24. Semaglutide was quantified using ELISA. [Figure 22C] The results of permeability tests using Franz cells are shown. In the tests, GSEL:permeability enhancer (PE):semaglutide (SEMA) (PE=GCA-NHCO) were compared to the control, semaglutide alone, semaglutide and SNAC in a 14:300 ratio, SEMA and GCA-NHCO, and SEMA and GSEL. The GSEL composition contained 6.25 mg of PDA nanoparticles and 2.45 mg of DA-HCl, with a DA-HCl:H2O2 ratio of 14.6:1 and a dispensing volume of 4 μL / mm2. GCA and NHCO were tested at 40 mg / mL (10 mg by mass). One-way ANOVA was used, with P<0.0001, confidence interval: 95%, n=8. [Figure 22D] The results of the permeability test in Franz cells are shown. In the test, 1xGSEL contained 6.25 mg of PDA nanoparticles and 2.45 mg of DA-HCl, with a DA-HCl:H2O2 ratio of 14.6:1, a dispensing volume of 2 μL / mm2, and PE mass (GCA+NHCO) of 2, 10, 20, or 40 mg. One-way ANOVA was used, with **P=0.0016, ****P<0.0001, confidence interval: 95%, n=22. [Figure 22E]The results of the permeability test in Franz cells are shown. In the test, the mass of PE was 20 mg (GCA 10 mg + NHCO 10 mg), and the masses of PDA nanoparticles and DA-HCl changed (1x = PDA nanoparticles 6.25 mg and DA-HCl = 2.45 mg, 2x = PDA nanoparticles 12.5 mg, DA-HCl = 4.9 mg, 4x = PDA nanoparticles 25 mg, DA-HCl = 9.8 mg, DA-HCl:H2O2 ratio of 14.6:1, dispensing volume of 2 μL / mm2). One-way ANOVA was used to obtain P=0.6906, *P=0.0498, confidence interval: 95%, n=8~12. [Figure 22F] The dynamic co-localization studies for FD4 performed in porcine jejunal tissue with and without GSEL, and at different GSEL concentrations, are shown. In the studies, permeabilis enhancer (PE): 40 mg / mL GCA + 40 mg / mL NHCO, and permeabilis enhancer:semaglutide ratio = 20:0.5, 1xGSEL with PDA 25 mg / mL and DA-HCl = 9.8 mg / mL, 2xGSEL with PDA nanoparticles 50 mg / mL and DA-HCl = 19.6 mg / mL, DA-HCl:H2O2 ratio 14.6:1, 6-inch tissue at 17.92°C at 3 mL per minute, using one-way ANOVA, P<0.0001, confidence interval: 95%, n=3. [Figure 22G] Static co-localization studies of FD4 in porcine duodenal tissue are presented. PE 20 mg (10 mg GCA + 10 mg NHCO), 1x GSEL with PDA 6.25 mg and DA-HCl = 2.45 mg, 2x GSEL with PDA 12.5 mg and DA-HCl = 4.9 mg, DA-HCl:H2O2 ratio of 14.6:1, dispensing volume of 2 μL / mm2. One-way ANOVA was used, ***P=0.0004, ****P<0.0001, confidence interval: 95%, n=4. [Figure 22H]The results of a dynamic co-localization study of semaglutide in porcine jejunal tissue, with and without GSEL, and at different permeabilis enhancer (PE) concentrations, are presented. The study involved 1xPE (40 mg / mL GCA + 40 mg / mL NHCO), or 0.1xPE (4 mg / mL GCA + 4 mg / mL NHCO), 50 mg / mL PDA nanoparticles, and DA-HCl = 19.6 mg / mL, with a DA-HCl:H2O2 ratio of 14.6:1, 6-inch tissue injected at 17.92°C for 1 minute, n=2. [Figure 22I] This shows porcine jejunal tissue after dynamic colocalization testing using FD4. [Figure 22J] This study shows the semaglutide permeability (mass, ug) by Franz cells at different permeation enhancer:semaglutide ratios (20:0.5, 20:1, 20:2, 20:4, 20:8) that increase semaglutide with 2x GSEL (12.5 mg PDA nanoparticles, 4.9 mg DA-HCl, 14.6:1 DA-HCl:H2O2 ratio, 2 μL / mm2 dispensing volume) and 1x permeation enhancer (PE) (10 mg GCA, 10 mg NHCO (20 mg total PE)). One-way ANOVA was used to determine **P=0.0044, ****P<0.0001, confidence interval: 95%, n=8~9. The permeation enhancer:semaglutide ratio was varied by adjusting the amount of semaglutide inside. [Figure 22K] The results of a static co-localization study of semaglutide in porcine duodenal tissue are shown. In the study, the total mass of the permeabilis enhancer used was 20 mg (10 mg GCA + 10 mg NHCO), with a permeabilis enhancer:semaglutide ratio of 20:2. For 1xGSEL, 6.25 mg of PDA nanoparticles and 2.45 mg of DA-HCl were used, and for 2xGSEL, 12.5 mg of PDA nanoparticles and 4.9 mg of DA-HCl were used, with a DA-HCl:H2O2 ratio of 14.6:1, a dispensing volume of 2 μL / mm2, and one-way ANOVA was used, resulting in *P=0.0155, confidence interval: 95%, n=4~10. [Figure 22L]The results of a dynamic co-localization study of semaglutide in porcine jejunal tissue are shown. PE:40 mg / mL GCA+40 mg / mL NHCO), PE:SEMA=20:0.5, 1xGSEL with PDA nanoparticles 25 mg / mL and DA-HCl=9.8 mg / mL, 2xGSEL with PDA nanoparticles 50 mg / mL and DA=19.6 mg / mL, DA-HCl:H2O2 ratio of 14.6:1, 4xGSEL=100 mg / mL PDA, DA-HCl=39.2 mg, DA-HCl:H2O2 ratio of 14.6:1, 6-inch tissue at 17.92° with 3 mL per minute, using an unpaired two-tailed t-test, **P=0.0286, no significant difference using one-way ANOVA, confidence interval: 95%, n=4. [Figure 22M] The results of Franz cell permeability (%) of semaglutide by Franz cells for different permeability accelerator:semaglutide ratios for 2xGSEL are shown. In the study, 2xGSEL contained 12.5 mg of PDA nanoparticles, 4.9 mg of DA-HCl, a DA-HCl:H2O2 ratio of 14.6:1, and 1xPE (10 mg of GCA, 10 mg of NHCO (20 mg total PE)), dispensed at a volume of 2 μL / mm2. One-way ANOVA was used to determine no significant difference between the groups, confidence interval: 95%, n=8. [Figure 23A] An example of endoscopic delivery of the suspension in vivo is shown. [Figure 23B] The pharmacokinetic curve for intravenous administration of 1 mg of semaglutide per pig is shown. N=2. [Figure 23C] Pharmacokinetic curves are shown for the control group (e.g., 1x permeation enhancer alone) and the experimental group administered the formulation via endoscopic placement into the duodenum (2x GSEL combined with 1x permeation enhancer). The graphs show the bioavailability achieved for the control (1xPE) and 2xGSEL_1xPE formulations in a 168-hour trial. *P=0.0316, nonparametric t-test used, confidence interval: 95%, n=4-5. [Figure 23D]The AUC values ​​up to 24 hours are shown for the control, (semaglutide alone), control (1x permeation enhancer alone), 1x GSEL combined with 1x permeation enhancer (1xGSEL_1xPE), and 2x GSEL combined with 1x permeation enhancer (2xGSEL_1xPE). 1xPE corresponds to 6.4 mg / kg of GCA and 6.4 mg / kg of NHCO, 1xGSEL contains 4.55 mg / kg of PDA nanoparticles and 1.8 mg / kg of DA-HCl, and 2xGSEL contains 9.1 mg / kg of PDA nanoparticles and 3.6 mg / kg of DA-HCl. [Figure 23E] The AUC values ​​up to 48 hours are shown for the control, (semaglutide alone), control (1x permeation enhancer alone), 1x GSEL combined with 1x permeation enhancer (1xGSEL_1xPE), and 2x GSEL combined with 1x permeation enhancer (2xGSEL_1xPE). 1xPE corresponds to 6.4 mg / kg of GCA and 6.4 mg / kg of NHCO, 1xGSEL contains 4.55 mg / kg of PDA nanoparticles and 1.8 mg / kg of DA-HCl, and 2xGSEL contains 9.1 mg / kg of PDA nanoparticles and 3.6 mg / kg of DA-HCl. [Figure 23F] The AUC values ​​up to 72 hours are shown for the control, (semaglutide alone), control (1x permeation enhancer alone), 1x GSEL combined with 1x permeation enhancer (1xGSEL_1xPE), and 2x GSEL combined with 1x permeation enhancer (2xGSEL_1xPE). 1xPE corresponds to 6.4 mg / kg of GCA and 6.4 mg / kg of NHCO, 1xGSEL contains 4.55 mg / kg of PDA nanoparticles and 1.8 mg / kg of DA-HCl, and 2xGSEL contains 9.1 mg / kg of PDA nanoparticles and 3.6 mg / kg of DA-HCl. [Figure 23G]The AUC values ​​up to 168 hours are shown for the control, (semaglutide alone), control (1x permeation enhancer alone), 1x GSEL combined with 1x permeation enhancer (1xGSEL_1xPE), and 2x GSEL combined with 1x permeation enhancer (2xGSEL_1xPE). 1xPE corresponds to 6.4 mg / kg of GCA and 6.4 mg / kg of NHCO, 1xGSEL contains 4.55 mg / kg of PDA nanoparticles and 1.8 mg / kg of DA-HCl, and 2xGSEL contains 9.1 mg / kg of PDA nanoparticles and 3.6 mg / kg of DA-HCl. [Figure 24] This shows the AUC values ​​up to 48 hours for various formulations with different GSEL concentrations. [Figure 25] The pharmacokinetic curves for control (1xPE), control (2xPE), and formulation groups with different GSEL concentrations and GSEL:PE ratios are shown. [Figure 26A] This document presents the results of an experiment in which pigs were administered Rybelsus® (1 mg / kg semaglutide) by endoscopically inserting Rybelsus® tablets (total 1 mg / kg semaglutide) into the stomach. The results for plasma semaglutide levels in the two administered pigs are also shown. [Figure 26B] The results for Rybelsus®, which overlays the control group (semaglutide + permeation enhancer) and two GSEL:PE formulations (1.5 mg / kg semaglutide), are shown. The control curve is the lowest curve in the figure. [Figure 26C] The bioavailability of each group shows an improvement of approximately 43-70% in the bioavailability of the GSEL:PE formulation group compared to the Rybelsus® group. [Modes for carrying out the invention]

[0016] This disclosure relates to a synthetic lining formed in situ within the gastrointestinal tract, such as the small intestine. Such a lining is called the gastrointestinal synthetic epithelial lining (GSEL). GSEL is a transient polymer lining supported (i.e., in contact with) the inner surface of the gastrointestinal tract. For example, dopamine can be polymerized in the small intestine to form a GSEL coating within the duodenum, jejunum, or ileum. This disclosure describes the use of GSEL in combination with drugs, and in combination with synergistic combinations of permeabilisers, which synergistically increase the absorption of drugs through intestinal tissue.

[0017] GSELs can be used to localize active pharmaceutical ingredients (APIs) to specific locations, resulting in prolonged contact with the gastrointestinal mucosa. Due to the extended contact with the mucosa, the API can be delivered over a longer period, which can be advantageous for APIs that are slowly absorbed or that perform best when administered over a longer period. GSELs can enable a higher percentage of API absorption compared to standard dosage forms, and this higher absorption percentage with GSELs may allow similar total API absorption to be achieved with lower doses of the API. GSELs can also reduce the frequency of API administration by resulting in sustained release of the API, compared to multiple administrations of conventional dose formulations over a set period.

[0018] Despite prolonged contact induced by GSELs, some APIs may not cross the gastrointestinal barrier in amounts sufficient to be therapeutically effective, or may not pass through at all. This disclosure describes synergistic permeabilisers for use with GSELs that enhance the permeation of active pharmaceutical ingredients (APIs) across the gastrointestinal mucosa, compared to GSELs with a single permeabiliser, GSELs with a non-synergistic combination of permeabilisers, or GSELs lacking permeabilisers. GSELs with such synergistic combinations of permeabilisers can provide efficient and effective delivery of APIs via intraintestinal administration.

[0019] To form GSELs, the GSEL composition is administered orally to the subject. Alternatively, the composition can be administered, for example, by a feeding tube to subjects with swallowing difficulties, or, if necessary, by using an endoscope to deliver the composition to the small intestine, stomach, or esophagus. The GSEL composition for administration comprises a polymer precursor (e.g., monomer, oligomer, or other prepolymer, e.g., dopamine, dopamine HCl, dopamine oligomer, or dopamine prepolymer). This polymer precursor is polymerized to form GSELs. The GSEL composition for administration also comprises an oxygen source (e.g., hydrogen peroxide or carbamide peroxide) which provides oxygen to the appropriate location in the gastrointestinal tract to induce polymerization of the polymer precursor. The GSEL composition for administration also comprises a synergistic combination of permeability enhancers described herein (e.g., sodium glycocholate and ammonium carbonate) to increase the permeability of the active pharmaceutical ingredient across the gastrointestinal barrier. The composition relies on one or more catalysts inherent in the gastrointestinal tract to convert the oxygen precursor to oxygen. The release of oxygen then leads to polymerization of the polymer precursor. The small intestine contains endogenous catalysts with peroxidase activity, such as catalase, which enable oxygen release, leading to the formation and deposition of GSELs at specific anatomical locations where the endogenous catalysts are located. GSEL compositions for administration may also contain active pharmaceutical ingredients (APIs). Thus, by forming GSELs with the relevant API, the synergistic combination of the API and the permeabilis enhancer is localized near the polymer. In this way, the depot of the synergistic combination of the API and the permeabilis enhancer can be retained at that location for an extended period for absorption at that specific anatomical location. For example, if a GSEL containing the synergistic combination of the API and the permeabilis enhancer is formed in the small intestine, the GSEL will retain the API in close proximity to the intestinal epithelium for a long period. In contrast, if the API is administered as a tablet that dissolves in the intestinal tract without a GSEL, the API may pass through the small intestine much faster, resulting in reduced absorption of the API or requiring administration of more API to achieve equivalent absorption.

[0020] Alternatively, the API may be administered in a composition separate from the GSEL precursor composition. When the API is administered in a separate composition, it may be administered before the administration of the GSEL precursor composition, simultaneously with the administration of the GSEL precursor composition, or after the administration of the GSEL precursor composition.

[0021] GSELs with a synergistic permeabilis-enhancing agent combination assist the passage of APIs across the gastrointestinal barrier, increasing API permeability across the gastrointestinal barrier in the presence of synergistic permeabilis-enhancing agents compared to API permeability with GSELs without permeabilis-enhancing agents, or API permeability with a single permeabilis-enhancing agent or a non-synergistic combination of permeabilis-enhancing agents. Even when APIs are administered separately from GSELs and synergistic permeabilis-enhancing agents, enhanced API permeability can occur when the API traverses the portion of the small intestine coated with GSELs with a synergistic permeabilis-enhancing agent.

[0022] The components of the GSEL composition for administration are discussed in more detail herein and are as follows: 1) a synergistic combination of a polymer precursor, 2) an oxygen source, and 3) a permeation enhancer. GSEL and the GSEL composition for administration may also contain 4) one or more active pharmaceutical ingredients (APIs). GSEL or the GSEL composition for administration may not contain any APIs, in which case one or more APIs may be administered separately. Alternatively, GSEL or the GSEL composition for administration may contain one or more APIs, and one or more APIs may also be administered separately from GSEL, at the option of. Endogenous catalysts that enable the formation of GSEL in situ are also discussed.

[0023] definition A “drug” is any substance intended for therapeutic, diagnostic, or nutritional use in a patient, individual, or subject. Drugs include, but are not limited to, drugs, nutrients, vitamins, and minerals. An “active drug component” (API) is a drug that is a component of a drug dose that produces a desired biological effect in the patient, individual, or subject to which the drug dose is administered.

[0024] An "excipient" is any substance added to a drug formulation, not the drug itself. Examples of excipients include, but are not limited to, binders, coatings, diluents, disintegrants, emulsifiers, flavorings, fluidizers, lubricants, and preservatives.

[0025] "Patient," "individual," or "subject" refers to a human or a non-human animal. Non-human animals include mammals, such as domesticated animals like dogs or cats, or commercially used animals such as cattle, pigs, horses, sheep, or goats. In a preferred embodiment, the patient, individual, or subject is a human.

[0026] "Treating" a disease or disorder with the compositions and methods disclosed herein is defined as administering one or more of the compositions disclosed herein, with or without additional agents, to a patient in need of treatment, to reduce or eliminate the disease or disorder, or one or more symptoms of the disease or disorder, to suppress the symptoms of the disease or disorder, to delay the progression of the disease or disorder or one or more symptoms of the disease or disorder, or to reduce the severity of the disease or disorder or one or more symptoms of the disease or disorder. Treatment may be initiated after the onset of symptoms of the disease or disorder, or before the onset of symptoms of the disease or disorder. Treatment may also be continued after the symptoms have disappeared.

[0027] The “therapeutic use” of the compositions disclosed herein is defined as using one or more of the compositions disclosed herein to treat the disease or disorder as defined above. The “therapeutic effective dose” of a therapeutic agent, such as a drug, is an amount of the agent sufficient to achieve the desired biological outcome when administered to a patient, individual, or subject, for example, sufficient to reduce or eliminate any one or more symptoms of a disease or disorder, or to slow the progression of a disease or disorder or one or more symptoms of a disease or disorder, or to reduce the severity of a disease or disorder or one or more symptoms of a disease or disorder. The therapeutic effective dose may be administered to a patient, individual, or subject as a single dose, or divided and administered as multiple doses.

[0028] "Permeation" of a drug or active pharmaceutical ingredient (API) that passes through a barrier refers to the amount of drug or API that can pass through the barrier.

[0029] A "permeation enhancer" refers to a substance that can increase the permeability of a drug or active pharmaceutical ingredient through a barrier.

[0030] The term "polymer" refers to a compound that contains 11 or more covalently bonded repeating units.

[0031] The term "oligomer" refers to a compound containing 2 to 10 covalently bonded repeating units.

[0032] The unit "kD" refers to the kilodalton.

[0033] As used herein, unless otherwise stated or explicitly indicated by the context, the singular forms "a," "an," and "the" include the plural referents.

[0034] Where a numerical value is expressed herein using the terms “about” or “approximately,” it is understood that this includes both the specified value and a value that is reasonably close to the specified value. For example, “about 50°C” or “approximately 50°C” includes both the disclosure of 50°C itself and a value that is close to 50°C. Thus, the phrase “about X” or “approximately X” includes a description of the value X itself. Where a range is given, such as “approximately 50°C to 60°C” or “approximately 50°C to 60°C,” it is understood that this includes both the value specified by the endpoint and, for each endpoint or both ends, a value that is close to each endpoint or both ends; that is, “approximately 50°C to 60°C” (or “approximately 50°C to 60°C”) is equivalent to stating both “50°C to 60°C” and “approximately 50°C to approximately 60°C” (or “approximately 50°C to 60°C”).

[0035] With respect to the numerical ranges disclosed herein, any disclosed upper limit for a component can be combined with any disclosed lower limit for that component to provide a range (provided that the upper limit is greater than the lower limit being combined). Each of these combinations of disclosed upper and lower limits is expressly assumed herein. For example, if the ranges of amounts for a particular component are given as 10% to 30%, 10% to 12%, and 15% to 20%, then the ranges of 10% to 20% and 15% to 30% are also assumed, while the combination of a lower limit of 15% and an upper limit of 12% is not possible and therefore not assumed.

[0036] Unless otherwise specified, the percentage of components in a composition is expressed as weight percentage or weight / weight percentage. References to relative weight percentages in a composition are understood to assume that the total weight percentage of all components in the composition equals 100. Furthermore, the relative weight percentage of one or more components may be adjusted upward or downward so that the combined weight percentage of all components in the composition equals 100, provided that the weight percentage of any particular component does not fall outside the range specified for that component.

[0037] Some embodiments described herein are described as "comprising" or "comprises" with respect to their various elements. In alternative embodiments, these elements may be described with the transitional phrase "consisting essentially of" or "consists essentially of" applicable to those elements. In further alternative embodiments, these elements may be described with the transitional phrase "consisting of" or "consists of" applicable to those elements. Thus, for example, if a composition or method is disclosed herein as comprising A and B, then alternative embodiments of that composition or method "consisting essentially of A and B," as well as alternative embodiments "consisting of A and B," are also disclosed herein. Similarly, embodiments described as "consisting essentially of" or "consisting of" with respect to their various elements may also be described as "comprising" applicable to those elements. Finally, embodiments described as "essentially consisting of" those various elements may also be described as "consisting of" those elements, and embodiments described as "consisting of" those various elements may also be described as "essentially consisting of" those elements.

[0038] Where a composition or system is described as "essentially consisting of" the enumerated elements, the composition or system may contain the explicitly enumerated elements and other elements that do not substantially affect the condition being treated (in the case of a composition for treating a condition) or the properties of the system described (in the case of a composition containing a system). However, the composition or system may not contain any other elements other than the explicitly enumerated elements that substantially affect the condition being treated (in the case of a composition for treating a system) or any other elements that substantially affect the properties of the system (in the case of a composition containing a system), or if the composition or system contains additional elements other than those enumerated that could substantially affect the condition being treated or the properties of the system, the composition or system may not contain any of those additional elements in concentrations or amounts sufficient to substantially affect the condition being treated or the properties of the system. Where a method is described as "essentially consisting of" the enumerated steps, the method may contain the enumerated steps and other steps that do not substantially affect the condition being treated or the properties of the system produced by the method, but the method may not contain any other steps other than those explicitly enumerated that substantially affect the condition being treated or the system produced.

[0039] This disclosure provides several embodiments. It is intended that any feature from any embodiment may be combined, where possible, with any feature from any other embodiment. Thus, hybrid configurations of the disclosed features are within the scope of this disclosure.

[0040] Gastrointestinal synthetic inner lining (GSEL) for drug administration A GSEL precursor composition for the formation of gastrointestinal synthetic lining epithelium (GSEL) comprises a synergistic combination of 1) a polymer precursor, 2) an oxygen source, and 3) a permeation enhancer. In one embodiment, each component of the composition can be administered as separate dosage forms for combination in the target gastrointestinal tract. In one embodiment, the polymer precursor and the oxygen source can be administered together in one dosage form, and the synergistic combination of permeation enhancers can be administered in a separate dosage form. In one embodiment, the synergistic combination of the polymer precursor, oxygen source, and permeation enhancer can be administered together in one dosage form.

[0041] The GSEL precursor composition may also contain a drug such as an active pharmaceutical ingredient (API), or the GSEL precursor composition may contain multiple drugs such as multiple APIs. The drug may be administered together with the other components of the GSEL precursor composition, as well as in a synergistic combination of the polymer precursor, oxygen source, and permeability enhancer. Alternatively, the API (or multiple APIs) may be administered in a separate composition before, simultaneously with, or after the administration of the other components of the GSEL precursor composition.

[0042] Polymer precursors for gastrointestinal synthetic lining epithelial precursor compositions In one embodiment, the present disclosure provides a method for forming a polymer in situ in a subject, comprising administering a composition to the subject comprising a combination of a polymer precursor, an oxygen source, and a synergistic permeation enhancer, wherein the polymer precursor and the oxygen source come into contact with a catalyst inherent in the subject, and the catalyst polymerizes the polymer precursor.

[0043] In some embodiments, polymerization of the polymer precursor is catalyzed when the oxygen source and the polymer precursor come into contact with an endogenous catalyst. In some embodiments, polymerization of the polymer precursor is catalyzed when the oxygen source and the polymer precursor come into contact with peroxidase in the small intestine. In some embodiments, polymerization of the polymer precursor is catalyzed when the oxygen source and the polymer precursor come into contact with peroxidase in the duodenum.

[0044] In some embodiments, the polymer precursor is a catechol-based polymer precursor. In some embodiments, the polymer precursor includes a 1,2-dihydroxybenzene moiety. In some embodiments, the polymer precursor includes an optionally substituted 1,2-dihydroxybenzene moiety. In some embodiments, the polymer precursor includes a 1,2-dihydroxyphenyl moiety. In some embodiments, the polymer precursor includes an optionally substituted 1,2-dihydroxyphenyl moiety.

[0045] In some embodiments, the polymer precursor is a 2-(3,4-dihydroxyphenyl)ethylamine-based polymer precursor. (2-(3,4-dihydroxyphenyl)ethylamine is commonly known as dopamine.) In certain embodiments, the polymer precursor comprises a 3,4-dihydroxyphenethylamine moiety. In certain embodiments, the polymer precursor comprises an optionally substituted 3,4-dihydroxyphenethylamine moiety. In certain embodiments, the polymer precursor comprises a 2-(3,4-dihydroxyphenyl)ethylamine moiety. In certain embodiments, the polymer precursor comprises an optionally substituted 2-(3,4-dihydroxyphenyl)ethylamine moiety.

[0046] In some embodiments, the polymer precursor is selected from the group consisting of dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, levodopa ethyl ester, their derivatives, and combinations thereof. In a particular embodiment, the polymer precursor is selected from the group consisting of dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, and levodopa ethyl ester.

[0047] In certain embodiments, the polymer precursor is a derivative of dopamine. In some embodiments, the polymer precursor includes dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, or levodopa ethyl ester.

[0048] In some embodiments, the derivative of the polymer precursor includes a polymer. In some embodiments, the polymer precursor includes dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, or levodopa ethyl ester, and at least one polymer. In certain embodiments, the polymer is alginate, hyaluronic acid, polyacrylic acid, polyethylene glycol, chondroitin sulfate, chitosan, or a combination thereof. In some embodiments, the polymer is alginate, hyaluronic acid, polyacrylic acid, polyethylene glycol, chondroitin sulfate, or chitosan. In certain embodiments, the polymer precursor includes (A) a dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, or levodopa ethyl ester moiety, which is bound to (B) alginate, hyaluronic acid, polyacrylic acid, polyethylene glycol, chondroitin sulfate, or chitosan. In certain embodiments, the polymer precursor comprises two or more moieties from (A) dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, and levodopa ethyl ester, which are bound to (B) alginate, hyaluronic acid, polyacrylic acid, polyethylene glycol, chondroitin sulfate, or chitosan.

[0049] In certain embodiments, the polymer precursor is selected from the structures listed in Table 1 or 2. [Table 1] [Table 2-1] [Table 2-2] Table 2-3 Table 2-4 Table 2-5 Table 2-6

[0050] In some embodiments, the polymer precursor comprises a single type of polymer precursor. In certain embodiments, the polymer precursor comprises a combination of polymer precursors. In certain embodiments, the polymer precursor comprises a combination of polymer precursors listed in Tables 1 and 2. In some embodiments, the combination of polymer precursors consists of two different polymer precursors. In some embodiments, the combination of polymer precursors consists of three different polymer precursors. In some embodiments, the combination of polymer precursors consists of four different polymer precursors. In some embodiments, the composition comprises 40% to 90% of the polymer precursor relative to (polymer precursor, oxygen source, and permeation enhancer). In some embodiments, the polymer precursor is dopamine (which may be provided in the form of dopamine HCl or another pharmaceutically acceptable salt of dopamine). In some embodiments, the composition contains about 0.001 to about 1000 mg / mL of dopamine. In some embodiments, the composition contains about 0.001 to about 500 mg / mL of dopamine. In some embodiments, the composition contains about 0.01 to about 100 mg / mL of dopamine. In some embodiments, the composition contains about 1 to about 100 mg / mL of dopamine. In some embodiments, the composition contains about 1 to about 50 mg / mL of dopamine. In some embodiments, the composition contains about 10 to about 40 mg / mL of dopamine. In some embodiments, the composition contains about 1 to about 20 mg / mL of dopamine. In some embodiments, the composition contains about 60 mg / mL of dopamine. In some embodiments, the composition contains about 50 mg / mL of dopamine. In some embodiments, the composition contains about 40 mg / mL of dopamine. In some embodiments, the composition contains about 30 mg / mL of dopamine. In some embodiments, the composition contains about 20 mg / mL of dopamine. In some embodiments, the composition contains about 10 mg / mL of dopamine. In some embodiments, the composition contains about 9.8 mg / mL of dopamine. In some embodiments, the composition contains about 18 mg / mL to about 20 mg / mL of dopamine.In some embodiments, the composition contains about 18.5 mg / mL of dopamine. In some embodiments, the composition contains about 19 mg / mL of dopamine. In some embodiments, the composition contains about 19.5 mg / mL of dopamine. In some embodiments, the composition contains about 19.6 mg / mL of dopamine. In some embodiments, the composition contains about 20 mg / mL of dopamine. The amount of dopamine contained in the composition can also be expressed as a weight-based dose such as mg / kg, and the amount of dopamine administered is determined by the body weight of the recipient of the composition. In some embodiments, the composition contains about 1 mg / kg to about 9 mg / kg of dopamine. In some embodiments, the composition contains about 3 mg / kg to about 10 mg / kg of dopamine. In some embodiments, the composition contains about 2 mg / kg to about 9 mg / kg of dopamine. In some embodiments, the composition contains about 3 mg / kg to about 9 mg / kg of dopamine. In some embodiments, the composition contains about 4 mg / kg to about 9 mg / kg of dopamine. In some embodiments, the composition contains about 5 mg / kg to about 9 mg / kg of dopamine. In some embodiments, the composition contains about 6 mg / kg to about 9 mg / kg of dopamine. In some embodiments, the composition contains about 7 mg / kg to about 9 mg / kg of dopamine. In some embodiments, the composition contains about 4 mg / kg to about 6 mg / kg of dopamine. In some embodiments, the composition contains about 8 mg / kg to about 9 mg / kg of dopamine. In some embodiments, the composition contains about 2 mg / kg to about 3 mg / kg of dopamine. In some embodiments, the composition contains about 3 mg / kg to about 4 mg / kg of dopamine. In some embodiments, the composition contains about 4 mg / kg to about 7 mg / kg of dopamine. In some embodiments, the composition contains about 5 mg / kg to about 6 mg / kg of dopamine. In some embodiments, the composition contains about 5 mg / kg to about 7 mg / kg of dopamine. In some embodiments, the composition contains about 7 mg / kg to about 8 mg / kg of dopamine. In some embodiments, the composition contains about 7 mg / kg to about 9 mg / kg of dopamine.In some embodiments, the composition contains about 8 mg / kg to about 9 mg / kg of dopamine. In some embodiments, the composition contains about 1.7 mg / kg of dopamine. In some embodiments, the composition contains about 1.75 mg / kg of dopamine. In some embodiments, the composition contains about 1.8 mg / kg of dopamine. In some embodiments, the composition contains about 1.85 mg / kg of dopamine. In some embodiments, the composition contains about 3.4 mg / kg of dopamine. In some embodiments, the composition contains about 3.45 mg / kg of dopamine. In some embodiments, the composition contains about 3.5 mg / kg of dopamine. In some embodiments, the composition contains about 3.55 mg / kg of dopamine. In some embodiments, the composition contains about 3.6 mg / kg of dopamine. In some embodiments, the composition contains about 3.65 mg / kg of dopamine. In some embodiments, the composition contains about 5.2 mg / kg of dopamine. In some embodiments, the composition contains about 5.25 mg / kg of dopamine. In some embodiments, the composition contains about 5.3 mg / kg of dopamine. In some embodiments, the composition contains about 5.35 mg / kg of dopamine. In some embodiments, the composition contains about 5.4 mg / kg of dopamine. In some embodiments, the composition contains about 5.45 mg / kg of dopamine. In some embodiments, the composition contains about 7.0 mg / kg of dopamine. In some embodiments, the composition contains about 7.05 mg / kg of dopamine. In some embodiments, the composition contains about 7.1 mg / kg of dopamine. In some embodiments, the composition contains about 7.15 mg / kg of dopamine. In some embodiments, the composition contains about 7.2 mg / kg of dopamine. In some embodiments, the composition contains about 7.25 mg / kg of dopamine. In some embodiments, the composition contains about 8.8 mg / kg of dopamine. In some embodiments, the composition contains about 8.9 mg / kg of dopamine. In some embodiments, the composition contains about 9 mg / kg of dopamine.In any of these embodiments, a pharmaceutically acceptable salt of dopamine, such as dopamine hydrochloride, may be used. In any of these embodiments, polydopamine, a mixture of dopamine and polydopamine, or a pharmaceutically acceptable salt thereof may be used instead of dopamine or a pharmaceutically acceptable salt of dopamine. In some embodiments, polydopamine is polydopamine nanoparticles. For example, in some embodiments, the composition contains about 0.001 to about 1000 mg / mL of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 0.001 to about 500 mg / mL of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 0.01 to about 100 mg / mL of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 1 to about 100 mg / mL of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 1 to about 50 mg / mL of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 10 to about 40 mg / mL of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 1 to about 20 mg / mL of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 60 mg / mL of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 50 mg / mL of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 40 mg / mL of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 30 mg / mL of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 25 mg / mL of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 20 mg / mL of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 10 mg / mL of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains approximately 9.8 mg / mL of polydopamine or polydopamine nanoparticles.The amount of polydopamine or polydopamine nanoparticles contained in the composition can also be expressed as a weight-based dose such as mg / kg, and the amount of polydopamine or polydopamine nanoparticles administered is determined by the body weight of the recipient of the composition. In some embodiments, the composition contains about 3 mg / kg to about 23 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 4 mg / kg to about 23 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 5 mg / kg to about 23 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 6 mg / kg to about 23 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 7 mg / kg to about 23 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 8 mg / kg to about 23 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 9 mg / kg to about 23 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 10 mg / kg to about 23 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 11 mg / kg to about 23 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 12 mg / kg to about 23 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 13 mg / kg to about 23 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 14 mg / kg to about 23 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 15 mg / kg to about 23 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 4 mg / kg to about 16 mg / kg of polydopamine or polydopamine nanoparticles.In some embodiments, the composition contains about 17 mg / kg to about 23 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 18 mg / kg to about 23 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 29 mg / kg to about 23 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 20 mg / kg to about 23 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 21 mg / kg to about 23 mg / kg of polydopamine. The composition contains polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 22 mg / kg to about 23 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 3 mg / kg to about 4 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 3 mg / kg to about 5 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 3 mg / kg to about 10 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 4 mg / kg to about 6 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 4 mg / kg to about 7 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 8 mg / kg to about 9 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 8 mg / kg to about 10 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 10 mg / kg to about 13 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 10 mg / kg to about 12 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 11 mg / kg to about 14 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 13 mg / kg to about 14 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 12 mg / kg to about 15 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 15 mg / kg to about 19 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 13 mg / kg to about 19 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition comprises about 17 mg / kg to about 19 mg / kg of polydopamine or polydopamine nanoparticles.In some embodiments, the composition contains about 18 mg / kg to about 19 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 18 mg / kg to about 20 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 21 mg / kg to about 22 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 20 mg / kg to about 22 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 22.25 mg / kg to about 23 mg / kg of polydopamine or polydopamine nanoparticles.

[0051] In some embodiments, the composition contains about 4.45 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 4.50 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 4.25 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 4.35 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 4.45 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 4.55 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 4.56 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 4.57 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 4.58 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 4.59 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 4.6 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 4.61 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 8.9 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 8.95 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 9.0 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 9.1 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 9.12 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 9.13 mg / kg of polydopamine or polydopamine nanoparticles.In some embodiments, the composition contains about 9.14 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 9.15 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 9.16 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 9.17 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 9.2 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 9.3 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 13.55 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 13.6 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 13.65 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 13.68 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 13.69 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 13.7 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 13.73 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 13.75 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 13.8 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 13.9 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 14 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 18 mg / kg of polydopamine or polydopamine nanoparticles.In some embodiments, the composition contains about 18.1 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 18.2 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 18.3 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 18.5 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 22 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 22.5 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 22.75 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains about 23 mg / kg of polydopamine or polydopamine nanoparticles. In some embodiments, the composition contains a mixture of dopamine and polydopamine in an amount of about 0.001 to about 1000 mg / mL. In some embodiments, the composition contains a mixture of dopamine and polydopamine in an amount of about 0.001 to about 500 mg / mL. In some embodiments, the composition contains a mixture of dopamine and polydopamine in an amount of about 0.01 to about 100 mg / mL. In some embodiments, the composition contains a mixture of dopamine and polydopamine in an amount of about 1 to about 100 mg / mL. In some embodiments, the composition contains a mixture of dopamine and polydopamine in an amount of about 1 to about 50 mg / mL. In some embodiments, the composition contains a mixture of dopamine and polydopamine in an amount of about 10 to about 40 mg / mL. In some embodiments, the composition contains a mixture of dopamine and polydopamine in an amount of about 1 to about 20 mg / mL. In some embodiments, the composition contains a mixture of dopamine and polydopamine in an amount of about 60 mg / mL. In some embodiments, the composition contains a mixture of dopamine and polydopamine in an amount of about 50 mg / mL. In some embodiments, the composition contains a mixture of dopamine and polydopamine in an amount of about 40 mg / mL. In some embodiments, the composition comprises a mixture of dopamine and polydopamine at approximately 30 mg / mL.In some embodiments, the composition contains a mixture of dopamine and polydopamine at approximately 20 mg / mL. In some embodiments, the composition contains a mixture of dopamine and polydopamine at approximately 10 mg / mL. In some embodiments, the composition contains a mixture of dopamine and polydopamine at approximately 9.8 mg / mL. In some embodiments, the composition contains a mixture of dopamine and polydopamine nanoparticles at approximately 0.001 to approximately 1000 mg / mL. In some embodiments, the composition contains a mixture of dopamine and polydopamine nanoparticles at approximately 0.001 to approximately 500 mg / mL. In some embodiments, the composition contains a mixture of dopamine and polydopamine nanoparticles at approximately 0.01 to approximately 100 mg / mL. In some embodiments, the composition contains a mixture of dopamine and polydopamine nanoparticles at approximately 1 to approximately 100 mg / mL. In some embodiments, the composition contains a mixture of dopamine and polydopamine nanoparticles at approximately 1 to approximately 50 mg / mL. In some embodiments, the composition contains a mixture of dopamine and polydopamine nanoparticles at a concentration of about 10 to about 40 mg / mL. In some embodiments, the composition contains a mixture of dopamine and polydopamine nanoparticles at a concentration of about 1 to about 20 mg / mL. In some embodiments, the composition contains a mixture of dopamine and polydopamine nanoparticles at a concentration of about 60 mg / mL. In some embodiments, the composition contains a mixture of dopamine and polydopamine nanoparticles at a concentration of about 50 mg / mL. In some embodiments, the composition contains a mixture of dopamine and polydopamine nanoparticles at a concentration of about 40 mg / mL. In some embodiments, the composition contains a mixture of dopamine and polydopamine nanoparticles at a concentration of about 30 mg / mL. In some embodiments, the composition contains a mixture of dopamine and polydopamine nanoparticles at a concentration of about 20 mg / mL. In some embodiments, the composition contains a mixture of dopamine and polydopamine nanoparticles at a concentration of about 10 mg / mL. In some embodiments, the composition contains a mixture of dopamine and polydopamine nanoparticles at a concentration of about 9.8 mg / mL. In some embodiments, the composition comprises dopamine and polydopamine.

[0052] When using a mixture of dopamine and polydopamine, the amount of dopamine relative to polydopamine on a weight basis (i.e., dopamine:polydopamine) is in the range of approximately 0.05:1 to approximately 1:0.05 on a weight / weight basis, for example, approximately 0.1:1, approximately 0.2:1, approximately 0.25:1, approximately 0.3:1. The ratios may be approximately 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.75:1, 0.8:1, 0.9:1, 1:1, 1:0.9, 1:0.8, 1:0.75, 1:0.7, 1:0.6, 1:0.5, 1:0.4, 1:0.3, 1:0.25, 1:0.2, or 1:0.1 dopamine:polydopamine. In some embodiments, the weight-based dopamine to polydopamine ratio may range from approximately 0.2:1 to approximately 0.6:1. In some embodiments, the weight-based dopamine to polydopamine ratio may range from approximately 0.3:1 to approximately 0.5:1. In some embodiments, the ratio of dopamine to polydopamine by weight is approximately 0.2:1, approximately 0.22:1, approximately 0.23:1, approximately 0.24:1, approximately 0.25:1, approximately 0.26:1, approximately 0.27:1, approximately 0.28:1, approximately 0.29:1, approximately 0.3:1, approximately 0.31:1, approximately 0.32:1, approximately 0.33:1, and approximately 0.3 The ratio may range from 4:1, approximately 0.35:1, approximately 0.36:1, approximately 0.37:1, approximately 0.38:1, approximately 0.39:1, approximately 0.4:1, approximately 0.41:1, approximately 0.42:1, approximately 0.43:1, approximately 0.44:1, approximately 0.45:1, approximately 0.46:1, approximately 0.47:1, approximately 0.48:1, approximately 0.49:1, or approximately 0.5:1. In some embodiments, the ratio of dopamine to polydopamine by weight is approximately 0.35:1. In some embodiments, the ratio of dopamine to polydopamine by weight is approximately 0.36:1. In some embodiments, the ratio of dopamine to polydopamine by weight is approximately 0.37:1. In some embodiments, the ratio of dopamine to polydopamine by weight is approximately 0.38:1. In some embodiments, the ratio of dopamine to polydopamine by weight is approximately 0.39:1. In some embodiments, the ratio of dopamine to polydopamine by weight is approximately 0.4:1.In some embodiments, the ratio of dopamine to polydopamine by weight is about 0.41:1. In some embodiments, the ratio of dopamine to polydopamine by weight is about 0.42:1. In some embodiments, the ratio of dopamine to polydopamine by weight is about 0.43:1. In some embodiments, the ratio of dopamine to polydopamine by weight is about 0.44:1. In some embodiments, the ratio of dopamine to polydopamine by weight is about 0.45:1. In some embodiments, the composition comprises dopamine and polydopamine nanoparticles. When using a mixture of dopamine and polydopamine nanoparticles, the amount of dopamine relative to the polydopamine nanoparticles on a weight basis (i.e., dopamine:polydopamine nanoparticles) is in the range of approximately 0.05:1 to approximately 1:0.05 on a weight / weight basis, for example, approximately 0.1:1, approximately 0.2:1, approximately 0.25: The dopamine:polydopamine nanoparticles may be in a ratio of approximately 1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.75:1, 0.8:1, 0.9:1, 1:1, 1:0.9, 1:0.8, 1:0.75, 1:0.7, 1:0.6, 1:0.5, 1:0.4, 1:0.3, 1:0.25, 1:0.2, or 1:0.1. In some embodiments, the weight ratio of dopamine to polydopamine nanoparticles may range from approximately 0.2:1 to approximately 0.6:1. In some embodiments, the weight ratio of dopamine to polydopamine nanoparticles may range from approximately 0.3:1 to approximately 0.5:1.In some embodiments, the ratio of dopamine amount to polydopamine nanoparticle amount by weight is approximately 0.2:1, approximately 0.22:1, approximately 0.23:1, approximately 0.24:1, approximately 0.25:1, approximately 0.26:1, approximately 0.27:1, approximately 0.28:1, approximately 0.29:1, approximately 0.3:1, approximately 0.31:1, approximately 0.32:1, approximately 0.33:1, approximately 0 The ratio may range from 0.34:1, approximately 0.35:1, approximately 0.36:1, approximately 0.37:1, approximately 0.38:1, approximately 0.39:1, approximately 0.4:1, approximately 0.41:1, approximately 0.42:1, approximately 0.43:1, approximately 0.44:1, approximately 0.45:1, approximately 0.46:1, approximately 0.47:1, approximately 0.48:1, approximately 0.49:1, or approximately 0.5:1. In some embodiments, the ratio of dopamine by weight to polydopamine nanoparticles is approximately 0.35:1. In some embodiments, the ratio of dopamine by weight to polydopamine nanoparticles is approximately 0.36:1. In some embodiments, the ratio of dopamine by weight to polydopamine nanoparticles is approximately 0.37:1. In some embodiments, the ratio of dopamine by weight to polydopamine nanoparticles is approximately 0.38:1. In some embodiments, the ratio of dopamine by weight to polydopamine nanoparticles is approximately 0.39:1. In some embodiments, the ratio of dopamine by weight to polydopamine nanoparticles is approximately 0.4:1. In some embodiments, the ratio of dopamine by weight to polydopamine nanoparticles is approximately 0.41:1. In some embodiments, the ratio of dopamine by weight to polydopamine nanoparticles is approximately 0.42:1. In some embodiments, the ratio of dopamine by weight to polydopamine nanoparticles is approximately 0.43:1. In some embodiments, the ratio of dopamine by weight to polydopamine nanoparticles is approximately 0.44:1. In some embodiments, the ratio of dopamine by weight to polydopamine nanoparticles is approximately 0.45:1.

[0053] In some embodiments, specific compositions within this range include 6.25 mg of polydopamine nanoparticles, 2.45 mg of dopamine-HCl, and 0.17 mg of hydrogen peroxide.

[0054] In some embodiments, specific compositions within this range include 12.5 mg of polydopamine nanoparticles, 4.9 mg of dopamine-HCl, and 0.34 mg of hydrogen peroxide.

[0055] In some embodiments, specific compositions within this range include 25 mg of polydopamine nanoparticles, 9.8 mg of dopamine-HCl, and 0.68 mg of hydrogen peroxide.

[0056] In some embodiments, specific compositions within this range include 4.567 mg / kg of polydopamine nanoparticles (PDA), 1.789 mg / kg of dopamine hydrochloride, and 0.122 mg / kg of hydrogen peroxide in Tris buffer (pH 8.5). The mg / kg represents a weight-based dose, where the weight is determined by the body weight of the subject to whom the composition is administered.

[0057] In some embodiments, specific compositions within this range include 9.133 mg / kg of polydopamine nanoparticles, 3.596 mg / kg of dopamine hydrochloride, and 0.244 mg / kg of hydrogen peroxide in Tris buffer (pH 8.5). The mg / kg represents a weight-based dose, where the weight is determined by the body weight of the subject to whom the composition is administered.

[0058] In some embodiments, specific compositions within this range include 13.7 mg / kg of polydopamine nanoparticles, 5.394 mg / kg of dopamine hydrochloride, and 0.366 mg / kg of hydrogen peroxide in Tris buffer (pH 8.5). The mg / kg represents a weight-based dose, where the weight is determined by the body weight of the subject to whom the composition is administered.

[0059] Where chemically feasible and pharmaceutically desirable, alternative pharmaceutically acceptable salts or free acids or bases of the aforementioned compounds may be used.

[0060] International patent applications WO2021 / 119350 and WO2021 / 119354, which are incorporated herein by reference in their entirety, describe methods for forming polymers in situ in a subject.

[0061] Oxygen source for gastrointestinal synthetic lining precursor composition In one embodiment, the present disclosure provides a composition comprising a polymer precursor, an oxygen source, and a permeation enhancer. In some embodiments, the oxygen source is hydrogen peroxide or carbamide peroxide. In some embodiments, the oxygen source is hydrogen peroxide. In some embodiments, the oxygen source is carbamide peroxide. When the oxygen source comes into contact with a catalyst inherent in the target, such as catalase or peroxidase, oxygen is released from the oxygen source, resulting in polymerization of the polymer precursor.

[0062] In some embodiments, the endogenous catalyst is selected from catalase or peroxidase. In some embodiments, the endogenous catalyst is a peroxidase. In certain embodiments, the peroxidase is eosinophil peroxidase, lactoperoxidase, or myeloperoxidase.

[0063] In some embodiments, the endogenous catalyst is catalase. In some embodiments, the catalase is bacterial catalase. In some embodiments, the catalase is human catalase.

[0064] In some embodiments, the endogenous catalyst is present in the gastrointestinal (GI) tract of the subject. In some embodiments, the endogenous catalyst is present in the small intestine of the subject. In some embodiments, the endogenous catalyst is present in the duodenum of the subject.

[0065] In some embodiments, the endogenous catalyst is located in the upper GI of the subject. In some embodiments, the endogenous catalyst is located in the stomach of the subject.

[0066] In some embodiments, the composition contains an oxygen source in an amount of 1% to 15% relative to (polymer precursor, oxygen source, and permeation enhancer).

[0067] In some embodiments, the composition contains an oxygen source of about 0.01 to about 100 mM. In some embodiments, the composition contains an oxygen source of about 0.1 to about 50 mM. In some embodiments, the composition contains an oxygen source of about 1 to about 30 mM. In some embodiments, the composition contains an oxygen source of about 20 mM. In some embodiments, the composition contains an oxygen source at a concentration suitable for intake by the subject. In some embodiments, the composition contains an oxygen source to dopamine ratio of about 10:1, about 20:1, about 15:1, about 14:1, or about 13:1 (oxygen source:dopamine). In some embodiments, the composition contains an oxygen source to dopamine ratio of 14.6:1. In some embodiments, the oxygen source is hydrogen peroxide. In some embodiments, the composition contains a hydrogen peroxide to dopamine ratio of about 10:1, about 20:1, about 15:1, about 14:1, or about 13:1 (hydrogen peroxide:dopamine). In some embodiments, the composition contains a hydrogen peroxide to dopamine ratio of 14.6:1.

[0068] Synergistic combination of permeability enhancers for gastrointestinal synthetic inner epithelium (GSEL) This disclosure provides combinations of permeabilis enhancers for the gastrointestinal synthetic lining (GSEL) that have been shown to produce a synergistic permeability-enhancing effect on active pharmaceutical ingredients (APIs). GSELs localize APIs to specific locations, resulting in prolonged contact with the gastrointestinal mucosa. However, despite the prolonged contact provided by GSELs, some APIs may not pass through the gastrointestinal barrier in amounts sufficient to be therapeutically effective, or may not permeate at all. Permeabilis enhancers can be used in combination with GSELs to increase the permeability of APIs through the gastrointestinal mucosa. Certain combinations of permeabilis enhancers have been found to function synergistically. Specifically, combinations of a) at least one of ammonium salts, carbonates, or bicarbonates and b) at least one of bile salts or bile acids have been found to have a synergistic effect on the permeability of drugs such as active pharmaceutical ingredients.

[0069] The first component of the synergistic permeation enhancer combination comprises one or more ammonium salts, carbonates, or bicarbonates. The first component may comprise one or more ammonium salts, one or more carbonates, one or more bicarbonates, or any number of ammonium salts, any number of carbonates, and / or any number of bicarbonates in combination.

[0070] In some embodiments, the composition contains an ammonium salt, which can be determined by the body weight of the subject. The composition contains about 1 mg / kg to about 100 mg / kg of ammonium salt. In some embodiments, the composition contains about 1 mg / kg to about 50 mg / kg of ammonium salt. In some embodiments, the composition contains about 1 mg / kg to about 25 mg / kg of ammonium salt. In some embodiments, the composition contains about 5 mg / kg to about 100 mg / kg of ammonium salt. In some embodiments, the composition contains about 5 mg / kg to about 50 mg / kg of ammonium salt. In some embodiments, the composition contains about 5 mg / kg to about 25 mg / kg of ammonium salt. In some embodiments, the composition contains about 10 mg / kg to about 30 mg / kg of ammonium salt. In some embodiments, the composition contains about 10 mg / kg to about 70 mg / kg of ammonium salt. In some embodiments, the composition contains about 10 mg / kg to about 100 mg / kg of ammonium salt. In some embodiments, the composition contains about 25 mg / kg to about 30 mg / kg of ammonium salt. In some embodiments, the composition contains about 25 mg / kg to about 50 mg / kg of ammonium salt. In some embodiments, the composition contains about 25 mg / kg to about 75 mg / kg of ammonium salt. In some embodiments, the composition contains about 25 mg / kg to about 100 mg / kg of ammonium salt. In some embodiments, the composition contains about 30 mg / kg to about 60 mg / kg of ammonium salt. In some embodiments, the composition contains about 30 mg / kg to about 80 mg / kg of ammonium salt. In some embodiments, the composition contains about 30 mg / kg to about 100 mg / kg of ammonium salt. In some embodiments, the composition contains about 50 mg / kg to about 100 mg / kg of ammonium salt. In some embodiments, the composition contains about 50 mg / kg to about 80 mg / kg of ammonium salt. In some embodiments, the composition contains about 50 mg / kg to about 100 mg / kg of ammonium salt. In some embodiments, the composition contains about 60 mg / kg to about 70 mg / kg of ammonium salt.In some embodiments, the composition contains about 70 mg / kg to about 80 mg / kg of ammonium salt. In some embodiments, the composition contains about 80 mg / kg to about 90 mg / kg of ammonium salt. In some embodiments, the composition contains about 70 mg / kg to about 80 mg / kg of ammonium salt. In some embodiments, the composition contains about 75 mg / kg to about 95 mg / kg of ammonium salt. In some embodiments, the composition contains about 80 mg / kg to about 95 mg / kg of ammonium salt.

[0071] Examples of ammonium salts for synergistic combinations include, but are not limited to, ammonium carbonate (NHCO), ammonium sulfate (NHSO), ammonium citrate (NHCA), ammonium phosphate (NHPO), diammonium phosphate (DAP), monoammonium phosphate (MAP), ammonium bicarbonate (NHHCO), or ammonium chloride (NHCl). Ammonium lactate, ammonium acetate, ammonium sulfate, ammonium sulfite, triammonium citrate, ammonium propionate, and ammonium sulfamate can also be used. One particularly useful ammonium salt is ammonium carbonate. Another particularly useful ammonium salt is ammonium bicarbonate. Abbreviations used herein, such as NHCO for ammonium carbonate, are not intended to specify a chemical formula, as the chemical formula for ammonium carbonate is (NH4)2CO3.

[0072] In some embodiments, the composition contains about 10 mg / ml to about 50 mg / mL of NHCO. In some embodiments, the composition contains about 15 mg / ml to about 40 mg / mL of NHCO. In some embodiments, the composition contains about 20 mg / mL to about 45 mg / mL of NHCO. In some embodiments, the composition contains about 30 mg / ml to about 42 mg / mL of NHCO. In some embodiments, the composition contains about 40 mg / ml to about 45 mg / mL of NHCO. In some embodiments, the composition contains about 20 mg / ml to about 35 mg / mL of NHCO. In some embodiments, the composition contains about 35 mg / ml to about 43 mg / mL of NHCO. In some embodiments, the composition contains about 39 mg / ml to about 45 mg / mL of NHCO. In some embodiments, the composition contains about 39 mg / ml to about 41 mg / mL of NHCO. In some embodiments, the composition contains about 40 mg / mL of NHCO.

[0073] In some embodiments, the composition contains approximately 6 mg / kg to approximately 8 mg / kg of NHCO in a weight-based dose. In some embodiments, the composition contains approximately 6 mg / kg to approximately 7 mg / kg of NHCO in a weight-based dose. In some embodiments, the composition contains approximately 6 mg / kg of NHCO in a weight-based dose. In some embodiments, the composition contains approximately 6.4 mg / kg of NHCO in a weight-based dose. In some embodiments, the composition contains approximately 7 mg / kg of NHCO in a weight-based dose. In some embodiments, the composition contains approximately 10 mg / kg to approximately 13 mg / kg of NHCO in a weight-based dose. In some embodiments, the composition contains approximately 11 mg / kg to approximately 13 mg / kg of NHCO in a weight-based dose. In some embodiments, the composition contains approximately 12 mg / kg to approximately 13 mg / kg of NHCO in a weight-based dose. In some embodiments, the composition contains 12.8 mg / kg of NHCO in a weight-based dose.

[0074] Examples of carbonates suitable for synergistic combinations include, but are not limited to, sodium carbonate (NaCO₃) or potassium carbonate (KCO₃). As mentioned earlier, these are abbreviations and not chemical formulas.

[0075] The bicarbonates used in this invention include, but are not limited to, sodium bicarbonate (NaHCO) or potassium bicarbonate (KHCO). As mentioned earlier, these are abbreviations and not chemical formulas.

[0076] The second component of the synergistic permeation enhancer combination comprises one or more bile salts or bile acids. The second component may include one or more bile salts, one or more bile acids, or any combination of any number of bile salts and / or bile acids. Liquid GSEL is formulated in aqueous solution, and depending on the pH of the formulation, the addition of a single bile acid or a single bile salt may result in a mixture of bile acids and their bile salts (i.e., conjugate bases of bile acids). For example, the pKa of cholic acid is given as 4.98 (URL pubchem.ncbi.nlm.nih.gov / compound / Cholic-acid (See Serjeant EP, Dempsey B; Ionization constants of organic acids in aqueous solution. IUPAC Chem Data Ser No.23. NY,NY:Pergamon pp.989 (1979)). When cholic acid is added to a formulation and the pH rises to approximately 8, the majority of the substance takes the form of cholate anions. Conversely, when cholate is added to a formulation and the pH drops to approximately 2, the majority of the substance takes the form of cholic acid. Therefore, when bile salts or bile acids are listed, it should be understood that the form of the substance may change depending on the pH; that is, depending on the pH of a formulation containing bile salts or bile acids, bile salts may be partially or largely converted to bile acids, and / or bile acids may be partially or largely converted to bile salts. The typical pH value of GSEL formulations is approximately 8.5 ± 1 pH units.

[0077] In some embodiments, the composition contains bile salts, which can be determined by the body weight of the subject. The composition contains bile salts in amounts ranging from about 1 mg / kg to about 100 mg / kg. In some embodiments, the composition contains bile salts in amounts ranging from about 1 mg / kg to about 50 mg / kg. In some embodiments, the composition contains bile salts in amounts ranging from about 1 mg / kg to about 25 mg / kg. In some embodiments, the composition contains bile salts in amounts ranging from about 5 mg / kg to about 100 mg / kg. In some embodiments, the composition contains bile salts in amounts ranging from about 5 mg / kg to about 50 mg / kg. In some embodiments, the composition contains bile salts in amounts ranging from about 5 mg / kg to about 25 mg / kg. In some embodiments, the composition contains bile salts in amounts ranging from about 10 mg / kg to about 30 mg / kg. In some embodiments, the composition contains bile salts in amounts ranging from about 10 mg / kg to about 70 mg / kg. In some embodiments, the composition contains bile salts in amounts ranging from about 10 mg / kg to about 100 mg / kg. In some embodiments, the composition contains about 25 mg / kg to about 30 mg / kg of bile salt. In some embodiments, the composition contains about 25 mg / kg to about 50 mg / kg of bile salt. In some embodiments, the composition contains about 25 mg / kg to about 75 mg / kg of bile salt. In some embodiments, the composition contains about 25 mg / kg to about 100 mg / kg of bile salt. In some embodiments, the composition contains about 30 mg / kg to about 60 mg / kg of bile salt. In some embodiments, the composition contains about 30 mg / kg to about 80 mg / kg of bile salt. In some embodiments, the composition contains about 30 mg / kg to about 100 mg / kg of bile salt. In some embodiments, the composition contains about 50 mg / kg to about 100 mg / kg of bile salt. In some embodiments, the composition contains about 50 mg / kg to about 80 mg / kg of bile salt. In some embodiments, the composition contains about 50 mg / kg to about 100 mg / kg of bile salt. In some embodiments, the composition contains about 60 mg / kg to about 70 mg / kg of bile salt. In some embodiments, the composition contains about 70 mg / kg to about 80 mg / kg of bile salt. In some embodiments, the composition contains about 80 mg / kg to about 90 mg / kg of bile salt. In some embodiments, the composition contains about 70 mg / kg to about 80 mg / kg of bile salt.In some embodiments, the composition contains about 75 mg / kg to about 95 mg / kg of bile salts. In some embodiments, the composition contains about 80 mg / kg to about 95 mg / kg of bile salts.

[0078] While not limited to specific bile acids, examples of bile acids used for synergistic combinations include cholic acid (CHA), glycocholic acid (GCA), deoxycholic acid (DCA), glycochenodeoxycholic acid (GCDCA), glycodeoxycholic acid (GDCA), taurodeoxycholic acid (TDCA), taurocholic acid (TCA), bovine bile (OX), chenodeoxycholic acid (CDCA), taurochenodeoxycholic acid (TCDCA), lithocholic acid (LCA), glycolicotocholic acid (GLC), glycohyocholic acid (GHC), and taurolithocholic acid. Examples include TLC, ursodeoxycholic acid (UDCA), tauroursodeoxycholic acid (TUDCA), glycoursodeoxycholic acid (GUDCA), 12-monoketocholic acid (12-MKC), 7-monoketocholic acid (7-MKC), 7,12-diketocholic acid (7,12-DKC), 3,7,12-tricetocholic acid (3,7,12-TKC), 12-monoketodeoxycholic acid (12-MKDC), or 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS). Glycocholic acid is a particularly useful bile acid.

[0079] While not limited to synergistic combinations, bile salts include salts of cholic acid, glycocholic acid, deoxycholic acid, glycochenodeoxykrylic acid, glycodeoxycholic acid, taurodeoxycholic acid, taurocholic acid, bovine bile, chenodeoxycholic acid, taurochenodeoxycholic acid, lithocholic acid, glycolytocholic acid, glycohyocholic acid, and tauroli bile. Examples include salts of tocholic acid, salts of ursodeoxycholic acid, salts of tauroursodeoxycholic acid, salts of glycoursodeoxycholic acid, salts of 12-monoketocholic acid, salts of 7-monoketocholic acid, salts of 7,12-diketocholic acid, salts of 3,7,12-tricetocholic acid, salts of 12-monoketodeoxycholic acid, or salts of 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate. Particularly useful bile salts are salts of glycocholic acid.

[0080] Bile salts may include, but are not limited to, sodium cholate, sodium glycocholate, sodium deoxycholate, sodium glycochenodeoxycholate, sodium glycodeoxycholate, sodium taurodeoxycholate, sodium taurocholate, sodium bovine bile sodium salts, sodium chenodeoxycholate, sodium taurochenodeoxycholate, sodium lithocholate, sodium glycococholate, sodium glycohyocholate, sodium taurolitocholate, sodium ursodeoxycholate, sodium tauroursodeoxycholate, sodium glycoursodeoxycholate, sodium 12-monoketocholate, sodium 7-monoketocholate, sodium 7,12-diketocholate, sodium 3,7,12-triketocholate, sodium 12-monoketodeoxycholate, or sodium 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate sodium, as well as sodium salts. A particularly useful sodium bile acid salt is sodium glycocholate (GCA). Specific synergistic combinations of permeabilis enhancers include the following: Glycocholic acid and ammonium carbonate, Salts of glycocholic acid and ammonium carbonate, and Sodium glycocholate and ammonium carbonate.

[0081] In some embodiments, the composition contains about 10 mg / ml to about 50 mg / mL of GCA. In some embodiments, the composition contains about 15 mg / ml to about 40 mg / mL of GCA. In some embodiments, the composition contains about 20 mg / ml to about 45 mg / mL of GCA. In some embodiments, the composition contains about 30 mg / ml to about 42 mg / mL of GCA. In some embodiments, the composition contains about 40 mg / ml to about 45 mg / mL of GCA. In some embodiments, the composition contains about 20 mg / ml to about 35 mg / mL of GCA. In some embodiments, the composition contains about 35 mg / ml to about 43 mg / mL of GCA. In some embodiments, the composition contains about 39 mg / ml to about 45 mg / mL of GCA. In some embodiments, the composition contains about 39 mg / ml to about 41 mg / mL of GCA. In some embodiments, the composition contains about 40 mg / mL of GCA.

[0082] In some embodiments, the composition contains approximately 6 mg / kg to approximately 8 mg / kg of GCA in a weight-based dose. In some embodiments, the composition contains approximately 6 mg / kg to approximately 7 mg / kg of GCA in a weight-based dose. In some embodiments, the composition contains approximately 6 mg / kg of GCA in a weight-based dose. In some embodiments, the composition contains approximately 6.4 mg / kg of GCA in a weight-based dose. In some embodiments, the composition contains approximately 7 mg / kg of GCA in a weight-based dose. In some embodiments, the composition contains approximately 10 mg / kg to approximately 13 mg / kg of GCA in a weight-based dose. In some embodiments, the composition contains approximately 11 mg / kg to approximately 13 mg / kg of GCA in a weight-based dose. In some embodiments, the composition contains approximately 12 mg / kg to approximately 13 mg / kg of GCA in a weight-based dose. In some embodiments, the composition contains 12.8 mg / kg of GCA in a weight-based dose.

[0083] A specific synergistic combination of permeation enhancers (expressed as a weight-based dosage) includes 6.4 mg / kg of glycocholic acid (GCA) and 6.4 mg / kg of ammonium carbonate (NHCO).

[0084] A specific synergistic combination of permeabilis enhancers (expressed as a weight-based dosage) includes 12.8 mg / kg of glycocholic acid (GCA) and 12.8 mg / kg of ammonium carbonate (NHCO).

[0085] Where chemically feasible and pharmaceutically desirable, alternative pharmaceutically acceptable salts or free acids or bases of the aforementioned compounds may be used.

[0086] Exemplary formulations containing permeation enhancers This specification also discloses formulations of GSEL precursors.

[0087] In some embodiments, the GSEL precursor preparation contains approximately 1–200 mg / ml of dopamine, approximately 1–200 mg / ml of polydopamine, approximately 0–8 mg / mL of an oxygen source, 1–100 mg / mL of bile salt, and 1–100 mg / mL of ammonium salt. In some embodiments, the ratio of dopamine to oxygen source is 20:1 (wt / wt) to 10:1 (wt / wt).

[0088] Specific formulations within the scope disclosed herein include 28 mg / kg of polydopamine nanoparticles, 11 mg / kg of dopamine hydrochloride, 1.6 mg / kg of hydrogen peroxide, and one or more permeabilizing agents. In some embodiments, the amount of one or more permeabilizing agents is determined by the weight ratio (wt / wt) of dopamine:hydrogen peroxide. In some embodiments, the dopamine:hydrogen peroxide ratio is 10:1. In some embodiments, the dopamine:hydrogen peroxide ratio is 20:1. In some embodiments, the dopamine:hydrogen peroxide ratio is 15:1. In some embodiments, the dopamine:hydrogen peroxide ratio is 15:1. In some embodiments, the dopamine:hydrogen peroxide ratio is 14:1. In some embodiments, the dopamine:hydrogen peroxide ratio is 14.6:1.

[0089] Specific formulations within these ranges are 4.567 mg / kg of polydopamine nanoparticles, 1.789 mg / kg of dopamine hydrochloride, 0.122 mg / kg of hydrogen peroxide, 6.4 mg / kg of GCA, and 6.4 mg / kg of NHCO.

[0090] Specific formulations within these ranges are 9.133 mg / kg of polydopamine nanoparticles, 3.596 mg / kg of dopamine hydrochloride, 0.244 mg / kg of hydrogen peroxide, 6.4 mg / kg of GCA, and 6.4 mg / kg of NHCO.

[0091] Specific formulations within these ranges are 13.7 mg / kg of polydopamine nanoparticles, 5.394 mg / kg of dopamine hydrochloride, 0.366 mg / kg of hydrogen peroxide, 6.4 mg / kg of GCA, and 6.4 mg / kg of NHCO.

[0092] Specific formulations within these ranges are 4.567 mg / kg of polydopamine nanoparticles (PDA), 1.789 mg / kg of dopamine hydrochloride, 0.122 mg / kg of hydrogen peroxide, 12.8 mg / kg of GCA, and 12.8 mg / kg of NHCO.

[0093] Specific formulations within these ranges are 9.133 mg / kg of polydopamine nanoparticles, 3.596 mg / kg of dopamine hydrochloride, 0.244 mg / kg of hydrogen peroxide, 12.8 mg / kg of GCA, and 12.8 mg / kg of NHCO.

[0094] Specific formulations within these ranges are 13.7 mg / kg of polydopamine nanoparticles, 5.394 mg / kg of dopamine hydrochloride, 0.366 mg / kg of hydrogen peroxide, 12.8 mg / kg of GCA, and 12.8 mg / kg of NHCO.

[0095] Where chemically feasible and pharmaceutically desirable, alternative pharmaceutically acceptable salts or free acids or bases of the aforementioned compounds may be used.

[0096] In some embodiments, any of the formulations disclosed herein is a powder formulation. In some embodiments, any of the formulations disclosed herein is a liquid formulation. [Examples]

[0097] This disclosure is further illustrated by the following non-limiting embodiments.

[0098] Example 1 Initial evaluation of permeability enhancers by screening 96-well plates

[0099] method:

[0100] Polydopamine nanoparticle synthesis: Polydopamine (PDA) nanoparticles were synthesized based on an established method. Following the protocol, 716.3 mL of ethanol, 1611.7 mL of deionized distilled water, and 72 mL of 28-30% w / v ammonium hydroxide were added with stirring at room temperature. After 30 minutes, 44.7 g of dopamine hydrochloride (dopamine-HCl) was added with stirring, and the reaction mixture was incubated at room temperature for 18 hours. The formed nanoparticles were pelletized by ultracentrifugation at 18,000 g for 30 minutes at room temperature. After centrifugation, 15% of the supernatant was discarded and replaced with an equal amount of deionized water to wash the nanoparticles and redisperse the pellet. The suspension was then centrifuged again at 18,000 g for 15 minutes at room temperature (first washing cycle). In the second and third washing cycles, 60-70% of the supernatant was removed, respectively. Next, the PDA nanoparticles were collected and freeze-dried under the following conditions: -80°C, vacuum <300 mTorr, to obtain approximately 10 g of PDA nanoparticles.

[0101] Ex vivo tissue preparation:

[0102] Pork duodenal or jejunal tissue was excised and rinsed with an antibiotic-antifungal solution diluted 1:20 in 1×PBS buffer (pH 7.4). The tissue was dissected into fragments of varying sizes depending on the tests performed.

[0103] 96-well plate screening:

[0104] Fresh porcine jejunal tissue was excised and washed with a series of salines supplemented with a 5% antibiotic-antifungal solution. The tissue was then placed on an expanded 96-well plate filled with buffer (a plate to receive the permeated drug) (Figures 1A and 1B). Tissue from multiple pigs was used to calculate the mean permeability and the standard deviation from the mean. Another 96-well plate was placed on top and secured with a magnet. Master plates were prepared by dispensing from the following three plates to prepare the donor solution: (1) The excipient and API plate contained excipients and drugs at 2.5 times the final concentration. Tris buffer and hydrogen peroxide were at 1.25 times the final concentration. (2) The polydopamine (PDA) plate contained PDA nanoparticles at 2.5 times the final concentration, as well as Tris buffer and hydrogen peroxide at 1.25 times the final concentration. (3) The dopamine plate contained dopamine at 5 times the final concentration. All formulations contained GSEL_40 (9.8 mg / mL dopamine HCl, 25 mg / mL PDA nanoparticles, 0.67 mg / mL hydrogen peroxide, 2.2 mg / mL Tris HCl, and 4.3 mg / mL Tris base). Master plates were collected from each plate in a volume ratio of 0.5:0.5:1. Next, the donor solution in the master plate was pipetted into a 96-well donor plate. The entire system was then covered and left at room temperature for 20–24 hours. Next, samples from the receiving 96-well plate were analyzed using LC-MS. The mean permeability percentage and / or magnification change was determined by comparing experimental samples tested in the same tissue with control samples. Permeability was calculated by comparing the amount of permeate added to the donor chamber. Magnification change was calculated by comparing the experimental sample with the control sample. More specifically, master plates were prepared using concentrated solutions of each component of GSEL. A concentrated permeabilis enhancer solution was prepared in 50 mM Tris buffer with one or two excipients at pH 8.5. Dilution was performed so that the final concentration of the permeabilis enhancer in the master plate was 40 mg / mL or 80 mg / mL.A solution of concentrated PDA nanoparticles, hydrogen peroxide, and semaglutide was prepared so that the final concentrations in the master plate were 25 mg / mL of PDA nanoparticles, 5 mg / mL of semaglutide, and 19.6 mM (0.67 mg / mL) of hydrogen peroxide. A concentrated dopamine solution was prepared using dopamine HCl and deionized water so that the final dopamine concentration in the master plate was 9.8 mg / mL. The master plate was prepared by adding a concentrated excipient solution, followed by a concentrated PDA nanoparticle / hydrogen peroxide / drug solution, and then the concentrated dopamine solution. The volume on the surface area was 50 μL / 40.15 mm. 2 A total of 61 single excipients were prepared, and each formulation underwent four repeated screenings. From the binary screening, 12 excipients were selected for further testing as combinations. The combinations were tested with different permeation enhancer-to-GSEL mass ratios (1:1 and 1:2). The combination screening was performed under the same experimental conditions as described above.

[0105] The receiver compartment was packed with 0.5% w / v ovalbumin in 1XPBS. Two plates contained jejunal tissue from one animal, and the other two plates contained tissue from a different animal. 50 μl was pipetted from the master plate to each tissue plate. To simulate gastric dilution that GSEL undergoes in the jejunum, 20 μL of donor fluid was replaced with Tris buffer at 15, 30, and 60 minutes after stamping. A total of four tissue plates were stamped and incubated at 37°C for 20 hours. After 20 hours, the plates were inverted and 80 μL of receiver fluid was collected in deep-well plates. Replication wells from tissue plates derived from the same animal were pooled. The deep-well plates were analyzed by LC-MS to determine the semaglutide concentration. Permeability was calculated using the following formula.

number

[0106] The excipients tested and their corresponding names are listed in Table E1. [Table 3-1] [Table 3-2] [Table 3-3]

[0107] Results: Combining GSEL with a single selected excipient significantly improved the permeability of the active pharmaceutical ingredient (API) (Figures 1A, 1B, 1C, 1D, 1E, 1F, Table E1). Certain classes of excipients, such as bile salts, chelators, and permeability enhancers, were found to significantly increase API permeability compared to GSEL alone (Figure 1G).

[0108] The effect of excipient concentration on API permeability was also evaluated (Figures 1H, 1I). Concentration affected API permeability for some excipients, but not for others. Increasing excipient concentrations beyond 25 mg / mL resulted in a decrease in the improvement of permeability.

[0109] Furthermore, excipients were tested in combination with each other and in formulations of various ratios (Figures 2A-2D, Tables E3 and E4). The top combinations of excipients that promoted permeability contained at least one bile salt, cholic acid or its salt, or glycocholic acid or its salt. Notable bile salt combinations included 80 mg / mL of poly(vinyl sulfonate) sodium salt, 40 mg / mL of ammonium carbonate, 80 mg / mL of salcaprozate sodium, 20 mg / mL of folic acid, 80 mg / mL of phytic acid, and 40 mg / mL of dodecyl sulfate sodium (Figures 3A, 3B, 3C, 3D, 3E, 4, and Table E5). [Table 4-1] [Table 4-2] [Table 5-1] [Table 5-2] [Table 5-3] [Table 6-1] [Table 6-2] [Table 7]

[0110] Example 2A Evaluation of permeability enhancers - Franz cell experiment Using Franz cells, different permeabilis enhancers were tested in ex vivo tissues derived from the small intestine, such as porcine duodenal tissue (or colon tissue). A water pump was attached to the Franz cell rack, and each Franz cell was maintained at 37°C. The Franz cells were placed on the rack and each cell was filled with 5 mL of phosphate-buffered saline. The tissue was cut into approximately 3.2 × 3.2 cm squares, and after removing large clumps of mucus or excrement, it was placed on the Franz cells. Next, the gastrointestinal synthetic lining of epithelium (GSEL) solution was prepared by first weighing dopamine HCl, polydopamine, and the permeabilis enhancer and placing them in a vial. Then, the selected active pharmaceutical ingredient (API), Tris buffer (50 mM, pH=8.5), and hydrogen peroxide (1 M) were added to the vial and vortexed until all solids were dissolved (brief sonication was used if necessary). Then, 250 μL of the final mixture was added to the donor compartment of each Franz cell. Samples were periodically collected from the receiving compartment from 0 to 24 hours, and the API concentration was measured. At each sample collection point, 200 μL of phosphate-buffered saline was added to replace the removed volume (200 μL).

[0111] The same experiment was conducted, except that no permeation enhancer was used in the GSEL solution. The increase in permeation induced by the permeation enhancer was measured by comparing the amount of API detected in the receiving compartment of the GSEL containing the permeation enhancer with the amount of API detected in the receiving compartment of the GSEL without the permeation enhancer at each time point.

[0112] Sample preparation consisted of protein precipitation in methanol. Samples were analyzed by LC-MS. In some tests, ELISA was used for semaglutide quantification. The permeability (Pm%) was calculated as follows.

number

[0113] Results: Excipients identified in the 96-well screening were further evaluated for efficacy in Franz cells. Delivery of APIs (e.g., semaglutide and tilzepatide) by liquid and powder formulations in GSELs was measured (Figures 5, 13A, 13B, and Table E6). For some excipient combinations, permeability was significantly improved when the API was delivered by liquid formulation compared to powder formulation (Figures 9 and 10).

[0114] Screening results for 50 single excipients indicated that bile salts were the most promising class for further investigation in combination with other excipients (n=4-15). Screening performed on semaglutides revealed that bile salts such as sodium glycocholate (GCA) and CHA, when combined with ammonium carbonate (NHCO), improved permeability to 24.8-35.8% (Figure 3B). Further permeability tests in Franz cells showed the same synergistic effect when bile salts were combined with other ammonium salts (Figure 3D). Based on dual excipient screening, another combination that showed a synergistic effect was CHA or GCA with SNAC (Figure 3C). This result was also supported by supplemental tests in Franz cells testing additional benzene ring molecules (Figure 3E).

[0115] FITC-dextran-4K (FD4) and FITC-dextran-40K (FD40) are molecules with molecular weights of approximately 4 kilodaltons and 40 kilodaltons, respectively. Excipients were tested for FD4 transport, demonstrating that transport increased with the inclusion of excipients (Figure 6A). Excipient combinations were also tested by evaluating the permeability of FD40 through GSEL (Figures 11A and 11B). The permeability of APIs using formulations containing GSEL, GCA, and NHCO was comparable to that of GCA and NHCO alone at 6 and 20 hours, suggesting that 40 mg / mL of GSEL did not inhibit the efficacy of GCA and NHCO as common excipients (Figure 6B).

[0116] Regarding FD4, the total amount of permeated FD4 increased as the ratio of excipients (GCA (40 mg / mL) and NHCO (40 mg / mL)) to GSEL increased, but the amount of permeated FD4 over time remained similar regardless of the GSEL formulation (Figures 7A, 7B, and 7C). Permeation was observed to occur at a linear rate (Figures 7A and 7B). The permeation accelerator (PE) used was a 1:1 combination of sodium glycocholate (GCA) and ammonium carbonate (NHCO) (40 mg / ml each), i.e., GCA-NHCO_40-40.

[0117] To confirm the effectiveness of the excipient-GSEL combination in multiple tissue types, assays using colon tissue were also performed. Total semaglutide permeation significantly increased with the addition of NHCO and GCA to GSEL (Figures 8, 9, 10A, 10B, 10C, 10D, 11A, 11B). The permeation rate of the API was low during the first 6 hours after GSEL delivery, but then increased linearly after 6 hours (Figures 10B, 10C).

[0118] Other excipient combinations were also confirmed by Franz Cell experiments (Figures 12A, 12B, 13A, and 13B). At 20 hours, semaglutide permeation across duodenal tissue using formulations containing GSEL, GCA, and NHCO was greater than that of GCA and NHCO alone, suggesting that 40 mg / mL of GSEL did not inhibit the efficacy of GCA and NHCO as common excipients (Figures 13A and 13B). This data also suggests that certain combinations of excipients facilitated the permeation of APIs through GSEL.

[0119] Example 2B Evaluation of permeability-enhancing agent formulations

[0120] method:

[0121] Exvivo GSEL coverage trial: Porcine duodenal samples were cut into circular pieces approximately 16.5 mm in diameter and placed in a 24-well plate with the luminal side facing upwards. The GSEL composition consisted of 25 mg / mL of PDA nanoparticles, 9.8 mg / mL of dopamine-HCl, and 0.67 mg / mL of hydrogen peroxide (H2O2). Immediately, 400 μL of the GSEL suspension was added to the tissue in the 24-well plate. At 0, 5, 10, 15, 20, 25, 30, and 120 minutes after solution addition, the tissue sample was removed from the solution in three repetitions. At each time point, the tissue sample was removed from the well and washed three times with PBS. The washed samples were then imaged and analyzed to evaluate the percentage of GSEL coverage on the tissue.

[0122] Ex vivo static colocalization test:

[0123] Pig duodenal sample (2.54 x 2.54 cm) 2 The tissue was placed flat on an aluminum foil tray. The luminal surface of the duodenum was exposed for testing the mucosal layer of the tissue, while the serosal side of the tissue was placed flat on the foil tray. The tissue was covered with a cylinder with an orifice diameter of 9 mm, and a GSEL suspension was added thereto for the static co-localization test. The GSEL composition for the test using FD dye was 6.25 mg of PDA and 2.45 mg of DA-HCl, with a DA-HCl:H2O2 weight ratio of 14.6:1, suspended in 50 mM Tris buffer (pH 8.5). The FD dye, fluorescein isothiocyanate-dextran 4 kDa, 10 kDa, or 40 kDa, was co-formulated at 0.078 to 0.156 mg, and dispensed at a volume of 2 μL / mm². 2 (125μL / 63.61mm 2 ) or 4 μL / mm 2 (250μL / 63.61mm 2 The PE system included either CHA 5-20 mg or GCA 10 mg + NHCO 10 mg. The groups were incubated for 30 minutes. The samples were collected from the donor chamber, and the FD dye was quantified by measuring fluorescence at excitation wavelength 490 nm and emission wavelength 520 nm.

[0124] In the semaglutide studies, different GSEL or PE formulation concentrations were tested. The GSEL compositions were as follows: 1xGSEL: 6.25 mg PDA, 2.45 mg dopamine-HCl, 0.17 mg H2O2; 2xGSEL: 12.5 mg PDA, 4.9 mg, 0.34 mg H2O2; 4xGSEL: 25 mg PDA, 9.8 mg, 0.68 mg H2O2. The PE system consisted of GCA / NHCO (0.1xPE: 1 mg GCA, 1 mg NHCO; 1xPE: 10 mg GCA, 10 mg NHCO). Semaglutide was co-formulated in varying amounts between 0.25 and 0.5 mg, and all formulations were suspended in 50 mM Tris buffer (pH 8.5). The surface area volume was 125 μL / 63.61 mm². 2 The following was done. Before each experiment, a fresh 1M hydrogen peroxide stock was prepared. GSEL suspension test groups were prepared by weighing PDA, dopamine hydrochloride, and PE in glass scintillation vials. Semaglutide stock was prepared in 50 mM Tris buffer (pH 8.5). Semaglutide solution and hydrogen peroxide were added to the vial and mixed for 1 minute by vortexing and sonication. Once the suspension was dispensed, the groups were incubated for 0.5 to 1 hour. Samples were taken from the apical surface of tissue, centrifuged at 16,000 × g for 8 minutes at 4°C, and the supernatant was collected, diluted with Tris buffer (50 mM, pH 8.5), and then mixed with boric acid (80 mg / mL, pH approximately 8.0) in a volume ratio of 1:2 (sample:boric acid) to further inhibit dopamine polymerization and precipitation. Next, the samples were stored in micronic HDPE containers and maintained at -20°C until analysis. The samples were thawed and then diluted with methanol before HPLC analysis.

[0125] The captured pigment or semaglutide (%) was calculated as follows:

number

[0126] Co-administration vs. co-formulation trial: In the co-formulation group, all GSEL components and cholic acid (CHA) were mixed and suspended simultaneously with FD 4kDa, while in the co-administration group, the GSEL components and CHA were first mixed and suspended, and FD 4kDa was added after 10 minutes. The co-formulation group versus the co-administration group was tested in liquid or solid form. For the liquid during the co-formulation test, all components (6.25 mg PDA, 2.45 mg DA-HCl, a DA-HCl:H2O2 weight ratio of 14.6:1, 10 mg CHA, 1 mg FD4) were added at 4 μL / mm 2 (250 μL / 63.61 mm 2 ) and suspended in Tris buffer. On the other hand, in co-administration, GSE+CHA was first suspended and added to Tris buffer, FD4 was added after 10 minutes, and similarly dissolved in Tris buffer. For the powder in the co-formulation, all components (6.25 mg PDA, 2.45 mg DA-HCl, a DA-HCl:urea peroxide weight ratio of 5.33:1, 10 mg CHA, 1 mg FD4, 1.04 mg Tris base, 0.56 mg Tris acid) were added simultaneously as a blend into the donor chamber, and after 10 minutes, water was added at 4 μL / mm 2 (250 μL / 63.61 mm 2 ). In co-administration, the GSEL components and CHA were added first, FD4 was added after 10 minutes, and the mixture was dissolved in water at a dispensed volume of 4 μL / mm 2 (250 μL / 63.61 mm 2 ). When samples were collected from the receiver chamber, all groups were incubated for 24 hours, and FD4 was quantified by measuring fluorescence at an excitation wavelength of 490 nm and an emission wavelength of 520 nm.

[0127] resultUsing FITC-dextran 4kDa (FD4), 10kDa (FD10), and 40kDa (FD40) as model polymers, the ability of GSELs to capture polymers was verified, and the permeability of GSELs in ex vivo tissues when combined with permeability enhancers was evaluated. To determine the rate of GSEL formation, GSEL components were administered to tissues and reacted for different time periods. These experiments showed that incubation of GSELs for more than 30 minutes did not appear to significantly alter the coverage area (Figure 14).

[0128] To test the co-localization of FD4 in duodenal tissue, liquid (e.g., suspension) formulations were prepared by simultaneously adding all components to aliquots of Tris buffer and then directly administering them to the tissue (Figure 15). For solid (e.g., powder) formulations, all powders and Tris salts were added as solids to the tissue surface, and water was added after 10 minutes (Figures 15, 16, and 17). The FD4 content of the supernatant was then measured.

[0129] In the suspension test, the co-formulation showed a 38.3% increase in permeability compared to co-administration, although this was not statistically significant. In contrast, in the solid form, the increase (69.4%) was more pronounced with the co-formulation delivery method, in contrast to co-administration. This suggests that FD4 present in the matrix during GSEL formation is important for co-localization (Figure 17).

[0130] GSEL alone was sufficient to capture the dye (Figures 16 and 18). Further co-localization studies using FD4, FD10, and FD40 showed that co-delivery with the GSEL suspension resulted in captures of 31.0±6.7%, 29.3±1.7%, and 25.8±3.0%, respectively, compared to the control group capture of <1% (Figure 18). The addition of the permeabilis enhancer sodium cholate (CHA) increased the capture of FD10 and FD40 (39.8±0.5% and 38.5±5.3%, respectively) (Figure 18). This suggests the possibility of synergistic effects with GSEL formulations for certain PEs.

[0131] GSEL powder was also tested with FD4 and showed improved capture efficiency (62.3 ± 9.0% co-localization) compared to delivery as a suspension (Figure 16).

[0132] It was found that substrates of various sizes permeated porcine duodenal tissue at a higher percentage when GSEL containing a permeability enhancer was applied compared to GSEL without a permeability enhancer (Figures 19, 20A, and 20B). More specifically, the addition of CHA resulted in increases of FD4, FD10, and FD40 (2.25, 2.74, and 3.58 times, respectively) after 24 hours (Figure 19).

[0133] Example 2C Evaluation of permeabilization enhancers - Dynamic assay

[0134] method: Ex vivo dynamic colocalization experiment

[0135] Porcine duodenal tissue was dissected into 6-inch segments and washed with an antibiotic-antifungal solution diluted 1:20 in 1×PBS, pH 7.4. The tissue was placed on an inclined surface (17.92°). GSEL suspensions (3 mL) containing different GSEL concentrations and / or permeabilis enhancers were dispensed into the tissue over 1 minute. The GSEL compositions were as follows: 1x GSEL contained 25 mg / mL PDA and 9.8 mg / mL DA-HCl in 50 mM Tris buffer (pH 8.5), and 2x GSEL contained 50 mg / mL PDA and 19.6 mg / mL DA, with a DA-HCl:H2O2 ratio of 14.6:1. The PE composition was 40 mg / mL GCA + 40 mg / mL NHCO, with concentrations of FD4 dye or semaglutide of 1 mg / mL or 2 mg / mL, respectively. The flow-through was collected in a tube, and the dye was quantified as described above for the static co-localization test. Semaglutide was tracked during the static co-localization test, and its capture was also evaluated using the same protocol.

[0136] The gastrointestinal tract is a dynamic environment. While low capture may allow for increased permeability under static conditions, in a dynamic environment, it can lead to decreased residence time and absorption. On the other hand, high levels of semaglutide capture within the GSEL platform may impair tissue permeability because semaglutide diffusion from the network is too slow. Therefore, we investigated how varying the ratios between GSEL, permeability enhancers (PE), and semaglutide affects colocalization and permeability. Dynamic assays included evaluating GSEL delivery in angled tissues (Figure 21).

[0137] GCA and NHCO were found to have a high synergistic effect with semaglutide and GSEL (Figures 22A and 22B), and the formulation was modified to improve co-localization and permeability. The formulation (1xGSEL_1xPE) was identified as containing 1xGSEL = 6.25 mg of polydopamine nanoparticles (PDA), 2.45 mg of dopamine hydrochloride (DA-HCl), 1xPE = 10 mg of GCA, and 10 mg of NHCO.

[0138] Using this formulation, permeability tests were conducted to test semaglutide co-formulated with GSEL and GCA-NHCO against controls (semaglutide alone, semaglutide + SNAC (based on Rybelsus® tablets, mass ratio 14:300), semaglutide + GSEL, and semaglutide + GCA + NHCO) (Figure 22C). In this static Franz cell test, GCA-NHCO was clearly a permeability enhancer system, significantly improving permeability by 19.9-fold or 15.5-fold with and without GSEL, respectively (Figure 22C). In contrast, SNAC did not enhance semaglutide permeability to a similar extent (Figure 22C). In particular, since the Franz test was a static test, it was hypothesized that GSEL may provide a local storage site, increasing the residence time at its deposition spot and potentially leading to higher absorption.

[0139] Changing the ratio of the permeability enhancer to GSEL from 1:1 to 0.5:1 or 2:1 did not statistically significantly improve permeability, and reducing the concentration of the permeability enhancer by half did not affect the improvement in permeability (Figure 22D).

[0140] By varying the GSEL content, it was revealed that 1×GSEL and 2×GSEL had no effect, while 4×GSEL significantly reduced permeability, indicating that an increase in the GSEL:PE ratio can adversely affect semaglutide release and tissue uptake (Figure 22E). Under static conditions, increasing the GSEL content relative to the PE concentration increased semaglutide capture (Figure 22K). However, under dynamic conditions, the GSEL content did not have a statistically significant effect on capture (Figure 22L). Using FD4 as an exemplary molecule with a size of 4 kDa, we further investigated whether increasing the GSEL concentration relative to the permeability enhancer led to increased capture in both static and dynamic assays (Figures 22F, 22G).

[0141] In ex vivo experiments, when the permeability enhancer content was reduced tenfold (0.1xPE relative to GSEL), higher co-localization was observed in preliminary dynamic tests (>60%, Figure 2H, 22I), but permeability decreased to 0.5% (Figure 22J).

[0142] Permeation enhancer: Different ratios of semaglutide were investigated, and here, the amount of semaglutide was increased and co-formulated with 2x GSEL and 1x permeation enhancer. All formulations showed similar permeability percentages (Figure 22M).

[0143] Example 3 Gastrointestinal synthetic endothelial preparation containing a permeability enhancer for administration to the target: Evaluation in a porcine model

[0144] method:

[0145] In vivo pharmacokinetic study All animal procedures were performed according to the IACUC-approved animal protocol G2022-142. The study was conducted at the Cummings University of Veterinary Medicine (Division of Animal Resources) at Tufts University. Yorkshire pigs weighing 40-80 kg each were used, aged at least 7 months, approximately 4-9 months. After prescribed preoperative fasting, the pigs were anesthetized, intubated, and maintained with isoflurane anesthesia during the procedure. Blood was collected for 1-7 days by inserting a marginal alar venous catheter. Dried GSEL powder containing a permeabilis enhancer and semaglutide was solubilized in Tris buffer immediately before administration. An endoscope-guided catheter was inserted into the proximal small intestine, and the GSEL suspension was injected therein. Blood was periodically collected from the aural venous catheter and immediately centrifuged in a serum collection tube. Samples were analyzed by ELISA and LC-MS. The pigs were awakened after 6 hours and monitored until full recovery.

[0146] More specifically, after preoperative fasting, the pigs were anesthetized, intubated, and maintained with isoflurane anesthesia during the procedure. An endoscopic guided catheter was placed in the duodenum to allow direct delivery of the formulation. The experimental group or control group was mixed and delivered via the catheter into the duodenum of fasted Yorkshire pigs at an administration rate of 1–3 mL / min. In the case of 1xGSEL pigs, the delivered formulation consisted of 4.567 mg / kg of PDA, 1.789 mg / kg of dopamine hydrochloride, and 0.122 mg / kg of hydrogen peroxide in Tris buffer (pH 8.5). In the case of 2xGSEL pigs, the delivered formulation consisted of 9.133 mg / kg of PDA, 3.596 mg / kg of dopamine hydrochloride, and 0.244 mg / kg of hydrogen peroxide in Tris buffer (pH 8.5). In the case of 3x GSEL pigs, the delivered formulation consisted of 13.7 mg / kg PDA, 5.394 mg / kg dopamine hydrochloride, and 0.366 mg / kg hydrogen peroxide in Tris buffer (pH 8.5). In the case of 1x PE pigs, the formulation consisted of 6.4 mg / kg GCA and 6.4 mg / kg NHCO. In the case of 2x PE pigs, the formulation consisted of 12.8 mg / kg GCA and 12.8 mg / kg NHCO. In all cases, the semaglutide dose was 1.5 mg / kg semaglutide. The suspension dose was 0.183 mL / kg. One pig was administered 1.5 mg / kg semaglutide by endoscopic placement into the duodenum with a semaglutide solution without the addition of a permeabilis enhancer. Two pigs (Group IV) were intravenously administered 1 mg of semaglutide in PBS (1 mg / mL) to enable the calculation of absolute bioavailability (F%). Plasma samples were collected at 0, 5, 15, 30, 45 minutes, and 1 hour, and then every hour up to 12, 24, 48, 72, 144, and 168 hours, and analyzed by LC-MS / MS (see below). Pharmacokinetic (PK) curves were plotted, and the area under the curve (AUC) was calculated using Prism. Bioavailability (F%) was calculated using the following formula.

number

[0147] Blood samples were collected and placed in K3EDTA tubes. The plasma layer was immediately isolated by centrifugation at 10,000 rpm for 5 minutes. The plasma samples were stored in a micronic storage container at -80°C until analysis. Sample preparation consisted of protein precipitation in methanol. LC-MS / MS (liquid chromatography-tandem mass spectrometry) was developed and validated to measure the concentration of semaglutide in the plasma.

[0148] In the following experiments, the formulation component ratios shown in Table E7 were used (for example, 2xGSEL, 6.4 mg / kg GCA, 6.4 mg / kg NHCO, semaglutide with a final ratio of permeabilis enhancer to semaglutide of 20:2.35, or 3xGSEL containing 2xPE (12.73 mg / kg GCA and 12.73 mg / kg NHCO)). [Table 9]

[0149] Results: GSEL formulations containing permeabilis enhancers were identified that resulted in significantly higher plasma semaglutide concentrations in pigs administered with GSEL formulations compared to pigs administered with non-GSEL formulations or pigs administered with semaglutide alone. GSEL suspensions resulted in increased plasma semaglutide levels and overall semaglutide exposure over 24 GSEL or 168 hours (Figure 23C and Table E8).

[0150] PK curves are presented comparing intravenous administration of semaglutide alone, endoscopic placement of semaglutide (control), endoscopic placement of semaglutide delivered with GSELs using various permeabilis enhancers, and endoscopic placement of semaglutide delivered with a permeabilis enhancer alone as a control (Figures 23A, 23B, and 23C). Based on the PK values, the area under the curve (AUC) for each group was calculated, and the results were plotted at different time points of 24, 48, 72, and 168 hours (Figures 23D, 23E, 23F, and 23G). In all cases, delivery of semaglutide with GSELs and permeabilis enhancers showed at least a three-fold increase in semaglutide uptake compared to the control (semaglutide administered with a permeabilis enhancer), while delivery of semaglutide without any PE showed zero absorption at a dose of 1.5 mg / kg (n=1). This result is likely due to the depot effect of GSEL, which increases the retention time of macromolecules in duodenal tissue, thereby improving absorption.

[0151] Absolute bioavailability (e.g., F = absorbed fraction) is shown in Table E8, and semaglutide delivered with GSEL / penetration enhancer achieved bioavailability in the range of 0.5–5.0%. The AUC, Cmax, and tmax for individual porcine studies in all groups are reported in Tables E9 and E10. All groups were delivered endoscopically to the duodenum, with the exception of the IV and Rybelsus® groups, which were delivered endoscopically to the stomach.

[0152] The GSEL / permeation enhancer formulation was observed to be more effective than GSEL alone, as indicated by the AUC up to 48 hours post-administration (Table E8). Relative bioavailability increased threefold compared to the control, with an absolute bioavailability of up to 2.4 ± 1.6% observed in the range of 0.5–4.5% (n=4). Further adjustment of the formulation resulted in an improved bioavailability of 5.0% (n=1).

[0153] Upon recalculation and / or addition of new data, observations from the area under the curve (AUC) revealed that GSEL:PE showed a 6-fold improvement compared to the control group, in which PE was formulated with semaglutide alone. To assess absolute bioavailability, semaglutide was administered intravenously to two pigs, and based on the PK curves of the two pigs, it showed an elimination half-life of 63.4 ± 1.5 hours (Figure 23B). Semaglutide delivered intraduodenum without PE showed no absorption at a dose of 1.5 mg / kg (n=1, Table E8). In particular, the GSEL:PE suspension system yielded an average bioavailability of 2.4 ± 1.6% (n=4, range 0.5–4.5%) compared to 0.4 ± 0.3% (range 0.1%–0.8%) in the 1xPE control group (n=5) (Figure 23C). This result is due to the depot and co-localization effects provided by GSEL:PE, which increased the retention time of semaglutide on duodenal tissue and enhanced its absorption.

[0154] Next, a series of preliminary studies were conducted to establish a correlation between drug absorption and formulation parameters. These studies evaluated the effects of different GSEL concentrations and GSEL:PE ratios (Tables E8 and E9). 2xGSEL_1xPE was more effective than 1xGSEL_1xPE (n=3) or 3xGSEL_1xPE (n=1) doses, as indicated by the AUC up to 48 hours (Table E8 and Figure 24), suggesting that an optimal GSEL:PE ratio exists for fixed concentration PE. Due to constraints limiting blood sampling from pigs in the 1xGSEL_1xPE group, comparisons were limited to 48-hour data (AUC). 48hThe tests were conducted using only ). Further experiments varied the GSEL:PE ratio by changing the PE concentration or GSEL concentration (Tables E8, E9, E10). These tests showed that increasing the PE concentration, with or without GSEL, did not improve bioavailability, as indicated by the trend in the PK curves (Figure 25). These results support the results from the ex vivo permeability tests and suggest that more complex interactions occur between PE, GSEL, and semaglutide (Figures 22C, 22D, 22E, 22J, 22K, 22L).

[0155] To compare with currently available oral products, Rybelsus® tablets were endoscopically delivered into the stomachs of two pigs (Table E8 and Figures 26A-26C). These pigs achieved bioavailability values ​​of 1.7% and 1.2% (mean 1.4% ± 0.3), which were similar to those reported for SNAC-based semaglutide formulations in large animals. The GSEL:PE formulations, 2xGSEL_1xPE and 3xGSEL_2xPE, reached a maximum bioavailability of 5.0%, with mean bioavailability values ​​of 2.4% ± 1.7% and 1.9% ± 2.1, respectively, representing improvements of approximately 70% and 40% compared to Rybelsus® (Figures 26A-26C and Table E9). These data demonstrate that GSEL:PE can enable novel SNAC-free formulations that further improve the oral bioavailability of peptide drugs. Interestingly, two pigs administered Rybelsus® were observed to experience consistent adverse effects (nausea, abdominal discomfort, lethargy) after administration, while these effects were hardly observed in GSEL:PE-treated pigs. It was hypothesized that increased gastric emptying time in pigs could contribute to increased nausea, but it should be noted that since Rybelsus® has been shown to be absorbed in the stomach, this increased time may also contribute to increased bioavailability. 24Pigs treated with Rybelsus® were also given a lower semaglutide dose (1 mg / kg) compared to GSEL:PE-treated pigs (1.5 mg / kg) to mitigate adverse effects, and adverse effects were repeatedly observed in the Rybelsus®-treated pigs. However, further experiments are needed to draw clear conclusions about the tolerability of SNACs for PE used in this study, and how the site of absorption (stomach vs. small intestine) may affect adverse effects.

[0156] A series of studies were conducted in pigs to establish a correlation between drug absorption and formulation parameters. These studies evaluated the effects of different GSEL concentrations and GSEL:PE ratios (Table E8). 2xGSEL_1xPE was more effective than 1xGSEL_1xPE (n=3) or 3xGSEL_1xPE (n=1) doses, as indicated by the AUC up to 48 hours (Figure 24 and Table E8), suggesting that an optimal GSEL:PE ratio exists for a fixed concentration of PE. As shown by the trend in the PK curve, increasing the PE concentration, with or without GSEL, did not improve bioavailability (Figure 25).

[0157] Oral delivery and tolerable use of high molecular weight permeabilis enhancers remain significant challenges due to insufficient co-localization of high molecular weight polymers with often low molecular weight PEs, and the short residue times of all components. These challenges significantly reduce administration efficiency, thereby limiting the viable dosage forms for commercialization. The formulations disclosed herein address these challenges by co-forming polymers with GSELs and permeabilis enhancers to provide targeted drug depots localized in the duodenum. Using the high-throughput screening shown in Figure 1C, synergistic combinations of GSELs and various permeabilis enhancer systems were identified for semaglutide. Using these synergistic combinations, studies in Yorkshire pigs showed that semaglutide combined with GSELs and synergistic SNAC-free PEs yielded an absolute bioavailability of 2.4%. This corresponds to a 6-fold increase in relative bioavailability compared to the control and a 1.7-fold increase in relative bioavailability compared to Rybelsus®. These trials demonstrate GSEL's ability to co-localize macromolecular drugs in the duodenum and provide a targeted depot for enhanced oral bioavailability. [Table 10-1] [Table 10-2] [Table 11] [Table 12]

[0158] Example 4 Gastrointestinal synthetic endothelial preparation containing a permeability enhancer for administration to the target: Evaluation in a canine model A total of 12 Beagles (6 males, 6 females) weighing 9-12 kg and approximately 6-14 months old were used. The dogs were trained to swallow capsules / tablets and given the test substance orally after fasting overnight. After administration, 15 mL of saline was administered as a post-administration flush using a syringe. Blood samples were collected by radial cephalic vein puncture over 48 hours (0, 0.33, 0.66, 1, 2, 4, 6, 8, 24, 48), and then daily for 7 days. Samples were collected in serum separation tubes. Samples were analyzed by ELISA and LC-MS. The following table shows one possible formulation of GSEL with a permeability enhancer in the canine study. [Table 13]

[0159] Any publications, patents, patent applications, and disclosures of published patent applications referenced herein by a citation identifier are incorporated herein by reference in their entirety.

[0160] Although the present invention described above has been described in some detail by examples and specific examples for the sake of clarity, it will be apparent to those skilled in the art that certain changes and modifications may be made. Therefore, the description and examples should not be construed as limiting the scope of the invention.

Claims

1. An orally administered composition for promoting drug permeation by forming a polymer in situ in a target, Polymer precursor and Oxygen source, A combination of a permeabilis enhancer comprising at least one of ammonium salts, carbonates, or bicarbonates, and at least one of bile salts or bile acids, The composition comprising the above.

2. The composition according to claim 1, further comprising one or more agents.

3. The composition according to claim 2, wherein the one or more drugs comprises one or more active pharmaceutical ingredients.

4. The composition according to any one of claims 1 to 3, wherein the ammonium salt, carbonate, or bicarbonate is an ammonium salt.

5. The composition according to any one of claims 1 to 3, wherein the ammonium salt, carbonate, or bicarbonate is a carbonate.

6. The composition according to any one of claims 1 to 3, wherein the ammonium salt, carbonate, or bicarbonate is a bicarbonate.

7. The composition according to any one of claims 1 to 6, wherein the bile salt or bile acid is a bile salt.

8. The composition according to any one of claims 1 to 6, wherein the bile salt or bile acid is a bile acid.

9. The composition according to any one of claims 1 to 4, 7, or 8, wherein the ammonium salt is ammonium carbonate (NHCO), ammonium sulfate (NHSO), ammonium citrate (NHCA), ammonium phosphate (NHPO), diammonium phosphate (DAP), monoammonium phosphate (MAP), ammonium bicarbonate (NHHCO), or ammonium chloride (NHCl).

10. The composition according to any one of claims 1 to 5, 7, or 8, wherein the ammonium salt is ammonium carbonate.

11. The composition according to any one of claims 1 to 4 or 6 to 8, wherein the ammonium salt is ammonium bicarbonate.

12. The composition according to any one of claims 1 to 3, 5, 7, or 8, wherein the carbonate is sodium carbonate or potassium carbonate.

13. The composition according to any one of claims 1 to 3 or 6 to 8, wherein the bicarbonate is sodium bicarbonate or potassium bicarbonate.

14. The aforementioned bile salt or bile acid is a bile acid, and the aforementioned bile acid is cholic acid (CHA), glycocholic acid (GCA), deoxycholic acid (DCA), glycochenodeoxycholic acid (GCDCA), glycodeoxycholic acid (GDCA), taurodeoxycholic acid (TDCA), taurocholic acid (TCA), bovine bile (OX), chenodeoxycholic acid (CDCA), taurochenodeoxycholic acid (TCDCA), litcholic acid (LCA), glycolitocholic acid (GLC), glycohyocholic acid (GHC), taurolithocholic acid (TLC), ursodeoxycholic acid The composition according to any one of claims 1 to 6 or 8 to 13, wherein the composition is an acid (UDCA), tauroursodeoxycholic acid (TUDCA), glycoursodeoxycholic acid (GUDCA), 12-monoketocholic acid (12-MKC), 7-monoketocholic acid (7-MKC), 7,12-diketocholic acid (7,12-DKC), 3,7,12-tricetocholic acid (3,7,12-TKC), 12-monoketodeoxycholic acid (12-MKDC), or 3-[(3-colamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS).

15. The composition according to any one of claims 1 to 6 or 8 to 13, wherein the bile salt or bile acid is a bile acid, and the bile acid is glycocholic acid.

16. The composition according to any one of claims 1 to 3, wherein the ammonium salt, carbonate, or bicarbonate is an ammonium salt, the ammonium salt is ammonium carbonate, the bile salt or bile acid is a bile acid, and the bile acid is glycocholic acid.

17. The composition according to any one of claims 1 to 3, wherein the ammonium salt, carbonate, or bicarbonate is an ammonium salt, the ammonium salt is ammonium bicarbonate, the bile salt or bile acid is a bile acid, and the bile acid is glycocholic acid.

18. The aforementioned bile salt or bile acid is a bile salt, and the aforementioned bile salt is a salt of cholic acid, a salt of glycocholic acid, a salt of deoxycholic acid, a salt of glycochenodeoxykrylic acid, a salt of glycodeoxycholic acid, a salt of taurodeoxycholic acid, a salt of bovine bile, a salt of chenodeoxycholic acid, a salt of taurochenodeoxycholic acid, a salt of litcholic acid, a salt of glycocolic acid, a salt of glycohyocholic acid, a salt of taurolitocholic acid, a salt of ursodeoxy The composition according to any one of claims 1 to 7 or 9 to 13, which is a salt of cholic acid, a salt of tauroursodeoxycholic acid, a salt of glycoursodeoxycholic acid, a salt of 12-monoketocholic acid, a salt of 7-monoketocholic acid, a salt of 7,12-diketocholic acid, a salt of 3,7,12-triketocholic acid, a salt of 12-monoketodeoxycholic acid, or a salt of 3-[(3-colamidopropyl)dimethylammonio]-1-propanesulfonate.

19. The composition according to any one of claims 1 to 7 or 9 to 13, wherein the bile salt or bile acid is a bile salt, and the bile salt is a salt of glycocholic acid.

20. The composition according to any one of claims 1 to 3, wherein the ammonium salt, carbonate, or bicarbonate is an ammonium salt, the ammonium salt is ammonium carbonate, the bile salt or bile acid is a bile salt, and the bile salt is a salt of glycocholic acid.

21. The composition according to any one of claims 1 to 3, wherein the ammonium salt, carbonate, or bicarbonate is an ammonium salt, the ammonium salt is ammonium bicarbonate, the bile salt or bile acid is a bile salt, and the bile salt is a salt of glycocholic acid.

22. The aforementioned bile salt or bile acid is a bile salt, and the aforementioned bile salt is sodium cholate, sodium glycocholate, sodium deoxycholate, sodium glycochenodeoxycholate, sodium glycodeoxycholate, sodium taurodeoxycholate, sodium taurocholate, sodium salt of bovine bile, sodium chenodeoxycholate, sodium taurochenodeoxycholate, sodium lithocholate, sodium glycocolithocholate, sodium glycohyocholate, sodium taurolithocholate The composition according to any one of claims 1 to 7 or 9 to 13, wherein the composition is sodium ursodeoxycholate, sodium tauroursodeoxycholate, sodium glycoursodeoxycholate, sodium 12-monoketocholate, sodium 7-monoketocholate, sodium 7,12-diketocholate, sodium 3,7,12-triketocholate, sodium 12-monoketodeoxycholate, or sodium 3-[(3-colamidopropyl)dimethylammonio]-1-propanesulfonate.

23. The composition according to any one of claims 1 to 7 or 9 to 13, wherein the bile salt or bile acid is a bile salt, and the bile salt is sodium glycocholate.

24. The composition according to any one of claims 1 to 3, wherein the ammonium salt, carbonate, or bicarbonate is an ammonium salt, the ammonium salt is ammonium carbonate, the bile salt or bile acid is a bile salt, and the bile salt is sodium glycocholate.

25. The composition according to any one of claims 1 to 3, wherein the ammonium salt, carbonate, or bicarbonate is an ammonium salt, the ammonium salt is ammonium bicarbonate, the bile salt or bile acid is a bile salt, and the bile salt is sodium glycocholate.

26. The composition according to any one of claims 1 to 25, further comprising a buffering agent.

27. The composition according to any one of claims 1 to 26, wherein the polymer precursor comprises one or both of a monomer and an oligomer precursor of a polymer.

28. The polymer precursor is selected from Table 1 or Table 2, or a combination thereof, as described in any one of claims 1 to 27.

29. The composition according to claim 27 or 28, wherein the monomer is dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, levodopa ethyl ester, or a combination thereof.

30. The composition according to claim 27 or 28, wherein the monomer is dopamine.

31. The composition according to any one of claims 27 to 30, wherein the oligomer precursor of the polymer is an oligomer of dopamine, an oligomer of levodopa, an oligomer of norepinephrine, an oligomer of methyldopa, an oligomer of levodopa methyl ester, an oligomer of levodopa ethyl ester, or an oligomer of any combination of dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, or levodopa ethyl ester.

32. The composition according to any one of claims 27 to 30, wherein the oligomeric precursor of the polymer is a dopamine oligomer.

33. The composition according to claim 27, wherein the monomer is dopamine, and the oligomeric precursor of the polymer is a dopamine oligomer.

34. The composition according to any one of claims 1 to 33, wherein the oxygen source is a substrate for an endogenous catalyst.

35. The composition according to any one of claims 1 to 34, wherein the oxygen source is urea peroxide or hydrogen peroxide.

36. A composition according to any one of claims 1 to 35, which is in oral dosage form.

37. The composition according to claim 36, wherein the oral dosage form is a solution, gel, tablet, powder, or capsule.

38. The composition according to claim 36, wherein the oral dosage form comprises one or more solutions, gels, tablets, powders, or capsules.

39. The composition according to claim 36, wherein the oral dosage form includes an enteric-coated dosage form.

40. The composition according to any one of claims 2 to 39, wherein the agent is a polymer having a molecular weight of about 1 kD to about 160 kD.

41. The composition according to claim 40, wherein the polymer is a polypeptide or a polynucleotide.

42. The composition according to claim 40, wherein the polymer is a polypeptide.

43. The composition according to claim 42, wherein the molecular weight of the polypeptide is about 1 kD to about 10 kD.

44. The composition according to claim 42, wherein the polypeptide comprises about 8 to about 80 amino acids.

45. The composition according to claim 42, wherein the polypeptide comprises insulin, a GLP-1 receptor agonist, liraglutide, desmopressin, octreotide, analgesic peptide, diferikephalin, H-20, an antibiotic, cyclosporine, vancomycin, lactase, beta-galactosidase, exenatide, teriparatide, nafarelin, buserelin, captopril, daptomycin, an antibody, caplacizumab, ozoralizumab, brolucizumab, ranibizumab, bevacizumab, trastuzumab, rituximab, adalimumab, an enzyme, lipase, protease, phenylalanine hydroxylase, carbamoyl phosphate synthetase I, glucose oxidase, or L-asparaginase.

46. The composition according to claim 42, wherein the polypeptide comprises semaglutide.

47. The composition according to claim 42, wherein the polypeptide comprises tilzepatide.

48. The composition according to claim 40, wherein the polymer is a polynucleotide.

49. The composition according to claim 48, wherein the molecular weight of the polynucleotide is about 5 kD to about 1500 kD.

50. The composition according to claim 48 or claim 49, wherein the polynucleotide is single-stranded.

51. The composition according to claim 48 or claim 49, wherein the polynucleotide is double-stranded.

52. The composition according to claim 48, wherein the polynucleotide is single-stranded and contains about 10 to about 5000 bases.

53. The composition according to claim 48, wherein the polynucleotide is single-stranded and contains about 10 to about 1000 bases.

54. The composition according to claim 48, wherein the polynucleotide is single-stranded and contains about 10 to about 30 bases.

55. The composition according to claim 48, wherein the polynucleotide is double-stranded and contains about 5 to about 2500 base pairs.

56. The composition according to claim 48, wherein the polynucleotide is double-stranded and contains about 5 to about 500 base pairs.

57. The composition according to claim 48, wherein the polynucleotide is double-stranded and contains about 5 to about 15 base pairs.

58. The composition according to claim 48, wherein the polynucleotide comprises an antisense oligonucleotide, mypomersen, patisirane, exondys, siRNA, or inflammatory bowel disease (IBD) targeted siRNA.

59. The composition according to any one of claims 2 to 39, wherein the drug is a small molecule having a molecular weight of 1 kD or less.

60. A method for forming a polymer coating in the gastrointestinal tract of a subject, comprising administering to the subject a composition according to any one of claims 1 to 59.

61. The method according to claim 60, wherein the polymer coating is formed in the small intestine of the subject.

62. The method according to claim 61, wherein the polymer coating is formed inside the duodenum of the subject.

63. A method for forming a polymer coating inside the target gastrointestinal tract, Polymer precursor and Oxygen source, A combination of a permeabilis enhancer comprising at least one of ammonium salts, carbonates, or bicarbonates, and at least one of bile salts or bile acids, This includes oral administration to the target population. The method comprising bringing the polymer precursor and the oxygen source into contact with a catalyst inherent in the target, the catalyst polymerizing the polymer precursor.

64. The method according to claim 63, wherein the polymer coating is formed in the small intestine of the subject.

65. The method according to claim 64, wherein the polymer coating is formed inside the duodenum of the subject.

66. The method according to any one of claims 63 to 65, further comprising administering one or more drugs to the subject.

67. The method according to any one of claims 63 to 66, wherein the combination of the polymer precursor, the oxygen source, and the permeation enhancer is administered as a single composition.

68. The method according to claim 66, wherein the polymer precursor, the oxygen source, the permeation enhancer, and the one or more agents are administered as a single composition.

69. The method according to claim 66, wherein the one or more agents are administered in a composition separate from the administration of the combination of the polymer precursor, the oxygen source, and the permeation enhancer.

70. The method according to any one of claims 66 to 69, wherein the drug is an active pharmaceutical ingredient.

71. An orally administered composition for promoting drug permeation by forming a polymer in situ in a target, Polymer precursor and Oxygen source, A combination of a permeation enhancer including a first permeation enhancer and a second permeation enhancer, Includes, The composition wherein the combination of the first permeation accelerator and the second permeation accelerator increases the permeation of the drug compared to the sum of the permeation of the individual drug by each accelerator.

72. The composition according to claim 71, wherein the first permeation enhancer is an ammonium salt.

73. The composition according to claim 71, wherein the first permeation enhancer is a carbonate.

74. The composition according to claim 71, wherein the first permeation enhancer is a bicarbonate.

75. The composition according to any one of claims 71 to 74, wherein the second permeation enhancer is a bile salt.

76. The composition according to any one of claims 71 to 74, wherein the second permeation enhancer is a bile acid.

77. The composition according to any one of claims 71 to 76, further comprising a drug.

78. The composition according to claim 77, wherein the aforementioned drug is an active pharmaceutical ingredient.

79. The composition according to any one of claims 71 to 77, wherein the agent comprises semaglutide.

80. The composition according to any one of claims 71 to 77, wherein the drug comprises tilzepatide.

81. The composition according to any one of claims 71 to 80, further comprising one or more additional agents.

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