Permeation enhancers for gastrointestinal synthetic epithelial lining

Abstract

The present disclosure relates to a "gastrointestinal synthetic epithelial lining" or "GSEL," a synthetic lining of the gastrointestinal (GI) tract that can modulate the absorption of drugs, nutrients, and other substances in the GI tract, and one or more permeation enhancers that aid in such absorption. GSELs are temporary linings on the inner surface of the lumen of the GI tract that maintain the active agent (e.g., drug, nutrient, or other substance) in intimate contact with the GI mucosa, allowing the active agent to be absorbed over an extended period of time.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 480,921, filed January 20, 2023, and U.S. Provisional Application No. 63 / 541,238, filed September 28, 2023, the contents of each of which are incorporated herein by reference in their entirety.

[0002] The present invention relates to synthetic linings of the gastrointestinal (GI) tract that can modulate the absorption of drugs, nutrients, and other substances in the GI tract, and to permeation enhancers that aid in such absorption. [Background technology]

[0003] The gastrointestinal (GI) tract of humans, vertebrates, and other animals functions as a 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 also widely used for the administration of pharmaceuticals. Multiple and diverse modes of oral administration of drugs are available, including both immediate-release and sustained-release formulations.

[0004] However, many medications cannot be administered orally because the epithelial layer acts as a barrier to certain types of substances. Various physical and chemical properties of certain medications prevent their passage across the epithelium lining the GI tract. Medications, particularly biologics, can be too large to be transported across the epithelium. Other properties that affect transport include charge and hydrophobicity.

[0005] The present disclosure describes compositions, methods, and kits for modulating absorption of pharmaceutical agents in the gastrointestinal tract, which can enhance drug absorption in the GI tract by prolonging contact with the gastric mucosa. The present disclosure also provides gastrointestinal synthetic epithelial linings (GSELs) in combination with one or more permeation enhancers, which enhance the absorption of pharmaceutical agents in the gastrointestinal tract. Summary of the Invention

[0006] The present disclosure relates to a synthetic lining formed in situ in the gastrointestinal tract, such as in the small intestine, which may be used in combination with a drug and one or more permeation enhancers, which increase absorption of the drug through intestinal tissue compared to the synthetic lining without the permeation enhancers. The synthetic lining itself is referred to as a gastrointestinal synthetic epithelial lining (GSEL).

[0007] Disclosed herein are compositions for oral administration to form a polymer in situ in a subject, the compositions comprising a polymer precursor, an oxygen source, and a permeation enhancer that promotes permeation of one or more active pharmaceutical ingredients. In some embodiments, the compositions comprise one or more active pharmaceutical ingredients. In some embodiments, the compositions further comprise a buffering agent. In some embodiments, the compositions further comprise one or more additional permeation enhancers. In some embodiments, the compositions comprise the polymer precursor in an amount of 40% to 90% relative to the (polymer precursor, oxygen source, and permeation enhancer). In some embodiments, the compositions comprise the oxygen source in an amount of 1% to 15% relative to the (polymer precursor, oxygen source, and permeation enhancer). In some embodiments, the compositions comprise the permeation enhancer in an amount of 0.1% to 60% relative to the (polymer precursor, oxygen source, and permeation enhancer). In some embodiments, the compositions comprise the polymer precursor in an amount of 40% to 90% relative to the (polymer precursor, oxygen source, permeation enhancer, and active pharmaceutical ingredient(s). In some embodiments, the composition comprises an oxygen source in an amount of 1% to 15% relative to the (polymer precursor, oxygen source, permeation enhancer, and active pharmaceutical ingredient(s)). In some embodiments, the composition comprises a permeation enhancer in an amount of 1% to 60% relative to the (polymer precursor, oxygen source, permeation enhancer, and active pharmaceutical ingredient(s)). In some embodiments, the composition comprises an active pharmaceutical ingredient(s) in an amount of 0.1% to 10% relative to the (polymer precursor, oxygen source, permeation enhancer, and active pharmaceutical ingredient(s)).

[0008] In some embodiments, the active pharmaceutical ingredient is a polymer having a molecular weight of about 1 kD to about 160 kD. In some embodiments, the polymer is a polypeptide or a 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, semaglutide, a GLP-1 receptor agonist, tirzepatide, liraglutide, desmopressin, octreotide, an analgesic peptide, difelikefalin, 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, a lipase, a protease, phenylalanine hydroxylase, carbamoyl phosphate synthetase I, glucose oxidase, or L-asparaginase. In some embodiments, the macromolecule is a polynucleotide. In some embodiments, the polynucleotide has a molecular weight of 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 comprises about 10 to about 5000 bases. In some embodiments, the polynucleotide is single-stranded and comprises about 10 to about 1000 bases. In some embodiments, the polynucleotide is single-stranded and comprises about 10 to about 30 bases. In some embodiments, the polynucleotide is double-stranded and comprises about 5 to about 2500 base pairs. In some embodiments, the polynucleotide is double-stranded and comprises about 5 to about 500 base pairs. In some embodiments, the polynucleotide is double-stranded and comprises about 5 to about 15 base pairs. In some embodiments, the polynucleotide comprises an antisense oligonucleotide, mipomersen, patisiran, exondys, siRNA, or inflammatory bowel disease (IBD)-targeting siRNA.In some embodiments, the active pharmaceutical ingredient is a small molecule having a molecular weight of 1 kD or less.

[0009] In some embodiments, the polymer precursor comprises one or both of a monomer and an oligomeric 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, dopamine HCl, levodopa, norepinephrine, methyldopa, levodopa methyl ester, levodopa ethyl ester, or a combination thereof. In some embodiments, the oxygen source is a substrate for an endogenous catalyst. In some embodiments, the oxygen source is urea peroxide or hydrogen peroxide. In some embodiments, the composition is in 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 of a solution, gel, tablet, powder, or capsule. In some embodiments, the oral dosage form is an enteric-coated dosage form.

[0010] In some embodiments, the permeation enhancer is carnitine. In some embodiments, the carnitine is an acylcarnitine. In some embodiments, the carnitine is selected from the group consisting of lauroylcarnitine, palmitoylcarnitine, and palmitoylcarnitine chloride (PCC). In some embodiments, the carnitine is lauroylcarnitine or palmitoylcarnitine. In some embodiments, the permeation enhancer is choline. In some embodiments, the choline is lysophosphatidylcholine. In some embodiments, the permeation enhancer is an aromatic alcohol. In some embodiments, the aromatic alcohol is selected from the group consisting of propyl gallate, butylhydroxytoluene, and butylhydroxyanisole. In some embodiments, the aromatic alcohol is benzyl alcohol, phenyl alcohol, or phenoxyethanol. In some embodiments, the permeation enhancer is a piperazine derivative. In some embodiments, the piperazine derivative is selected from the group consisting of 1-phenylpiperazine, 1-methyl-4-phenylpiperazine, 1-(4-methylphenyl)piperazine, and 1-benzylpiperazine. In some embodiments, the piperazine derivative is 1-phenylpiperazine or 1-methyl-4-piperazine. In some embodiments, the permeation enhancer is a mucoadhesive polymer. In some embodiments, the mucoadhesive polymer is selected from the group consisting of chitosan, chitosan hydrochloride, trimethylated chitosan chloride, and N,N,N-trimethylchitosan chloride. In some embodiments, the mucoadhesive polymer is trimethylated chitosan chloride. In some embodiments, the permeation enhancer is a cell-penetrating peptide. In some embodiments, the cell-penetrating peptide is selected from the group consisting of transportan and penetratin. In some embodiments, the cell-penetrating peptide is selected from the group consisting of oligoarginine, polyarginine, oligolysine, polylysine, oligotryptophan, and polytryptophan. In some embodiments, the permeation enhancer is an amino acid. In some embodiments, the amino acid is tryptophan. In some embodiments, the permeation enhancer is an ionic liquid.In some embodiments, the ionic solution is selected from the group consisting of choline geranate, nicotinic acid, and trigonelline. In some embodiments, the ionic solution is choline geranate. In some embodiments, the permeation enhancer is an organic solvent. In some embodiments, the solvent is selected from the group consisting of ethanol, 2-propanol, 1-propanol, and 2-methyl-2-propanol. In some embodiments, the organic solvent is selected from the group consisting of dimethyl sulfoxide, ethyl acetate, and acetone. In some embodiments, the permeation enhancer is an anionic surfactant. In some embodiments, the anionic surfactant is sodium dodecyl sulfate or an alternative pharmaceutically acceptable salt thereof. In some embodiments, the anionic surfactant is sodium cholate or an alternative pharmaceutically acceptable salt thereof. In some embodiments, the permeation enhancer is a chelating agent. In some embodiments, the chelating agent is selected from the group consisting of EDTA, EGTA, and DTPA. In some embodiments, the chelating agent is EDTA. In some embodiments, the permeation enhancer is a non-ionic surfactant. In some embodiments, the non-ionic surfactant is an ethoxylate. In some embodiments, the nonionic surfactant is an alcohol ethoxylate (C. X E Ywhere X is the number of carbon atoms in the alcohol and Y is the number of ethylene oxide units. In some embodiments, the nonionic surfactant is a medium or long chain fatty acid sugar ester. In some embodiments, the nonionic surfactant is a medium or long chain fatty acid sucrose ester. In some embodiments, the nonionic surfactant is an ethoxylated fatty acid sugar ester. In some embodiments, the nonionic surfactant is an ethoxylated sorbitan ester. In some embodiments, the nonionic surfactant is an ethoxylated glyceride. In some embodiments, the nonionic surfactant is selected from the group consisting of macrogol-8 glyceride, sucrose esters, sucrose laurate, ethoxylates, alkyl maltosides, dodecyl maltoside, short-chain polyethylene glycols, Brij® series, polyoxyethylene (10) oleyl ether, polyoxyethylene (23) lauryl ether, polysorbates, polysorbate series PS20, PS40, PS60, PS65, PS80, and Triton® X-100. In some embodiments, the nonionic surfactant is caprylocaproyl polyoxyl-8 glyceride (LABRASOL®), poloxamer, polyoxylglyceride, or polyethylene monostearate. In some embodiments, the permeation enhancer is a nonionic detergent. In some embodiments, the nonionic detergent is sucrose monolaurate or n-tetradecyl β-D-maltopyranoside (TDM). In some embodiments, the non-ionic detergent is sucrose monolaurate. In some embodiments, the non-ionic detergent is n-tetradecyl β-D-maltopyranoside (TDM). In some embodiments, the permeation enhancer is a fatty acid, a fatty acid salt, an ethoxylated fatty acid ester, a sugar fatty acid ester, or an ethoxylated sugar fatty acid ester. In some embodiments, the fatty acid salt is sodium caprate (C 10 ), or an alternative pharmaceutically acceptable salt thereof. In some embodiments, the fatty acid salt is sodium caprylate (C8), or an alternative pharmaceutically acceptable salt thereof, or sodium laurate (C 12), or an alternative pharmaceutically acceptable salt thereof. In some embodiments, the sugar fatty acid ester is a fatty acid ester of a monosaccharide. In some embodiments, the sugar fatty acid ester is an ethoxylated fatty acid ester of a monosaccharide. In some embodiments, the sugar fatty acid ester is a fatty acid ester of sorbitan or glucose. In some embodiments, the sugar fatty acid ester is an ethoxylated fatty acid ester of sorbitan or glucose. In some embodiments, the sugar fatty acid ester is a fatty acid ester of a disaccharide. In some embodiments, the sugar fatty acid ester is an ethoxylated fatty acid ester of a disaccharide. In some embodiments, the sugar fatty acid ester is a fatty acid ester of sucrose or maltose. In some embodiments, the sugar fatty acid ester is an ethoxylated fatty acid ester of sucrose or maltose. In some embodiments, the fatty acid, ethoxylated fatty acid ester, sugar fatty acid ester, or ethoxylated sugar fatty acid ester is selected from the group consisting of dodecyl maltoside, sodium dodecyl sulfate, nonaethylene glycol monododecyl ether (C 12 E9), sodium laurate (C 12 ), Sodium Nonanoate (C9), Sodium Undecanoate (C 11 ), sodium undecylenate (C11:1), sodium oleate, linoleic acid, and sucrose monolaurate, and pharmaceutically acceptable salts thereof or alternative pharmaceutically acceptable salts thereof. In some embodiments, the fatty acid, ethoxylated fatty acid ester, sugar fatty acid ester, or ethoxylated sugar fatty acid ester is selected from the group consisting of nonaethylene glycol monododecyl ether (C 12E9). In some embodiments, the permeation enhancer is an endogenous secretory product. In some embodiments, the endogenous secretory product is a bile salt. In some embodiments, the bile salt is selected from the group consisting of sodium taurodeoxycholate, sodium taurocholate, sodium cholate, sodium deoxycholate, sodium glycodeoxycholate, sodium glycochenodeoxycholate, sodium glycocholate, sodium chenodeoxycholate, sodium taurochenodeoxycholate, sodium lithocholate, and mixed sodium taurodihydrofusidate, or alternative pharmaceutically acceptable salts thereof. In some embodiments, the bile salt is sodium cholate, or alternative pharmaceutically acceptable salts thereof. In some embodiments, the permeation enhancer is an N-acylated acid. In some embodiments, the N-acylated acid is acetylsalicylic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, the N-acylated acid is sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC), or an alternative pharmaceutically acceptable salt thereof, or its corresponding acid. In some embodiments, the N-acylated acid is 8-(N-2-hydroxy-5-chloro-benzoyl)-amino-caprylic acid (5-CNAC), or an alternative pharmaceutically acceptable salt thereof, or its corresponding acid. In some embodiments, the N-acylated acid is 4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid (4-CNAB), or an alternative pharmaceutically acceptable salt thereof, or its corresponding acid. In some embodiments, the N-acylated acid is N-(10-[2-hydroxybenzoyl]-amino)decanoic acid (SNAD), or an alternative pharmaceutically acceptable salt thereof, or its corresponding acid. In some embodiments, the N-acylated acid is N-(4-chlorosalicyloyl)-4-aminobutyric acid monosodium (5-CNAB), or an alternative pharmaceutically acceptable salt thereof, or its corresponding acid. In some embodiments, the N-acylated acid is N-[8-(2-hydroxy-4-methoxy)benzoyl]aminocaprylic acid (4-MOAC), or a pharmaceutically acceptable salt thereof.In some embodiments, the N-acylated acid is sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC), or an alternative pharmaceutically acceptable salt thereof, or its corresponding acid. In some embodiments, the permeation enhancer is a high molecular weight polymer. In some embodiments, the high molecular weight polymer is a polysaccharide. In some embodiments, the high molecular weight polymer is an antimicrobial toxin. In some embodiments, the antimicrobial toxin is selected from the group consisting of zonula occludens toxin analog, viral protein 8 analog, and Clostridium perfringens enterotoxin analog. In some embodiments, the high molecular weight polymer is chitosan or carboxymethylcellulose. In some embodiments, the permeation enhancer is caprylocaproyl PEG-8 glyceride. In some embodiments, the permeation enhancer is a sugar-based surfactant. In some embodiments, the sugar-based surfactant is dodecyl-β-D-maltopyranoside (DDM). In some embodiments, the permeation enhancer is glyceryl monocaprate. In some embodiments, the permeation enhancer is urea. In some embodiments, the permeation enhancer is docusate sodium, or an alternative pharmaceutically acceptable salt thereof, or its corresponding acid. In some embodiments, the permeation enhancer is citric acid, or a pharmaceutically acceptable salt thereof. In some embodiments, the permeation enhancer promotes paracellular transport. In some embodiments, the permeation enhancer promotes transcellular transport. In some embodiments, the permeation enhancer promotes paracellular and transcellular transport.

[0011] Disclosed herein is a method of forming a polymeric coating in the small intestine of a subject, the method comprising administering to the subject any one of the compositions disclosed herein.

[0012] Disclosed herein are methods for forming a polymer coating in the small intestine of a subject, the method comprising orally administering to the subject a polymer precursor, an oxygen source, and a permeation enhancer that promotes the uptake of one or more active pharmaceutical ingredients, wherein the polymer precursor and oxygen source contact a catalyst present in the subject, and the catalyst polymerizes the polymer precursor. In some embodiments, the method further comprises administering an active pharmaceutical ingredient to the subject. In some embodiments, the polymer precursor, oxygen source, and permeation enhancer are administered as a single composition. In some embodiments, the polymer precursor, oxygen source, permeation enhancer, and active pharmaceutical ingredient are administered as a single composition. In some embodiments, the polypeptide comprises semaglutide. In some embodiments, the polypeptide comprises tirzepatide. [Brief explanation of the drawings]

[0013] [Figure 1A] Figure 1 shows the permeability (expressed as fold change) of the active pharmaceutical ingredient (API) semaglutide delivered using GSEL. Each data point represents the average permeability for an individual formulation. The short horizontal bars represent the mean values. Data were normalized to the permeability of GSEL_40 and are sorted by the average permeability. The x-axis displays the excipient abbreviation and concentration in mg / ml (e.g., CHA_80 indicates 80 mg / ml CHA, where CHA indicates cholic acid sodium salt). All formulations contained GSEL_40 (9.8 mg / mL dopamine HCl, 25 mg / mL PDA, 0.67 mg / mL hydrogen peroxide, 2.2 mg / mL Tris HCl, 4.3 mg / mL Tris base). Table E1 in Example 1 provides a list of abbreviations used for the excipients. [Figure 1B]The mean percent permeability of the active pharmaceutical ingredient (API) tirzepatide is shown. Pm = (amount permeated through the 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 an individual formulation. The short horizontal bars represent the mean. Data are arranged by mean permeability. The x-axis displays the excipient abbreviation and concentration in mg / ml (e.g., CHA_80 indicates 80 mg / ml CHA, where CHA indicates cholic acid sodium salt). All formulations contained GSEL_40 (9.8 mg / mL dopamine HCl, 25 mg / mL PDA, 0.67 mg / mL hydrogen peroxide, 2.2 mg / mL Tris HCl, 4.3 mg / mL Tris base; values ​​may vary ±5%; pH 8.5). Table E1 in Example 1 provides a list of abbreviations used for the excipients, and Table E2 lists the percent permeability (%Pm). [Figure 1C] A summary of the values ​​determined for each GSEL-single excipient combination is shown. The active pharmaceutical ingredient (API) delivered is semaglutide. Fold Change GSEL (FC GSEL) measures the fold change in permeability for each formulation with excipients and normalizes it to the permeability of GSEL alone. Data are ordered by mean permeability. Numbers indicate excipient concentration (e.g., GSEL-GCA_40-40 indicates 40 mg / ml GSEL and 40 mg / ml sodium glycocholate). Pm = (amount permeated through the 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 1D]A summary of the values ​​determined for each GSEL-single excipient combination is shown. The active pharmaceutical ingredient (API) delivered is tirzepatide. Fold Change GSEL (FC GSEL) measures the fold change in permeability for each formulation with excipient and normalizes it to the permeability of GSEL alone. Data are ordered by mean permeability. Values ​​indicate excipient concentration. Pm = (amount permeated through the 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 2A] Shown are the mean fold changes in gastrointestinal synthetic epithelial lining (GSEL) permeability clustered by excipient class. The active pharmaceutical ingredient (API) delivered is semaglutide. Fold Change GSEL (FC GSEL) measures the fold change in permeability for each formulation with excipients and normalizes to the permeability of GSEL alone. Each data point represents the mean permeability for an individual formulation. The short bars represent the mean values. Data are sorted by class mean permeability. Values ​​indicate excipient concentration (mg / ml). [Figure 2B] Shown are the mean fold changes in gastrointestinal synthetic epithelial lining (GSEL) permeability clustered by excipient class. The active pharmaceutical ingredient (API) delivered is tirzepatide. Fold Change GSEL (FC GSEL) measures the fold change in permeability for each formulation with excipient and normalizes it to the permeability of GSEL alone. Each data point represents the mean permeability for an individual formulation. The short horizontal bars represent the mean values. The data are ordered by class mean permeability. Values ​​indicate excipient concentration (mg / ml). [Figure 2C] The mean fold change in gastrointestinal synthetic epithelial lining (GSEL) permeability is shown. The active pharmaceutical ingredient (API) delivered is semaglutide. Fold Change GSEL (FC GSEL) measures the fold change in permeability for each formulation with excipients and normalizes to the permeability of GSEL alone. Each data point represents the mean permeability for an individual formulation. The short horizontal bars represent the mean values. The data are sorted by class mean permeability. The numbers on the x-axis (e.g., 20, 40, 80) indicate excipient concentration (mg / ml). [Figure 3]Figure 1 shows the mean percent permeability of gastrointestinal synthetic epithelial lining (GSEL). The active pharmaceutical ingredient (API) delivered is tirzepatide. Each data point represents the mean permeability of an individual formulation. The short horizontal bars represent the mean values. The data are sorted by mean permeability. The numbers on the x-axis (e.g., 20, 40, 80) indicate excipient concentration (mg / ml). Table E1 in Example 1 provides a list of abbreviations used for excipients, and Table E3 lists the percent permeability (%Pm). [Figure 4A-1] The mean percent gastrointestinal synthetic epithelial lining (GSEL) permeability for each excipient combination is shown. The active pharmaceutical ingredient (API) delivered is semaglutide. Fold Change GSEL (FC GSEL) measures the fold change in permeability for each formulation with excipients and is normalized to the permeability of GSEL alone. Each data point represents the mean permeability for an individual formulation. The short horizontal bars represent the mean value. The data are sorted by class mean permeability. Numbers on the x-axis (e.g., 20, 40, 80) indicate excipient concentration (mg / ml). GSEL_80 represents twice the amount of ingredients in GSEL_40, except for Tris. GSEL_40 contains 9.8 mg / mL dopamine HCl, 25 mg / mL PDA, 0.67 mg / mL hydrogen peroxide, 2.2 mg / mL Tris HCl, and 4.3 mg / mL Tris base (approximately pH 8.5). GSEL_80 contains 19.6 mg / mL dopamine HCl, 50 mg / mL PDA, 1.34 mg / mL hydrogen peroxide, 2.2 mg / mL Tris HCl, and 4.3 mg / mL Tris base (values ​​may vary ±5%). The solutions were approximately pH 8.5. [Figure 4A-2]The mean percent gastrointestinal synthetic epithelial lining (GSEL) permeability for each excipient combination is shown. The active pharmaceutical ingredient (API) delivered is semaglutide. Fold Change GSEL (FC GSEL) measures the fold change in permeability for each formulation with excipients and is normalized to the permeability of GSEL alone. Each data point represents the mean permeability for an individual formulation. The short horizontal bars represent the mean value. The data are sorted by class mean permeability. Numbers on the x-axis (e.g., 20, 40, 80) indicate excipient concentration (mg / ml). GSEL_80 represents twice the amount of ingredients in GSEL_40, except for Tris. GSEL_40 contains 9.8 mg / mL dopamine HCl, 25 mg / mL PDA, 0.67 mg / mL hydrogen peroxide, 2.2 mg / mL Tris HCl, and 4.3 mg / mL Tris base (approximately pH 8.5). GSEL_80 contains 19.6 mg / mL dopamine HCl, 50 mg / mL PDA, 1.34 mg / mL hydrogen peroxide, 2.2 mg / mL Tris HCl, and 4.3 mg / mL Tris base (values ​​may vary ±5%). The solutions were approximately pH 8.5. [Figure 4A-3] The mean percent gastrointestinal synthetic epithelial lining (GSEL) permeability for each excipient combination is shown. The active pharmaceutical ingredient (API) delivered is semaglutide. Fold Change GSEL (FC GSEL) measures the fold change in permeability for each formulation with excipients and is normalized to the permeability of GSEL alone. Each data point represents the mean permeability for an individual formulation. The short horizontal bars represent the mean value. The data are sorted by class mean permeability. Numbers on the x-axis (e.g., 20, 40, 80) indicate excipient concentration (mg / ml). GSEL_80 represents twice the amount of ingredients in GSEL_40, except for Tris. GSEL_40 contains 9.8 mg / mL dopamine HCl, 25 mg / mL PDA, 0.67 mg / mL hydrogen peroxide, 2.2 mg / mL Tris HCl, and 4.3 mg / mL Tris base (approximately pH 8.5). GSEL_80 contains 19.6 mg / mL dopamine HCl, 50 mg / mL PDA, 1.34 mg / mL hydrogen peroxide, 2.2 mg / mL Tris HCl, and 4.3 mg / mL Tris base (values ​​may vary ±5%). The solutions were approximately pH 8.5. [Figure 4B-1]The mean percent gastrointestinal synthetic epithelial lining (GSEL) permeability for each excipient combination is shown. The active pharmaceutical ingredient (API) delivered is semaglutide. Fold Change GSEL (FC GSEL) measures the fold change in permeability for each formulation with excipients and is normalized to the permeability of GSEL alone. Each data point represents the mean permeability for an individual formulation. The short horizontal bars represent the mean value. The data are sorted by class mean permeability. Numbers on the x-axis (e.g., 20, 40, 80) indicate excipient concentration (mg / ml). GSEL_80 represents twice the amount of ingredients in GSEL_40, except for Tris. GSEL_40 contains 9.8 mg / mL dopamine HCl, 25 mg / mL PDA, 0.67 mg / mL hydrogen peroxide, 2.2 mg / mL Tris HCl, and 4.3 mg / mL Tris base (approximately pH 8.5). GSEL_80 contains 19.6 mg / mL dopamine HCl, 50 mg / mL PDA, 1.34 mg / mL hydrogen peroxide, 2.2 mg / mL Tris HCl, and 4.3 mg / mL Tris base (values ​​may vary ±5%). The solutions were approximately pH 8.5. [Figure 4B-2] The mean percent gastrointestinal synthetic epithelial lining (GSEL) permeability for each excipient combination is shown. The active pharmaceutical ingredient (API) delivered is semaglutide. Fold Change GSEL (FC GSEL) measures the fold change in permeability for each formulation with excipients and is normalized to the permeability of GSEL alone. Each data point represents the mean permeability for an individual formulation. The short horizontal bars represent the mean value. The data are sorted by class mean permeability. Numbers on the x-axis (e.g., 20, 40, 80) indicate excipient concentration (mg / ml). GSEL_80 represents twice the amount of ingredients in GSEL_40, except for Tris. GSEL_40 contains 9.8 mg / mL dopamine HCl, 25 mg / mL PDA, 0.67 mg / mL hydrogen peroxide, 2.2 mg / mL Tris HCl, and 4.3 mg / mL Tris base (approximately pH 8.5). GSEL_80 contains 19.6 mg / mL dopamine HCl, 50 mg / mL PDA, 1.34 mg / mL hydrogen peroxide, 2.2 mg / mL Tris HCl, and 4.3 mg / mL Tris base (values ​​may vary ±5%). The solutions were approximately pH 8.5. [Figure 4B-3]The mean percent gastrointestinal synthetic epithelial lining (GSEL) permeability for each excipient combination is shown. The active pharmaceutical ingredient (API) delivered is semaglutide. Fold Change GSEL (FC GSEL) measures the fold change in permeability for each formulation with excipients and is normalized to the permeability of GSEL alone. Each data point represents the mean permeability for an individual formulation. The short horizontal bars represent the mean value. The data are sorted by class mean permeability. Numbers on the x-axis (e.g., 20, 40, 80) indicate excipient concentration (mg / ml). GSEL_80 represents twice the amount of ingredients in GSEL_40, except for Tris. GSEL_40 contains 9.8 mg / mL dopamine HCl, 25 mg / mL PDA, 0.67 mg / mL hydrogen peroxide, 2.2 mg / mL Tris HCl, and 4.3 mg / mL Tris base (approximately pH 8.5). GSEL_80 contains 19.6 mg / mL dopamine HCl, 50 mg / mL PDA, 1.34 mg / mL hydrogen peroxide, 2.2 mg / mL Tris HCl, and 4.3 mg / mL Tris base (values ​​may vary ±5%). The solutions were approximately pH 8.5. [Figure 5A-1] The mean percent permeability of gastrointestinal synthetic epithelial lining (GSEL) permeability for each excipient combination is shown. The active pharmaceutical ingredient (API) transported is tirzepatide. Percent Pm = (amount permeated through the 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 an individual formulation. The short horizontal bars represent the mean. The data are sorted by mean permeability of the class. The numbers on the x-axis (e.g., 20, 40, 80) indicate excipient concentration (mg / ml). [Figure 5A-2]The mean percent permeability of gastrointestinal synthetic epithelial lining (GSEL) permeability for each excipient combination is shown. The active pharmaceutical ingredient (API) transported is tirzepatide. Percent Pm = (amount permeated through the 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 an individual formulation. The short horizontal bars represent the mean. The data are sorted by mean permeability of the class. The numbers on the x-axis (e.g., 20, 40, 80) indicate excipient concentration (mg / ml). [Figure 5A-3] The mean percent permeability of gastrointestinal synthetic epithelial lining (GSEL) permeability for each excipient combination is shown. The active pharmaceutical ingredient (API) transported is tirzepatide. Percent Pm = (amount permeated through the 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 an individual formulation. The short horizontal bars represent the mean. The data are sorted by mean permeability of the class. The numbers on the x-axis (e.g., 20, 40, 80) indicate excipient concentration (mg / ml). [Figure 5B] The mean percent permeability of gastrointestinal synthetic epithelial lining (GSEL) permeability for each excipient combination is shown. The active pharmaceutical ingredient (API) transported is tirzepatide. Percent Pm = (amount permeated through the 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 an individual formulation. The short horizontal bars represent the mean. The data are sorted by mean permeability of the class. The numbers on the x-axis (e.g., 20, 40, 80) indicate excipient concentration (mg / ml). [Figure 5C-1]The mean percent permeability of gastrointestinal synthetic epithelial lining (GSEL) permeability for each excipient is shown. The active pharmaceutical ingredient (API) transported is tirzepatide. Percent Pm = (amount permeated through the 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 an individual formulation. The short horizontal bars represent the mean. The data are sorted by mean permeability for the class. The numbers on the x-axis (e.g., 20, 40, 80) indicate the excipient concentration (mg / ml). Table E1 in Example 1 provides a list of abbreviations used for excipients, and Table E4 lists the %Pm. [Figure 5C-2] The mean percent permeability of gastrointestinal synthetic epithelial lining (GSEL) permeability for each excipient is shown. The active pharmaceutical ingredient (API) transported is tirzepatide. Percent Pm = (amount permeated through the 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 an individual formulation. The short horizontal bars represent the mean. The data are sorted by mean permeability for the class. The numbers on the x-axis (e.g., 20, 40, 80) indicate the excipient concentration (mg / ml). Table E1 in Example 1 provides a list of abbreviations used for excipients, and Table E4 lists the %Pm. [Figure 5C-3] The mean percent permeability of gastrointestinal synthetic epithelial lining (GSEL) permeability for each excipient is shown. The active pharmaceutical ingredient (API) transported is tirzepatide. Percent Pm = (amount permeated through the 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 an individual formulation. The short horizontal bars represent the mean. The data are sorted by mean permeability for the class. The numbers on the x-axis (e.g., 20, 40, 80) indicate the excipient concentration (mg / ml). Table E1 in Example 1 provides a list of abbreviations used for excipients, and Table E4 lists the %Pm. [Figure 5C-4]The mean percent permeability of gastrointestinal synthetic epithelial lining (GSEL) permeability for each excipient is shown. The active pharmaceutical ingredient (API) transported is tirzepatide. Percent Pm = (amount permeated through the 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 an individual formulation. The short horizontal bars represent the mean. The data are sorted by mean permeability for the class. The numbers on the x-axis (e.g., 20, 40, 80) indicate the excipient concentration (mg / ml). Table E1 in Example 1 provides a list of abbreviations used for excipients, and Table E4 lists the %Pm. [Figure 5D-1] Figure 1 shows the mean percent permeability of gastrointestinal synthetic epithelial lining (GSEL) permeability for single excipients and excipient combinations. The active pharmaceutical ingredient (API) transported is tirzepatide. Percent Pm (%Pm) = (amount permeated through the 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 an individual formulation. The short horizontal bars represent the mean. The data are arranged by mean permeability for the class. The numbers on the x-axis (e.g., 20, 40, 80) indicate the excipient concentration (mg / ml). Table E1 in Example 1 provides a list of abbreviations used for excipients, and Table E4 lists the %Pm. [Figure 5D-2]Figure 1 shows the mean percent permeability of gastrointestinal synthetic epithelial lining (GSEL) permeability for single excipients and excipient combinations. The active pharmaceutical ingredient (API) transported is tirzepatide. Percent Pm (%Pm) = (amount permeated through the 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 an individual formulation. The short horizontal bars represent the mean. The data are arranged by mean permeability for the class. The numbers on the x-axis (e.g., 20, 40, 80) indicate the excipient concentration (mg / ml). Table E1 in Example 1 provides a list of abbreviations used for excipients, and Table E4 lists the %Pm. [Figure 5D-3] Figure 1 shows the mean percent permeability of gastrointestinal synthetic epithelial lining (GSEL) permeability for single excipients and excipient combinations. The active pharmaceutical ingredient (API) transported is tirzepatide. Percent Pm (%Pm) = (amount permeated through the 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 an individual formulation. The short horizontal bars represent the mean. The data are arranged by mean permeability for the class. The numbers on the x-axis (e.g., 20, 40, 80) indicate the excipient concentration (mg / ml). Table E1 in Example 1 provides a list of abbreviations used for excipients, and Table E4 lists the %Pm. [Figure 5D-4]Figure 1 shows the mean percent permeability of gastrointestinal synthetic epithelial lining (GSEL) permeability for single excipients and excipient combinations. The active pharmaceutical ingredient (API) transported is tirzepatide. Percent Pm (%Pm) = (amount permeated through the 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 an individual formulation. The short horizontal bars represent the mean. The data are arranged by mean permeability for the class. The numbers on the x-axis (e.g., 20, 40, 80) indicate the excipient concentration (mg / ml). Table E1 in Example 1 provides a list of abbreviations used for excipients, and Table E4 lists the %Pm. [Figure 5E] Figure 1 shows the mean percent permeability of the gastrointestinal synthetic epithelial lining (GSEL) for single excipients and excipient combinations. The active pharmaceutical ingredient (API) transported is tirzepatide. Percent Pm (%Pm) = (amount permeated through the 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 an individual formulation. The short horizontal bars represent the mean. The data are sorted by mean permeability within the class. The numbers on the x-axis (e.g., 20, 40, 80) indicate the excipient concentration (mg / ml). Table E1 in Example 1 provides a list of abbreviations used for excipients, and Table E5 lists the %Pm. [Figure 5F]Figure 1 shows the mean percent permeability of the gastrointestinal synthetic epithelial lining (GSEL) for single excipients and excipient combinations. The active pharmaceutical ingredient (API) transported is tirzepatide. Percent Pm (%Pm) = (amount permeated through the 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 an individual formulation. The short horizontal bars represent the mean. The data are sorted by mean permeability within the class. The numbers on the x-axis (e.g., 20, 40, 80) indicate the excipient concentration (mg / ml). Table E1 in Example 1 provides a list of abbreviations used for excipients, and Table E5 lists the %Pm. [Figure 6-1] The mean fold change in gastrointestinal synthetic epithelial lining (GSEL) permeability for each combination of excipients is shown. The excipients shown at the top of each graph are held constant across combinations with the excipients shown on the x-axis. The active pharmaceutical ingredient (API) delivered is semaglutide. Fold Change GSEL (FC GSEL) measures the fold change in permeability for each formulation with excipients and is normalized by the permeability of GSEL alone. Each data point represents the mean permeability for an individual formulation. The short horizontal bars represent the mean value. The long horizontal line across each graph is the mean fold change in permeability for the excipients shown at the top of the graph. The data are ordered by mean permeability. Numbers on the x-axis (e.g., 20, 40, 80) indicate excipient concentration (mg / ml). [Figure 6-2] The mean fold change in gastrointestinal synthetic epithelial lining (GSEL) permeability for each combination of excipients is shown. The excipients shown at the top of each graph are held constant across combinations with the excipients shown on the x-axis. The active pharmaceutical ingredient (API) delivered is semaglutide. Fold Change GSEL (FC GSEL) measures the fold change in permeability for each formulation with excipients and is normalized by the permeability of GSEL alone. Each data point represents the mean permeability for an individual formulation. The short horizontal bars represent the mean value. The long horizontal line across each graph is the mean fold change in permeability for the excipients shown at the top of the graph. The data are ordered by mean permeability. Numbers on the x-axis (e.g., 20, 40, 80) indicate excipient concentration (mg / ml). [Figure 7] Figure 1 shows the mean percent permeability of the active pharmaceutical ingredient (API) (semaglutide) delivered by GSEL using combinations of bile salts (CHA = sodium cholate, GCA = sodium glycocholate) with various concentrations of ammonium carbonate (NHCO), as well as GSEL with ammonium carbonate alone, ammonium carbonate without GSEL, and GSEL without a permeation enhancer. Each data point represents the mean permeability of an individual formulation. The short bars represent the mean value. The data are ordered by mean permeability. The numbers on the x-axis (e.g., 20, 40, 80) indicate the excipient concentration (mg / ml). [Figure 8] The mean percent permeability (%Pm) of the active pharmaceutical ingredient (API) (semaglutide) is shown. Data are ordered by total mass of CHA (sodium cholic acid) and / or NHCO (ammonium carbonate). Numbers on the x-axis (e.g., 20, 40, 80) indicate excipient concentrations (mg / ml). [Figure 9] Figure 1 shows the mean percent permeability (Pm) of tirzepatide transported across porcine duodenal tissue 20 hours after delivery as a solid powder. Numbers on the x-axis (e.g., 40) indicate excipient concentration (mg / ml). [Figure 10] Figure 1 shows the mean percent permeability (Pm) of tirzepatide transported across porcine duodenal tissue 20 hours after delivery of GSEL as a suspension. Numbers on the x-axis (e.g., 40) indicate excipient concentration (mg / ml). [Figure 11A] The percent of FITC-dextran-40K (FD40) permeated 20 hours after GSEL delivery is shown. Numbers on the x-axis indicate excipient concentration (mg / ml). [Figure 11B] The percent of FITC-dextran-40K (FD40) permeated at 6 and 20 hours after GSEL delivery is shown. [Figure 12A]The amount (μg) of permeated FITC-dextran-4K (FD4) over time after GSEL delivery is shown with and without various ratios of permeation enhancer (PE), which is a 1:1 combination of sodium glycocholate (GCA) and ammonium carbonate (NHCO), each at 40 mg / ml, i.e., GCA-NHCO_40-40. [Figure 12B] The amount (μg) of FITC-dextran-4K (FD4) permeated over time after delivery of various GSEL formulations is shown. Values ​​are ratios. [Figure 12C] 1 shows a table summarizing the amount (μg) of FITC-dextran-4K (FD4) permeated over time following delivery of various GSEL formulations. Values ​​represent ratios. [Figure 12D] Franz cell FITC-dextran-4K (FD4) permeation experiments with and without permeation enhancers are shown. **P=0.029, confidence level=95%, n=7. [Figure 13] Figure 1 shows the mean percent permeability (Pm) of the active pharmaceutical ingredient (API) (semaglutide), where porcine colon tissue is used as the barrier. [Figure 14] Figure 1 shows the mean percent permeability of semaglutide in Franz cell experiments comparing bile salts alone and in combination with other excipients as permeation enhancers. [Figure 15A] Figure 1 shows the mean percent permeation of semaglutide at 20 hours in a Franz cell study comparing a combination of sodium glycocholate (GCA) and ammonium carbonate (NHCO) with a combination of sodium glycocholate (GCA) and sodium carbonate (NaCO) as permeation enhancers. [Figure 15B] Figure 15B shows the amount of semaglutide (μg) at 7 hours in a Franz cell study comparing sodium glycocholate (GCA) in combination with ammonium carbonate (NHCO) with sodium glycocholate (GCA) in combination with sodium carbonate (NaCO) as permeation enhancers. Figure 15B is a zoomed-in view of an earlier time point in the graph shown in Figure 15C. [Figure 15C]Figure 15B shows the amount of semaglutide (μg) permeated at 20 hours in a Franz cell study comparing a combination of sodium glycocholate (GCA) and ammonium carbonate (NHCO) with a combination of sodium glycocholate (GCA) and sodium carbonate (NaCO) as permeation enhancers. Figure 15B is a zoomed-in view of an earlier time point in the graph shown in Figure 15C. [Figure 15D] Figure 1 shows the calculated mean percent permeation of semaglutide permeated at 20 hours in a Franz cell study comparing a combination of sodium glycocholate (GCA) and ammonium carbonate (NHCO) with a combination of sodium glycocholate (GCA) and sodium carbonate (NaCO) as permeation enhancers. [Figure 16A] Figure 1 shows the mean percent permeability of semaglutide in comparison with various ammonium salts, such as ammonium carbonate (NHCO), ammonium sulfate (NHSO), and ammonium bicarbonate (NHHCO) salts, in combination with cholic acid sodium salt (CHA) as a permeation enhancer. [Figure 16B] Figure 1 shows the measured mean percent permeability values ​​of semaglutide after 20 hours in comparison with various ammonium carbonate (NHCO) salts in combination with cholic acid sodium salt (CHA) as a permeation enhancer. [Figure 17A] Figure 1 shows the mean percent permeability of semaglutide compared with the bile salts taurocholic acid (TCA) and taurochenodeoxycholic acid (TCDCA) as permeation enhancers. [Figure 17B] The measured mean percent permeability values ​​for semaglutide after 20 hours are shown in comparison with bile salts as permeation enhancers. [Figure 18A] Figure 1 shows the mean percent permeation of semaglutide after 20 hours comparing cholic acid (CHA) with NHCO or SNAC and GCA with SNAC as permeation enhancers. [Figure 18B]Figure 1 shows the measured mean percent permeability values ​​of semaglutide after 20 hours in comparison with cholic acid (CHA) with NHCO or SNAC and GCA with SNAC as permeation enhancers. [Figure 19A] Figure 1 shows the mean percent permeability of semaglutide across duodenal tissue in comparison with GCA and NHCO, or GCA, NHCO and GSEL, as permeation enhancers. [Figure 19B] Figure 1 shows the measured mean percent permeability of semaglutide through duodenal tissue in comparison with GCA and NHCO, or GCA, NHCO and GSEL, as permeation enhancers. [Figure 20A] 1 shows that surface coverage with GSEL does not increase significantly after 30 minutes of incubation. [Figure 20B] FIG. 1 shows a schematic of a Franz cell experiment testing co-administration versus co-formulation. [Figure 20C] Percentage of dye (FITC-dextran-4K) entrapped on duodenal tissue with or without GSEL and / or CHA (as permeation enhancers) is shown, and formulations administered as liquids (e.g., suspensions) compared to solid formulations. ****P<0.0001 using one-way ANOVA. Confidence interval: 95%, n=4-8. [Figure 20D] Shown is the percent of dye (FITC-dextran-4K) permeated onto duodenal tissue when administered as a liquid (e.g., suspension) compared to a solid formulation. * indicates p<0.05. [Figure 20E]The percent of dye (FITC-dextran 4K, FITC-dextran 10K, or FITC-dextran 40K) entrapped on porcine duodenal tissue in the presence of GSEL, or GSEL and a permeation enhancer (CHA) is shown. Values ​​were compared using a two-way analysis of variance followed by Dunnett's multiple comparison test. **** indicates p<0.0001. The table summarizes the percent of FITC-dextran 4K, FITC-dextran 10K, or FITC-dextran 40K entrapped on tissue in the presence of GSEL, or GSEL and a permeation enhancer (CHA). The formulations were delivered as liquids (e.g., suspensions). [Figure 20F] The percentage of dyes (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) is shown. Values ​​were compared using a two-way analysis of variance followed by Sidak'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 20G] We present results from screening bile salts using the GSEL platform in Franz cells. The GSEL contained 6.25 mg PDA, 2.45 mg DA-HCl, with a DA-HCl:H2O2 ratio of 14.6:1 and a volume of distribution of 4 μL / mm2. CHA was tested at 40 mg / mL (10 mg mass), n = 4-8. Semaglutide was quantified using ELISA. The formulation was delivered as a liquid (e.g., suspension). [Figure 20H]Results of permeability studies are shown. In the studies, GSEL was combined with increasing concentrations of the bile salt CHA. GSEL contained 6.25 mg PDA, 2.45 mg DA-HCl, with a DA-HCl:H2O2 ratio of 14.6:1 and a volume of distribution of 4 μL / mm2. CHA was tested at doses ranging from 40 to 160 mg / mL (mass 10 to 40 mg), n = 7 to 24. Semaglutide was quantified using ELISA. The formulations were delivered as liquids (e.g., suspensions). [Figure 21] The setup for a dynamic colocalization study performed on porcine jejunum tissue (6 inches long) at an angle of 17.92° for FD4 or semaglutide, with and without GSEL, and at different GSEL concentrations is shown. The suspension was dispensed at 3 mL / min, and the flow-through was collected and analyzed for the amount of non-colocalized FD4 or semaglutide. [Figure 22A] Results of a Franz cell permeability study are shown. In the study, GSEL was combined with the bile salt CHA and different ammonium salts in a Franz cell. GSEL contained 6.25 mg of PDA and 2.45 mg of DA-HCl, with a DA-HCl:H2O2 ratio of 14.6:1 and a volume of distribution of 4 μL / mm2. The ammonium salts were tested at a GSEL concentration of 40 mg / mL (10 mg mass). n = 7-24. Semaglutide was quantified using ELISA. [Figure 22B] The results of a Franz cell permeability study are shown. In the study, GSEL was combined with the bile salts CHA and SNAC or other benzene ring-based excipients. GSEL contained 6.25 mg of PDA and 2.45 mg of DA-HCl, with a DA-HCl:H2O2 ratio of 14.6:1 and a volume of distribution of 4 μL / mm2. The benzene ring-based excipients were tested at 40 mg / mL (10 mg mass), n = 7-24. Semaglutide was quantified using ELISA. [Figure 22C]Results of a Franz cell permeability study are shown. The study compared GSEL:permeation enhancer (PE):semaglutide (SEMA) (PE=GCA-NHCO) to control, semaglutide alone, semaglutide and SNAC 14:300, SEMA and GCA-NHCO, and SEMA and GSEL. The GSEL composition contained 6.25 mg PDA and 2.45 mg DA-HCl, with a DA-HCl:H2O2 ratio of 14.6:1 and a volume of distribution of 4 μL / mm2, with GCA and NHCO tested at 40 mg / mL (10 mg mass). One-way analysis of variance was used; ****P<0.0001, 95% confidence interval, n=8. [Figure 22D] The results of a Franz cell permeability study are shown. In the study, 1xGSEL contained 6.25 mg of PDA and 2.45 mg of DA-HCl, with a DA-HCl:H2O2 ratio of 14.6:1, a volume of distribution of 2 μL / mm2, and PE mass (GCA + NHCO) of 2, 10, 20, or 40 mg, using one-way ANOVA: **P=0.0016, ****P<0.0001, 95% confidence interval, n=22. [Figure 22E] The results of a permeability test using a Franz cell are shown below. The mass of PE was 20 mg (10 mg GCA + 10 mg NHCO), and the masses of PDA and DA-HCl were varied (1x = 6.25 mg PDA and 2.45 mg DA-HCl, 2x = 12.5 mg PDA, 4.9 mg DA-HCl, 4x = 25 mg PDA, 9.8 mg DA-HCl, 14.6:1 DA-HCl:HO ratio, 2 μL / mm volume of distribution). Using one-way ANOVA, P = 0.6906, *P = 0.0498, confidence interval: 95%, n = 8–12. [Figure 22F]Dynamic colocalization studies were performed on porcine jejunum tissue for FD4 with and without GSEL and at different GSEL concentrations. The study consisted of permeation enhancer (PE): 40 mg / mL GCA + 40 mg / mL NHCO, and a permeation enhancer:semaglutide ratio of 20:0.5. For 1xGSEL, PDA 25 mg / mL and DA-HCl 9.8 mg / mL. For 2xGSEL, PDA 50 mg / mL and DA-HCl 19.6 mg / mL. DA-HCl:HO ratio 14.6:1. 17.92°C, 3 mL to 6 inches of tissue in 1 minute. ****P<0.0001, 95% confidence interval, n=3, using one-way ANOVA. [Figure 22G] Static colocalization study in porcine duodenal tissue for FD4: PE 20 mg (10 mg GCA + 10 mg NHCO), PDA 6.25 mg and DA-HCl = 2.45 mg for 1x GSEL, PDA 12.5 mg and DA-HCl = 4.9 mg for 2x GSEL, DA-HCl:H2O2 ratio of 14.6:1, volume of distribution 2 μL / mm2, using one-way ANOVA; ***P = 0.0004, ****P < 0.0001, 95% confidence interval, n = 4. [Figure 22H] Dynamic colocalization studies of semaglutide with and without GSEL and at different permeation enhancer (PE) concentrations in porcine jejunal tissue are shown. The study consisted of 1xPE (40 mg / mL GCA + 40 mg / mL NHCO), or 0.1xPE (4 mg / mL GCA + 4 mg / mL NHCO), PDA 50 mg / mL and DA-HCl = 19.6 mg / mL, DA-HCl:H2O2 ratio of 14.6:1, 17.92°C, 3 mL to 6 inches of tissue in 1 minute, n=2. [Figure 22I] 1 shows porcine jejunum tissue after dynamic co-localization testing using FD4. [Figure 22J]Semaglutide permeation (mass, μg) through Franz cells at different permeation enhancer:semaglutide ratios (20:0.5, 20:1, 20:2, 20:4, 20:8) is shown, increasing semaglutide with 2x GSEL (PDA 12.5 mg, DA-HCl = 4.9 mg, DA-HCl:H2O2 ratio of 14.6:1, 2 μL / mm2 volume of distribution) and 1x permeation enhancer (PE) (GCA 10 mg, NHCO 10 mg (total PE 20 mg)). One-way ANOVA was used to determine **P = 0.0044, ****P < 0.0001, 95% confidence interval, n = 8-9. The permeation enhancer:semaglutide ratio was varied by adjusting the amount of semaglutide inside. [Figure 22K] This shows the results of a static colocalization study of semaglutide in porcine duodenal tissue. In the study, the total mass of permeation enhancer used was 20 mg (10 mg GCA + 10 mg NHCO), the permeation enhancer:semaglutide ratio was 20:2, with 6.25 mg PDA and 2.45 mg DA-HCl for 1xGSEL and 12.5 mg PDA and 4.9 mg DA-HCl for 2xGSEL, a 14.6:1 DA-HCl:H2O2 ratio, and a volume of distribution of 2 μL / mm2. Using one-way ANOVA, *P=0.0155, 95% confidence interval, n=4-10. [Figure 22L] Dynamic colocalization study results in porcine jejunal tissue for semaglutide (PE: 40 mg / mL GCA + 40 mg / mL NHCO), PE:SEMA = 20:0.5, PDA 25 mg / mL and DA-HCl = 9.8 mg / mL for 1xGSEL, PDA 50 mg / mL and DA = 19.6 mg / mL for 2xGSEL, DA-HCl:H2O2 ratio of 14.6:1, 4xGSEL = PDA 25 mg, DA-HCl = 9.8 mg, DA-HCl:H2O2 ratio of 14.6:1, 17.92°, 3 mL in 1 minute to 6 inches of tissue, **P = 0.0286 using unpaired two-tailed t-test, not significant using one-way ANOVA, confidence interval: 95%, n = 4. [Figure 22M]The results show the Franz cell permeation (%) of semaglutide at different permeation enhancer:semaglutide ratios (20:0.5, 20:1, 20:2, 20:4, 20:8) for 2xGSEL. In the study, 2xGSEL contained PDA 12.5 mg, DA-HCl=4.9 mg, a DA-HCl:H2O2 ratio of 14.6:1, and 1xPE (GCA 10 mg, NHCO 10 mg (total PE 20 mg)), with a volume of distribution of 2 μL / mm2. Using one-way ANOVA, there were no significant differences between any of the groups, with a 95% confidence interval (CI), n=8. [Figure 23A] The pharmacokinetic curve is shown when 1 mg of semaglutide is administered intravenously per pig. N=2 [Figure 23B] Pharmacokinetic curves are shown for a control group (eg, 1x permeation enhancer alone) and an experimental group (2x GSEL in combination with 1x permeation enhancer) that received the formulation by endoscopic placement into the duodenum. [Figure 23C] Pharmacokinetic curves for a control group (e.g., 1x permeation enhancer alone) and an experimental group (2xGSEL combined with 1x permeation enhancer) receiving the formulation via endoscopic administration are shown. Figure 23C is an enlarged view of Figure 23B. [Figure 23D] AUC values ​​up to 24 hours are shown for control (semaglutide alone), control (1x permeation enhancer alone), 1xGSEL combined with 1x permeation enhancer (1xGSEL_1xPE), and 2xGSEL combined with 1x permeation enhancer (2xGSEL_1xPE). 1xPE corresponds to 6.4mg / kg GCA and 6.4mg / kg NHCO, 1xGSEL contains 4.55mg / kg PDA and 1.8mg / kg DA-HCl, and 2xGSEL contains 9.1mg / kg PDA and 3.6mg / kg DA-HCl. [Figure 23E]AUC values ​​up to 48 hours are shown for control (semaglutide alone), control (1x permeation enhancer alone), 1xGSEL combined with 1x permeation enhancer (1xGSEL_1xPE), and 2xGSEL combined with 1x permeation enhancer (2xGSEL_1xPE). 1xPE corresponds to 6.4mg / kg GCA and 6.4mg / kg NHCO, 1xGSEL contains 4.55mg / kg PDA and 1.8mg / kg DA-HCl, and 2xGSEL contains 9.1mg / kg PDA and 3.6mg / kg DA-HCl. [Figure 23F] AUC values ​​up to 72 hours are shown for control (semaglutide alone), control (1x permeation enhancer alone), 1xGSEL combined with 1x permeation enhancer (1xGSEL_1xPE), and 2xGSEL combined with 1x permeation enhancer (2xGSEL_1xPE). 1xPE corresponds to 6.4mg / kg GCA and 6.4mg / kg NHCO, 1xGSEL contains 4.55mg / kg PDA and 1.8mg / kg DA-HCl, and 2xGSEL contains 9.1mg / kg PDA and 3.6mg / kg DA-HCl. [Figure 23G] AUC values ​​up to 168 hours are shown for control (semaglutide alone), control (1x permeation enhancer alone), 1xGSEL combined with 1x permeation enhancer (1xGSEL_1xPE), and 2xGSEL combined with 1x permeation enhancer (2xGSEL_1xPE). 1xPE corresponds to 6.4mg / kg GCA and 6.4mg / kg NHCO, 1xGSEL contains 4.55mg / kg PDA and 1.8mg / kg DA-HCl, and 2xGSEL contains 9.1mg / kg PDA and 3.6mg / kg DA-HCl. DETAILED DESCRIPTION OF THE INVENTION

[0014] The present disclosure relates to synthetic linings formed in situ within the gastrointestinal tract, such as the small intestine. Such linings are called gastrointestinal synthetic epithelial linings (GSELs). GSELs are temporary polymeric linings that are supported by (i.e., in contact with) the inner surface of the gastrointestinal tract. For example, dopamine can be polymerized within the small intestine to form a GSEL coating within the duodenum, jejunum, or ileum. The present disclosure also describes the use of GSELs in combination with a drug and one or more permeation enhancers. The one or more permeation enhancers increase the absorption of the drug through intestinal tissue compared to GSELs without the permeation enhancers.

[0015] GSELs can be used to localize active pharmaceutical ingredients (APIs) to specific locations, resulting in prolonged contact with the gastrointestinal mucosa. Because of this prolonged contact with the mucosa, the API can be delivered over an extended period of time, which can be advantageous for slowly absorbed APIs or APIs best administered over an extended period of time. GSELs can enable a higher percentage of the API to be absorbed compared to standard dosage forms, and this higher absorption percentage with GSELs can allow for the administration of a lower dose of the API to achieve similar total API absorption. GSELs can also reduce the frequency of API administration by providing sustained release of the API compared to multiple administrations of conventional dosage formulations over a period of time.

[0016] Despite the prolonged contact provided by GSELs, some APIs may not cross the gastrointestinal barrier in sufficient amounts to be therapeutically effective, or may not permeate at all. The present disclosure describes permeation enhancers for use with GSELs that enhance permeation of an active pharmaceutical ingredient (API) through the gastrointestinal mucosa compared to GSELs lacking the permeation enhancer. The present disclosure also describes permeation enhancers for use with GSELs that enhance permeation of an active pharmaceutical ingredient (API) through the gastrointestinal mucosa compared to GSELs lacking the permeation enhancer, and that can be used to increase permeation of APIs that may not permeate in sufficient amounts without the permeation enhancer. GSELs with one or more permeation enhancers can provide efficient and effective administration of APIs via enteral administration.

[0017] To form the GSEL, the GSEL composition is orally administered to the subject. Alternatively, the composition can be administered via a feeding tube, for example, to subjects with impaired swallowing ability, or, if necessary, the composition can be administered using an endoscope to deliver the composition to the small intestine, stomach, or esophagus. The GSEL composition for administration includes a polymer precursor (e.g., a monomer, oligomer, or other prepolymer, such as dopamine, a dopamine oligomer, or a dopamine prepolymer). The polymer precursor is polymerized to form the GSEL. The GSEL composition for administration also includes an oxygen source (e.g., hydrogen peroxide or urea peroxide), which provides oxygen to the appropriate location in the gastrointestinal tract to cause polymerization of the polymer precursor. The GSEL composition for administration also includes one or more permeation enhancers described herein (e.g., sodium caprate, sodium caprylate, sodium glycocholate, and / or ammonium carbonate) to increase permeation of the active pharmaceutical ingredient through the gastrointestinal barrier. The composition relies on one or more catalysts inherent in the gastrointestinal tract to convert the oxygen precursor to oxygen. The liberation of oxygen then results in polymerization of the polymer precursor. The small intestine contains endogenous catalysts with peroxidase activity, such as catalase, which allow for the liberation of oxygen, resulting in the formation and deposition of GSELs at specific anatomical locations where the endogenous catalysts are located. GSEL compositions for administration can also include an active pharmaceutical ingredient (API). Thus, by forming a GSEL with the associated API, the API and one or more permeation enhancers are localized in close proximity to the polymer. In this way, a depot of the API and one or more permeation enhancers can be maintained in place for extended periods of time for absorption at specific anatomical locations. For example, when a GSEL containing an API and one or more permeation enhancers is formed in the small intestine, the GSEL retains the API in close proximity to the intestinal epithelium for extended periods of time. In contrast, if the API is administered as a tablet that dissolves in the intestine without a GSEL, the API may transit the small intestine much more rapidly, resulting in decreased absorption of the API or requiring the administration of more API to achieve comparable absorption.

[0018] Alternatively, the API can be administered in a composition separate from the GSEL precursor composition. When the API is administered in a separate composition, the API can be administered prior to, concurrently with, or after administration of the GSEL precursor composition.

[0019] GSELs with one or more permeation enhancers aid in the passage of an API through the gastrointestinal barrier, leading to increased permeation of the API through the gastrointestinal barrier in the presence of one or more permeation enhancers compared to the permeation of the API using GSEL without the permeation enhancers. Enhanced permeation of the API can occur when the API crosses a portion of the small intestine coated with GSEL with one or more permeation enhancers, even when the API is administered separately from the GSEL and one or more permeation enhancers.

[0020] The components of GSEL compositions for administration are discussed in more detail herein and include: 1) polymer precursors, 2) oxygen sources, and 3) permeation enhancers. GSELs and GSEL compositions for administration may also contain 4) one or more active pharmaceutical ingredients (APIs). GSELs or GSEL compositions for administration may not contain any APIs, in which case one or more APIs may be administered separately. Alternatively, GSELs or GSEL compositions for administration may contain one or more APIs, which may also optionally be administered separately from the GSEL. Endogenous catalysts that enable in situ formation of GSELs are also discussed.

[0021] 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 pharmaceutical ingredient" (API) is a drug that is the component in a pharmaceutical dosage that produces a desired biological effect in the patient, individual, or subject to whom the pharmaceutical dosage is administered.

[0022] An "excipient" is any substance added to a drug formulation other than the drug itself. Excipients include, but are not limited to, binders, coating agents, diluents, disintegrants, emulsifiers, flavorings, flow agents, lubricants, and preservatives.

[0023] A "patient," "individual," or "subject" refers to a human or non-human animal. Non-human animals include mammals, including domestic animals such as dogs or cats, or commercially used animals such as cows, pigs, horses, sheep, or goats. In a preferred embodiment, the patient, individual, or subject is a human.

[0024] "Treating" a disease or disorder with the compositions and methods disclosed herein is defined as administering to a patient in need of treatment one or more of the compositions disclosed herein, with or without additional agents, to either reduce or eliminate the disease or disorder or one or more symptoms of the disease or disorder, or to suppress the symptoms of the disease or disorder, or to slow 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 can begin after symptoms of the disease or disorder appear, or can begin before symptoms of the disease or disorder appear. Treatment can also be continued after symptoms have disappeared.

[0025] The "therapeutic use" of the compositions disclosed herein is defined as using one or more of the compositions disclosed herein to treat a disease or disorder as defined above. A "therapeutically effective amount" of a therapeutic agent, such as a drug, when administered to a patient, individual, or subject is an amount of the agent sufficient to achieve a desired biological result, for example, to reduce or eliminate a disease or disorder, or 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. A therapeutically effective amount can be administered to a patient, individual, or subject as a single dose, or can be divided and administered as multiple doses.

[0026] "Permeation" of a drug or active pharmaceutical ingredient (API) through a barrier refers to the amount of drug or API that can pass through the barrier.

[0027] "Permeation enhancer" refers to a substance that can increase the permeation of a drug or active pharmaceutical ingredient through a barrier.

[0028] The term "polymer" refers to a compound containing 10 or more covalently linked repeating units.

[0029] The term "oligomer" refers to a compound containing 2 to 10 covalently linked repeating units.

[0030] The unit "kD" refers to kilodaltons.

[0031] As used herein, the singular forms "a," "an," and "the" include plural referents unless stated otherwise or the context clearly dictates otherwise.

[0032] When numerical values ​​are expressed herein using the term "about" or "approximately," it is understood to include both the specified value and values ​​reasonably close to the specified value. For example, "about 50°C" or "approximately 50°C" includes both a disclosure of 50°C itself and values ​​close to 50°C. Thus, the phrase "about X" or "approximately X" includes a description of the value X itself. When a range is given, such as "approximately 50°C to 60°C" or "approximately 50°C to 60°C," it is understood to include both values ​​specified by the endpoints, and for each endpoint, values ​​close to each endpoint; i.e., "approximately 50°C to 60°C" (or "approximately 50°C to 60°C") is equivalent to describing both "50°C to 60°C" and "approximately 50°C to approximately 60°C" (or "approximately 50°C to 60°C").

[0033] With respect to the numerical ranges disclosed herein, any disclosed upper limit for a given ingredient can be combined with any disclosed lower limit for that ingredient to provide a range (provided the upper limit is greater than the combined lower limit). Each of these combinations of disclosed upper and lower limits is expressly contemplated herein. For example, if ranges of amounts for a particular ingredient are given as 10% to 30%, 10% to 12%, and 15% to 20%, then ranges of 10% to 20% and 15% to 30% are also contemplated, while a combination of a lower limit of 15% with an upper limit of 12% is not possible and therefore not contemplated.

[0034] Unless otherwise specified, the percentages of components in a composition are expressed as weight percent or weight / weight percent. Reference to relative weight percentages in a composition is understood to assume that the combined weight percentages of all components in the composition total 100. Furthermore, it is understood that the relative weight percentages of one or more components can be adjusted upward or downward so that the weight percentages of the components in the composition together total 100, provided that the weight percentage of any particular component does not fall outside the range specified for that component.

[0035] Some embodiments described herein are described as "comprising" or "comprises" with respect to their various elements. In alternative embodiments, these elements can be described with the transitional phrase "consisting essentially of" or "consists essentially of" applied to those elements. In further alternative embodiments, these elements can be described with the transitional phrase "consisting of" or "consists of" applied to those elements. Thus, for example, if a composition or method is disclosed herein as comprising A and B, alternative embodiments of that composition or method that "consist essentially of A and B," as well as alternative embodiments of that composition or method that "consist of A and B," are also considered to be disclosed herein. Similarly, embodiments described as "consisting essentially of" or "consisting of" with respect to their various elements can also be described as "comprising" applied to those elements. Finally, embodiments described as "consisting essentially of" with respect to their various elements can also be described as "consisting of" applied to those elements, and vice versa.

[0036] When a composition or system is described as "consisting essentially of" recited elements, the composition or system contains the explicitly recited elements and may contain 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 described system (in the case of a composition comprising a system). However, the composition or system does not contain other elements other than the explicitly recited elements that substantially affect the condition being treated (in the case of a composition for treating a system) or that substantially affect the properties of the system (in the case of a composition comprising a system); or, if the composition or system contains additional elements other than those recited that may substantially affect the condition being treated or the properties of the system, the composition or system does not contain those additional elements in concentrations or amounts sufficient to substantially affect the condition being treated or the properties of the system. When a method is described as "consisting essentially of" recited steps, the method contains the recited steps and may contain other steps that do not substantially affect the condition being treated by the method or the properties of the system produced by the method, but the method does not contain other steps other than the explicitly recited steps that substantially affect the condition being treated or the system produced.

[0037] The present disclosure provides several embodiments. It is contemplated that any feature from any embodiment may be combined, where possible, with any feature from any other embodiment. As such, hybrid configurations of the disclosed features are within the scope of the present disclosure.

[0038] Gastrointestinal synthetic epithelial lining (GSEL) for drug administration A GSEL precursor composition for the formation of a gastrointestinal synthetic epithelial lining (GSEL) comprises 1) a polymer precursor, 2) an oxygen source, and 3) one or more permeation enhancers. In one embodiment, each component of the composition can be administered as a separate dosage form for combination in the gastrointestinal tract of a subject. In one embodiment, the polymer precursor and the oxygen source can be administered together in one dosage form, and the one or more permeation enhancers can be administered in a separate dosage form. In one embodiment, the polymer precursor, the oxygen source, and the one or more permeation enhancers can be administered together in one dosage form.

[0039] The GSEL precursor composition can also include a drug, such as 4) an active pharmaceutical ingredient (API), or the GSEL precursor composition can include multiple drugs, such as multiple APIs. Similar to the polymer precursor, oxygen source, and one or more permeation enhancers, the drug can be administered together with the other components of the GSEL precursor composition. Alternatively, the API (or APIs) can be administered in a separate composition prior to, simultaneously with, or after the administration of the other components of the GSEL precursor composition.

[0040] Polymer precursors for gastrointestinal synthetic epithelial lining precursor compositions In one aspect, the present disclosure provides a method of forming a polymer in situ in a subject, the method comprising administering to the subject a composition comprising a polymer precursor, an oxygen source, and one or more permeation enhancers, wherein the polymer precursor and oxygen source contact a catalyst endogenous to the subject, and the catalyst polymerizes the polymer precursor.

[0041] In some embodiments, polymerization of the polymer precursor is catalyzed when the oxygen source and polymer precursor contact an endogenous catalyst. In some embodiments, polymerization of the polymer precursor is catalyzed when the oxygen source and polymer precursor contact a peroxidase in the small intestine. In some embodiments, polymerization of the polymer precursor is catalyzed when the oxygen source and polymer precursor contact a peroxidase in the duodenum.

[0042] In some embodiments, the polymer precursor is a catechol-based polymer precursor. In some embodiments, the polymer precursor comprises a 1,2-dihydroxybenzene moiety. In some embodiments, the polymer precursor comprises an optionally substituted 1,2-dihydroxybenzene moiety. In some embodiments, the polymer precursor comprises a 1,2-dihydroxyphenyl moiety. In some embodiments, the polymer precursor comprises an optionally substituted 1,2-dihydroxyphenyl moiety.

[0043] 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 2-(3,4-dihydroxyphenyl)ethylamine. In certain embodiments, the polymer precursor comprises an optionally substituted 2-(3,4-dihydroxyphenyl)ethylamine moiety.

[0044] In some embodiments, the polymer precursor is selected from the group consisting of dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, levodopa ethyl ester, derivatives thereof, and combinations thereof. In certain embodiments, the polymer precursor is selected from the group consisting of dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, and levodopa ethyl ester.

[0045] In certain embodiments, the polymer precursor is a derivative of dopamine, hi some embodiments, the polymer precursor comprises dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, or levodopa ethyl ester.

[0046] In some embodiments, the derivative of the polymer precursor comprises a polymer. In some embodiments, the polymer precursor comprises 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 comprises (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 (A) two or more of dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, and levodopa ethyl ester moieties, which are conjugated to (B) alginate, hyaluronic acid, polyacrylic acid, polyethylene glycol, chondroitin sulfate, or chitosan. In certain embodiments, the polymer precursor comprises (A) two or more of dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, and levodopa ethyl ester moieties, which are conjugated to (B) two or more of alginate, hyaluronic acid, polyacrylic acid, polyethylene glycol, chondroitin sulfate, and chitosan.

[0047] In certain embodiments, the polymer precursor is selected from the structures listed in Tables 1 or 2. [Table 1] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6]

[0048] 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.

[0049] In some embodiments, the composition comprises 40% to 90% polymer precursor relative to the total weight of the 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 comprises about 0.001 to about 1000 mg / mL of dopamine. In some embodiments, the composition comprises about 0.001 to about 500 mg / mL of dopamine. In some embodiments, the composition comprises about 0.01 to about 100 mg / mL of dopamine. In some embodiments, the composition comprises about 1 to about 100 mg / mL of dopamine. In some embodiments, the composition comprises about 1 to about 50 mg / mL of dopamine. In some embodiments, the composition comprises about 10 to about 40 mg / mL of dopamine. In some embodiments, the composition comprises about 1 to about 20 mg / mL of dopamine. In some embodiments, the composition comprises about 60 mg / mL of dopamine. In some embodiments, the composition comprises about 50 mg / mL dopamine. In some embodiments, the composition comprises about 40 mg / mL dopamine. In some embodiments, the composition comprises about 30 mg / mL dopamine. In some embodiments, the composition comprises about 20 mg / mL dopamine. In some embodiments, the composition comprises about 10 mg / mL dopamine. In some embodiments, the composition comprises about 9.8 mg / mL dopamine. In any of these embodiments, a pharmaceutically acceptable salt of dopamine, such as dopamine hydrochloride, can be used. In any of these embodiments, polydopamine, a mixture of dopamine and polydopamine, or a pharmaceutically acceptable salt thereof can be used in place of dopamine or a pharmaceutically acceptable salt of dopamine. For example, in some embodiments, the composition comprises about 0.001 to about 1000 mg / mL polydopamine. In some embodiments, the composition comprises about 0.001 to about 500 mg / mL polydopamine. In some embodiments, the composition comprises about 0.01 to about 100 mg / mL of polydopamine, hi some embodiments, the composition comprises about 1 to about 100 mg / mL of polydopamine.In some embodiments, the composition comprises about 1 to about 50 mg / mL of polydopamine. In some embodiments, the composition comprises about 10 to about 40 mg / mL of polydopamine. In some embodiments, the composition comprises about 1 to about 20 mg / mL of polydopamine. In some embodiments, the composition comprises about 60 mg / mL of polydopamine. In some embodiments, the composition comprises about 50 mg / mL of polydopamine. In some embodiments, the composition comprises about 40 mg / mL of polydopamine. In some embodiments, the composition comprises about 30 mg / mL of polydopamine. In some embodiments, the composition comprises about 20 mg / mL of polydopamine. In some embodiments, the composition comprises about 10 mg / mL of polydopamine. In some embodiments, the composition comprises about 9.8 mg / mL of polydopamine. In some embodiments, the composition comprises about 0.001 to about 1000 mg / mL of a mixture of dopamine and polydopamine. In some embodiments, the composition comprises about 0.001 to about 500 mg / mL of a mixture of dopamine and polydopamine. In some embodiments, the composition comprises about 0.01 to about 100 mg / mL of a mixture of dopamine and polydopamine. In some embodiments, the composition comprises about 1 to about 100 mg / mL of a mixture of dopamine and polydopamine. In some embodiments, the composition comprises about 1 to about 50 mg / mL of a mixture of dopamine and polydopamine. In some embodiments, the composition comprises about 10 to about 40 mg / mL of a mixture of dopamine and polydopamine. In some embodiments, the composition comprises about 1 to about 20 mg / mL of a mixture of dopamine and polydopamine. In some embodiments, the composition comprises about 60 mg / mL of a mixture of dopamine and polydopamine. In some embodiments, the composition comprises about 50 mg / mL of a mixture of dopamine and polydopamine. In some embodiments, the composition comprises about 40 mg / mL of a mixture of dopamine and polydopamine. In some embodiments, the composition comprises about 30 mg / mL of a mixture of dopamine and polydopamine, hi some embodiments, the composition comprises about 20 mg / mL of a mixture of dopamine and polydopamine.In some embodiments, the composition comprises about 10 mg / mL of a mixture of dopamine and polydopamine, hi some embodiments, the composition comprises about 9.8 mg / mL of a mixture of dopamine and polydopamine. When a mixture of dopamine and polydopamine is used, the amount of dopamine to polydopamine by weight can range from about 0.05:1 dopamine:polydopamine to about 1:0.05 dopamine:polydopamine on a weight / weight basis, for example, about 0.1:1, about 0.2:1, about 0.25:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.75:1, about 0.8:1, about 0.9:1, about 1:1, about 1:0.9, about 1:0.8, about 1:0.75, about 1:0.7, about 1:0.6, about 1:0.5, about 1:0.4, about 1:0.3, about 1:0.25, about 1:0.2, or about 1:0.1 dopamine:polydopamine.

[0050] International Patent Applications WO2021 / 119350 and WO2021 / 119354, which are incorporated herein by reference in their entireties, describe methods for forming polymers in situ in a subject.

[0051] Oxygen Source for Gastrointestinal Synthetic Epithelial Lining Precursor Compositions In one aspect, 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 urea peroxide. In some embodiments, the oxygen source is hydrogen peroxide. In some embodiments, the oxygen source is urea peroxide. When the oxygen source contacts an endogenous catalyst, such as catalase or peroxidase, oxygen is liberated from the oxygen source, resulting in polymerization of the polymer precursor.

[0052] In some embodiments, the endogenous catalyst is selected from catalase or peroxidase. In some embodiments, the endogenous catalyst is peroxidase. In certain embodiments, the peroxidase is eosinophil peroxidase, lactoperoxidase, or myeloperoxidase.

[0053] In some embodiments, the endogenous catalyst is catalase. In some embodiments, the catalase is bacterial catalase. In some embodiments, the catalase is human catalase.

[0054] 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.

[0055] In some embodiments, the endogenous catalyst is present in the upper GI of the subject. In some embodiments, the endogenous catalyst is present in the stomach of the subject.

[0056] In some embodiments, the composition comprises an oxygen source in an amount of 1% to 15% relative to (polymer precursor, oxygen source, and permeation enhancer).

[0057] In some embodiments, the composition comprises about 0.01 to about 100 mM of the oxygen source. In some embodiments, the composition comprises about 0.1 to about 50 mM of the oxygen source. In some embodiments, the composition comprises about 1 to about 30 mM of the oxygen source. In some embodiments, the composition comprises about 20 mM of the oxygen source. In some embodiments, the composition comprises a concentration of the oxygen source compatible with ingestion by a subject.

[0058] Permeation enhancers for the gastrointestinal synthetic epithelial lining (GSEL) This disclosure describes permeation enhancers for gastrointestinal synthetic epithelial linings (GSELs) that promote the penetration of active pharmaceutical ingredients (APIs) through the gastrointestinal mucosa. GSELs localize the API to a specific location, resulting in prolonged contact with the gastrointestinal mucosa. However, despite the prolonged contact provided by GSELs, some APIs may not cross the gastrointestinal barrier in sufficient amounts to be therapeutically effective, or may not penetrate at all. Permeation enhancers can be used in combination with GSELs to increase the permeation of the API through the gastrointestinal mucosa.

[0059] A permeation enhancer may promote paracellular transport. Paracellular transport is the passive transport of substances or molecules (e.g., active pharmaceutical ingredients) between adjacent epithelial cells. A permeation enhancer that improves paracellular transport may function, for example, by increasing the permeability of tight junctions. In some embodiments, a permeation enhancer promotes paracellular transport. A permeation enhancer may promote transcellular transport. Transcellular transport is an active process by which substances or molecules (e.g., active pharmaceutical ingredients) are transported through cells using cellular transport mechanisms. In some embodiments, a permeation enhancer promotes transcellular transport. In some embodiments, a permeation enhancer promotes both paracellular transport and transcellular transport.

[0060] In some embodiments, the composition comprises a polymer precursor, an oxygen source, and a permeation enhancer. In some embodiments, the composition comprises a polymer precursor, an oxygen source, and one or more permeation enhancers.

[0061] In some embodiments, the composition includes one or more permeation enhancers in an amount of 0.1% to 60% relative to the total (polymer precursor, oxygen source, and one or more permeation enhancers). In some embodiments, the composition includes one or more permeation enhancers in an amount of about 0.1% to about 50%, about 0.1% to about 40%, about 0.1% to about 30%, about 0.1% to about 20%, about 0.1% to about 10%, about 1% to about 60%, about 10% to about 60%, about 20% to about 60%, about 30% to about 60%, about 40% to about 60%, or about 50% to about 60% relative to the total (polymer precursor, oxygen source, and one or more permeation enhancers).

[0062] In some embodiments, ammonium salts may be used as permeation enhancers. These salts 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 may 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, to represent ammonium carbonate, are not intended to specify a chemical formula, as the chemical formula for ammonium carbonate is (NH4)2CO3.

[0063] In some embodiments, carbonate salts can be used as permeation enhancers. These salts include, but are not limited to, sodium carbonate (NaCO) or potassium carbonate (KCO). As mentioned above, these are abbreviations, not chemical formulas.

[0064] In some embodiments, bicarbonate salts can be used as permeation enhancers, including, but not limited to, sodium bicarbonate (NaHCO) or potassium bicarbonate (KHCO). As noted above, these are abbreviations, not chemical formulas.

[0065] In some embodiments, the permeation enhancer is an endogenous secretory substance. In some embodiments, the endogenous secretory substance is a bile salt. In some embodiments, the endogenous secretory substance is a bile acid.

[0066] In some embodiments, bile salts or bile acids can be used as permeation enhancers. The bile salts or bile acids can include one or more bile salts, one or more bile acids, or a combination of any number of bile salts and / or bile acids. Liquid GSELs are formulated in aqueous solution, and depending on the pH of the formulation, the addition of a single bile acid or a single bile salt can result in a mixture of the bile acid and its bile salt (i.e., the bile acid's conjugate base). For example, the pKa of cholic acid is reported to be 4.98 (see URL pubchem.ncbi.nlm.nih.gov / compound / Cholic-acid; Sergeant 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 is raised to about 8, the majority of the substance is in the anionic form of cholate. Conversely, when cholate is added to a formulation and the pH is lowered to about 2, the majority of the material will be in the form of cholic acid. Thus, when bile salts or bile acids are listed, it is understood that the form of the material may vary with pH, ​​i.e., bile salts may be partially or mostly converted to bile acids, and / or bile acids may be partially or mostly converted to bile salts, depending on the pH of the formulation containing the bile salt or bile acid. Typical pH values ​​for GSEL formulations are about 8.5±1 pH unit.

[0067] Bile acids used as permeation enhancers include, but are not limited to, 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), glycolithocholic acid (GLC), glycohyocholic acid (GHC), taurolithocholic acid (TLC), and ox bile. Examples of bile acids include 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-triketocholic acid (3,7,12-TKC), 12-monoketodeoxycholic acid (12-MKDC), taurodihydrofusidic acid, or 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS). A particularly useful bile acid is glycocholic acid.

[0068] Bile salts used as permeation enhancers include, but are not limited to, salts of cholic acid, salts of glycocholic acid, salts of deoxycholic acid, salts of glycochenodeoxyacrylic acid, salts of glycodeoxycholic acid, salts of taurodeoxycholic acid, salts of taurocholic acid, salts of bovine bile, salts of chenodeoxycholic acid, salts of taurochenodeoxycholic acid, salts of lithocholic acid, salts of glycolithocholic acid, salts of glycohyocholic acid, salts of taurolithocholic acid, salts of ... The bile salts include 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-triketocholic acid, salts of 12-monoketodeoxycholic acid, salts of taurodihydrofusidic acid, and salts of 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate. A particularly useful bile salt is the salt of glycocholic acid.

[0069] The bile salt may be a sodium salt, including, but not limited to, sodium cholate, sodium glycocholate, sodium deoxycholate, sodium glycochenodeoxycholate, sodium glycodeoxycholate, sodium taurodeoxycholate, sodium taurocholate, the sodium salt of ox bile, sodium chenodeoxycholate, sodium taurochenodeoxycholate, sodium lithocholate, sodium glycolithocholate, sodium glycohyocholate, sodium taurolithocholate, sodium ursodeoxycholate, sodium tauroursodeoxycholate, sodium glycoursodeoxycholate, sodium 12-monoketocholate, sodium 7-monoketocholate, sodium 7,12-diketocholate, sodium 3,7,12-triketocholate, sodium 12-monoketodeoxycholate, sodium taurodihydrofusidate, or sodium 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate. A particularly useful sodium salt of a bile acid is sodium glycocholate.

[0070] In some embodiments, the permeation enhancer is carnitine. In some embodiments, the carnitine is an acylcarnitine. In some embodiments, the carnitine is selected from the group consisting of lauroylcarnitine, palmitoylcarnitine, and palmitoylcarnitine chloride (PCC). In some embodiments, the carnitine is lauroylcarnitine. In some embodiments, the carnitine is palmitoylcarnitine.

[0071] In some embodiments, the permeation enhancer is choline. In some embodiments, the choline is lysophosphatidylcholine.

[0072] In some embodiments, the permeation enhancer is an aromatic alcohol. In some embodiments, the aromatic alcohol is selected from the group consisting of benzyl alcohol, phenyl alcohol, phenoxyethanol, propyl gallate, butylhydroxytoluene, and butylhydroxyanisole. In some embodiments, the aromatic alcohol is benzyl alcohol, phenyl alcohol, or phenoxyethanol.

[0073] In some embodiments, the permeation enhancer is a piperazine derivative. In some embodiments, the piperazine derivative is selected from the group consisting of 1-phenylpiperazine, 1-methyl-4-phenylpiperazine, 1-(4-methylphenyl)piperazine, and 1-benzylpiperazine. In some embodiments, the piperazine derivative is 1-phenylpiperazine or 1-methyl-4-piperazine.

[0074] In some embodiments, the permeation enhancer is a mucoadhesive polymer. In some embodiments, the mucoadhesive polymer is selected from the group consisting of chitosan, chitosan hydrochloride, trimethylated chitosan chloride, and N,N,N-trimethylchitosan chloride. In some embodiments, the mucoadhesive polymer is trimethylated chitosan chloride.

[0075] In some embodiments, the penetration enhancer is a cell-penetrating peptide, hi some embodiments, the cell-penetrating peptide is selected from the group consisting of transportan, penetratin, oligoarginine, polyarginine, oligolysine, polylysine, oligotryptophan, and polytryptophan.

[0076] In some embodiments, the permeation enhancer is an amino acid, hi some embodiments, the amino acid is tryptophan.

[0077] In some embodiments, the permeation enhancer is an ionic liquid. In some embodiments, the ionic liquid is selected from the group consisting of choline geranate, nicotinic acid, and trigonelline. In some embodiments, the ionic liquid is choline geranate.

[0078] In some embodiments, the permeation enhancer is an organic solvent, hi some embodiments, the solvent is selected from the group consisting of ethanol, 2-propanol, 1-propanol, 2-methyl-2-propanol, dimethyl sulfoxide, ethyl acetate, and acetone.

[0079] In some embodiments, the permeation enhancer is an anionic surfactant. In some embodiments, the anionic surfactant is sodium cholate or sodium dodecyl sulfate. In some embodiments, the anionic surfactant is sodium cholate. In some embodiments, the anionic surfactant is sodium dodecyl sulfate. Where chemically feasible and pharmaceutically desirable, alternative pharmaceutically acceptable salts or free acids of the foregoing compounds can be used.

[0080] In some embodiments, the permeation enhancer is a chelating agent. In some embodiments, the chelating agent is selected from the group consisting of EDTA, EGTA, and DTPA. In some embodiments, the chelating agent is EDTA.

[0081] In some embodiments, the permeation enhancer is a non-ionic surfactant. In some embodiments, the non-ionic surfactant is an ethoxylate. In some embodiments, the non-ionic surfactant is an alcohol ethoxylate (C X E Y where X is the carbon number of the alcohol and Y is the ethylene oxide number.

[0082] In some embodiments, the nonionic surfactant is a medium or long chain fatty acid sugar ester. In some embodiments, the medium or long chain fatty acid sugar ester is sodium laurate. In some embodiments, the nonionic surfactant is a medium or long chain fatty acid sucrose ester. In some embodiments, the nonionic surfactant is an ethoxylated fatty acid sugar ester. In some embodiments, the nonionic surfactant is an ethoxylated sorbitan ester. In some embodiments, the nonionic surfactant is an ethoxylated glyceride. In some embodiments, the nonionic surfactant is selected from the group consisting of macrogol-8 glyceride, sucrose esters (e.g., sucrose laurate), ethoxylates, alkyl maltosides (e.g., dodecyl maltoside), short-chain polyethylene glycols, the Brij® series (polyoxyethylene (10) oleyl ether, polyoxyethylene (23) lauryl ether, etc.), polysorbates (polysorbate series PS20, PS40, PS60, PS65, PS80), and Triton® X-100. In some embodiments, the nonionic surfactant is caprylocaproyl polyoxyl-8 glyceride (LABRASOL®), poloxamer, polyoxylglyceride, polyethylene monostearate.

[0083] In some embodiments, the permeation enhancer is a non-ionic detergent. In some embodiments, the non-ionic detergent is sucrose monolaurate or n-tetradecyl β-D-maltopyranoside (TDM). In some embodiments, the non-ionic detergent is sucrose monolaurate. In some embodiments, the non-ionic detergent is n-tetradecyl β-D-maltopyranoside (TDM).

[0084] In some embodiments, the permeation enhancer is a fatty acid, a fatty acid salt, an ethoxylated fatty acid ester, a sugar fatty acid ester, or an ethoxylated sugar fatty acid ester. In some embodiments, the fatty acid salt is sodium caprate (C 10). In some embodiments, the fatty acid salt is sodium caprylate (C8). In some embodiments, the fatty acid ester is nonaethylene glycol monododecyl ether (C12E9). In some embodiments, the sugar fatty acid ester is a fatty acid ester of a monosaccharide. In some embodiments, the sugar fatty acid ester is an ethoxylated fatty acid ester of a monosaccharide. In some embodiments, the sugar fatty acid ester is a fatty acid ester of sorbitan or glucose. In some embodiments, the sugar fatty acid ester is an ethoxylated fatty acid ester of sorbitan or glucose. In some embodiments, the sugar fatty acid ester is a fatty acid ester of a disaccharide. In some embodiments, the sugar fatty acid ester is an ethoxylated fatty acid ester of a disaccharide. In some embodiments, the sugar fatty acid ester is a fatty acid ester of sucrose or maltose. In some embodiments, the sugar fatty acid ester is an ethoxylated fatty acid ester of sucrose or maltose. In some embodiments, the fatty acid or fatty acid salt is dodecyl maltoside, sodium dodecyl sulfate, nonaethylene glycol monododecyl ether (C 12 E9), sodium laurate (C 12 ), Sodium Nonanoate (C9), Sodium Undecanoate (C 11 ), sodium undecylenate (C11:1), sodium oleate, linoleic acid, and sucrose monolaurate. Where chemically possible and pharmaceutically desirable, alternative pharmaceutically acceptable salts or free acids of the foregoing compounds may be used.

[0085] In some embodiments, the permeation enhancer is an N-acylating acid. In some embodiments, the N-acylating acid is acetylsalicylic acid. In some embodiments, the N-acylating acid is sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC). In some embodiments, the N-acylating acid is 8-(N-2-hydroxy-5-chloro-benzoyl)-amino-caprylic acid (5-CNAC). In some embodiments, the N-acylating acid is 4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid (4-CNAB). In some embodiments, the N-acylating acid is N-(10-[2-hydroxybenzoyl]amino)decanoic acid (SNAD). In some embodiments, the N-acylating acid is monosodium N-(4-chlorosalicyloyl)-4-aminobutyrate (5-CNAB). In some embodiments, the N-acylated acid is N-[8-(2-hydroxy-4-methoxy)benzoyl]aminocaprylic acid (4-MOAC). In some embodiments, the N-acylated acid is sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC). Where chemically feasible and pharmaceutically desirable, either pharmaceutically acceptable salts or the free acids of the aforementioned compounds can be used.

[0086] In some embodiments, the permeation enhancer is a high molecular weight polymer. In some embodiments, the high molecular weight polymer is a polysaccharide. In some embodiments, the high molecular weight polymer is an antimicrobial toxin. In some embodiments, the antimicrobial toxin is selected from the group consisting of zonula occludens toxin analog, viral protein 8 analog, and Clostridium perfringens enterotoxin analog. In some embodiments, the high molecular weight polymer is chitosan or carboxymethylcellulose.

[0087] In some embodiments, the permeation enhancer is caprylocaproyl PEG8 glyceride.

[0088] In some embodiments, the permeation enhancer is a sugar-based surfactant. In some embodiments, the sugar-based surfactant is dodecyl-β-D-maltopyranoside (DDM).

[0089] In some embodiments, the permeation enhancer is glyceryl monocaprate.

[0090] In some embodiments, the permeation enhancer is urea.

[0091] In some embodiments, the permeation enhancer is docusate sodium. Where chemically possible and pharmaceutically desirable, alternative pharmaceutically acceptable salts or free acids of the foregoing compounds may be used.

[0092] In some embodiments, the permeation enhancer is citric acid. Where pharmaceutically desirable, pharmaceutically acceptable salts of the foregoing compounds can be used.

[0093] Combinations of permeation enhancers may be used, including but not limited to: glycocholate and ammonium carbonate, Glycocholate and ammonium carbonate, and Sodium glycocholate and ammonium carbonate. Exemplary compositions for gastrointestinal synthetic epithelial linings

[0094] Compositions used to form gastrointestinal synthetic epithelial linings can be provided in solid or liquid form. While examples of such compositions are provided, it will be understood that a wide variety of formulations can be used and that compositions for use in forming GSELs are not limited to these examples.

[0095] Liquid formulations Polymer precursor: The composition may contain about 0.001 to about 1000 mg / mL, about 0.001 to about 500 mg / mL, about 0.01 to about 100 mg / mL, about 1 to about 50 mg / mL, about 10 to about 40 mg / mL, about 1 to about 20 mg / mL, about 10 mg / mL, or about 9.8 mg / mL of polymer precursor (e.g., dopamine, polydopamine, a mixture of dopamine and polydopamine, or a pharmaceutically acceptable salt thereof). In some embodiments, the composition contains 5.4 mg / mL of polymer precursor. In some embodiments, the composition contains 9.8 mg / mL of polymer precursor. In some embodiments, the composition contains about 13.7 mg / mL of polymer precursor. In some embodiments, the composition contains about 19.6 mg / mL of polymer precursor. In some embodiments, the composition contains about 25 mg / mL of polymer precursor. In some embodiments, the composition contains about 29.4 mg / mL of polymer precursor. In some embodiments, the composition comprises about 50 mg / ml of polymer precursor. In some embodiments, the composition comprises about 75 mg / ml of polymer precursor. In some embodiments, the composition comprises about 5 mg / ml to about 75 mg / ml of polymer precursor, about 5 mg / ml to about 25 mg / ml of polymer precursor, about 5 mg / ml to about 50 mg / ml of polymer precursor, about 25 mg / ml to about 50 mg / ml of polymer precursor, about 25 mg / ml to about 75 mg / ml of polymer precursor, or about 50 mg / ml to about 75 mg / ml of polymer precursor.

[0096] Oxygen Source: The composition may comprise about 0.01 to about 100 mM, about 0.1 to about 50 mM, about 1 to about 30 mM, about 20 mM, or about 19.7 mM of oxygen source, or the composition may comprise an oxygen source at a concentration compatible with ingestion by a subject. In some embodiments, the composition comprises about 0.1 mM to about 10 mM, about 1 mM to about 25 mM, about 1 mM to about 50 mM, about 10 mM to about 25 mM, about 10 mM to about 50 mM, about 25 mM to about 50 mM, about 25 mM to about 75 mM, about 25 mM to about 100 mM, about 50 mM to about 75 mM, about 50 mM to about 100 mM, or about 75 mM to about 100 mM of oxygen source.

[0097] Permeation enhancer: The composition includes a permeation enhancer in an amount of about 0.1% to about 60%, about 0.1% to about 50%, about 0.1% to about 40%, about 0.1% to about 30%, about 0.1% to about 20%, about 0.1% to about 10%, about 1% to about 60%, about 10% to about 60%, about 20% to about 60%, about 30% to about 60%, about 40% to about 60%, or about 50% to about 60% based on the total weight of the polymer precursor, oxygen source, and permeation enhancer. In some embodiments, the amount of permeation enhancer is about 40 mg / ml, about 50 mg / ml, about 60 mg / ml, or about 70 mg / ml to about 80 mg / ml. In some embodiments, the amount of permeation enhancer is 40 mg / ml. In some embodiments, the amount of permeation enhancer is 80 mg / ml. In some embodiments, the amount of permeation enhancer is about 40 mg / ml to about 80 mg / ml, or about 40 mg / ml to about 50 mg / ml, about 40 mg / ml to about 60 mg / ml, about 40 mg / ml to about 70 mg / ml, about 50 mg / ml to about 60 mg / ml, about 50 mg / ml to about 70 mg / ml, about 50 mg / ml to about 80 mg / ml, about 60 mg / ml to about 70 mg / ml, about 60 mg / ml to about 80 mg / ml, or 70 mg / ml to about 80 mg / ml.

[0098] API: The active pharmaceutical ingredient may comprise about 0.01% to about 10%, about 0.1 to about 10%, about 1% to about 10%, about 5% to about 10%, about 0.1% to about 5%, or about 1% to about 5% of the API relative to (polymer precursor, oxygen source, permeation enhancer, and API). In some embodiments, the amount of API is about 0.5 mg / ml to 25 mg / ml. In some embodiments, the amount of API is about 0.67 mg / ml to about 15 mg / ml, about 1 mg / ml to about 10 mg / ml, about 1 mg / ml to about 15 mg / ml, about 1 mg / ml to about 20 mg / ml, about 1 mg / ml to about 25 mg / ml, about 5 mg / ml to about 10 mg / ml, about 5 mg / ml to about 15 mg / ml, about 5 mg / ml to about 20 mg / ml, or about 5 mg / ml to about 25 mg / ml, about 10 mg / ml to about 15 mg / ml, about 10 mg / ml to about 20 mg / ml, about 10 mg / ml to about 25 mg / ml, about 15 mg / ml to about 20 mg / ml, about 15 mg / ml to about 25 mg / ml, about 20 mg / ml to about 25 mg / ml, about 16 mg / ml, about 17 mg / ml, about 18 mg / ml, about 19 mg / ml, or about 20 mg / ml. In some embodiments, the amount of API is 0.67 mg / ml. In some embodiments, the amount of API is 15 mg / ml. In some embodiments, the amount of API is about 20 mg / ml. In some embodiments, the active pharmaceutical ingredient is semaglutide.

[0099] Optionally, viscosity modifiers such as xanthan gum, hydroxypropyl methylcellulose, methylcellulose, carboxymethylcellulose, chitosan, hydroxyethylcellulose, or sodium alginate can be added. The viscosity can be adjusted to about 0.01 to about 50 Pascal seconds at a shear rate of 0.1 per second.

[0100] A buffering agent can be added to maintain an appropriate pH of the liquid formulation, for example, from about pH 7 to about pH 10, for example, pH 7.4.

[0101] Specific formulations that fall within these ranges include: 9.8 mg / mL dopamine hydrochloride and 25 mg / mL polydopamine (34.9 mg / mL polymer precursor) as polymer precursors; 0.67 mg / mL hydrogen peroxide (19.7 mM) as an oxygen source; 20 mg / mL sodium caprate (sodium caprate constitutes 36% by weight of dopamine hydrochloride, polydopamine, hydrogen peroxide, and sodium caprate) as a permeation enhancer; 0.67 mg / mL semaglutide (API) (API comprises dopamine hydrochloride, polydopamine, hydrogen peroxide, sodium caprate, and 1.2% of the amount of semaglutide) and 50 mM Tris buffer.

[0102] Another specific formulation falling within these ranges is 9.8 mg / mL dopamine hydrochloride and 25 mg / mL polydopamine (34.9 mg / mL polymer precursor) as the polymer precursor; 0.67 mg / mL hydrogen peroxide (19.7 mM) as an oxygen source; 20 mg / mL sodium glycocholate and ammonium carbonate (comprising 36% by weight of dopamine hydrochloride, polydopamine, hydrogen peroxide, sodium glycocholate, and ammonium carbonate) as a permeation enhancer; 0.67 mg / mL semaglutide (API) (API comprises dopamine hydrochloride, polydopamine, hydrogen peroxide, sodium glycocholate, ammonium carbonate, and 1.2% of the amount of semaglutide) and 50 mM Tris buffer.

[0103] Solid Formulations Polymer Precursor: The composition may comprise about 10% to about 75%, about 20% to about 75%, about 30% to about 75%, about 40% to about 75%, or about 50% to about 75% polymer precursor (e.g., dopamine, polydopamine, a mixture of dopamine and polydopamine, or a pharmaceutically acceptable salt thereof).

[0104] Oxygen Source: The composition may comprise about 1% to about 15%, about 1% to about 10%, about 1% to about 5%, about 5% to about 15%, or about 10% to about 15% of an oxygen source, or the composition may comprise an amount of an oxygen source compatible with ingestion by a subject.

[0105] Permeation Enhancer: The composition comprises a permeation enhancer in an amount of about 0.1% to about 60%, about 0.1% to about 50%, about 0.1% to about 40%, about 0.1% to about 30%, about 0.1% to about 20%, about 0.1% to about 10%, about 1% to about 60%, about 10% to about 60%, about 20% to about 60%, about 30% to about 60%, about 40% to about 60%, or about 50% to about 60% relative to (polymer precursor, oxygen source, and permeation enhancer).

[0106] API: The active pharmaceutical ingredient may comprise about 0.01% to about 10%, about 0.1 to about 10%, about 1% to about 10%, about 5% to about 10%, about 0.1% to about 5%, or about 1% to about 5% of the API relative to (polymer precursor, oxygen source, permeation enhancer, and API).

[0107] Optionally, xanthan gum, hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose, chitosan, hydroxyethylcellulose, or sodium alginate can be added to the solid formulation to increase viscosity when the formulation solubilizes in the digestive tract.

[0108] Solid buffers can be used to control the pH when the formulation solubilizes in the gastrointestinal tract.

[0109] Specific solid formulations that fall within these ranges include: 18.8 wt. % dopamine hydrochloride and 47.95 wt. % polydopamine (66.75% polymer precursor), 3.54% by weight of urea peroxide, 16.58% by weight sodium caprylate (sodium caprate constitutes 19% by weight of the dopamine hydrochloride, polydopamine, urea peroxide, and sodium caprate); 0.52% by weight methotrexate (methotrexate comprises 0.6% by weight of dopamine hydrochloride, polydopamine, urea peroxide, sodium caprate, and methotrexate); 4.30% by weight of Tris base, and 8.31% by weight of Tris hydrochloride.

[0110] Specific solid formulations that fall within these ranges include: 18.8 wt. % dopamine hydrochloride and 47.95 wt. % polydopamine (66.75% polymer precursor), 3.54% by weight of urea peroxide, 16.58% by weight sodium caprylate (sodium caprylate constitutes 19% by weight of the dopamine hydrochloride, polydopamine, urea peroxide, and sodium caprylate); 0.52% by weight methotrexate (methotrexate comprises 0.6% by weight of dopamine hydrochloride, polydopamine, urea peroxide, sodium caprate, and methotrexate); 4.30% by weight of Tris base, and 8.31% by weight of Tris hydrochloride.

[0111] Specific solid formulations that fall within these ranges include: 18.8 wt. % dopamine hydrochloride and 47.95 wt. % polydopamine (66.75% polymer precursor), 3.54% by weight of urea peroxide, 16.58% by weight sodium caprate (sodium caprate constitutes 19% by weight of the dopamine hydrochloride, polydopamine, urea peroxide, and sodium caprate); 0.52% by weight methotrexate (methotrexate comprises 0.6% by weight of dopamine hydrochloride, polydopamine, urea peroxide, sodium caprate, and methotrexate); 4.30% by weight of Tris base, and 8.31% by weight of Tris hydrochloride.

[0112] Specific solid formulations that fall within these ranges include: 18.8 wt. % dopamine hydrochloride and 47.95 wt. % polydopamine (66.75% polymer precursor), 3.54% by weight of urea peroxide, 16.58% by weight sodium glycocholate and XX% ammonium carbonate (sodium glycocholate and ammonium carbonate constitute 19% by weight of the dopamine hydrochloride, polydopamine, urea peroxide, sodium glycocholate, and ammonium carbonate); 0.52% by weight methotrexate (methotrexate comprises 0.6% by weight of dopamine hydrochloride, polydopamine, urea peroxide, sodium caprate, and methotrexate); 4.30% by weight of Tris base, and 8.31% by weight of Tris hydrochloride.

[0113] Where chemically possible and pharmaceutically desirable, alternative pharmaceutically acceptable salts or free acids or free bases of the aforementioned compounds may be used.

[0114] Evaluation of permeation enhancers Various assays for measuring the absorption of APIs through the gastrointestinal tract are well known and can be adapted to evaluate the ability of permeation enhancers to promote the permeation of active pharmaceutical ingredients using gastrointestinal synthetic epithelial linings (GSELs). Franz cells are often used in such assays. A Franz cell has an upper chamber, called the donor compartment or chamber, and a lower chamber, called the receiving compartment or chamber. An appropriate solution, such as phosphate-buffered saline (PBS), is added to each compartment. The receiving compartment also contains a sample port for withdrawing an aliquot for analysis and typically a magnetic stir bar or other mechanism for uniformly mixing the solution in the receiving compartment. The receiving compartment may be covered by a water bath to maintain a constant temperature. The two compartments are separated by a barrier to be tested and secured by a junction formed by the donor and receiving compartments. A diagram of the Franz cell is shown in Figure 1B of Pulsoni et al., “Comparison Between Franz Diffusion Cell and a Novel Microphysiological System for In Vitro Penetration Assay Using Different Skin Models,” SLAS Technology 27(3):161 (2022), doi.org / 10.1016 / j.slast.2021.12.006.

[0115] To test GSEL permeation enhancers, sections of intestinal tissue are obtained, for example, from pigs or human cadavers, in accordance with all applicable legal and ethical regulations. GSEL may be deposited on the intestinal tissue before the tissue is placed in the Franz cell. Alternatively, the intestinal tissue may be placed in the Franz cell, and GSEL may be deposited on the tissue within the Franz cell. The tissue may be rinsed to remove excess GSEL solution, and permeation of the active pharmaceutical ingredient (API) through the GSEL-coated tissue may be measured. Controls may include tissue without GSEL and tissue with GSEL lacking the permeation enhancer. Testing of permeation enhancers may involve a system of intestinal tissue with GSEL containing a permeation enhancer, where the tissue is placed in a Franz cell, after which the API is added to the donor compartment (e.g., added to a solution in the donor compartment), and then permeation of the API into the recipient compartment is measured at various time points to determine the amount of API that crosses the intestinal tissue and enters the recipient compartment. Alternatively, testing of permeation enhancers in GSELs can involve a system of intestinal tissue with a GSEL containing the permeation enhancer and an API, where the API is contained in the GSEL and intimately associated with the intestinal tissue as a component of the GSEL. Again, permeation of the API into the receiving compartment is then measured at various time points to determine the amount of API that crosses the intestinal tissue and enters the receiving compartment. Typically, a minimal volume is removed and replaced at each time point. Comparing the amount of permeation through the GSEL with and without the permeation enhancer demonstrates the effectiveness of a particular permeation enhancer for a particular API. Further details of these comparative experiments for evaluating permeation enhancers are provided in the Examples section of this specification.

[0116] Substitute or proxy molecules such as fluorescein isothiocyanate-dextran (FITC-dextran) of various molecular weights can be used as test molecules for permeation enhancers. For example, 4,000 MW FITC-dextran (FITC-dextran-4k) can be used in place of the API to test the effectiveness of permeation enhancers.

[0117] In some embodiments, the permeation enhancer in the GSEL increases the amount of API permeated through intestinal tissue by about 1.2 to about 5-fold at a given time point in a Franz cell using phosphate buffered saline as the donor and receiver compartment fluid compared to GSEL without the permeation enhancer. In some embodiments, the permeation enhancer in the GSEL increases the amount of API permeated through intestinal tissue by up to about 1.5-fold, up to about 2-fold, up to about 3-fold, up to about 4-fold, or up to about 5-fold at a given time point in a Franz cell using phosphate buffered saline as the donor and receiver compartment fluid compared to GSEL without the permeation enhancer, e.g., by about 1.2 to about 5-fold, about 1.5 to about 5-fold, about 2 to about 5-fold, about 3 to about 5-fold, or about 4 to about 5-fold. For example, at a given time point, if 1 mg of API was transported across intestinal tissue with GSEL lacking a permeation enhancer and 1.5 mg of API was transported across intestinal tissue with GSEL containing a permeation enhancer, the amount permeated increased by 1.5-fold.

[0118] In some embodiments, the permeation enhancer in the GSEL increases the total permeation of the API through the intestinal tissue over a 24-hour period by about 1.2 to about 50-fold compared to the GSEL without the permeation enhancer in a Franz cell using phosphate-buffered saline as the donor and recipient compartment fluids. A measure of the total amount of API transported from the donor compartment to the recipient compartment over a given period is the AUC in vivo. 0~24In some embodiments, the permeation enhancer in the GSEL increases the total permeation of the API through intestinal tissue by up to about 1.2-fold, about 1.5-fold, about 2-fold, about 5-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold, e.g., about 1.2 to about 50-fold, about 1.5 to 50-fold, about 2 to 50-fold, about 5 to 50-fold, about 10 to 50-fold, about 20 to 50-fold, about 30 to 50-fold, about 40 to 50-fold, about 1.2 to 40-fold, about 1.2 to 30-fold, about 1.2 to 20-fold, about 1.2 to 10-fold, or about 1.2 to 5-fold, in a 24-hour period, compared to GSEL without the permeation enhancer, in a Franz cell using phosphate-buffered saline as the donor and recipient compartment fluid.

[0119] Active pharmaceutical ingredients (APIs) for administration using gastrointestinal synthetic epithelial linings In one aspect, the present disclosure provides a composition comprising an active pharmaceutical ingredient. In some embodiments, the composition comprises a polymer precursor, an oxygen source, a permeation enhancer, and an active pharmaceutical ingredient. In some embodiments, the oxygen source contacts a catalyst endogenous to the subject, resulting in polymerization of the polymer precursor. In some embodiments, the polymer precursor is polymerized into a polymer. In some embodiments, the active pharmaceutical ingredient is retained or encapsulated in the polymer. In some embodiments, the active pharmaceutical ingredient is retained in the polymer.

[0120] For any of the active pharmaceutical ingredients disclosed herein, the API or APIs may be combined with the GSEL composition for administration. For any of the active pharmaceutical ingredients disclosed herein, the API or APIs may be administered in a dosage form separate from the GSEL composition for administration. For any of the active pharmaceutical ingredients disclosed herein, the API or APIs may be combined with the GSEL composition for administration and administered in a dosage form separate from the GSEL composition for administration. When the API or APIs are administered in a dosage form separate from the GSEL composition for administration, the API or APIs may be administered before, simultaneously with, or after administration of the GSEL composition.

[0121] In some embodiments, the composition comprises active pharmaceutical ingredient(s) in an amount of 0.1% to 10% relative to (polymer precursor, oxygen source, permeation enhancer, and active pharmaceutical ingredient(s)).

[0122] In some embodiments, the active pharmaceutical ingredient is a statin.

[0123] In some embodiments, the active pharmaceutical ingredient treats obesity.

[0124] In some embodiments, the active pharmaceutical ingredient treats type 2 diabetes.

[0125] In some embodiments, the active pharmaceutical ingredient treats metabolic syndrome.

[0126] In some embodiments, the active pharmaceutical ingredient treats non-alcoholic fatty liver disease.

[0127] In some embodiments, the active pharmaceutical ingredient treats non-alcoholic steatohepatitis.

[0128] In some embodiments, the active pharmaceutical ingredient treats Crohn's disease.

[0129] In some embodiments, the active pharmaceutical ingredient treats an infectious disease. In some embodiments, the active pharmaceutical ingredient is an antibiotic. In some embodiments, the active pharmaceutical ingredient is an antiparasitic agent. In some embodiments, the active pharmaceutical ingredient is an anthelmintic agent. In some embodiments, the active pharmaceutical ingredient is an antiviral agent.

[0130] In some embodiments, the active pharmaceutical ingredient is a contraceptive.

[0131] organic small molecules In some embodiments, the composition comprises an active pharmaceutical ingredient, and the active pharmaceutical ingredient is a small organic molecule. In some embodiments, the active pharmaceutical ingredient is a small molecule having a molecular weight of about 1 kD or less. In certain embodiments, the active pharmaceutical ingredient is an antibiotic. Exemplary antibiotics include penicillins (e.g., penicillin, amoxicillin), cephalosporins (e.g., cephalexin), macrolides (e.g., erythromycin, clarithromycin, azithromycin, troleandomycin), fluoroquinolones (e.g., ciprofloxacin, levofloxacin, ofloxacin), sulfonamides (e.g., cotrimoxazole, trimethoprim), tetracyclines (e.g., tetracycline, chlortetracycline, oxytetracycline, demeclocycline, methacycline, sancycline, doxycycline), and the like. Antibiotics include, but are not limited to, doxycline, aureomycin, terramycin, minocycline, 6-deoxytetracycline, lymecycline, meclocycline, methacycline, rolitetracycline, and glycylcycline antibiotics (e.g., tigecycline), aminoglycosides (e.g., gentamicin, tobramycin, paromomycin), aminocyclitols (e.g., spectinomycin), chloramphenicol, sparsomycin, quinupristin / dalfoprisin (Syndercid™). In certain embodiments, the antibiotic is a ribosome-targeting antibiotic.

[0132] Polymer active pharmaceutical ingredients In some embodiments, the composition comprises an active pharmaceutical ingredient, wherein the active pharmaceutical ingredient is a polymer. In some embodiments, the composition comprises an active pharmaceutical ingredient, wherein the active pharmaceutical ingredient is a polymer having a molecular weight of about 1 kD to about 160 kD, e.g., about 1 kD to about 10 kD, or about 1 kD to about 5 kD. In some embodiments, the composition comprises an active pharmaceutical ingredient, wherein the active pharmaceutical ingredient is a polymer having a molecular weight of about 1 kD to about 125 kD, about 1 kD to about 100 kD, about 1 kD to about 75 kD, about 1 kD to about 50 kD, or about 1 kD to about 25 kD.

[0133] Peptides and Proteins In some embodiments, the composition comprises an active pharmaceutical ingredient, wherein the active pharmaceutical ingredient is a polymer, wherein the polymer is a polypeptide. In some embodiments, the polypeptide has a molecular weight of less than about 10 kD, at least about 1 kD, or between 1 kD and 10 kD. In some embodiments, the polypeptide comprises less than about 80 amino acids, at least about 8 amino acids, or between about 8 amino acids and about 80 amino acids. In some embodiments, the polypeptide comprises insulin, semaglutide, a GLP-1 receptor agonist, tirzepatide, liraglutide, desmopressin, octreotide, an analgesic peptide, difelikefalin, 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, a lipase, a protease, phenylalanine hydroxylase, carbamoyl phosphate synthetase I, glucose oxidase, or L-asparaginase.

[0134] nucleic acid In some embodiments, the composition comprises an active pharmaceutical ingredient, wherein the active pharmaceutical ingredient is a polymer, and the polymer is a polynucleotide. In some embodiments, the polynucleotide has a molecular weight of less than about 1.5 million, at least about 5 kD, or between about 5 kD and about 1500 kD, between about 5 kD and about 1000 kD, between about 5 kD and about 750 kD, between about 5 kD and about 500 kD, between about 5 kD and about 250 kD, between about 5 kD and about 100 kD, between about 5 kD and about 50 kD, between about 5 kD and about 25 kD, or between about 5 kD and about 10 kD. In some embodiments, the polynucleotide is single-stranded. In some embodiments, the polynucleotide is double-stranded. In some embodiments, the polynucleotide comprises less than about 5,000 bases, at least about 10 bases, or from about 10 to about 5,000 bases, from about 10 to about 2,500 bases, from about 10 to about 1,000 bases, from about 10 to about 500 bases, from about 10 to about 100 bases, from about 10 to about 50 bases, or from about 10 to about 25 bases. In some embodiments, the polynucleotide comprises less than about 2,500 base pairs, at least about 5 base pairs, or from about 5 to about 2,500 base pairs, from about 5 to about 1,000 base pairs, from about 5 to about 500 base pairs, from about 5 to about 250 base pairs, from about 5 to about 100 base pairs, from about 5 to about 50 base pairs, from about 5 to about 25 base pairs, or from about 5 to about 10 base pairs. In some embodiments, the polynucleotide comprises less than about 15 base pairs, at least about 5 base pairs, or from about 5 to about 15 base pairs. In some embodiments, the polynucleotide comprises an antisense oligonucleotide, mipomersen, patisiran, exondys, siRNA, or an IBD-targeting siRNA.

[0135] Dosage form The gastrointestinal synthetic epithelial lining (GSEL) composition for forming a gastrointestinal synthetic epithelial lining (GSEL) is administered orally.

[0136] The compositions and uses described herein include administering to a subject an effective amount of a composition comprising a polymer precursor, an oxygen source, and a permeation enhancer that promotes the permeation of one or more active pharmaceutical ingredients. In some embodiments, the composition further comprises an active pharmaceutical ingredient (API).

[0137] Further provided herein, in certain aspects, are compositions comprising dopamine, an oxygen source, a permeation enhancer, and optionally a buffering agent.

[0138] In some embodiments, the composition comprises a polymer precursor, an oxygen source, a permeation enhancer that promotes uptake of one or more active pharmaceutical ingredients, and optionally a buffer. In some embodiments, the buffer comprises phosphate, acetate, citrate, N-[tris(hydroxymethyl)methyl]glycine), (tris(hydroxymethyl)aminomethane), or (2-(bis(2-hydroxyethyl)amino)acetic acid). In some embodiments, the buffer comprises tris(hydroxymethyl)aminomethane.

[0139] In some embodiments, the composition further comprises an enzyme, a nutritional blocker, a radioprotectant, a nutritional supplement, a diagnostic agent, or a combination thereof. In some embodiments, the composition further comprises an enzyme. In some embodiments, the composition further comprises a radioprotectant. In some embodiments, the composition further comprises an active pharmaceutical ingredient. In some embodiments, the composition further comprises a diagnostic agent. In some embodiments, the composition further comprises a combination of two or more of an enzyme, a nutritional supplement, a radioprotectant, an active pharmaceutical ingredient, and a diagnostic agent.

[0140] In some embodiments, the composition is administered orally. In some embodiments, the composition is in a liquid or solid dosage form. In some embodiments, the composition is in the form of a solution, gel, powder, tablet, or capsule.

[0141] In some embodiments, the composition is in solution and has a pH of about 7 to about 10. In some embodiments, the composition is in solution and has a pH of about 7 to about 9. In some embodiments, the composition is in solution and has a pH of about 8.5. In some embodiments, the composition is in solution and has a pH of about 7.4.

[0142] In certain embodiments, the subject to which the composition is administered is a human. In certain embodiments, the subject to which the composition is administered is an animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In other embodiments, the subject is an experimental animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate.

[0143] The compositions may be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. A "unit dose" is a discrete amount of a composition comprising a specified amount of a drug or active ingredient. The amount of drug or active ingredient generally corresponds to the dosage of the drug or active ingredient that would be administered to a subject and / or a convenient fraction of that dosage, e.g., one-half or one-third of that dosage.

[0144] The compositions provided herein are generally formulated in unit dosage form for ease of administration and uniformity of dosage.However, it is understood that the total daily use amount of the compositions described herein is determined by a doctor within the scope of sound medical judgment.The specific therapeutically effective dose level for any specific subject or organism will depend on various factors, such as the severity of the disease and disorder being treated; the activity of the specific drug or active ingredient used; the specific composition used; the age, weight, general health, sex and diet of the subject; the time of administration and the excretion rate of the specific drug or active ingredient used; the duration of treatment; the drug used in combination with or simultaneously with the specific drug or active ingredient used and similar factors well known in the medical field.

[0145] The compositions provided herein can be administered by enteral (eg, oral) administration or by feeding or gastric tube.

[0146] The exact amount of agent or active ingredient required to achieve an effective dose will vary depending, for example, on the subject's race, age, and general condition, the severity of any side effects or disorders, the nature of the particular agent or active ingredient, the mode of administration, etc. An effective amount may be contained in a single dose (e.g., a single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject, any two doses of the multiple doses may contain different amounts of an agent or active ingredient described herein, or substantially the same amount of an agent or active ingredient described herein. In certain embodiments, when multiple doses are administered to a subject, the frequency with which the multiple doses are administered to the subject or applied to a tissue or cell is three doses per day, two doses per day, one dose per day, one dose every other day, one dose every three days, one dose per week, one dose per two weeks, one dose every three weeks, or one dose per four weeks. In certain embodiments, the frequency with which the multiple doses are administered to a subject is one dose per day. In certain embodiments, the frequency of administering multiple doses to the subject is 2 doses per day.In certain embodiments, the frequency of administering multiple doses to the subject is 3 doses per day.In certain embodiments, when administering multiple doses to the subject, the period between the first dose and the last dose of the multiple doses can be 1 day, 2 days, 4 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, 5 years, 7 years, 10 years, 15 years, 20 years or the lifetime of the subject.In certain embodiments, the period between the first dose and the last dose of the multiple doses is 3 months, 6 months or 1 year.In certain embodiments, the period between the first dose and the last dose of the multiple doses is the lifetime of the subject.

[0147] The compositions described herein can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically effective agents). The compositions can be administered in combination with additional pharmaceutical agents that improve activity (e.g., potency and / or efficacy), improve bioavailability, improve safety, reduce drug resistance, and / or alter metabolism, inhibit excretion, and / or alter distribution in the subject in treating a disease in a subject in need thereof.

[0148] The compositions may be administered concurrently with, prior to, or subsequent to, one or more additional pharmaceutical agents, which may be useful, for example, as a combination therapy.

[0149] Any of the monomers, polymer precursors, prepolymers, permeation enhancers, and active pharmaceutical ingredients can be administered as a pharmaceutically acceptable salt if chemically possible and pharmaceutically desirable. Alternatively, any of the monomers, polymer precursors, prepolymers, permeation enhancers, and active pharmaceutical ingredients described herein as salts can be used as a free acid or free base if chemically possible and pharmaceutically desirable. Common pharmaceutically acceptable salts include hydrochloride, sodium salt, sulfate, acetate, phosphate, diphosphate, chloride salt, potassium salt, maleate, calcium salt, citrate, mesylate, nitrate, tartrate, aluminum salt, and gluconate salt. Additional pharmaceutically acceptable salts are listed in Gupta et al., Salts of Therapeutic Agents: Chemical, Physicochemical, and Biological Considerations. Molecules. 2018 Jul 14;23(7):1719. doi: 10.3390 / molecules23071719. PMID:30011904; PMCID:PMC6100526, and Berge et al., J Pharm Sci. 1977 Jan;66(1):1-19. doi:10.1002 / jps.2600660104. PMID:833720.

[0150] Enumeration of Embodiments The present disclosure is further illustrated by the following enumerated embodiments. Where practicable, the various embodiments can be combined in any manner.

[0151] Embodiment 1. A composition for oral administration for forming a polymer in situ in a subject, comprising: polymer precursors, an oxygen source, and A permeation enhancer that promotes the penetration of one or more active pharmaceutical ingredients.

[0152] Embodiment 2. The composition of embodiment 1, further comprising one or more active pharmaceutical ingredients.

[0153] Embodiment 3. The composition of embodiment 1 or embodiment 2, further comprising a buffering agent.

[0154] Embodiment 4. The composition of any one of embodiments 1-3, further comprising one or more additional permeation enhancers.

[0155] Embodiment 5. The composition of any one of embodiments 1-4, comprising a polymer precursor in an amount of 40% to 90% relative to (polymer precursor, oxygen source, and permeation enhancer).

[0156] Embodiment 6. The composition of any one of embodiments 1 to 5, comprising an oxygen source in an amount of 1% to 15% relative to (the polymer precursor, the oxygen source, and the permeation enhancer).

[0157] Embodiment 7. The composition of any one of embodiments 1-6, comprising a permeation enhancer in an amount of 0.1% to 60% relative to (the polymer precursor, the oxygen source, and the permeation enhancer).

[0158] Embodiment 8. The composition of any one of embodiments 1-7, comprising a polymer precursor in an amount of 40% to 90% relative to (polymer precursor, oxygen source, permeation enhancer, and active pharmaceutical ingredient(s)).

[0159] Embodiment 9. The composition of any one of embodiments 1 to 8, comprising an oxygen source in an amount of 1% to 15% relative to (the polymer precursor, the oxygen source, the permeation enhancer, and the active pharmaceutical ingredient(s)).

[0160] Embodiment 10. The composition of any one of embodiments 1-9, comprising a permeation enhancer in an amount of 1% to 60% relative to (the polymer precursor, oxygen source, permeation enhancer, and active pharmaceutical ingredient(s)).

[0161] Embodiment 11. The composition of any one of embodiments 1-10, comprising the active pharmaceutical ingredient(s) in an amount of 0.1% to 10% relative to (the polymer precursor, oxygen source, permeation enhancer, and active pharmaceutical ingredient(s)).

[0162] Embodiment 12. The composition of any one of embodiments 2 to 11, wherein the active pharmaceutical ingredient is a polymer having a molecular weight of about 1 kD to about 160 kD.

[0163] Embodiment 13. The composition of embodiment 12, wherein the macromolecule is a polypeptide or a polynucleotide.

[0164] Embodiment 14. The composition of embodiment 12, wherein the macromolecule is a polypeptide.

[0165] Embodiment 15. The composition of embodiment 14, wherein the polypeptide has a molecular weight of about 1 kD to about 10 kD.

[0166] Embodiment 16. The composition of embodiment 14, wherein the polypeptide comprises about 8 to about 80 amino acids.

[0167] Embodiment 17. The composition of embodiment 14, wherein the polypeptide comprises insulin, semaglutide, a GLP-1 receptor agonist, tirzepatide, liraglutide, desmopressin, octreotide, an analgesic peptide, difelikefalin, 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, a lipase, a protease, phenylalanine hydroxylase, carbamoyl phosphate synthetase I, glucose oxidase, or L-asparaginase.

[0168] Embodiment 18. The composition of embodiment 12, wherein the macromolecule is a polynucleotide.

[0169] Embodiment 19. The composition of embodiment 18, wherein the polynucleotide has a molecular weight of about 5 kD to about 1500 kD.

[0170] Embodiment 20. The composition of embodiment 18 or embodiment 19, wherein the polynucleotide is single-stranded.

[0171] Embodiment 21. The composition of embodiment 18 or embodiment 19, wherein the polynucleotide is double-stranded.

[0172] Embodiment 22. The composition of embodiment 18, wherein the polynucleotide is single-stranded and comprises from about 10 to about 5000 bases.

[0173] Embodiment 23. The composition of embodiment 18, wherein the polynucleotide is single-stranded and comprises from about 10 to about 1000 bases.

[0174] Embodiment 24. The composition of embodiment 18, wherein the polynucleotide is single-stranded and comprises about 10 to about 30 bases.

[0175] Embodiment 25. The composition of embodiment 18, wherein the polynucleotide is double-stranded and comprises from about 5 to about 2500 base pairs.

[0176] Embodiment 26. The composition of embodiment 18, wherein the polynucleotide is double-stranded and comprises from about 5 to about 500 base pairs.

[0177] Embodiment 27. The composition of embodiment 18, wherein the polynucleotide is double-stranded and comprises from about 5 to about 15 base pairs.

[0178] Embodiment 28. The composition of embodiment 18, wherein the polynucleotide comprises an antisense oligonucleotide, mipomersen, patisiran, exondys, siRNA, or an inflammatory bowel disease (IBD)-targeting siRNA.

[0179] Embodiment 29. The composition of any one of embodiments 2 to 11, wherein the active pharmaceutical ingredient is a small molecule having a molecular weight of 1 kD or less.

[0180] Embodiment 30. The composition of any one of embodiments 1 to 29, wherein the polymer precursor comprises one or both of a monomer and an oligomeric precursor of a polymer.

[0181] Embodiment 31. The composition of any one of embodiments 1 to 30, wherein the polymer precursor is selected from Table 1 or Table 2, or a combination thereof.

[0182] Embodiment 32. The composition of embodiment 31, wherein the monomer is dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, levodopa ethyl ester, or a combination thereof.

[0183] Embodiment 33. The composition of any one of embodiments 1 to 32, wherein the oxygen source is a substrate for an endogenous catalyst.

[0184] Embodiment 34. The composition of embodiment 33, wherein the oxygen source is urea peroxide or hydrogen peroxide.

[0185] Embodiment 35. The composition of any one of embodiments 1 to 34, which is in an oral dosage form.

[0186] Embodiment 36. The composition of embodiment 35, wherein the oral dosage form is a solution, gel, tablet, powder, or capsule.

[0187] Embodiment 37. The composition of embodiment 35, wherein the oral dosage form comprises one or more of a solution, gel, tablet, powder, or capsule.

[0188] Embodiment 38. The composition of embodiment 35, wherein the oral dosage form is an enteric-coated dosage form.

[0189] Embodiment 39. The composition of any one of embodiments 1 to 38, wherein the permeation enhancer is carnitine.

[0190] Embodiment 40. The composition of embodiment 41, wherein the carnitine is an acylcarnitine.

[0191] Embodiment 41. The composition of embodiment 39 or 40, wherein the carnitine is selected from the group consisting of lauroylcarnitine, palmitoylcarnitine, and palmitoylcarnitine chloride (PCC).

[0192] Embodiment 42. The composition of embodiment 39 or 40, wherein the carnitine is lauroylcarnitine or palmitoylcarnitine.

[0193] Embodiment 43. The composition of any one of embodiments 1 to 38, wherein the permeation enhancer is choline.

[0194] Embodiment 44. The composition of embodiment 43, wherein the choline is lysophosphatidylcholine.

[0195] Embodiment 45. The composition of any one of embodiments 1 to 38, wherein the permeation enhancer is an aromatic alcohol.

[0196] Embodiment 46. The composition of embodiment 45, wherein the aromatic alcohol is selected from the group consisting of propyl gallate, butylhydroxytoluene, and butylhydroxyanisole.

[0197] Embodiment 47. The composition of embodiment 46, wherein the aromatic alcohol is benzyl alcohol, phenyl alcohol, or phenoxyethanol.

[0198] Embodiment 48. The composition of any one of embodiments 1 to 38, wherein the permeation enhancer is a piperazine derivative.

[0199] Embodiment 49. The composition of embodiment 48, wherein the piperazine derivative is selected from the group consisting of 1-phenylpiperazine, 1-methyl-4-phenylpiperazine, 1-(4-methylphenyl)piperazine, and 1-benzylpiperazine.

[0200] Embodiment 50. The composition of embodiment 49, wherein the piperazine derivative is 1-phenylpiperazine or 1-methyl-4-piperazine.

[0201] Embodiment 51. The composition of any one of embodiments 1 to 38, wherein the permeation enhancer is a mucoadhesive polymer.

[0202] Embodiment 52. The composition of embodiment 51, wherein the mucoadhesive polymer is selected from the group consisting of chitosan, chitosan hydrochloride, trimethylated chitosan chloride, and N,N,N-trimethylchitosan chloride.

[0203] Embodiment 53. The composition of embodiment 52, wherein the mucoadhesive polymer is trimethylated chitosan chloride.

[0204] Embodiment 54. The composition of any one of embodiments 1 to 38, wherein the penetration enhancer is a cell-penetrating peptide.

[0205] Embodiment 55. The composition of embodiment 54, wherein the cell-penetrating peptide is selected from the group consisting of transportan and penetratin.

[0206] Embodiment 56. The composition of embodiment 54, wherein the cell-penetrating peptide is selected from the group consisting of oligoarginine, polyarginine, oligolysine, polylysine, oligotryptophan, and polytryptophan.

[0207] Embodiment 57. The composition of any one of embodiments 1 to 38, wherein the permeation enhancer is an amino acid.

[0208] Embodiment 58. The composition of embodiment 57, wherein the amino acid is tryptophan.

[0209] Embodiment 59. The composition of any one of embodiments 1 to 38, wherein the permeation enhancer is an ionic solution.

[0210] Embodiment 60. The composition of embodiment 59, wherein the ionic solution is selected from the group consisting of choline geranate, nicotinic acid, and trigonelline.

[0211] Embodiment 61. The composition of embodiment 59 or 60, wherein the ionic solution is choline geranate.

[0212] Embodiment 62. The composition of any one of embodiments 1 to 38, wherein the permeation enhancer is an organic solvent.

[0213] Embodiment 63. The composition of embodiment 62, wherein the solvent is selected from the group consisting of ethanol, 2-propanol, 1-propanol, and 2-methyl-2-propanol.

[0214] Embodiment 64. The composition of embodiment 62 or 63, wherein the organic solvent is selected from the group consisting of dimethyl sulfoxide, ethyl acetate, and acetone.

[0215] Embodiment 65. The composition of any one of embodiments 1 to 38, wherein the permeation enhancer is an anionic surfactant.

[0216] Embodiment 66. The composition of embodiment 65, wherein the anionic surfactant is sodium dodecyl sulfate, or an alternative pharmaceutically acceptable salt thereof.

[0217] Embodiment 67. The composition of embodiment 65, wherein the anionic surfactant is sodium cholate, or an alternative pharmaceutically acceptable salt thereof.

[0218] Embodiment 68. The composition of any one of embodiments 1 to 38, wherein the permeation enhancer is a chelating agent.

[0219] Embodiment 69. The composition of embodiment 68, wherein the chelating agent is selected from the group consisting of EDTA, EGTA, and DTPA.

[0220] Embodiment 70. The composition of embodiment 68 or 69, wherein the chelating agent is EDTA.

[0221] Embodiment 71. The composition of any one of embodiments 1 to 38, wherein the permeation enhancer is a non-ionic surfactant.

[0222] Embodiment 72. The composition of embodiment 71, wherein the nonionic surfactant is an ethoxylate.

[0223] Embodiment 73. The nonionic surfactant is an alcohol ethoxylate (C X E Y wherein X is the number of carbon atoms in the alcohol and Y is the number of ethylene oxide units.

[0224] Embodiment 74. The composition of embodiment 71, wherein the nonionic surfactant is a medium or long chain fatty acid sugar ester.

[0225] Embodiment 75. The composition of embodiment 71, wherein the nonionic surfactant is a medium or long chain fatty acid sucrose ester.

[0226] Embodiment 76. The composition of embodiment 71, wherein the nonionic surfactant is an ethoxylated fatty acid sugar ester.

[0227] Embodiment 77. The composition of embodiment 71, wherein the nonionic surfactant is an ethoxylated sorbitan ester.

[0228] Embodiment 78. The composition of embodiment 71, wherein the nonionic surfactant is an ethoxylated glyceride.

[0229] Embodiment 79. The composition of embodiment 71, wherein the nonionic surfactant is selected from the group consisting of macrogol-8 glycerides, sucrose esters, sucrose laurate, ethoxylates, alkyl maltosides, dodecyl maltoside, short-chain polyethylene glycols, Brij® series, polyoxyethylene (10) oleyl ether, polyoxyethylene (23) lauryl ether, polysorbates, polysorbate series PS20, PS40, PS60, PS65, PS80, and Triton® X-100.

[0230] Embodiment 80. The composition of embodiment 71, wherein the nonionic surfactant is caprylocaproyl polyoxyl-8 glyceride (LABRASOL®), a poloxamer, a polyoxylglyceride, or polyethylene monostearate.

[0231] Embodiment 81. The composition of any one of embodiments 1 to 38, wherein the permeation enhancer is a non-ionic detergent.

[0232] Embodiment 82. The composition of embodiment 81, wherein the nonionic detergent is sucrose monolaurate or n-tetradecyl β-D-maltopyranoside (TDM).

[0233] Embodiment 83. The composition of embodiment 81, wherein the nonionic detergent is sucrose monolaurate.

[0234] Embodiment 84. The composition of any one of embodiments 1 to 38, wherein the nonionic detergent is n-tetradecyl β-D-maltopyranoside (TDM).

[0235] Embodiment 85. The composition of any one of embodiments 1 to 38, wherein the permeation enhancer is a fatty acid, a fatty acid salt, an ethoxylated fatty acid ester, a sugar fatty acid ester, or an ethoxylated sugar fatty acid ester.

[0236] Embodiment 86. The fatty acid salt is sodium caprate (C 10 ) or an alternative pharmaceutically acceptable salt thereof.

[0237] Embodiment 87. The fatty acid salt is sodium caprylate (C8), or an alternative pharmaceutically acceptable salt thereof, or sodium laurate (C 12 ), or an alternative pharmaceutically acceptable salt thereof.

[0238] Embodiment 88. The composition of embodiment 85, wherein the sugar fatty acid ester is a fatty acid ester of a monosaccharide.

[0239] Embodiment 89. The composition of embodiment 85, wherein the sugar fatty acid ester is an ethoxylated fatty acid ester of a monosaccharide.

[0240] Embodiment 90. The composition of embodiment 85, wherein the sugar fatty acid ester is a fatty acid ester of sorbitan or glucose.

[0241] Embodiment 91. The composition of embodiment 85, wherein the sugar fatty acid ester is an ethoxylated fatty acid ester of sorbitan or glucose.

[0242] Embodiment 92. The composition of embodiment 85, wherein the sugar fatty acid ester is a fatty acid ester of a disaccharide.

[0243] Embodiment 93. The composition of embodiment 85, wherein the sugar fatty acid ester is an ethoxylated fatty acid ester of a disaccharide.

[0244] Embodiment 94. The composition of embodiment 85, wherein the sugar fatty acid ester is a fatty acid ester of sucrose or maltose.

[0245] Embodiment 95. The composition of embodiment 85, wherein the sugar fatty acid ester is an ethoxylated fatty acid ester of sucrose or maltose.

[0246] Embodiment 96. The fatty acid, ethoxylated fatty acid ester, sugar fatty acid ester, or ethoxylated sugar fatty acid ester is selected from the group consisting of dodecyl maltoside, sodium dodecyl sulfate, nonaethylene glycol monododecyl ether (C 12 E9), sodium laurate (C 12 ), Sodium Nonanoate (C9), Sodium Undecanoate (C 11 ), sodium undecylenate (C11:1), sodium oleate, linoleic acid, and sucrose monolaurate, and pharmaceutically acceptable salts thereof or alternative pharmaceutically acceptable salts thereof.

[0247] Embodiment 97. The fatty acid, ethoxylated fatty acid ester, sugar fatty acid ester, or ethoxylated sugar fatty acid ester is nonaethylene glycol monododecyl ether (C 12 E9).

[0248] Embodiment 98. The composition of any one of embodiments 1 to 38, wherein the permeation enhancer is an endogenous secretion.

[0249] Embodiment 99. The composition of embodiment 98, wherein the endogenous secretion is a bile salt.

[0250] Embodiment 100. The composition of embodiment 99, wherein the bile salt is selected from the group consisting of sodium taurodeoxycholate, sodium taurocholate, sodium cholate, sodium deoxycholate, sodium glycodeoxycholate, sodium glycochenodeoxycholate, sodium glycocholate, sodium chenodeoxycholate, sodium taurochenodeoxycholate, sodium lithocholate, and mixed sodium taurodihydrofusidate, or alternative pharmaceutically acceptable salts thereof.

[0251] Embodiment 101. The composition of embodiment 98 or 99, wherein the bile salt is sodium cholate, or an alternative pharmaceutically acceptable salt thereof.

[0252] Embodiment 102. The composition of any one of embodiments 1 to 38, wherein the permeation enhancer is an N-acylated acid.

[0253] Embodiment 103. The composition of embodiment 102, wherein the N-acylated acid is acetylsalicylic acid, or a pharmaceutically acceptable salt thereof.

[0254] Embodiment 104. The composition of embodiment 102, wherein the N-acylated acid is sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC), or an alternative pharmaceutically acceptable salt thereof, or its corresponding acid.

[0255] Embodiment 105. The composition of embodiment 102, wherein the N-acylated acid is 8-(N-2-hydroxy-5-chloro-benzoyl)-amino-caprylic acid (5-CNAC), or an alternative pharmaceutically acceptable salt thereof, or its corresponding acid.

[0256] Embodiment 106. The composition of embodiment 102, wherein the N-acylated acid is 4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid (4-CNAB), or an alternative pharmaceutically acceptable salt thereof, or its corresponding acid.

[0257] Embodiment 107. The N-acylated acid is N-(10-[2-

[0258] hydroxybenzoyl]-amino)decanoic acid (SNAD), or an alternative pharmaceutically acceptable salt thereof, or its corresponding acid.

[0259] Embodiment 108. The composition of embodiment 102, wherein the N-acylated acid is monosodium N-(4-chlorosalicyloyl)-4-aminobutyrate (5-CNAB), or an alternative pharmaceutically acceptable salt thereof, or its corresponding acid.

[0260] Embodiment 109. The composition of embodiment 102, wherein the N-acylated acid is N-[8-(2-hydroxy-4-methoxy)benzoyl]aminocaprylic acid (4-MOAC), or a pharmaceutically acceptable salt thereof.

[0261] Embodiment 110. The composition of embodiment 102, wherein the N-acylated acid is sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC), or an alternative pharmaceutically acceptable salt thereof, or its corresponding acid.

[0262] Embodiment 111. The composition of any one of embodiments 1 to 38, wherein the permeation enhancer is a high molecular weight polymer.

[0263] Embodiment 112. The composition of embodiment 111, wherein the high molecular weight polymer is a polysaccharide.

[0264] Embodiment 113. The composition of embodiment 111, wherein the high molecular weight polymer is an antimicrobial toxin.

[0265] Embodiment 114. The composition of embodiment 113, wherein the antimicrobial toxin is selected from the group consisting of zonula occludens toxin analogs, viral protein 8 analogs, and Clostridium perfringens enterotoxin analogs.

[0266] Embodiment 115. The composition of embodiment 111, wherein the high molecular weight polymer is chitosan or carboxymethylcellulose.

[0267] Embodiment 116. The composition of any one of embodiments 1 to 38, wherein the permeation enhancer is caprylocaproyl PEG8 glyceride.

[0268] Embodiment 117. The composition of any one of embodiments 1 to 38, wherein the permeation enhancer is a sugar-based surfactant.

[0269] Embodiment 118. The composition of embodiment 117, wherein the sugar-based surfactant is dodecyl-β-D-maltopyranoside (DDM).

[0270] Embodiment 119. The composition of any one of embodiments 1 to 38, wherein the permeation enhancer is glyceryl monocaprate.

[0271] Embodiment 120. The composition of any one of embodiments 1 to 38, wherein the permeation enhancer is urea.

[0272] Embodiment 121. The composition of any one of embodiments 1 to 38, wherein the permeation enhancer is docusate sodium, or an alternative pharmaceutically acceptable salt thereof, or its corresponding acid.

[0273] Embodiment 122. The composition of any one of embodiments 1 to 38, wherein the permeation enhancer is citric acid, or a pharmaceutically acceptable salt thereof.

[0274] Embodiment 123. The composition of any one of embodiments 1 to 122, wherein the permeation enhancer promotes paracellular transport.

[0275] Embodiment 124. The composition of any one of embodiments 1 to 122, wherein the permeation enhancer promotes transcellular transport.

[0276] Embodiment 125. The composition of any one of embodiments 1 to 122, wherein the permeation enhancer promotes paracellular and transcellular transport.

[0277] Embodiment 126. A method for forming a polymer coating in the small intestine of a subject, comprising administering to the subject a composition described in any one of embodiments 1 to 125.

[0278] Embodiment 127. A method of forming a polymer coating in the small intestine of a subject, comprising administering to the subject: polymer precursors, an oxygen source, and a permeation enhancer that enhances the uptake of one or more active pharmaceutical ingredients; The method, wherein the polymer precursor and the oxygen source are contacted with a catalyst endogenous to the locus, and the catalyst polymerizes the polymer precursor.

[0279] Embodiment 128. The method of embodiment 127, further comprising administering to the subject an active pharmaceutical ingredient.

[0280] Embodiment 129. The method of embodiment 127, wherein the polymer precursor, the oxygen source, and the permeation enhancer are administered as a single composition.

[0281] Embodiment 130. The method of embodiment 128, wherein the polymer precursor, the oxygen source, the permeation enhancer, and the active pharmaceutical ingredient are administered as a single composition.

[0282] Embodiment 131. The composition of embodiment 14, wherein the polypeptide comprises semaglutide.

[0283] Embodiment 132. The composition of embodiment 14, wherein the polypeptide comprises tirzepatide. [Example]

[0284] The present disclosure is further illustrated by the following non-limiting examples.

[0285] Example 1 Initial evaluation of permeation enhancers - Evaluation by screening in 96-well plates Methods: Fresh porcine jejunal tissue was excised and washed with a series of saline solutions supplemented with 5% antibiotic-antimycotic solution. The tissue was then placed in an expanded 96-well plate filled with buffer (the plate that received the permeated drug). Tissue from multiple pigs was used so that the average permeability and standard deviation from the mean could be calculated. Another 96-well plate was clamped on top and secured with a magnet. To prepare donor solutions, master plates were generated by aliquoting from the following three plates: (1) the excipient and API plate contained excipient and drug at 2.5x the final concentrations, Tris buffer and hydrogen peroxide at 1.25x the final concentrations, (2) the polydopamine (PDA) plate contained PDA at 2.5x the final concentrations, and Tris buffer and hydrogen peroxide at 1.25x the final concentrations, and (3) the dopamine plate contained dopamine at 5x the final concentration. All formulations contained GSEL_40 (9.8 mg / mL dopamine HCl, 25 mg / mL PDA, 0.67 mg / mL hydrogen peroxide, 2.2 mg / mL Tris HCl, and 4.3 mg / mL Tris base). A master plate was dispensed from each plate at a volumetric ratio of 0.5:0.5:1. The donor solution in the master plate was then pipetted into the donor 96-well plate. The entire system was then covered and left at room temperature for 20-24 hours. Samples from the receiving 96-well plate were then analyzed using HPLC. The average percent permeability and / or fold change was determined by comparing experimental and control samples tested on the same tissue. Permeability was calculated by comparing the amount of permeant added to the donor chamber. The fold change was calculated by comparing the experimental sample to the control sample. The excipients tested and their corresponding names are listed in Table E1. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4]

[0286] Results: Combining GSEL with selected single excipients significantly improved the permeability of the active pharmaceutical ingredient (API) (Figure 1A, Figure 1B, Figure 1C, Figure 1D, Table E1). Specific classes of excipients, such as bile salts and chelators, were identified to significantly increase API permeability compared with GSEL alone (Figure 2A, Figure 2B, Figure 2C). Screening of 50 single excipients with semaglutide revealed that the bile salt family was the most effective excipient class in promoting semaglutide permeability, with a 10% permeability reduction when combined with GSEL (Figure 2C). These results were supported by Franz cell tests in duodenal tissue, where increasing CHA concentrations also resulted in increased permeability (Figure 2I).

[0287] The effect of excipient concentration on API permeability was also evaluated (Figures 1F and 1G). Concentration affected API permeability for some excipients, but did not affect mean permeability for others. Increasing excipient concentration beyond 25 mg / mL resulted in diminishing improvements in permeability.

[0288] Excipients were also tested in combination with each other and in various ratios of formulation (Figure 3, Figure 4A, Figure 4B, Figure 5A, Figure 5B, Figure 5C, Figure 5D, Figure 5E, Figure 5F, Tables E2, E3, E4, and E5). The top excipient combinations that promoted permeability included at least one bile salt, cholic acid or its salts, or glycocholic acid or its salts. Further permeability studies in Franz cells demonstrated the same synergistic effect when combining bile salts with other ammonium salts (Figure 22B). Based on dual excipient screening, another combination that demonstrated synergy was the combination of the bile salts CHA and GCA with SNAC (Figure 4A, Figure 18A, and Figure 18B). This was also supported by supplemental studies in Franz cells in which additional benzene ring-based molecules were tested (Figure 23A). A notable bile salt combination included 80 mg / mL poly(vinyl sulfonic acid) sodium salt, 40 mg / mL ammonium carbonate, 80 mg / mL sarcaprozate sodium, 20 mg / mL folic acid, 80 mg / mL phytic acid, and 40 mg / mL sodium dodecyl sulfate (Figure 6, Figure 7, Figure 8, Table E6). [Table 4-1] [Table 4-2] [Table 5-1] [Table 5-2] [Table 5-3] [Table 6-1] [Table 6-2] [Table 6-3] [Table 7-1] [Table 7-2] [Table 7-3] [Table 8-1] [Table 8-2] [Table 9]

[0289] Example 2A Evaluation of permeation enhancers - validation of permeation enhancer combinations Franz cells were used to test different permeation enhancers on ex vivo tissues derived from the small intestine, such as porcine duodenal tissue (also referred to as colonic tissue). A water pump was attached to the Franz cell rack, and each Franz cell was maintained at 37°C. The Franz cells were then placed on the rack and filled with 5 mL of phosphate-buffered saline. The tissue was cut into approximately 3.2 x 3.2 cm squares, and after removing any large clumps of mucus or feces, the cells were placed on the Franz cells. Next, gastrointestinal synthetic epithelial lining (GSEL) solutions were prepared by first weighing out dopamine HCl, polydopamine, and the permeation enhancer and placing them in vials. The selected active pharmaceutical ingredient (API), Tris buffer (50 mM, pH 8.5), and hydrogen peroxide (1 M) were then added to the vial, followed by vortexing (using brief sonication if necessary) until all solids had dissipated. 250 μL of the final mixture was then added to the donor compartment of each Franz cell. Samples from the receiving compartment were collected periodically from 0 to 24 hours to measure the concentration of API. At each sampling point, 200 μL of phosphate-buffered saline was added to replace the volume removed (200 μL).

[0290] The same experiment was performed, except that no permeation enhancer was used in the GSEL solution. The amount of API detected in the receiving compartment of the GSEL containing the permeation enhancer was compared to the amount of API detected in the receiving compartment of the GSEL without the permeation enhancer at each time point to determine the increase in permeation provided by the permeation enhancer. [Table 10]

[0291] Results: Excipients identified in the 96-well screen were further evaluated for efficacy in Franz cells. Delivery of APIs (e.g., semaglutide and tirzepatide) by liquid and powder formulations of GSEL was measured (Figures 9, 10, 14, and Table E7). For several excipient combinations, permeability was significantly improved when the API was delivered by the liquid formulation compared to the powder formulation.

[0292] FITC-dextran molecules were also tested to determine whether pharmaceutical components of various sizes could be delivered by GSEL. FITC-dextran-4K (FD4) is a molecule with an approximate molecular weight of 4 kilodaltons. The total amount of permeated FD4 increased with increasing ratios of excipients (GCA (40 mg / mL) and NHCO (40 mg / mL)) to GSEL, but the amount of FD4 permeated over time remained similar regardless of GSEL formulation (Figures 12A, 12B, and 12C). Permeation was observed to occur at a linear rate (Figures 12C and 12D). The permeation enhancer (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.

[0293] FITC-dextran-40K (FD40) is a molecule with an approximate molecular weight of 40 kilodaltons. Excipient combinations were tested by assessing the permeability of FD40 through GSEL (Figures 11A and 11B). API permeation using a formulation containing GSEL, GCA, and NHCO was comparable to GCA and NHCO alone at 6 and 20 hours, suggesting that 40 mg / mL of GSEL did not inhibit the effectiveness of GCA and NHCO as common excipients (Figures 11A and 11B).

[0294] To confirm that the excipient-GSEL combination was effective in multiple tissue types, assays using colonic tissue were also performed. The total permeation of semaglutide was significantly increased by adding NHCO and GCA to GSEL (Figures 13, 14, 15, and 16). The permeation rate of the API was low for the first 6 hours, but then increased linearly over the next 6 hours after delivery (Figures 15B and 15C).

[0295] Other excipient combinations were also confirmed by Franz cell experiments (Figures 17, 18, and 19). Semaglutide permeation across duodenal tissue using a formulation containing GSEL, GCA, and NHCO was found to be greater than that of GCA and NHCO alone at 20 hours, suggesting that 40 mg / mL of GSEL did not inhibit the effectiveness of GCA and NHCO as common excipients (Figures 19A and 19B). The data also suggest that certain combinations of excipients facilitated the permeation of the API through GSEL.

[0296] Example 2B Evaluation of permeation enhancer formulations FITC-dextran 4 kDa (FD4), 10 kDa (FD10), and 40 kDa (FD40) were used as model macromolecules to verify the ability of GSELs to entrap macromolecules and to evaluate the permeability of GSELs in ex vivo tissues when combined with permeation enhancers. To determine the rate of GSEL formation, GSEL components were administered to tissues and allowed to react for different periods of time. These experiments showed that incubation of GSELs for more than 30 minutes did not appear to significantly alter coverage (Figure 20A).

[0297] To test the colocalization of FD4 in duodenal tissue, liquid (e.g., suspension) formulations were prepared by simultaneously adding all components to an aliquot of Tris buffer and then administered directly to the tissue (Figure 20B). For solid (e.g., powder) formulations, all powders and Tris salts were added as solids to the tissue surface, and water was added 10 minutes later (Figures 20B, 20C, and 20D). The FD4 content of the supernatant was then measured.

[0298] Results: GSEL alone was sufficient to capture the dye (Figures 20C and 20E). Further colocalization studies using FD4, FD10, and FD40 showed that co-delivery with GSEL suspension resulted in 31.0 ± 6.7%, 29.3 ± 1.7%, and 25.8 ± 3.0% capture (Figure 20E), respectively, compared to <1% capture in the control group (Figure 20E). Addition of the permeation enhancer sodium cholate (CHA) increased the capture of FD10 and FD40 (39.8 ± 0.5% and 38.5 ± 5.3%, respectively) (Figure 20E). However, it was found that substrates of various sizes penetrated the porcine duodenal tissue at a higher percentage when GSEL containing a permeation enhancer was applied compared to GSEL without a permeation enhancer (Figures 20F, 20G, and 20H). More specifically, addition of CHA resulted in a 2.25-, 2.74-, and 3.58-fold increase in FD4, FD10, and FD40 (respectively) after 24 hours (Figure 20F).

[0299] Example 2C Evaluation of permeation enhancers - kinetic assay The gastrointestinal tract is a dynamic environment. While low entrapment may allow for increased permeability under static conditions, in a dynamic environment, it may lead to reduced residence time and absorption. On the other hand, high levels of semaglutide entrapment within the GSEL platform may impair tissue permeability because semaglutide diffuses too slowly from the network. Therefore, we investigated how varying the ratio between GSEL, permeation enhancer (PE), and semaglutide affects colocalization and permeability. The dynamic assay involved evaluating GSEL delivery in tissue mounted at an angle (Figure 21).

[0300] GCA and NHCO were found to be highly synergistic with semaglutide and GSEL (Figures 22A and 22B), and the formulation was modified to improve colocalization and penetration. A formulation (1xGSEL_1xPE) was identified containing 1xGSEL = 6.25 mg polydopamine nanoparticles (PDA), 2.45 mg dopamine hydrochloride (DA-HCl), 1xPE = 10 mg GCA and 10 mg NHCO.

[0301] Using this formulation, a permeability study was performed to test semaglutide co-formulated with GSEL and GCA-NHCO against controls (semaglutide only, semaglutide + SNAC (based on Ryvelsus tablets, mass ratio 14:300), semaglutide + GSEL, and semaglutide + GCA + NHCO) (Figure 22C). This static Franz cell study revealed that GCA-NHCO was a permeation enhancer system that significantly improved permeability by 19.9-fold or 15.5-fold without or with GSEL, respectively (Figure 22C). In contrast, SNAC did not enhance semaglutide permeation to the same extent (Figure 22C). Notably, because the Franz study was static, it was hypothesized that GSEL might provide a localized depot, increasing residence time at that deposition spot and leading to higher absorption.

[0302] Changing the ratio of permeation enhancer to GSEL from 1x to 0.5x or 2x did not result in a statistically significant improvement in permeability, indicating that reducing the concentration of permeation enhancer by half did not affect the permeability enhancement (Figure 22D).

[0303] Varying the GSEL content revealed that 1xGSEL and 2xGSEL appeared to have no effect, while 4xGSEL significantly reduced permeability, indicating that increasing the GSEL:PE ratio can adversely affect semaglutide release and tissue absorption (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 verified that increasing the concentration of GSEL relative to the permeation enhancer led to increased capture in both static and dynamic assays (Figures 22F and 22G).

[0304] In ex vivo experiments, when the permeation enhancer content was reduced 10-fold (0.1xPE relative to GSEL), preliminary kinetic studies showed higher colocalization (>60%, Figures 2H, 22I), but permeability was reduced to 0.5% (Figure 22J).

[0305] Different ratios of permeation enhancer:semaglutide were investigated, where increasing amounts of semaglutide were co-formulated with 2x GSEL and 1x permeation enhancer, and all formulations showed similar percent permeation (Figure 22M).

[0306] Example 3 Gastrointestinal synthetic epithelial lining formulations containing permeation enhancers for administration to subjects: Evaluation in a porcine model Yorkshire pigs, weighing 40–80 kg each, were used at 7 months or older, approximately 4–9 months of age. After a prescribed preoperative fasting period, the pigs were anesthetized, intubated, and maintained with isoflurane anesthesia throughout the procedure. A marginal ear vein catheter was inserted to collect blood samples, which were continued for 1–7 days. Dried GSEL powder containing a permeation enhancer and semaglutide was solubilized in Tris buffer immediately before administration. An endoscopic guide catheter was inserted into the proximal small intestine, and the GSEL suspension was injected into it. Blood samples were periodically collected from the ear vein catheter and immediately centrifuged into serum collection tubes. Samples were analyzed by ELISA and LC-MS. After 6 hours, the pigs were awakened and monitored until they fully recovered.

[0307] In the following experiments, the formulation component ratios presented in Table E8 were used (e.g., 2xGSEL, 6.4mg / kg GCA, 6.4mg / kg NHCO, semaglutide for a final ratio of permeation enhancer to semaglutide of 20:2.35). [Table 11] *AUC = ng*h / mL, dose = mg / kg, F = fraction absorbed.

[0308] Results: A GSEL formulation containing a permeation enhancer was identified that resulted in significantly higher plasma concentrations of semaglutide in pigs treated with the GSEL formulation compared with pigs treated with a non-GSEL formulation or pigs treated with semaglutide alone.

[0309] PK curves are presented comparing intravenous administration of semaglutide alone, endoscopic placement of semaglutide (control), endoscopic placement of semaglutide delivered with GSEL using permeation enhancers in various formulations, and endoscopic placement of semaglutide delivered with permeation enhancers 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 for different time points: 24, 48, 72, and 168 hours (Figures 23D, 23E, 23F, and 23G). In all cases, delivery of semaglutide with GSEL and permeation enhancers showed at least a three-fold increase in semaglutide uptake compared to the control (semaglutide administered with permeation enhancers), 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 provided by GSEL, which increases the retention time of macromolecules on the duodenal tissue and improves absorption. Absolute bioavailability (e.g., F = fraction absorbed) is shown in Table E9, and semaglutide delivered with GSEL / permeation enhancer achieved bioavailability ranging from 1.9 to 3.1%. The GSEL / permeation enhancer formulation was observed to be more effective than GSEL alone, as indicated by AUC up to 48 hours after administration (Table E9). [Table 12]

[0310] Example 4 Gastrointestinal synthetic epithelial lining formulations containing permeation enhancers for subject administration: Evaluation in a dog model A total of 12 beagles (6 males and 6 females) weighing 9-12 kg and approximately 6-14 months of age will be used. The dogs will be trained to swallow capsules / tablets and fasted overnight before oral administration of the test article. After dosing, 15 mL of saline will be administered using a syringe as a post-dose flush. Blood samples will be collected by 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 will be collected in serum separator tubes. Samples will be analyzed by ELISA and LC-MS. The following table shows one possible formulation of GSEL with a permeation enhancer in dog studies. [Table 13]

[0311] The disclosures of all publications, patents, patent applications, and published patent applications referred to herein by a citation identifier are hereby incorporated by reference in their entirety.

[0312] Although the foregoing invention has been described in some detail by way of illustration and specific example for clarity of understanding, it will be apparent to those skilled in the art that certain changes and modifications may be practiced. Therefore, the descriptions and examples should not be construed as limiting the scope of the invention.

Claims

1. 1. A composition for oral administration for forming a polymer in situ in a subject, comprising: polymer precursors, an oxygen source, and the composition comprising a permeation enhancer that enhances the permeation of one or more active pharmaceutical ingredients.

2. 10. The composition of claim 1, further comprising one or more active pharmaceutical ingredients.

3. 3. The composition of claim 1 or claim 2, further comprising a buffering agent.

4. The composition of any one of claims 1 to 3, further comprising one or more additional permeation enhancers.

5. The composition of any one of claims 1 to 4, comprising a polymer precursor in an amount of 40% to 90% relative to (polymer precursor, oxygen source, and permeation enhancer).

6. The composition of any one of claims 1 to 5, comprising an oxygen source in an amount of 1% to 15% relative to (polymer precursor, oxygen source, and permeation enhancer).

7. The composition of any one of claims 1 to 6, comprising a permeation enhancer in an amount of 0.1% to 60% relative to (polymer precursor, oxygen source, and permeation enhancer).

8. 8. The composition of any one of claims 1 to 7, comprising polymer precursor in an amount of 40% to 90% relative to (polymer precursor, oxygen source, permeation enhancer, and active pharmaceutical ingredient(s)).

9. 9. The composition of any one of claims 1 to 8, comprising an oxygen source in an amount of 1% to 15% relative to (polymer precursor, oxygen source, permeation enhancer, and active pharmaceutical ingredient(s)).

10. 10. The composition of any one of claims 1 to 9, comprising a permeation enhancer in an amount of 1% to 60% relative to (polymer precursor, oxygen source, permeation enhancer, and active pharmaceutical ingredient(s)).

11. 11. The composition of any one of claims 1 to 10, comprising active pharmaceutical ingredient(s) in an amount of 0.1% to 10% relative to (polymer precursor, oxygen source, permeation enhancer, and active pharmaceutical ingredient(s)).

12. The composition of any one of claims 2 to 11, wherein the active pharmaceutical ingredient is a polymer having a molecular weight of about 1 kD to about 160 kD.

13. The composition of claim 12 , wherein the polymer is a polypeptide or a polynucleotide.

14. The composition of claim 12 , wherein the polymer is a polypeptide.

15. The composition of claim 14, wherein the polypeptide has a molecular weight of about 1 kD to about 10 kD.

16. 15. The composition of claim 14, wherein the polypeptide comprises from about 8 to about 80 amino acids.

17. 15. The composition of claim 14, wherein the polypeptide comprises insulin, semaglutide, a GLP-1 receptor agonist, tirzepatide, liraglutide, desmopressin, octreotide, an analgesic peptide, difelikefalin, 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, a lipase, a protease, phenylalanine hydroxylase, carbamoyl phosphate synthetase I, glucose oxidase, or L-asparaginase.

18. The composition of claim 12 , wherein the polymer is a polynucleotide.

19. 19. The composition of claim 18, wherein the polynucleotide has a molecular weight of about 5 kD to about 1500 kD.

20. 20. The composition of claim 18 or claim 19, wherein the polynucleotide is single-stranded.

21. 20. The composition of claim 18 or claim 19, wherein the polynucleotide is double-stranded.

22. 19. The composition of claim 18, wherein the polynucleotide is single-stranded and comprises from about 10 to about 5000 bases.

23. 19. The composition of claim 18, wherein the polynucleotide is single-stranded and comprises from about 10 to about 1000 bases.

24. 19. The composition of claim 18, wherein the polynucleotide is single-stranded and comprises from about 10 to about 30 bases.

25. 19. The composition of claim 18, wherein the polynucleotide is double-stranded and comprises from about 5 to about 2500 base pairs.

26. 19. The composition of claim 18, wherein the polynucleotide is double-stranded and comprises from about 5 to about 500 base pairs.

27. 19. The composition of claim 18, wherein the polynucleotide is double-stranded and comprises from about 5 to about 15 base pairs.

28. 19. The composition of claim 18, wherein the polynucleotide comprises an antisense oligonucleotide, mipomersen, patisiran, exondys, siRNA, or an inflammatory bowel disease (IBD)-targeting siRNA.

29. The composition of any one of claims 2 to 11, wherein the active pharmaceutical ingredient is a small molecule having a molecular weight of 1 kD or less.

30. 30. The composition of any one of claims 1 to 29, wherein the polymer precursor comprises one or both of a monomer and an oligomeric precursor of a polymer.

31. The composition of any one of claims 1 to 30, wherein the polymer precursor is selected from Table 1 or Table 2, or a combination thereof.

32. 32. The composition of claim 31, wherein the monomer is dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, levodopa ethyl ester, or a combination thereof.

33. The composition of any one of claims 1 to 32, wherein the oxygen source is a substrate for an endogenous catalyst.

34. 34. The composition of claim 33, wherein the oxygen source is urea peroxide or hydrogen peroxide.

35. The composition of any one of claims 1 to 34, which is in oral dosage form.

36. 36. The composition of claim 35, wherein the oral dosage form is a solution, gel, tablet, powder, or capsule.

37. 36. The composition of claim 35, wherein the oral dosage form comprises one or more of a solution, gel, tablet, powder, or capsule.

38. 36. The composition of claim 35, wherein the oral dosage form is an enteric-coated dosage form.

39. 39. The composition of any one of claims 1 to 38, wherein the permeation enhancer is carnitine.

40. 40. The composition of claim 39, wherein the carnitine is an acylcarnitine.

41. 41. The composition of claim 39 or 40, wherein the carnitine is selected from the group consisting of lauroylcarnitine, palmitoylcarnitine, and palmitoylcarnitine chloride (PCC).

42. 41. The composition of claim 39 or 40, wherein the carnitine is lauroylcarnitine or palmitoylcarnitine.

43. The composition of any one of claims 1 to 38, wherein the permeation enhancer is choline.

44. 44. The composition of claim 43, wherein the choline is lysophosphatidylcholine.

45. The composition of any one of claims 1 to 38, wherein the permeation enhancer is an aromatic alcohol.

46. 46. ​​The composition of claim 45, wherein the aromatic alcohol is selected from the group consisting of propyl gallate, butylhydroxytoluene, and butylhydroxyanisole.

47. 47. The composition of claim 46, wherein the aromatic alcohol is benzyl alcohol, phenyl alcohol, or phenoxyethanol.

48. The composition of any one of claims 1 to 38, wherein the permeation enhancer is a piperazine derivative.

49. 49. The composition of claim 48, wherein the piperazine derivative is selected from the group consisting of 1-phenylpiperazine, 1-methyl-4-phenylpiperazine, 1-(4-methylphenyl)piperazine, and 1-benzylpiperazine.

50. 50. The composition of claim 49, wherein the piperazine derivative is 1-phenylpiperazine or 1-methyl-4-piperazine.

51. The composition of any one of claims 1 to 38, wherein the permeation enhancer is a mucoadhesive polymer.

52. 52. The composition of claim 51, wherein the mucoadhesive polymer is selected from the group consisting of chitosan, chitosan hydrochloride, trimethylated chitosan chloride, and N,N,N-trimethylchitosan chloride.

53. 53. The composition of claim 52, wherein the mucoadhesive polymer is trimethylated chitosan chloride.

54. The composition of any one of claims 1 to 38, wherein the penetration enhancer is a cell-penetrating peptide.

55. 55. The composition of claim 54, wherein the cell-penetrating peptide is selected from the group consisting of transportan and penetratin.

56. 55. The composition of claim 54, wherein the cell-penetrating peptide is selected from the group consisting of oligoarginine, polyarginine, oligolysine, polylysine, oligotryptophan, and polytryptophan.

57. The composition of any one of claims 1 to 38, wherein the permeation enhancer is an amino acid.

58. 58. The composition of claim 57, wherein the amino acid is tryptophan.

59. The composition of any one of claims 1 to 38, wherein the permeation enhancer is an ionic liquid.

60. 60. The composition of claim 59, wherein the ionic solution is selected from the group consisting of choline geranate, nicotinic acid, and trigonelline.

61. 61. The composition of claim 59 or 60, wherein the ionic solution is choline geranate.

62. The composition of any one of claims 1 to 38, wherein the permeation enhancer is an organic solvent.

63. 63. The composition of claim 62, wherein the solvent is selected from the group consisting of ethanol, 2-propanol, 1-propanol, and 2-methyl-2-propanol.

64. 64. The composition of claim 62 or 63, wherein the organic solvent is selected from the group consisting of dimethyl sulfoxide, ethyl acetate, and acetone.

65. The composition of any one of claims 1 to 38, wherein the permeation enhancer is an anionic surfactant.

66. 66. The composition of claim 65, wherein the anionic surfactant is sodium dodecyl sulfate, or an alternative pharmaceutically acceptable salt thereof.

67. 66. The composition of claim 65, wherein the anionic surfactant is sodium cholate, or an alternative pharmaceutically acceptable salt thereof.

68. The composition of any one of claims 1 to 38, wherein the permeation enhancer is a chelating agent.

69. 69. The composition of claim 68, wherein the chelating agent is selected from the group consisting of EDTA, EGTA, and DTPA.

70. 70. The composition of claim 68 or 69, wherein the chelating agent is EDTA.

71. The composition of any one of claims 1 to 38, wherein the permeation enhancer is a non-ionic surfactant.

72. 72. The composition of claim 71, wherein the nonionic surfactant is an ethoxylate.

73. The nonionic surfactant is an alcohol ethoxylate (C Ｘ E Ｙ 72. The composition of claim 71, wherein X is the number of carbon atoms in the alcohol and Y is the number of ethylene oxide units.

74. 72. The composition of claim 71, wherein the nonionic surfactant is a medium or long chain fatty acid sugar ester.

75. 72. The composition of claim 71, wherein the nonionic surfactant is a medium or long chain fatty acid sucrose ester.

76. 72. The composition of claim 71, wherein the nonionic surfactant is an ethoxylated fatty acid sugar ester.

77. 72. The composition of claim 71, wherein the nonionic surfactant is an ethoxylated sorbitan ester.

78. 72. The composition of claim 71, wherein the nonionic surfactant is an ethoxylated glyceride.

79. 72. The composition of claim 71, wherein the nonionic surfactant is selected from the group consisting of macrogol-8 glyceride, sucrose esters, sucrose laurate, ethoxylates, alkyl maltosides, dodecyl maltoside, short chain polyethylene glycols, Brij® series, polyoxyethylene (10) oleyl ether, polyoxyethylene (23) lauryl ether, polysorbates, polysorbate series PS20, PS40, PS60, PS65, PS80, and Triton® X-100.

80. 72. The composition of claim 71, wherein the nonionic surfactant is caprylocaproyl polyoxyl-8 glyceride (LABRASOL®), a poloxamer, a polyoxylglyceride, or polyethylene monostearate.

81. The composition of any one of claims 1 to 38, wherein the permeation enhancer is a non-ionic detergent.

82. 82. The composition of claim 81, wherein the non-ionic detergent is sucrose monolaurate or n-tetradecyl β-D-maltopyranoside (TDM).

83. 82. The composition of claim 81, wherein the non-ionic detergent is sucrose monolaurate.

84. A composition according to any preceding claim, wherein the non-ionic detergent is n-tetradecyl β-D-maltopyranoside (TDM).

85. 39. The composition of any one of claims 1 to 38, wherein the permeation enhancer is a fatty acid, a fatty acid salt, an ethoxylated fatty acid ester, a sugar fatty acid ester, or an ethoxylated sugar fatty acid ester.

86. The fatty acid salt is sodium caprate (C １０ 86. The composition of claim 85, wherein the compound is:

87. The fatty acid salt is sodium caprylate (C ８ ), or an alternative pharmaceutically acceptable salt thereof, or sodium laurate (C １２ 86. The composition of claim 85, wherein the compound is:

88. 86. The composition of claim 85, wherein the sugar fatty acid ester is a fatty acid ester of a monosaccharide.

89. 86. The composition of claim 85, wherein the sugar fatty acid ester is an ethoxylated fatty acid ester of a monosaccharide.

90. 86. The composition of claim 85, wherein the sugar fatty acid ester is a fatty acid ester of sorbitan or glucose.

91. 86. The composition of claim 85, wherein the sugar fatty acid ester is an ethoxylated fatty acid ester of sorbitan or glucose.

92. 86. The composition of claim 85, wherein the sugar fatty acid ester is a fatty acid ester of a disaccharide.

93. 86. The composition of claim 85, wherein the sugar fatty acid ester is an ethoxylated fatty acid ester of a disaccharide.

94. 86. The composition of claim 85, wherein the sugar fatty acid ester is a fatty acid ester of sucrose or maltose.

95. 86. The composition of claim 85, wherein the sugar fatty acid ester is an ethoxylated fatty acid ester of sucrose or maltose.

96. The fatty acid, ethoxylated fatty acid ester, sugar fatty acid ester, or ethoxylated sugar fatty acid ester is selected from the group consisting of dodecyl maltoside, sodium dodecyl sulfate, nonaethylene glycol monododecyl ether (C １２ E ９ ), sodium laurate (C １２ ), sodium nonanoate (C ９ ), sodium undecanoate (C １１ ), sodium undecylenate (C11:1), sodium oleate, linoleic acid, and sucrose monolaurate, and pharmaceutically acceptable salts thereof or alternative pharmaceutically acceptable salts thereof.

97. The fatty acid, ethoxylated fatty acid ester, sugar fatty acid ester, or ethoxylated sugar fatty acid ester is selected from the group consisting of nonaethylene glycol monododecyl ether (C １２ E ９ 86. The composition of claim 85, wherein

98. The composition of any one of claims 1 to 38, wherein the permeation enhancer is an endogenous secretion.

99. 99. The composition of claim 98, wherein the endogenous secretion is a bile salt.

100. 100. The composition of claim 99, wherein the bile salt is selected from the group consisting of sodium taurodeoxycholate, sodium taurocholate, sodium cholate, sodium deoxycholate, sodium glycodeoxycholate, sodium glycochenodeoxycholate, sodium glycocholate, sodium chenodeoxycholate, sodium taurochenodeoxycholate, sodium lithocholate, and mixed sodium taurodihydrofusidate, or alternative pharmaceutically acceptable salts thereof.

101. 100. The composition of claim 98 or 99, wherein the bile salt is sodium cholate, or an alternative pharmaceutically acceptable salt thereof.

102. The composition of any one of claims 1 to 38, wherein the permeation enhancer is an N-acylated acid.

103. 103. The composition of claim 102, wherein the N-acylated acid is acetylsalicylic acid, or a pharmaceutically acceptable salt thereof.

104. 103. The composition of claim 102, wherein the N-acylated acid is sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC), or an alternative pharmaceutically acceptable salt thereof, or its corresponding acid.

105. 103. The composition of claim 102, wherein the N-acylated acid is 8-(N-2-hydroxy-5-chloro-benzoyl)-amino-caprylic acid (5-CNAC), or an alternative pharmaceutically acceptable salt thereof, or its corresponding acid.

106. 103. The composition of claim 102, wherein the N-acylated acid is 4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid (4-CNAB), or an alternative pharmaceutically acceptable salt thereof, or its corresponding acid.

107. 103. The composition of claim 102, wherein the N-acylated acid is N-(10-[2-hydroxybenzoyl]-amino)decanoic acid (SNAD), or an alternative pharmaceutically acceptable salt thereof, or its corresponding acid.

108. 103. The composition of claim 102, wherein the N-acylated acid is monosodium N-(4-chlorosalicyloyl)-4-aminobutyrate (5-CNAB), or an alternative pharmaceutically acceptable salt thereof, or its corresponding acid.

109. 103. The composition of claim 102, wherein the N-acylated acid is N-[8-(2-hydroxy-4-methoxy)benzoyl]aminocaprylic acid (4-MOAC), or a pharmaceutically acceptable salt thereof.

110. 103. The composition of claim 102, wherein the N-acylated acid is sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC), or an alternative pharmaceutically acceptable salt thereof, or its corresponding acid.

111. The composition of any one of claims 1 to 38, wherein the permeation enhancer is a high molecular weight polymer.

112. 112. The composition of claim 111, wherein the high molecular weight polymer is a polysaccharide.

113. 112. The composition of claim 111, wherein the high molecular weight polymer is an antimicrobial toxin.

114. 114. The composition of claim 113, wherein the antimicrobial toxin is selected from the group consisting of zonula occludens toxin analog, viral protein 8 analog, and Clostridium perfringens enterotoxin analog.

115. 112. The composition of claim 111, wherein the high molecular weight polymer is chitosan or carboxymethylcellulose.

116. The composition of any one of claims 1 to 38, wherein the permeation enhancer is caprylocaproyl PEG8 glyceride.

117. The composition of any one of claims 1 to 38, wherein the permeation enhancer is a sugar-based surfactant.

118. 118. The composition of claim 117, wherein the sugar-based surfactant is dodecyl-β-D-maltopyranoside (DDM).

119. The composition of any one of claims 1 to 38, wherein the permeation enhancer is glyceryl monocaprate.

120. The composition of any one of claims 1 to 38, wherein the permeation enhancer is urea.

121. 39. The composition of any one of claims 1 to 38, wherein the permeation enhancer is docusate sodium, or an alternative pharmaceutically acceptable salt thereof, or its corresponding acid.

122. 39. The composition of any one of claims 1 to 38, wherein the permeation enhancer is citric acid, or a pharmaceutically acceptable salt thereof.

123. 123. The composition of any one of claims 1 to 122, wherein the permeation enhancer promotes paracellular transport.

124. 123. The composition of any one of claims 1 to 122, wherein the permeation enhancer promotes transcellular transport.

125. 123. The composition of any one of claims 1 to 122, wherein the permeation enhancer promotes paracellular and transcellular transport.

126. 126. A method of forming a polymeric coating in the small intestine of a subject, the method comprising administering to the subject a composition according to any one of claims 1 to 125.

127. 1. A method of forming a polymeric coating in the small intestine of a subject, comprising administering to the subject: polymer precursors, an oxygen source, and a permeation enhancer that enhances the uptake of one or more active pharmaceutical ingredients; The method, wherein the polymer precursor and the oxygen source are contacted with a catalyst endogenous to the locus, and the catalyst polymerizes the polymer precursor.

128. 128. The method of claim 127, further comprising administering to the subject an active pharmaceutical ingredient.

129. 128. The method of claim 127, wherein the polymer precursor, the oxygen source, and the permeation enhancer are administered as a single composition.

130. 129. The method of claim 128, wherein the polymer precursor, the oxygen source, the permeation enhancer, and the active pharmaceutical ingredient are administered as a single composition.

131. The composition of claim 14, wherein the polypeptide comprises semaglutide.

132. The composition of claim 14 , wherein the polypeptide comprises tirzepatide.

133. 10. The composition of claim 1, comprising at least two different permeation enhancers selected from the group comprising ammonium salts, carbonates, bicarbonates, endogenous secretions, bile salts, bile acids, mixtures of bile salts and bile acids, carnitine, acylcarnitines, choline, aromatic alcohols, piperazine derivatives, mucoadhesive polymers, cell-penetrating peptides, amino acids, ionic solutions, organic solvents, anionic surfactants, chelating agents, nonionic surfactants, nonionic detergents, fatty acids, fatty acid salts, ethoxylated fatty acid esters, sugar fatty acid esters, ethoxylated sugar fatty acid esters, N-acylated acids, high molecular weight polymers, sugar-based surfactants, pharmaceutically acceptable salts of any of the foregoing acids or salts, alternative pharmaceutically acceptable salts of any of the foregoing salts, the free acid of any of the foregoing acid salts, and the free base of any of the foregoing base salts.

134. Ammonium carbonate, ammonium sulfate, ammonium citrate, ammonium phosphate, diammonium phosphate, monoammonium phosphate, ammonium bicarbonate, ammonium chloride, ammonium lactate, ammonium acetate, ammonium sulfate, ammonium sulfite, triammonium citrate, ammonium propionate, ammonium sulfamate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cholic acid, glycocholic acid, deoxycholic acid, glycochenodeoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, taurocholic acid, ox bile, chenodeoxycholic acid, taurochenodeoxycholic acid, lithocholic acid, glycolithocholic acid, glycohyocholic acid, taurolithocholic acid, ursodeoxycholic acid, tauroursodeoxycholic acid, glycoursodeoxycholic acid, 12-monoketocholic acid (12-MKC), 7-monoketocholic acid (7- MKC), 7,12-diketocholic acid (7,12-DKC), 3,7,12-triketocholic acid (3,7,12-TKC), 12-monoketodeoxycholic acid (12-MKDC), taurodihydrofusidic acid, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), salts of cholic acid, salts of glycocholic acid, salts of deoxycholic acid, salts of glycochenodeoxycholic acid, salts of glycodeoxycholic acid , salts of taurodeoxycholic acid, salts of taurocholic acid, salts of ox bile, salts of chenodeoxycholic acid, salts of taurochenodeoxycholic acid, salts of lithocholic acid, salts of glycolithocholic acid, salts of glycohyocholic acid, salts of taurolithocholic 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, 3,7,Salts of 12-triketocholic acid, salts of 12-monoketodeoxycholic acid, salts of taurodihydrofusidic acid, salts of 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate, sodium cholate, sodium glycocholate, sodium deoxycholate, sodium glycochenodeoxycholate, sodium glycodeoxycholate, sodium taurodeoxycholate, sodium taurocholate, sodium salt of ox bile, sodium chenodeoxycholate, sodium taurochenodeoxycholate, sodium lithocholate, sodium glycolithocholate, sodium glycohyocholate, sodium taurolithocholate, sodium ursodeoxycholate, sodium tauroursodeoxycholate, sodium glycoursodeoxycholate, 12 -Sodium monochenocholate, 7-sodium monoketocholate, 7,12-sodium diketocholate, 3,7,12-sodium triketocholate, 12-sodium monoketodeoxycholate, sodium taurodihydrofusidate, sodium 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate, lauroylcarnitine, palmitoylcarnitine, palmitoylcarnitine chloride (PCC), lysophosphatidylcholine, benzyl alcohol, phenyl alcohol, phenoxyethanol, propyl gallate, butylhydroxytoluene, butylhydroxyanisole, 1-phenylpiperazine, 1-methyl-4-phenylpiperazine, 1-(4-methylphenyl)piperazine, chitosan, chitosan hydrochloride, trimethylated chitosan chloride, N,N,N-trimethylchitosan chloride, transportan, penetratin, oligoarginine, polyarginine, oligolysine, polylysine, oligotryptophan, polytryptophan, tryptophan, choline geranic acid, nicotinic acid, trigonelline, ethanol, 2-propanol, 1-propanol, 2-methyl-2-propanol, dimethyl sulfoxide, ethyl acetate, acetone, sodium cholate, pharmaceutically acceptable salts of cholic acid, cholic acid, a mixture of cholic acid and a pharmaceutically acceptable salt of cholic acid, sodium dodecyl sulfate, a pharmaceutically acceptable salt of dodecyl hydrogen sulfate, dodecyl hydrogen sulfate, a mixture of dodecyl hydrogen sulfate and sodium dodecyl sulfate, EDTA, EGTA, DTPA, ethoxylates, alcohol ethoxylates (C, Ｘ E Ｙ (wherein X is the number of carbon atoms in the alcohol and Y is the number of ethylene oxide units), medium- or long-chain fatty acid sugar esters, sodium laurate, medium- or long-chain fatty acid sucrose esters, ethoxylated fatty acid sugar esters, ethoxylated sorbitan esters, ethoxylated glycerides, macrogol-8 glycerides, sucrose esters, sucrose laurate, alkyl maltosides, dodecyl maltosides, short-chain polyethylene glycols, Brij® series (such as polyoxyethylene (10) oleyl ether and polyoxyethylene (23) lauryl ether), polysorbates, polysorbate series PS20, PS40, PS60, PS65, PS80, Triton®X-100, caprylocaproyl polyoxyl-8 glyceride, poloxamer, polyoxyglyceride, polyethylene monostearate, sucrose monolaurate, n-tetradecyl β-D-maltopyranoside, sodium caprate, sodium caprylate, nonaethylene glycol monododecyl ether, fatty acid esters of monosaccharides, ethoxylated fatty acid esters of monosaccharides, fatty acid esters of sorbitan, fatty acid esters of glucose, ethoxylated fatty acid esters of sorbitan, ethoxylated fatty acid esters of glucose, fatty acid esters of disaccharides, Ethoxylated fatty acid esters of disaccharides, fatty acid esters of sucrose, fatty acid esters of maltose, ethoxylated fatty acid esters of sucrose, ethoxylated fatty acid esters of maltose, dodecyl maltoside, sodium dodecyl sulfate, nonaethylene glycol monododecyl ether, sodium laurate, sodium nonanoate, sodium undecanoate, sodium undecylenate, sodium oleate, linoleic acid, sucrose monolaurate, acetylsalicylic acid, sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC), 8-(N-2-hydroxy-5-chloro-benzoyl)-amino-caprylic acid (5-CNAC), 4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid (4-CNAB), N-(10-[2-hydroxybenzoyl]-amino)decanoic acid (SNAD), N-(4-chlorosalicyloyl)-4-aminobutyric acid monosodium (5-CNAB), N-[8-(2-hydroxy-4-methoxy)benzoyl]aminocaprylic acid (4-MOAC), polysaccharides, antibacterial toxins, zonula occludens toxin analogs, viral protein 8 analogs, welsh 10. The composition of claim 1, comprising at least two different permeation enhancers selected from the group consisting of a Clostridium perfringens enterotoxin analog, chitosan, carboxymethylcellulose, caprylocaproyl PEG-8 glyceride, dodecyl-β-D-maltopyranoside (DDM), glyceryl monocaproate, urea, docusate sodium, citric acid, a pharmaceutically acceptable salt of any of the foregoing acids or bases, an alternative pharmaceutically acceptable salt of any of the foregoing salts, the free acid of any of the foregoing acid salts, and the free base of any of the foregoing base salts.

135. 130. The composition of any one of claims 1 to 125 or the method of any one of claims 126 to 130, wherein the permeation enhancer is a bile salt.

136. 131. The composition of any one of claims 1-125 or the method of any one of claims 126-130, wherein the permeation enhancer is selected from the group consisting of sodium taurodeoxycholate, sodium taurocholate, sodium cholate, sodium deoxycholate, sodium glycodeoxycholate, sodium glycochenodeoxycholate, sodium glycocholate, sodium chenodeoxycholate, sodium taurochenodeoxycholate, sodium lithocholate, and mixed sodium taurodihydrofusidate, their corresponding acids, alternative pharmaceutically acceptable salts thereof, and mixtures of salts and acids thereof.

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