Patent Application
20230101687
Tissue barriers covering most parts of the body are not only protective shields against physical abrasion, chemical stress, environmental stress, xenobiotics, and microbial pathogens, but also dynamic linings for signal sensing (e.g., of temperature, viruses, and bacteria), molecule transport (e.g., of oxygen, nutrients, and drugs), and immunity coordination (e.g., cytokine, mucin, and host-defense peptides).9-19 Disruption of tissue barrier functions is associated with the pathogenesis of many human diseases.14-19 Selective intervention of a specific tissue barrier is pertinent in disease treatment and health management. In parallel, to address the challenge of efficiently and specifically restoring or augmenting functions of tissue barriers, a large variety of meticulously designed biotechnologies have been developed. These particular technologies, leveraging either tissue adhesives or tissue substitutes, are effective tools for facilitating restoration of tissue barrier dysfunctions and treatment of systemic diseases[0001]1,[0001]2,[0001]3,[0001]4[0001]4,[0001]5,[0001]6. Despite these advances in research laboratories, broad adoption of these technologies in medical laboratories and healthcare clinics has been limited, consequently stifling their impact. This narrow implementation is a result of multiple factors: invasive transplantation, potential immunogenicity, toxicity, and most importantly the inaccuracy, instability and inconvenience of current tissue targeting strategies, restricting selective tissue barrier access.
Described herein are compositions, methods, and kits that enable the growth of monomers such as polydopamine (PDA) in contact with epithelial tissue and provide a nontoxic, stable, transient synthetic tissue barrier with adjustable functions, which allows for easy, non-invasive transplantation. The polymeric coating relies on dopamine polymerization catalyzed by an endogenous cellular enzyme (e.g., catalase or “CAT”), strong tissue-adhesion generated through chemical crosslinking, and, optionally, functional agents incorporated through facile conjugation. The present disclosure relates in part to a library of tissue-active monomers, including monomers comprising macromolecules, that provides a broad set of material choices for synthetic tissue barriers. Based on a whole-body survey, the tissue-accelerated polymerization material library allows for the provision of new formulations applied in different tissues sites for various therapeutic strategies, including for the treatment of hemostasis (e.g., in upper gastrointestinal bleeding), and improvement of administration efficiency (e.g., sustained drug release) in the eye conjunctiva, cartilage, and oral cavity (e.g., protection of epithelium against environmental stresses in the oral cavity).
In one aspect, provided herein is a method of forming a polymer in situ in a subject, the method comprising administering to the subject a composition comprising a monomer and an oxygen source, wherein the monomer and oxygen source contact a catalyst endogenous to the subject in vivo, and wherein the catalyst polymerizes the monomer.
In one aspect, the disclosure provides a composition comprising (i) a monomer selected from dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, levodopa ethyl ester, or a monomer comprising: dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, or levodopa ethyl ester and a macromolecule selected from one or more of alginate, hyaluronic acid, polyacrylic acid, polyethylene glycol, chondroitin sulfate, or chitosan, (ii) an oxygen source, (iii) optionally, a buffer, and (iv) optionally, an agent.
In another aspect, the disclosure provides a method of treating a disease or disorder comprising administering an effective amount of a composition as described herein to a subject in need thereof.
Further provided are methods of preventing a disease or disorder comprising administering an effective amount of a composition as described herein to a subject in need thereof.
In a further aspect, provided herein is a method of treating bleeding, comprising administering an effective amount of a composition as described herein to a subject in need thereof.
The disclosure also provides kits comprising a composition as described herein and instructions for administering the same.
The details of certain embodiments of the invention are set forth in the Detailed Description of Certain Embodiments, as described below. Other features, objects, and advantages of the invention will be apparent from the Definitions, Examples, and Claims.
Unless otherwise required by context, singular terms shall include pluralities, and plural terms shall include the singular.
The language “in some embodiments” and “in certain embodiments” are used interchangeably.
The following definitions are more general terms used throughout the present application:
The singular terms “a,” “an,” and “the” include plural references unless the context clearly indicates otherwise. Similarly, the word “or” is intended to include “and” unless the context clearly indicates otherwise.
Other than in the examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as modified in all instances by the term “about.” “About” and “approximately” shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, or more typically, within 5%, 4%, 3%, 2%, or 1% of a given value or range of values.
When a range of values (“range”) is listed, it is intended to encompass each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided.
The terms “composition” and “formulation” are used interchangeably.
A “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal. The term “patient” refers to a human subject in need of treatment of a disease.
The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a composition described herein in or on a subject.
The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
The terms “condition,” “disease,” and “disorder” are used interchangeably.
An “effective amount” of a polymer or composition described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a polymer or composition described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the polymer or composition, the condition being treated, the mode of administration, and the age and health of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound, polymer, or composition described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound, polymer, or composition described herein in multiple doses.
The term “cancer” refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. See, e.g., Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990.
An “autoimmune disease” refers to a disease arising from an inappropriate immune response of the body of a subject against substances and tissues normally present in the body. In other words, the immune system mistakes some part of the body as a pathogen and attacks its own cells. This may be restricted to certain organs (e.g., in autoimmune thyroiditis) or involve a particular tissue in different places (e.g., Goodpasture's disease which may affect the basement membrane in both the lung and kidney). The treatment of autoimmune diseases is typically with immunosuppression, e.g., medications which decrease the immune response.
The term “inflammatory disease” refers to a disease caused by, resulting from, or resulting in inflammation. The term “inflammatory disease” may also refer to a dysregulated inflammatory reaction that causes an exaggerated response by macrophages, granulocytes, and/or T-lymphocytes leading to abnormal tissue damage and/or cell death. An inflammatory disease can be either an acute or chronic inflammatory condition and can result from infections or non-infectious causes.
The term “polymer” refers to a compound comprising eleven or more covalently connected repeating units. In certain embodiments, a polymer is naturally occurring. In certain embodiments, a polymer is synthetic (i.e., not naturally occurring).
As used herein, the term “assembly” or “assembling” refers to the formation of a polymer by covalent connection of repeating units. For example, a polymer may be assembled from any of the monomers disclosed herein.
The term “nanoparticle” refers to a particle having an average (e.g., mean) dimension (e.g., diameter) of between about 1 nanometer (nm) and about 1 micrometer (μm) (e.g., between about 1 nm and about 300 nm, between about 1 nm and about 100 nm, between about 1 nm and about 30 nm, between about 1 nm and about 10 nm, or between about 1 nm and about 3 nm), inclusive.
As used herein, the term “agent” means a molecule, group of molecules, complex or substance administered to an organism for diagnostic, therapeutic, preventative medical, or veterinary purposes. In certain embodiments, the agent is an active pharmaceutical agent, a diagnostic agent, or a prophylactic agent). In certain embodiments, the polymers and compositions disclosed herein comprise an agent(s), e.g., a first agent (e.g., at least one (including, e.g., at least two, at least three). In some embodiments, the polymers and compositions can further comprise a second agent. In some embodiments, the agent is an enzyme (e.g., a digestive enzyme), a nutrient blocker (e.g., a crosslinking agent), an aptamer, an antibody, a neutralizing agent, a diagnostic agent, a radioprotective agent, a nutraceutical, an active pharmaceutical agent, or a combination thereof.
As used herein, the term “radioprotective agent” means an agent that protects biological systems exposed to radiation, either naturally or through radiation leakage. In certain embodiments, radioprotective agents protect normal cells from radiation injury in cancer patients undergoing radiotherapy
As used herein, the term “neutralizing agent” means an agent that neutralizes an acid or base. In some embodiments, the neutralizing agent is an acid. In some embodiments, the neutralizing agent is a base. In certain embodiments, the neutralizing agent is a buffer.
As used herein, the term “diagnostic agent” means an imaging agent or contrast agent. The terms “imaging agent” and “contrast agent” refer to a substance used to enhance the contrast of structures or fluids within the body in medical imaging. It is commonly used to enhance the visibility of blood vessels and the gastrointestinal tract in medical imaging.
As used herein, the term “active pharmaceutical agent” includes an agent that is capable of providing a local or systemic biological, physiological, or therapeutic effect in the biological system to which it is applied. For example, an active pharmaceutical agent can act to control tumor growth, control infection or inflammation, act as an analgesic, promote anti-cell attachment, and enhance bone growth, among other functions. Other suitable active pharmaceutical agents can include anti-viral agents, hormones, antibodies, or therapeutic proteins. Other active pharmaceutical agents include prodrugs, which are agents that are not biologically active when administered but, upon administration to a subject are converted to biologically active agents through metabolism or some other mechanism.
An active pharmaceutical agent can be a compound, e.g., small organic or inorganic molecules; saccharines; oligosaccharides; polysaccharides; biological macromolecule, e.g., peptides, proteins, and peptide analogs and derivatives; peptidomimetics; antibodies and antigen binding fragments thereof; nucleic acids; nucleic acid analogs and derivatives; an extract made from biological materials such as bacteria, plants, fungi, or animal cells; animal tissues; naturally occurring or synthetic compositions; and any combinations thereof.
Examples of active pharmaceutical agents include, but are not limited to, antimicrobial agents, analgesics, antinflammatory agents, counterirritants, coagulation modifying agents, diuretics, sympathomimetics, anorexics, antacids and other gastrointestinal agents; antiparasitics, antidepressants, anti-hypertensives, anticholinergics, stimulants, antihormones, central and respiratory stimulants, drug antagonists, lipid-regulating agents, uricosurics, cardiac glycosides, electrolytes, ergot and derivatives thereof, expectorants, hypnotics and sedatives, antidiabetic agents, dopaminergic agents, antiemetics, muscle relaxants, para-sympathomimetics, anticonvulsants, antihistamines, beta-blockers, purgatives, antiarrhythmics, contrast materials, radiopharmaceuticals, antiallergic agents, tranquilizers, vasodilators, antiviral agents, and antineoplastic or cytostatic agents or other agents with anti-cancer properties, or a combination thereof. Other suitable active pharmaceutical agents include contraceptives and vitamins as well as micro- and macronutrients. Still other examples include antiinfectives such as antibiotics and antiviral agents; analgesics and analgesic combinations; anorexics; antiheimintics; antiarthritics; antiasthmatic agents; anticonvulsants; antidepressants; antidiuretic agents; antidiarrleals; antihistamines; antiinflammatory agents; antimigraine preparations; antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics, antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations including calcium channel blockers and beta-blockers such as pindolol and antiarrhythmics; anti-hypertensives; diuretics; vasodilators including general coronary, peripheral and cerebral; central nervous system stimulants; cough and cold preparations, including decongestants; hormones such as estradiol and other steroids, including corticosteroids; hypnotics; immunosuppressives; muscle relaxants; parasympatholytics; psychostimulants; sedatives; and tranquilizers; and naturally derived or genetically engineered proteins, polysaccharides, glycoproteins, or lipoproteins. The disclosure is not intended to be limited in any manner by the above exemplary terms. Additional terms may be defined in other sections of this disclosure.
Before the disclosed systems, hydrogels compositions, methods, uses, and kits are described in more detail, it should be understood that the aspects described herein are not limited to specific embodiments, methods, systems, apparati, or configurations, and as such can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting.
In one aspect, the disclosure provides a method of forming a polymer in situ in a subject, the method comprising administering to a subject a composition comprising a monomer and an oxygen source, wherein the monomer and the oxygen source contact a catalyst endogenous to the subject and the catalyst polymerizes the monomer.
In some embodiments, the monomer is catalyzed when the oxygen source and monomer contact the endogenous catalyst. In some embodiments, the monomer is catalyzed when the oxygen source and monomer contact a blood cell.
In some embodiments, the oxygen source is hydrogen peroxide or urea hydrogen peroxide. In some embodiments, the oxygen source is hydrogen peroxide. In some embodiments, the oxygen source is urea hydrogen peroxide.
In some embodiments, the endogenous catalyst is selected from catalases or peroxidases. In some embodiments, the endogenous catalyst is a peroxidase. In certain embodiments, the peroxidase is eosinophil peroxidase, lactoperoxidase, or myeloperoxidase.
In some embodiments, the endogenous catalyst is a catalase. In some embodiments, the catalase is a bacterial catalase. In some embodiments, the catalase is a human catalase.
In certain embodiments, the endogenous catalyst is located in the respiratory, urinary, lymphatic, circulatory, integumentary system, skeletal, muscular, nervous, digestive, or endocrine system. In some embodiments, the endogenous catalyst is located in the gastrointestinal (GI) tract of the subject. In some embodiments, the endogenous catalyst is located in the upper GI of the subject. In some embodiments, the endogenous catalyst is located in the gut of the subject. In some embodiments, the endogenous catalyst is located in the stomach of the subject. In some embodiments, the endogenous catalyst is located in a cell. In some embodiments, the endogenous catalyst is located in a blood cell. In some embodiments, the endogenous catalyst is located on a cell. In some embodiments, the endogenous catalyst is located on a blood cell. In some embodiments, the endogenous catalyst is located in a cell. In some embodiments, the endogenous catalyst is secreted by a blood cell. In some embodiments, the endogenous catalyst is located on a cell. In some embodiments, the endogenous catalyst is secreted by a blood cell.
In some embodiments, the monomer is a catechol-based monomer. In some embodiments, the monomer comprises a 1,2-dihydroxybenzene moiety. In some embodiments, the monomer comprises an optionally substituted 1,2-dihydroxybenzene moiety. In some embodiments, the monomer comprises 1,2-dihydroxyphenyl. In some embodiments, the monomer comprises an optionally substituted 1,2-dihydroxyphenyl.
In some embodiments, the monomer is a 2-(3,4-dihydroxyphenyl)ethylamine-based monomer. In certain embodiments, the monomer comprises a 3,4-dihydroxyphenethylamine moiety. In certain embodiments, the monomer comprises an optionally substituted 3,4-dihydroxyphenethylamine moiety. In certain embodiments, the monomer comprises 2-(3,4-dihydroxyphenyl)ethylamine. In certain embodiments, the monomer comprises an optionally substituted 2-(3,4-dihydroxyphenyl)ethylamine moiety.
In some embodiments, the monomer 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 monomer is selected from the group consisting of dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, and levodopa ethyl ester.
In certain embodiments, the monomer is a derivative of dopamine. In some embodiments, the monomer comprises dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, or levodopa ethyl ester.
In some embodiments, the derivative of the monomer comprises a macromolecule. In some embodiments, the monomer comprises dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, or levodopa ethyl ester and at least one macromolecule. In certain embodiments the macromolecule is alginate, hyaluronic acid, polyacrylic acid, polyethylene glycol, chondroitin sulfate, chitosan, or a combination thereof. In some embodiments the macromolecule is alginate, hyaluronic acid, polyacrylic acid, polyethylene glycol, chondroitin sulfate, or chitosan. In certain embodiments the monomer comprises (A) dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, or levodopa ethyl ester moieties bound to (B) alginate, hyaluronic acid, polyacrylic acid, polyethylene glycol, chondroitin sulfate, or chitosan. In certain embodiments the monomer comprises (A) more than one of dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, and levodopa ethyl ester moieties bound to (B) alginate, hyaluronic acid, polyacrylic acid, polyethylene glycol, chondroitin sulfate, or chitosan. In certain embodiments the monomer comprises (A) more than one of dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, and levodopa ethyl ester moieties bound to (B) more than one of alginate, hyaluronic acid, polyacrylic acid, polyethylene glycol, chondroitin sulfate, and chitosan.
In certain embodiments, the monomer is selected from the structures listed in Table 1 or 2.
In some embodiments, the monomer consists of a single type of monomer. In certain embodiments, the monomer comprises a combination of monomers. In certain embodiments, the monomer comprises a combination of monomers listed in Tables 1 and 2. In some embodiments, the combination of monomers consists of two different monomers. In some embodiments, the combination of monomers consists of three different monomers. In some embodiments, the combination of monomers consists of four different monomers.
In some embodiments, the composition further comprises an agent selected from active pharmaceutical agents, cosmetic agents, nutraceutical agents, imaging agents, diagnostic agents, radioprotective agents, nutraceutical agents, enzymes, nutrient blockers, aptamers, antibodies, neutralizing agents, and combinations thereof. active pharmaceutical agent In some embodiments, the composition further comprises an enzyme. In some embodiments, the composition further comprises a nutrient blocker. In some embodiments, the composition further comprises a radioprotective agent. In some embodiments, the composition further comprises an active pharmaceutical agent. In some embodiments, the composition further comprises a diagnostic agent. In some embodiments, the composition further comprises a combination of two or more of enzymes, nutrient blockers, radioprotective agents, active pharmaceutical agents, and diagnostic agents.
In certain embodiments, the composition further comprises a buffer.
In some embodiments, the composition further comprises an exogenous catalyst.
In some embodiments, at least one of the monomer and the oxygen source is stable in the stomach of the subject. In some embodiments, at least one of the monomer and the oxygen source is stable in the stomach for at least 30 minutes of the subject. In some embodiments, at least one of the monomer and the oxygen source is stable in the stomach for at least 60 minutes of the subject.
In some embodiments, the composition is stable in the stomach of the subject. In some embodiments, the composition is stable in the stomach for at least 30 minutes of the subject. In some embodiments, the composition is stable in the stomach for at least 60 minutes of the subject.
In some embodiments, at least one of the monomer and the oxygen source is stable in that it does not decompose in the stomach of the subject. In some embodiments, at least 95% of at least one of the monomer and the oxygen source remains after the composition passes out of the stomach of the subject. In some embodiments, at least 90% of at least one of the monomer and the oxygen source remains after the composition passes out of the stomach of the subject. In some embodiments, at least 80% of at least one of the monomer and the oxygen source remains after the composition passes out of the stomach of the subject.
In some embodiments, the composition comprises about 0.001 to about 1000 mg/mL monomer. In some embodiments, the composition comprises about 0.01 to about 100 mg/mL of monomer. In some embodiments, the composition comprises about 0.01 to about 50 mg/mL of monomer. In some embodiments, the composition comprises about 1 to about 20 mg/mL of monomer. In some embodiments, the composition comprises 10 mg/mL of monomer. In some embodiments, the composition comprises 20 mg/mL of monomer.
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 oxygen source compatible with ingestion by the subject.
In some embodiments, the composition has a pH of about 7 to about 10. In some embodiments, the composition has a pH of about 7 to about 9. In some embodiments, the composition has a pH of about 8.5. In some embodiments, the composition has a pH of about 7.4.
In certain embodiments, the composition is administered directly to the target site of polymerization. In some embodiments, the composition is directly applied to the site of polymerization. In certain embodiments, the composition is applied to eye wherein polymerization occurs. In some embodiments, the composition is administered indirectly to the target site of polymerization. In certain embodiments, the composition is administered orally and the site of polymerization is within the GI tract. In some embodiments, the composition is administered by intra-articular injection and the site of polymerization is within a joint.
In some embodiments, the composition is administered by a route selected from oral, rectal, injection, sublingual, buccal, vaginal, ocular, otic, inhalation, or cutaneous. In some embodiments, the composition is administered orally. In certain embodiments, the composition is administered by intra-articular injection. In certain embodiments, the composition is administered topically. In certain embodiments, the composition is administered dermally. In certain embodiments, the composition is administered ophthalmically.
In some embodiments, the composition is a liquid or a solid dosage form.
In some embodiments, the composition is in the form of a solution, a gel, a tablet, a powder, a capsule, eye drops, foam, a transdermal patch, or combinations thereof. In some embodiments, the composition is in the form of a solution, a gel, a tablet, or a capsule. In some embodiments, the composition is in the form of a solution. In some embodiments, the composition is in the form of a solution. In some embodiments, the composition is in the form of eye drops. In some embodiments, the composition is in the form of a powder. In some embodiments, the composition is in the form of a transdermal patch.
In some embodiments, the polymer adheres to a tissue of the subject. In certain embodiments, the polymer forms in contact with and adheres to a tissue in the subject. In some embodiments, the polymer adheres to a tissue of the subject
In some embodiments, the location of polymer formation is based on expression levels of the catalyst. In certain embodiments, the polymer forms substantially on a particular tissue based on high expression levels of catalyst. In some embodiments, the polymer does not substantially form on a particular tissue due to low expression levels of catalyst. In some embodiments, the location of polymer formation is based on expression levels of catalase. In certain embodiments, the polymer forms substantially on a particular tissue based on expression levels of catalase. In some embodiments, the polymer does not substantially form on a particular tissue due to low expression levels of catalase.
In certain embodiments, the polymer forms on and adheres to tissue in one or more of the respiratory, urinary, lymphatic, circulatory, integumentary system, skeletal, muscular, nervous, digestive, or endocrine systems. In certain embodiments, the polymer forms in contact with and adheres to one or more of the dorsal portion of the tongue, buccal mucosa, labial mucosa, palate, nasal mucosa, conjunctiva, hypodermis, muscle, trachea mucosa, lung surface, lung tissue, gallbladder mucosa, gallbladder serosa, tunica intima, cartilage, lymph node, bladder mucosa, bladder serosa, kidney surface, kidney tissue, endocardium, myocardium, pancreas tissue, nerve, liver surface, liver tissue, spleen tissue, small intestine, colon, ventral tongue, sclera, epidermis, bladder serosa, epicardium, liver surface, esophagus, peritoneum, or stomach. In some embodiments, the polymer forms in or on the dorsal portion of the tongue, buccal mucosa, labial mucosa, palate, nasal mucosa, conjunctiva, hypodermis, muscle, trachea mucosa, lung surface, lung tissue, gallbladder mucosa, gallbladder serosa, tunica intima, cartilage, lymph node, bladder mucosa, bladder serosa, kidney surface, kidney tissue, endocardium, myocardium, pancreas tissue, nerve, liver surface, liver tissue, spleen tissue, small intestine, or colon. In some embodiments, the polymer forms in or on the trachea, lung, kidney, bladder, lymph node, heart, blood vessel, skin, cartilage, muscle, nerve, mouth, liver, spleen, gallbladder, pancreas, or small bowel. In certain embodiments, the polymer forms on one or more of the tongue, the buccal mucosa, and the labial mucosa. In some embodiments, the polymer forms on the conjunctiva of the eye. In some embodiments, the polymer forms on cartilage. In some embodiments, polymer forms on cartilage in a joint.
In some embodiments, the polymer does not substantially form on the ventral site of the tongue. In some embodiments, the polymer does not substantially form on the palate. In some embodiments, the polymer does not substantially form on the sclera. In some embodiments, the polymer does not substantially form on the ventral portion of the tongue, sclera, epidermis, bladder serosa, epicardium, liver surface, esophagus, or stomach. In some embodiments, the polymer does not substantially form on the ventral portion of the tongue, sclera, epidermis, epicardium, esophagus, or stomach.
In certain embodiments, the tissue is epithelium. In some embodiments, the epithelium is intestinal epithelium. In some embodiments, the polymer forms in contact with the epithelium of the subject. In some embodiments, the epithelium is intestinal epithelium. In some embodiments, the polymer forms on the small intestine. In certain embodiments, the polymer forms in the lumen of the small intestine. In certain embodiments, the polymer forms on the epithelium of the duodenum of the subject.
In some embodiments, the polymer forms on the epithelium of the gastrointestinal tract of the subject. In some embodiments, the polymer forms on the epithelium of the small intestine of the subject.
In some embodiments, the polymer does not form on the epithelium of the gastrointestinal tract outside the small intestine of the subject.
In some embodiments, the polymer forms on the epithelium of one or more of the duodenum, the jejunum, the ileum, the colon, the esophagus, or the stomach of the subject. In some embodiments, the polymer forms on the epithelium of the duodenum of the subject. In some embodiments, the polymer forms on the epithelium of the jejunum of the subject. In some embodiments, the polymer forms on the epithelium of the ileum of the subject. In some embodiments, the polymer forms on the epithelium of the colon of the subject.
In some embodiments, the polymer does not substantially form on the epithelium of one or more of the esophagus or stomach of the subject. In some embodiments, substantially no polymer forms on the stomach and the esophagus of the subject. In some embodiments, polymer does not form on the stomach and the esophagus of the subject.
In some embodiments, less is polymer formed on the ileum and the colon of the subject as compared to the duodenum and the jejunum of the subject.
In some embodiments, the polymer forms on the villi of the epithelium of the subject.
In some embodiments, the polymer binds with chemical moieties exposed on the surface of tissue in the respiratory, urinary, lymphatic, circulatory, integumentary system, skeletal, muscular, nervous, digestive, or endocrine system. In some embodiments, the polymer binds with amine moieties exposed on the surface of tissue in the respiratory, urinary, lymphatic, circulatory, integumentary system, skeletal, muscular, nervous, digestive, or endocrine system.
In some embodiments, the polymer binds with amine moieties exposed on the luminal surface of the epithelium of the subject. In some embodiments, the polymer crosslinks with amine moieties exposed on the luminal surface of the epithelium of the subject.
In some embodiments, the polymer is rapidly formed. In some embodiments, the polymer is formed in less than about 20 minutes. In some embodiments, the polymer is formed in less than about 15 minutes. In some embodiments, the polymer is formed in less than about 12 minutes. In some embodiments, the polymer is formed in less than about 10 minutes. In some embodiments, the polymer is formed in less than about 5 minutes. In some embodiments, the polymer is formed in less than about 3 minutes. In some embodiments, the polymer is formed in less than about 2 minutes. In some embodiments, the polymer is formed in less than about 1 minute. In some embodiments, the polymer forms almost instantly.
In some embodiments, the rate of polymerization increases by at least 10 times as compared to polymer formation without endogenous catalase. In some embodiments, the rate of polymerization increases by at least 50 times as compared to polymer formation without endogenous catalase. In some embodiments, the rate of polymerization increases by at least 100 times as compared to polymer formation without endogenous catalase. In some embodiments, the rate of polymerization increases by at least 150 times as compared to polymer formation without endogenous catalase. In some embodiments, the rate of polymerization increases by at least 200 times as compared to polymer formation without endogenous catalase.
In some embodiments, the polymer forms a temporary barrier in vivo. In some embodiments, the polymer forms a transient barrier in vivo.
In some embodiments, the polymer lasts for about 30 minutes. In some embodiments, the polymer lasts for about 1 hour. In some embodiments, the polymer lasts for about 6 hours. In some embodiments, the polymer lasts for about 12 hours. In some embodiments, the polymer lasts for about 24 hours.
In some embodiments, about 20 to about 70% of the transient barrier remains after 12 hours. In some embodiments, about 30 to about 50% of the transient barrier remains after 12 hours. In some embodiments, about 20% of the transient barrier remains after 12 hours. In some embodiments, about 20 to about 70% of the transient barrier remains after 6 hours. In some embodiments, about 30 to about 50% of the transient barrier remains after 6 hours. In some embodiments, about 20% of the transient barrier remains after 6 hours. In some embodiments, about 20 to about 70% of the transient barrier remains after 3 hours. In some embodiments, about 30 to about 50% of the transient barrier remains after 3 hours. In some embodiments, about 20% of the transient barrier remains after 3 hours.
In some embodiments, the polymer is cleared from the subject after about 3 hours. In some embodiments, the polymer is cleared from the subject after about 6 hours. In some embodiments, the polymer is cleared from the subject after about 12 hours. In some embodiments, the polymer is cleared from the subject after about 24 hours. In some embodiments, the polymer is cleared from the subject after about 48 hours.
In some embodiments, the polymer barrier provides for selective molecular transport in the patient.
In some embodiments, the method is a method of modulating diffusion in the subject at the site of polymerization. In some embodiments, the method modulates diffusion of one or more of a salt, an ion, water, oxygen, carbon dioxide, carbonate anion, an acid, a base, a carbohydrate, a lipid, a protein, a nucleic acid, a nutrient, or an active pharmaceutical agent in the subject.
In some embodiments, polymer modulates absorption of one or more nutrients or active pharmaceutical agents within the small intestine.
In some embodiments, polymer substantially impedes absorption of one or more nutrients to the epithelium on which the polymer is formed, to the intestinal wall of the subject, or to the blood stream of the subject.
In some embodiments, the method is a method of delivering an agent to the subject. In some embodiments, the agent is an active pharmaceutical agent. In some embodiments, the agent is an enzyme. In some embodiments, the agent is a radioprotective agent.
In some embodiments, the method enables sustained release of the agent in the subject. In some embodiments, the agent is an active pharmaceutical agent. In some embodiments, the agent is an enzyme. In some embodiments, the agent is a radioprotective agent. In certain embodiments, the method enables sustained release of an active pharmaceutical agent in the eye conjunctiva. In certain embodiments, n the method enables sustained release of an active pharmaceutical agent in cartilage. In certain embodiments, the method enables sustained release of an active pharmaceutical agent in the oral cavity.
In some embodiments, the method is a method of immobilizing an agent in a subject. In some embodiments, the agent is an active pharmaceutical agent. In some embodiments, the agent is an enzyme. In some embodiments, the agent is a radioprotective agent.
In some embodiments, the method is a method of localized delivery of an agent in a subject. In some embodiments, the agent is an active pharmaceutical agent. In some embodiments, the agent is an enzyme. In some embodiments, the agent is a radioprotective agent.
In some embodiments, the method is a method of reducing the dosing frequency of the agent. In some embodiments, the agent is an active pharmaceutical agent. In some embodiments, the agent is an enzyme. In some embodiments, the agent is a radioprotective agent.
In some embodiments, the method is a method of increasing the half-life of the agent in the subject. In some embodiments, the agent is an active pharmaceutical agent. In some embodiments, the agent is an enzyme. In some embodiments, the agent is a radioprotective agent.
In some embodiments, the method is a method of increasing residence time of the agent in the subject. In some embodiments, the agent is an active pharmaceutical agent. In some embodiments, the agent is an enzyme. In some embodiments, the agent is a radioprotective agent.
In some embodiments, the method is a method of treating or preventing a disease in a subject. In some embodiments, the method is a method of treating a disease in a subject. In some embodiments, the method is a method of preventing a disease in a subject.
In some embodiments, the method is a method of aiding in tissue recovery and regeneration in the subject at the site of polymerization. In some embodiments, the method is a method of aiding in tissue recovery in the subject at the site of polymerization. In some embodiments, the method is a method of aiding in tissue regeneration in the subject at the site of polymerization.
In some embodiments, the method causes the intestinal lumen of the subject to remain expanded.
In some embodiments, the method is a method of preventing a bowel adhesion in the subject.
In some embodiments, the method is a method of preventing a bowel obstruction in the subject.
In some embodiments, the method is a method of treating bleeding in the subject. In some embodiments, bleeding is in the upper GI tract.
In some embodiments, the polymer and composition further comprises an enzyme. In some embodiments, the enzyme is a digestive enzyme. In some embodiments, the digestive enzyme is lactase, peptidase, sucrase, maltase, amylase, a lipase, or a protease. In some embodiments, the digestive enzyme is β-galactosidase.
In some embodiments, the method is a method of improving digestion efficiency by the subject.
In some embodiments, the method is a method of augmenting digestion of a sugar by the subject. In some embodiments, the method is a method of augmenting digestion of lactose by the subject.
In some embodiments, the method is a method of treating lactose intolerance in the subject.
In some embodiments, the enzyme improves digestion efficiency of a sugar of the subject by about 5 times. In some embodiments, the enzyme improves digestion efficiency of a sugar of the subject by about 10 times. In some embodiments, the enzyme improves digestion efficiency of a sugar of the subject by about 20 times. In some embodiments, the enzyme improves digestion efficiency of lactose of the subject by about 40 times. In some embodiments, the enzyme improves digestion efficiency of a sugar of the subject by about 50 times.
In some embodiments, β-galactosidase improves digestion efficiency of lactose of the subject by about 5 times. In some embodiments, β-galactosidase improves digestion efficiency of lactose of the subject by about 10 times. In some embodiments, β-galactosidase improves digestion efficiency of lactose of the subject by about 20 times. In some embodiments, β-galactosidase improves digestion efficiency of lactose of the subject by about 40 times. In some embodiments, β-galactosidase improves digestion efficiency of lactose of the subject by about 50 times.
In some embodiments, the polymer barrier does not inhibit the intrinsic digestive enzyme activity of the epithelium of the subject.
In some embodiments, the polymer and composition further comprises a nutrient blocker.
In some embodiments, the method is a method of preventing nutrient absorption in the subject.
In some embodiments, the method is a method of modulating or regulating sugar absorption by the subject. In some embodiments, the sugar is selected from glucose, lactose, fructose, maltose, dextrose, galactose, sucrose, and isomaltose. In some embodiments, the method is a method of modulating or regulating glucose absorption by the subject.
In some embodiments, the method prevents absorption for less than about 48 hours. In some embodiments, the method prevents absorption for less than about 24 hours. In some embodiments, the method prevents absorption for less than about 12 hours. In some embodiments, the method prevents absorption for less than about 6 hours. In some embodiments, the method prevents absorption for less than about 3 hours.
In some embodiments, the method is a method of treating obesity in the subject.
In some embodiments, the method is a method of treating hyperinsulinemia in the subject.
In some embodiments, the method is a method of treating diabetes mellitus in the subject. In some embodiments, the diabetes mellitus is type 2 diabetes mellitus.
In some embodiments, the method is a method of treating non-alcoholic fatty liver disease. In some embodiments, the method is a method of treating nonalcoholic steatohepatitis.
In some embodiments, the composition further comprises a crosslinking agent.
In some embodiments, the crosslinking agent comprises a nanoparticle. In some embodiments, the crosslinking agent comprises polydopamine. In some embodiments, the crosslinking agent is a nutrient blocker. In some embodiments, the crosslinking agent improves the nutrient blocking ability of the polymer.
In some embodiments, glucose absorption is modulated by tuning the crosslinking density of polymer.
In some embodiments, the method reduces glucose absorption by the subject by at least about 50%, at least about 60%, or at least about 70% for a period of 3 hours following administration of the composition. In some embodiments, the method reduces glucose absorption by the subject by at least about 70% for a period of 3 hours following administration of the composition. In some embodiments, the method reduces glucose absorption by the subject by at least about 50%, at least about 60%, or at least about 70% for a period of 2 hours following administration of the composition. In some embodiments, the method reduces glucose absorption by the subject by at least about 50%, at least about 60%, or at least about 70% for a period of 1 hours following administration of the composition.
In some embodiments, the method is a method of regulating or modulating nutrient uptake by the subject.
In some embodiments, the composition further comprises an active pharmaceutical agent. In some embodiments, the active pharmaceutical agent treats an infectious disease. In some embodiments, the active pharmaceutical agent is an antiparasitic drug. In some embodiments, the active pharmaceutical agent is an anthelmintic drug. In some embodiments, the active pharmaceutical agent is praziquantel. In some embodiments, the active pharmaceutical agent is an antiviral drug. In some embodiments, the active pharmaceutical agent treats influenza. In some embodiments, the active pharmaceutical agent treats SARS-CoV-2.
In certain embodiments, the active pharmaceutical ingredient is a contraceptive, a statin, an anti-hypertensive, or an antibiotic.
In some embodiments, the active pharmaceutical agent treats psychiatric disorders, Alzheimer's disease, infection diseases, or transplant rejection.
In some embodiments, the active pharmaceutical agent treats type 2 diabetes.
In some embodiments, the active pharmaceutical agent treats non-alcoholic fatty liver disease. In some embodiments, the active pharmaceutical agent treats nonalcoholic steatohepatitis.
In some embodiments, the active pharmaceutical agent treats ocular diseases.
In some embodiments, the active pharmaceutical agent treats Crohn's disease.
In some embodiments, the active pharmaceutical agent treats osteoarthritis.
In some embodiments, the active pharmaceutical agent treats Alzheimer's disease.
In some embodiments, the active pharmaceutical agent is an anti-cancer agent. Anti-cancer agents encompass biotherapeutic anti-cancer agents as well as chemotherapeutic agents. Exemplary biotherapeutic anti-cancer agents include, but are not limited to, interferons, cytokines (e.g., tumor necrosis factor, interferon α, interferon γ), vaccines, hematopoietic growth factors, monoclonal serotherapy, immunostimulants and/or immunodulatory agents (e.g., IL-1, 2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF) and antibodies (e.g. HERCEPTIN (trastuzumab), T-DM1, AVASTIN (bevacizumab), ERBITUX (cetuximab), VECTIBIX (panitumumab), RITUXAN (rituximab), BEXXAR (tositumomab)). Exemplary chemotherapeutic agents include, but are not limited to, anti-estrogens (e.g. tamoxifen, raloxifene, and megestrol), LHRH agonists (e.g. goscrclin and leuprolide), anti-androgens (e.g. flutamide and bicalutamide), photodynamic therapies (e.g. vertoporfin (BPD-MA), phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A (2BA-2-DMHA)), nitrogen mustards (e.g. cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g. carmustine (BCNU) and lomustine (CCNU)), alkylsulphonates (e.g. busulfan and treosulfan), triazenes (e.g. dacarbazine, temozolomide), platinum containing compounds (e.g. cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g. vincristine, vinblastine, vindesine, and vinorelbine), taxoids (e.g. paclitaxel or a paclitaxel equivalent such as nanoparticle albumin-bound paclitaxel (ABRAXANE), docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin), polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX), the tumor-activated prodrug (TAP) ANG1005 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognizing peptide EC-1), and glucose-conjugated paclitaxel, e.g., 2′-paclitaxel methyl 2-glucopyranosyl succinate; docetaxel, taxol), epipodophyllins (e.g. etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, mytomycin C), anti-metabolites, DHFR inhibitors (e.g. methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g. mycophenolic acid, tiazofurin, ribavirin, and EICAR), ribonuclotide reductase inhibitors (e.g. hydroxyurea and deferoxamine), uracil analogs (e.g. 5-fluorouracil (5-FU), floxuridine, doxifluridine, ratitrexed, tegafur-uracil, capecitabine), cytosine analogs (e.g. cytarabine (ara C), cytosine arabinoside, and fludarabine), purine analogs (e.g. mercaptopurine and Thioguanine), Vitamin D3 analogs (e.g. EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (e.g. lovastatin), dopaminergic neurotoxins (e.g. 1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g. staurosporine), actinomycin (e.g. actinomycin D, dactinomycin), bleomycin (e.g. bleomycin A2, bleomycin B2, peplomycin), anthracycline (e.g. daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDR inhibitors (e.g. verapamil), Ca2+ ATPase inhibitors (e.g. thapsigargin), imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN™, AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib (TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT®, SU11248), toceranib (PALLADIA®), vandetanib (ZACTIMA®, ZD6474), vatalanib (PTK787, PTK/ZK), trastuzumab (HERCEPTIN®), bevacizumab (AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib (NEXAVAR®), everolimus (AFINITOR®), alemtuzumab (CAMPATH®), gemtuzumab ozogamicin (MYLOTARG®), temsirolimus (TORISEL®), ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK™), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and/or XL228), proteasome inhibitors (e.g., bortezomib (VELCADE)), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OSI-027 (OSI)), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone, dexamethasone, campathecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, melphalan, leurosidine, leurosine, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin, aminopterin, and hexamethyl melamine.
In certain embodiments, the active pharmaceutical agent is selected from the group including, but not limited to, anti-proliferative agents, anti-cancer agents, anti-angiogenesis agents, anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, and pain-relieving agents. In certain embodiments, the active pharmaceutical agent is an anti-proliferative agent. In certain embodiments, the active pharmaceutical agent is an anti-cancer agent. In certain embodiments, the active pharmaceutical agent is an anti-viral agent.
Exemplary active pharmaceutical agents include, but are not limited to, antibiotics, anti-viral agents, anesthetics, anti-coagulants, inhibitors of an enzyme, steroidal agents, steroidal or non-steroidal anti-inflammatory agents, antihistamine, immunosuppressant agents, antigens, vaccines, antibodies, decongestant, sedatives, opioids, pain-relieving agents, analgesics, anti-pyretics, hormones, and prostaglandins, etc. Active pharmaceutical agent include small organic molecules such as drug compounds (e.g., compounds approved by the US Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells.
In certain embodiments, the active pharmaceutical agent is an antibiotic. Exemplary antibiotics include, but are not limited to, penicillins (e.g., penicillin, amoxicillin), cephalosporins (e.g., cephalexin), macrolides (e.g., erythromycin, clarithormycin, azithromycin, troleandomycin), fluoroquinolones (e.g., ciprofloxacin, levofloxacin, ofloxacin), sulfonamides (e.g., co-trimoxazole, trimethoprim), tetracyclines (e.g., tetracycline, chlortetracycline, oxytetracycline, demeclocycline, methacycline, sancycline, doxycline, aureomycin, terramycin, minocycline, 6-deoxytetracycline, lymecycline, meclocycline, methacycline, rolitetracycline, and glycylcycline antibiotics (e.g., tigecycline)), aminoglycosides (e.g., gentamicin, tobramycin, paromomycin), aminocyclitol (e.g., spectinomycin), chloramphenicol, sparsomycin, quinupristin/dalfoprisin (Syndercid™). In certain embodiments, the antibiotic is a ribosome-targeting antibiotic.
In some embodiments, the active pharmaceutical agent is retained or encapsulated in the polymer. In some embodiments, the active pharmaceutical agent is retained on the polymer.
In some embodiments, the method is a method of prolonging the residence time of an active pharmaceutical agent in the subject as compared to the administration of the active pharmaceutical agent in the absence of the polymer. In some embodiments, the method is a method of prolonging the residence time of an active pharmaceutical agent at the site of polymerization in the subject as compared to the administration of the active pharmaceutical agent in the absence of the polymer.
In some embodiments, the method is a method of providing for sustained release of an active pharmaceutical agent as compared to the administration of the active pharmaceutical agent in the absence of the polymer.
In some embodiments, the method is a method of reducing the dosing frequency of an active pharmaceutical agent as compared to the administration of the active pharmaceutical agent in the absence of the polymer. In some embodiments, the dosing frequency is once per day. In some embodiments, the dosing frequency is twice per day.
In some embodiments, the method is a method of increasing the half-life of the active pharmaceutical agent as compared to the administration of the active pharmaceutical agent in the absence of the polymer. In some embodiments, the method increases the half-life of the active pharmaceutical agent by at least about 2-fold as compared to the administration of the active pharmaceutical agent in the absence of the polymer. In some embodiments, the method increases the half-life of the active pharmaceutical agent by at least about 4-fold as compared to the administration of the active pharmaceutical agent in the absence of the polymer. In some embodiments, the method increases the half-life of the active pharmaceutical agent by at least about 6-fold as compared to the administration of the active pharmaceutical agent in the absence of the polymer. In some embodiments, the method increases the half-life of the active pharmaceutical agent by at least about 10-fold as compared to the administration of the active pharmaceutical agent in the absence of the polymer.
In some embodiments, the method is a method of increasing the AUC of the active pharmaceutical agent as compared to the administration of the active pharmaceutical agent in the absence of the polymer. In some embodiments, the method increases the AUC by at least about 2-fold as compared to the administration of the active pharmaceutical agent in the absence of the polymer. In some embodiments, the method increases the AUC by at least about 3-fold as compared to the administration of the active pharmaceutical agent in the absence of the polymer. In some embodiments, the method increases the AUC by at least about 4-fold as compared to the administration of the active pharmaceutical agent in the absence of the polymer.
In some embodiments, the method is a method of modulating the Cmax of the active pharmaceutical agent as compared to the administration of the active pharmaceutical agent in the absence of the polymer. In certain embodiments, the method of modulating is increasing. In certain embodiments, the method of modulating is decreasing.
In some embodiments, the method is a method of modulating the Tmax of the active pharmaceutical agent as compared to the administration of the active pharmaceutical agent in the absence of the polymer. In certain embodiments, the method of modulating is increasing. In certain embodiments, the method of modulating is decreasing.
In some embodiments, the method does not affect drug metabolism once the active pharmaceutical agent is absorbed by the small intestine.
In some embodiments, the method is a method of treating schistosomiasis in the subject.
In some embodiments, the composition further comprises a radioprotective agent. In certain embodiments, the radioprotective agent is an antioxidant, a thiol-containing compound, or a nitroxide. In certain embodiments, the radioprotective agent is thalidomide, cysteine, amifostine, palifermin, or 1-carnitine. In certain embodiments, the radioprotective agent is thalidomide.
In some embodiments, the nutraceutical agent is vitamin D or iron.
In some embodiments, the method provides for targeting the small intestine.
In some embodiments, the method is a method of decreasing uptake by the small intestine. In some embodiments, the method is a method of decreasing uptake of one or more nutrients and active pharmaceutical agents by the small intestine. In some embodiments, the method is a method of decreasing uptake of one or more nutrients by the small intestine. In some embodiments, the method is a method of decreasing uptake of one or more active pharmaceutical agents by the small intestine.
In some embodiments, the method is a method of increasing residence time in the small intestine. In some embodiments, the method is a method of increasing residence time of one or more of nutrients and active pharmaceutical agents in the small intestine. In some embodiments, the method is a method of increasing residence time of one or more of nutrients in the small intestine. In some embodiments, the method is a method of increasing residence time of one or more active pharmaceutical agents in the small intestine.
In some embodiments, the method causes the intestinal lumen to remain expanded.
In some embodiments, the method is a method of treating or preventing a bowel adhesion in the subject. In some embodiments, the method is a method of preventing a bowel adhesion in the subject.
In some embodiments, the method is a method of treating or preventing bowel obstruction in the subject. In some embodiments, the method is a method of preventing bowel obstruction in the subject.
In some embodiments, the method is a method of treating bleeding in the subject. In some embodiments, the method is a method of treating bleeding in the small intestine of the subject. In some embodiments the bleeding is in the upper GI tract. In some embodiments, the bleeding is in the stomach. In some embodiments, the method of treating bleeding is a method of treating hemo stasis.
In some embodiments, the polymer modulates absorption within the small intestine. In some embodiments, the polymer modulates absorption of one or more nutrients or active pharmaceutical agents, or combinations thereof, within the small intestine. In some embodiments, the polymer modulates absorption of one or more nutrients and active pharmaceutical agents within the small intestine. In some embodiments, the polymer modulates absorption of one or more nutrients within the small intestine. In some embodiments, the polymer modulates absorption of one or more active pharmaceutical agents within the small intestine.
In some embodiments, the polymer modulates digestion within the small intestine. In some embodiments, the polymer modulates digestion of one or more nutrients within the small intestine.
In certain embodiments, the polymer substantially impedes absorption by the small intestine. In some embodiments, the polymer substantially impedes absorption of one or more nutrients or active pharmaceutical agents, or combinations thereof, to the epithelium on which the polymer is formed. In some embodiments, the polymer substantially impedes absorption of one or more nutrients to the epithelium on which the polymer is formed. In some embodiments, the polymer substantially impedes absorption of one or more active pharmaceutical agents to the epithelium on which the polymer is formed.
In some embodiments, the polymer substantially impedes absorption of one or more nutrients or active pharmaceutical agents, or combinations thereof, to the intestinal wall of the subject. In some embodiments, the polymer substantially impedes absorption of one or more nutrients to the intestinal wall of the subject. In some embodiments, the polymer substantially impedes absorption of one or more active pharmaceutical agents to the intestinal wall of the subject.
In some embodiments, the polymer substantially impedes absorption of one or more nutrients or active pharmaceutical agents, or combinations thereof, to the blood stream of the subject. In some embodiments, the polymer substantially impedes absorption of one or more nutrients to the blood stream of the subject. In some embodiments, the polymer substantially impedes absorption of one or more active pharmaceutical agents to the blood stream of the subject.
In some embodiments, the method is a method of immobilizing an enzyme in a subject.
In some embodiments, the method is a method of delivering an active pharmaceutical agent to the subject.
In some embodiments, the method is a method of supplementing the digestion in a subject.
In some embodiments, the polymer induces blood gelation. In certain embodiments, the polymer induces coagulation. In some embodiments, the composition is in the form of a powder. In certain embodiments, the method comprises spraying the powder onto an affected area on or within the subject.
In some embodiments, the composition is administered via a scope. In certain embodiments, the composition is administered via an endoscope, arthroscope, cystoscope, colposcope, colonoscope, bronchoscope, ureteroscope, anoscope, esophago scope, gastroscope, laparoscope, laryngoscope, neuroendoscope, proctoscope, sigmoidoscope, or thoracoscope.
In some embodiments, the polymer is nontoxic. In some embodiments, the composition is nontoxic. In some embodiments, the composition and its components are nontoxic.
In some embodiments, the polymer is stable to physical and chemical forces. In some embodiments, the polymer is stable to one or more of intestinal fluid, intestinal acid, gastric acid, chyme, ethanol, and saline. In some embodiments, the polymer decomposes by less than about 25% upon exposure to one or more of intestinal fluid, intestinal acid, gastric acid, chyme, ethanol, or saline. In some embodiments, the polymer decomposes by less than about 20% upon exposure to one or more of intestinal fluid, intestinal acid, gastric acid, chyme, ethanol, or saline. In some embodiments, the polymer decomposes by less than about 10% upon exposure to one or more of intestinal fluid, intestinal acid, gastric acid, chyme, ethanol, or saline. In some embodiments, the polymer decomposes by less than about 5% upon exposure to one or more of intestinal fluid, intestinal acid, gastric acid, chyme, ethanol, or saline. In some embodiments, the physical forces are selected from one or more of peristalsis and segmentation.
In another aspect, the disclosure provides a method of treating a disease or disorder comprising administering an effective amount of a composition as described herein to a subject in need thereof.
Further provided by the disclosure is a method of preventing a disease or disorder comprising administering an effective amount of a composition as described herein to a subject in need thereof.
In some embodiments, the disease or disorder is an eye disease, a joint disease, a metabolic disorder, a systemic disease, a digestive disorder, cancer, bleeding, an ulcer, a bowel obstruction, an infectious disease, mesenteric ischemia, obesity, a psychiatric disorder, Alzheimer's disease, or transplant rejection. In some embodiments, the disease or disorder is an eye disease, a joint disease, a metabolic disorder, a systemic disease, a digestive disease, cancer, bleeding, an ulcer, a bowel obstruction, an infectious disease, mesenteric ischemia, or obesity. In some embodiments, the disease or disorder is a psychiatric disorder, Alzheimer's disease, or transplant rejection.
In some embodiments, the disease is cancer. Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett's adenocarcinoma); Ewing's sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenström's macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia/lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget's disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).
In some embodiments, the disease is glaucoma.
In some embodiments, the metabolic disorder is hyperinsulinemia.
In some embodiments, the digestive disease is Crohn's disease, ulcerative colitis, malabsorption, inflammatory bowel disease, irritable bowel syndrome, lactose intolerance, or Celiac disease. In some embodiments, the disease is Crohn's disease.
In some embodiments, the disease is a psychiatric disorder.
In some embodiments, the disease is Alzheimer's disease.
In some embodiments, the disorder is transplant rejection.
In some embodiments, the systemic disease is an autoimmune disease. Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodpasture's syndrome, necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemic lupus erythematosis, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosis, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis/polymyositis, anti-phospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener's granulomatosis, microscopic polyangiitis), uveitis, Sjogren's syndrome, Crohn's disease, Reiter's syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, and cardiomyopathy.
In some embodiments, the systemic disease is mastocytosis, chronic fatigue syndrome, systemic vasculitis, sarcoidosis, hypothyroidism, diabetes, fibromyalgia, adrenal insufficiency, celiac disease, ulcerative colitis, Crohn's disease, hypertension, metabolic syndrome, AIDS, Graves' disease, systemic lupus erythematosus, arthritis, atherosclerosis, sickle cell disease, myasthenia gravis, systemic sclerosis, inflammatory disease, or sinusitis.
In some embodiments, the disease is an inflammatory disease. Inflammatory diseases include, without limitation, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren's syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto's thyroiditis, Graves' disease, Goodpasture's disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, pernicious anemia, inflammatory dermatoses, usual interstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener's granulomatosis and related forms of angiitis (temporal arteritis and polyarteritis nodosa), inflammatory dermatoses, hepatitis, delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory tract inflammation, Adult Respiratory Distress Syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hayfever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host-versus-graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis. An ocular inflammatory disease includes, but is not limited to, post-surgical inflammation. In some embodiments, the disease is an inflammatory joint disease. In some embodiments, the disease is arthritis. In certain embodiments, the disease is osteoarthritis. In some embodiments, the disease is rheumatoid arthritis.
In some embodiments, the disease is conjunctivitis.
In some embodiments, the disease is aphthous stomatitis.
In some embodiments, the disease is obesity, hyperinsulinemia, or diabetes. In some embodiments, the disease is obesity. In some embodiments, the disease is hyperinsulinemia. In some embodiments, the disease is diabetes. In some embodiments, the disease is type 2 diabetes. In some embodiments, the disease is non-alcoholic fatty liver disease. In some embodiments, the disease is nonalcoholic steatohepatitis.
In some embodiments, the disease is an infectious disease. In some embodiments, the disease is a bacterial, viral, fungal, or parasitic infection. In some embodiments, the disease is a parasitic disease. In some embodiments, the disease is giardiasis, ascariasis, or a tape worm infection. In some embodiments, the disease is schistosomiasis. In some embodiments, the disease is a viral infection. In some embodiments, the disease is influenza. In some embodiments, the disease is SARS-CoV-2 (COVID-19).
In some embodiments, the disease is lactose intolerance.
In certain embodiments, the disease or disorder is a mucosal injury. In some embodiments, the mucosal injury is caused by external agents. In certain embodiments, the mucosal injury is associated with radiation or chemotherapy. In certain embodiments, the mucosal injury is caused by radiation or chemotherapy. In some embodiments, the disease or disorder is mucositis.
In some embodiments, the disorder is a bowel obstruction. In some embodiments, the disorder is a bowel adhesion. In certain embodiments, the methods and compositions described herein prevent re-adhesion and/or re-obstruction of the bowel.
In some embodiments, the disease is trauma.
In some embodiments, the disease is Alzheimer's disease.
In certain embodiments, the polymers and compositions provided herein are contraceptives.
In certain embodiments, the disease is trauma.
In another aspect, the disclosure provides for the use of a composition to form a polymer in vivo comprising administering to a subject a composition comprising a monomer and an oxygen source, wherein the monomer and the oxygen source contact a catalyst endogenous to the subject in vivo and the catalyst polymerizes the monomer, or salt thereof, in situ, and wherein the oxygen source is hydrogen peroxide or urea hydrogen peroxide, and endogenous catalyst is selected from a catalase or a peroxidase. In embodiments, the provided is the use of a composition to form a polymer in vivo comprising administering to a subject a composition comprising a monomer and an oxygen source, wherein the monomer and the oxygen source contact a catalyst endogenous to the subject in vivo and the catalyst polymerizes the monomer, or salt thereof, in situ, and wherein the endogenous catalyst is selected from a catalase or a peroxidase.
In one aspect, the disclosure provides for the use of an effective amount of a composition as described herein to treat a disease or disorder in a subject in need thereof.
In a further aspect, the disclosure provides for the use of an effective amount of a composition as described herein to prevent a disease or disorder in a subject in need thereof.
Compositions
In certain aspects, further provided herein are compositions comprising a monomer, an oxygen source, optionally a buffer, and optionally, an agent. In some embodiments, the composition further comprises an exogenous catalyst.
In some embodiments, the composition comprises a monomer selected from dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, levodopa ethyl ester, or a monomer comprising: dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, or levodopa ethyl ester; and a macromolecule selected from one or more of alginate, hyaluronic acid, polyacrylic acid, polyethylene glycol, chondroitin sulfate, or chitosan; an oxygen source; optionally, a buffer; and optionally, an agent. In some embodiments, the agent is selected from an active pharmaceutical agent, a cosmetic agent, a nutraceutical agent, an imaging agent, a radioprotective agent, a nutraceutical, an enzyme, an aptamer, an antibody, a neutralizing agent, or a nutrient blocker.
In some embodiments, the composition comprises about 0.001 to about 1000 mg/mL monomer, about 0.01 to about 100 mM of the oxygen source, and optionally, a buffer.
In some embodiments, the composition comprises about 0.001 to about 1000 mg/mL of monomer. In some embodiments, the composition comprises about 0.001 to about 500 mg/mL of monomer. In some embodiments, the composition comprises about 0.01 to about 100 mg/mL of monomer. In some embodiments, the composition comprises about 1 to about 20 mg/mL of monomer. In some embodiments, the composition comprises about 10 mg/mL of monomer. In some embodiments, the composition comprises about 20 mg/mL of monomer.
In some embodiments, the composition comprises 10 mg/mL of a monomer selected from Table 1. In certain embodiments, the composition comprises 10 mg/mL of a monomer selected from Table 1 and 10 mg/mL of a monomer selected from Table 2. In certain embodiments, the composition comprises 10 mg/mL of a monomer selected from Table 1 and 5 mg/mL each of two separate monomers selected from Table 2.
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 oxygen source compatible with ingestion by the subject.
In some embodiments, the composition has a pH of about 7 to about 10. In some embodiments, the composition has a pH of about 7 to about 9. In some embodiments, the composition has a pH of about 8.5. In some embodiments, the composition has a pH of about 7.4.
In some embodiments, the composition comprises about 10 mg/mL of monomer, about 20 mM hydrogen peroxide or urea hydrogen peroxide, and optionally, a buffer. In some embodiments, the composition comprises about 20 mg/mL of monomer(s), about 20 mM hydrogen peroxide or urea hydrogen peroxide, 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.
In some embodiments, the composition is a liquid or solid dosage form. In some embodiments, the composition is in the form of a solution, a foam, a gel, a tablet, or a capsule, or combinations thereof.
In another aspect, the disclosure provide a method of treating bleeding, comprising administering an effective amount of a composition as described herein to a subject in need thereof. In some embodiments, the bleeding is in the upper GI tract. In certain embodiments, the bleeding is in the stomach. In some embodiments the method of treating bleeding is a method of treating hemo stasis.
Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise a composition described herein and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container).
The disclosure also provides kits. In one aspect, the disclosure provides a kit comprising: a composition as described herein, and instructions for administering the composition to a subject. In some embodiments, the composition comprises: a monomer as described herein; an oxygen source as described herein; optionally, a buffer as described herein; and optionally, one or more agents as described herein. In some embodiments, the composition comprises: a monomer; an oxygen source; optionally, a buffer; and optionally, one or more agents; and instructions for administering the monomer, and the oxygen source, and optionally the buffer and/or the one or more agents to a subject, such that the monomer and oxygen source contact a catalyst endogenous to the subject in vivo, and wherein the catalyst polymerizes the monomer in situ. In some embodiments, the kit further comprises an exogenous catalyst.
In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a composition described herein. In some embodiments, the composition described herein provided in the first container and the second container are combined to form one unit dosage form.
Thus, in one aspect, provided are kits including a first container comprising a composition described herein. In certain embodiments, the kits are useful for treating a disease in a subject in need thereof. In certain embodiments, the kits are useful for preventing a disease in a subject in need thereof. In certain embodiments, the kits are useful for reducing the risk of developing a disease in a subject in need thereof.
In certain embodiments, a kit described herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for treating a disease in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease (in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing a disease in a subject in need thereof. A kit described herein may include one or more additional agents described herein as a separate composition.
The methods and uses described herein comprise administering to a subject an effective amount of a composition comprising a monomer and an oxygen source (i.e., to form a polymer in situ (e.g., in order to treat or prevent a disease).
In some embodiments, the composition is administered orally. In some embodiments, the composition is a liquid or a solid dosage form. In some embodiments, the composition is in the form of a solution, a gel, a foam, a tablet, or a capsule, or combinations thereof.
In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is an amount effective for treating an infectious disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing an infectious disease in a subject in need thereof. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is an amount effective for treating a proliferative disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a proliferative disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a hematological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a hematological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a neurological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a neurological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a in a painful condition subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a painful condition in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a psychiatric disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a psychiatric disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a metabolic disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a metabolic disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for reducing the risk of developing a disease (e.g., infectious disease, proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for inhibiting the activity (e.g., aberrant activity, such as increased activity) of an organism in a subject or cell.
In certain embodiments, the subject is an animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject described herein is a human. In some embodiments, the subject is an adult human. In certain embodiments, the subject is a child. In certain embodiments, the subject is a non-human 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 domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. 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 another embodiment, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs). In certain embodiments, the subject is a fish or reptile.
Compositions can 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 the composition comprising a predetermined amount of the agent or active ingredient. The amount of the agent or active ingredient is generally equal to the dosage of the agent or active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.
Although the descriptions of compositions provided herein are principally directed to compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.
Compositions provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific agent or active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific agent or active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific agent or active ingredient employed; and like factors well known in the medical arts.
The compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, ophthalmic, intravaginal, intraperitoneal, topical, mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. Also, contemplated routes are direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). In some embodiments, the route of administration is topical (to skin, eye, ear, mouth, or affected site).
The exact amount of agent or agent or active ingredient required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular agent or active ingredient, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of an agent or active ingredient described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell.
A composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents). The compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof, and/or in inhibiting the activity of an organism in a subject or cell), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects.
The composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies.
In order that the present disclosure may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this Application are offered to illustrate the compounds, pharmaceutical compositions, methods, and uses provided herein and are not to be construed in any way as limiting their scope.
To develop a comprehensive TPA-positive tissue map, fresh tissues from 10 major body systems, including of the respiratory, urinary, lymphatic, circulatory, integumentary, skeletal, muscular, nervous, digestive and endocrine systems (
A combinatorial library of CAT-responsive polymer assemblies was created through three steps: (1) the screening of dopamine analogs to discover additional types of TPA monomers; (2) the conjugation of these TPA monomers onto various polymer backbones to synthesize a series of TPA conjugates and (3) the combination of TPA monomers with TPA conjugates to provide a library of TPA assemblies. The testing solutions contain: 10 mg/ml M1-M6 (one of each), 20 mM H2O2, and 50 mM Tris (pH 8.5). The above solution (180 μl for each and total 6 solutions) were prepared fresh and added into 96-well plates, followed by addition of 10 ul catalase (1 mg/ml). The reaction mixture was maintained at 37° C. Extinction of solutions at 700 nm was measured using a plate reader (Tecan). For the controls, the solutions were kept at 37° C. without adding catalase.
To expand the material combinations of synthetic tissue barriers, monomers other than dopamine were investigated for use in tissue-accelerated polymerization. After screening molecules with similar chemical structures compared to dopamine, five other TPA monomers (M2-M6), including levodopa, norepinephrine, methyldopa, levodopa methyl ester, and levodopa ethyl ester, were discovered as tissue-accelerated polymerization monomers (
Next, these 6 monomers were conjugated with different biocompatible macromolecules, including alginate, hyaluronic acid, polyacrylic acid, polyethylene glycol, chondroitin sulfate, and chitosan, generating a series of TPA-macromolecule conjugates. After conjugation of TPA components onto the backbones of macromolecules, additional physical and biological functions of these macromolecules could be incorporated into TPA molecules. In this study, six different carboxyl-rich macromolecules were chosen (sodium alginate, hyaluronate, polyacrylic acid, polyethylene glycol, chondroitin sulfate and chitosan) and 21 different TPA-macromolecule conjugates were synthesized (C1-C21;
Next, the 6 tissue-accelerated polymerization monomers (M1-M6) and 21 tissue-accelerated polymerization monomers comprising macromolecules (C1-C21) were systematically combined, resulting in crosslinking of multiple polymer networks and the subsequent synthesis of 1,142-membered TPA assemblies. As shown in
To evaluate the therapeutic value of the TPA map and TPA library, three different clinical scenarios are exemplified: improvement of administration efficiency for medications in the eye, protection of epithelium against environmental stresses in the oral cavity, and hemostasis treatment of bleeding in the stomach. The TPA map was utilized as a guide for specific tissue-targeting in multiple different tissue sites including conjunctiva, tongue, buccal, and gastric mucosa. Additionally, the TPA library was applied to develop functional barriers across different therapeutic formulations including liquid drops, composite patches, and sprayable powder. In vivo TPA performance was evaluated in a large animal model, Yorkshire pigs (45-75 kg). It is worth noting that pigs were chosen as the model due to their genomic and anatomic similarities to human body systems30,46.
First, the TPA technology was investigated as a system for ocular drug delivery, showing its ability for sustained release of therapeutics in the eye (e.g., for the treatment of conjunctivitis). Conjunctivitis is an ocular disease caused by inflammation or infection of the conjunctiva that affects millions of people annually and imposes huge economic and social burdens.31 Corticosteroids, such as dexamethasone, are frequently used to treat conjunctivitis, and are recommended to be frequently administered as eye drops six times per day, which can lead to poor patient adherence and increased risk of glaucoma.32-33 The development of ophthalmic sustained-release corticosteroids is limited due to the protective mechanism of the eye, which induces drug spillover, tear production, blinking, and nasolacrimal drainage, causing low bioavailability of corticosteroids. The TPA technology disclosed herein can provide a topically applied, conjunctiva-targeted platform for prolonging conjunctival retention and sustained release of drugs in the eye, reducing dosing frequency, and enhancing medication adherence. The TPA map (
Histological analyses were also performed on the conjunctival epithelium 24 hours after polymer assembly. As shown in
Next, dexamethasone was chosen as the model drug to incorporate into TPA eye drops. The surface of the dexamethasone particles was first coated with M1, which enabled chemical crosslinking and incorporation of M1-coated-dexamethasone into polymer assemblies on the conjunctival surface, washed and lyophilized, then resuspended in a solution of trace amounts of H2O2 and M1. The solution of coated dexamethasone was dark in color due to the suspension of the TP-coated dexamethasone particles. This coating process enables the drug to crosslink within the TP polymer upon exposure to the CAT on the conjunctiva. Ocular drug release studies were carried out using a single ocular administration of TPA-dexamethasone eye drops in pigs. TPA eyedrops containing suspended M1-coated-dexamethasone particles (dark-black color) were administered to the eyes of pigs in the same manner as described above. After administration, isotonic solution was applied to extract the drug from the conjunctival epithelium at various time points. Drug concentration in the extract was analyzed by liquid chromatography-tandem mass spectroscopy. TPA eye drops (
Functional TPA barriers to protect tissues against environmental stresses were developed. The ability of TPA barriers to protect the oral mucosa against chemical and radiation stresses was demonstrated. Oral mucosal diseases, specifically mucositis and aphthous stomatitis, are common ailments that affect numerous people worldwide.34-35 Oral mucositis, the inflammation and ulceration of oral mucosa, is an especially common complication among patients who receive radiotherapy and chemotherapy.34 This inadvertent damage to healthy mucosal tissues may lead to treatment discontinuation, and even result in treatment failure and death.36 In addition to mucositis, aphthous stomatitis can also cause painful inflamed ulcers in the oral cavity.35 The treatment of aphthous stomatitis may take several weeks, during which there are many occasions for exacerbated pain, injury, and reinjury due to abrasion or exposure to acidic or spicy foods or drinks. The application of a TP-patch to an ulcer prior to eating could prevent further injury or rupture. In addition, intraoral radiation for the treatment of oral cavity and oropharyngeal cancer can result in inadvertent damage to surrounding healthy tissues. Lead or low-fusing alloy protective splints are widely implemented to prevent damage to adjacent tissues during radiation treatment. Covering mucosal tissues with different protective TPA barriers could enable blocking of both radiation and chemical (acidic) stresses, improving patient prognosis and quality of life. To enable strong tissue-adhesion and flexible protection, TPA barriers were designed as composite patches (
Additionally, the hydrogel shed from the tongue 24 hours after application (
A variation of the TP-patch was designed for testing with pH paper interfacing with the tissue on the tongue. Upon application of acid to the tongue without the TP-patch, the pH drops to an average of 3. When the TP-patch is adhered and acid applied, the pH remains at levels comparable to that of the control normal pH of the tongue. The resilience of pH levels in the presence of acid with the TP-patch demonstrate the protective capabilities of the TP-patch for resistance against acidic foods that could further irritate ulcers in the mouth.
Next, tissue-adhesion and chemical permeability of the TPA-PVC patches were tested. To validate the blocking function against chemicals, specifically acid, TPA-PVC patches were placed onto the surface of the tongues of sedated pigs, citric acid solution (pH 3) was applied on top of the patches after 15 minutes of application, and the pH of the mucosa underneath the patches was measured to quantify the acid blocking efficiency. As shown in
TPA technology was used to treat upper gastrointestinal bleeding by generating a TPA barrier specifically over the bleeding site in the stomach (
Blood coagulation in Yorkshire pigs in vivo was then tested in a stomach bleeding model. The advantages of using pigs as the large animal model include their extensive homology with the human genome, anatomical similarity to the human gastrointestinal tract, and physiological likeness to the human digestive system. Gastrointestinal endoscopy together with forceps were used to induce the bleeding in the stomach to mimic the acute upper gastrointestinal bleeding. After inducing bleeding, tissue-accelerated polymerization powder (T1 (500 mg), M7 (50 mg), Tris or sodium carbonate or potassium carbonate powder (60 mg), solid urea H2O2 (50 mg)) was continuously sprayed to the bleeding sites through a delivery catheter that was inserted inside the working channel of the endoscopy. The end of the spray device was connected with compressed air setup to propel the tissue-accelerated polymerization powder out of the catheter. Gastrointestinal endoscopy was used for real-time recording of blood gelation and coagulation after spraying the tissue-accelerated polymerization powder. As shown in
As shown in
To demonstrate the versatility of the tissue-accelerated polymerization platform, the material retention of tissue-accelerated polymerization formulation in eye conjunctiva, cartilage, and oral cavity was evaluated.
A solution formulation was prepared for the eye comprising 10 mg/ml M1 and 20 mM H2O2, dissolved in 50 mM Tris buffer (pH 8.5). The solution (1 ml) was applied onto the conjunctiva for 15 minutes and then washed with water.
A solution formulation was prepared for the cartilage comprising 10 mg/ml M1 and 20 mM H2O2 dissolved in 50 mM Tris buffer (pH 8.5). The solution (3 ml) was intra-articular injected into the cartilage through needles. After 15 minutes, the cartilage was taken out and washed with water for evaluation.
A powder formulation was prepared for the oral cavity comprising M1 (500 mg), M7 (50 mg), Tris or sodium carbonate or potassium carbonate powder (60 mg), solid urea H2O2 (50 mg). The powder was sprayed on top of the tongue or buccal and after 15 minutes, the tissue was washed with water for evaluation. In some embodiments, different drugs are incorporated into the system to treat eye disease (e.g. glaucoma) by eye drop formulation, to treat joint diseases (e.g. osteoarthritis) as intra-articular injection formulation, to protect oral mucosa from damage as barrier coatings or drug patches. In some embodiments, drugs are incorporated as a powder, particle, oil, or dissolved liquid forms and are co-delivered together with the tissue-accelerated polymerization formulation. After in-situ polymerization and crosslinking, these drugs are trapped into the polymer, that enable slow and sustained release. In embodiments, the drug is timolol, latanoprost, or bimatoprost and are used to treat the eye. In certain embodiments, the drug is an interleukin 1 receptor antagonist, insulin-like growth factor 1, dexamethasone, or triamcinolone and are used for intra-articular injection. In some embodiments, the drug is nystatin, clotrimazole, fluconazole, or dexamethasone and are used for delivery to the oral cavity.
TPA technology has been developed to be applicable to human tissues and suitable for clinical translation. To confirm the reliability of the porcine-based TPA-positive tissue map described above for potential human trials, fresh resected tissue specimens from humans were tested for compatibility with TPA technology. Similar to the porcine TPA-map study, human tissue specimens were incubated with the TPA solution containing M1, and subsequently CAT-accelerated chromogenic M1 assembly was characterized. As shown in
Gastroenterol. 98, 1494-1499 (2003).
Adv. Mater. 31, (2019).
In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.
This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.
Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.
This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application, U.S. Ser. No. 62/947,582, filed Dec. 13, 2019, U.S. Provisional Patent Application, U.S. Ser. No. 63/050,206, filed Jul. 10, 2020, and U.S. Provisional Patent Application, U.S. Ser. No. 63/050,216, filed Jul. 10, 2020, the contents of each of which are incorporated herein by reference in their entireties.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2020/064368 | 12/10/2020 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63050206 | Jul 2020 | US | |
| 63050216 | Jul 2020 | US | |
| 62947582 | Dec 2019 | US |
