Alginate GEL for prevention or reduction of aspiration prior to intubation

Abstract

Disclosed are various methods for the prevention or reduction of pulmonary aspiration of gastric contents in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one compound comprising sodium alginate, calcium, and bicarbonate, or a pharmaceutically acceptable salt thereof. Also disclosed herein is a kit comprising at least one compound comprising sodium alginate, calcium, and bicarbonate, or a pharmaceutically acceptable salt thereof; and one or more of at least one agent known to increase gastrointestinal motility, at least one agent known to decrease stomach acid production, at least one agent known to treat a condition associated with pulmonary aspiration of gastric contents, at least one agent known to treat a condition having an increased risk of pulmonary aspiration of gastric contents, or instructions for preventing pulmonary aspiration of gastric contents.

Description

[0001] Docket No. MOF 24MB038 PCT ALGINATE GEL FOR PREVENTION OR REDUCTION OF ASPIRATION PRIOR TO INTUBATION CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and benefit of U.S. Provisional Application No. 63 / 779,613, filed March 28, 2025, which is hereby incorporated herein by reference in its entirety.

[0003] BACKGROUND OF THE INVENTION

[0004] Pulmonary aspiration of gastric contents poses a significant risk to the patient, resulting in morbidity and mortality. The risk of perioperative pulmonary aspiration of gastric contents is a major concern due to commonly present risk factors - widespread use of GLP-1 receptor agonists (due to slowing gastric emptying), increasing rates of diabetes and associated g astroparesis, and worldwide increases in surgical volumes. Current strategies to mitigate aspiration risk include appropriate nil per os (NPO) time, use of non-particulate antacids, placement of pre-induction nasogastric tube (NGT), physical maneuvers such as cricoid pressure and upright positioning, and rapid sequence intubation for securement of the airway. However, these measures can often fail to reduce the risk of aspiration, make intubation more difficult, and, in some cases, may not be feasible (e.g., emergency cases, pregnancy, trauma, etc.).

[0005] SUMMARY OF THE INVENTION

[0006] In accordance with the purpose(s) of the present disclosure, as embodied and broadly described herein, the present disclosure, in various aspects, relates to methods for the prevention or reduction of pulmonary aspiration of gastric contents in a mammal involving the step of administering to the mammal a therapeutically effective amount of at least one compound comprising sodium alginate, calcium, and bicarbonate, or a pharmaceutically acceptable salt thereof.

[0007] In various embodiments of the present disclosure, the mammal is a human.

[0008] In some embodiments, the mammal has been diagnosed with a condition having increased risk of pulmonary aspiration of gastric contents prior to the administering step.

[0009] In some embodiments, the method further involves the step of identifying a mammal in need of prevention or reduction of pulmonary aspiration of gastric contents.

[0010] In some embodiments, the mammal has been diagnosed with a condition associated with increased risk of pulmonary aspiration of gastric contents. In some examples, the condition can be pregnancy, diabetes, gastroparesis, peripheral neuropathy, gastrointestinal obstruction, esophageal cancer, surgical absence of lower 1

[0011] 45829115.1Docket No. MOF 24MB038 PCT esophageal sphincter (or portions of esophagus), dysphagia, hiatal hernia, obesity, traumatic brain injury, gastroesophageal reflux disease, esophageal dysmotility, gas bloat, large paraesophageal hernia, or achalasia.

[0012] In some embodiments, the compound can further involve at least one of a proton pump inhibitor (PPI), an antacid, a histamine (H2)-receptor antagonist, or a combination of any thereof.

[0013] Also disclosed herein are various methods for physically restricting gastric contents from refluxing into an esophagus in a mammal involving the step of administering to the mammal a therapeutically effective amount of at least one compound comprising sodium alginate, calcium, and bicarbonate, or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the mammal has been diagnosed with a condition having increased risk of gastric contents refluxing into the esophagus prior to the administering step.

[0015] In some embodiments, the method further involves identifying a mammal in need of physical restriction of gastric contents from refluxing into the esophagus.

[0016] In some embodiments, the mammal has been diagnosed with a condition associated with increased risk of gastric contents refluxing into the esophagus. In some examples, the condition can be pregnancy, diabetes, gastroparesis, peripheral neuropathy, gastrointestinal obstruction, esophageal cancer, hiatal hernia, obesity, traumatic brain injury, gastroesophageal reflux disease, esophageal dysmotility, gas bloat, large paraesophageal hernia, or achalasia.

[0017] Also disclosed herein are various embodiments of a kit having at least one compound comprising sodium alginate, calcium, and bicarbonate, or a pharmaceutically acceptable salt thereof; and one or more of: at least one agent known to increase gastrointestinal motility, at least one agent known to decrease stomach acid production, at least one agent known to treat a condition associated with pulmonary aspiration of gastric contents, at least one agent known to treat a condition having an increased risk of pulmonary aspiration of gastric contents, or instructions for preventing or reducing pulmonary aspiration of gastric contents.

[0018] In some embodiments, the at least one compound and the at least one agent are co-formulated. In other embodiments, the at least one compound and the at least one agent are co-packaged. In some embodiments, the kit can further have instructions to provide the compound in connection with intubation or administration of anesthesia.

[0019] 2

[0020] 45829115.1Docket No. MOF 24MB038 PCT In some embodiments, the instructions provide that intubation is performed or anesthesia is administered after the administering of at least one compound.

[0021] In some embodiments, the instructions provide that the administering of at least one compound is to effect prevention or reduction of pulmonary aspiration of gastric contents.

[0022] In some embodiments, the kit can further comprise a plurality of dosage forms, the plurality comprising one or more doses; wherein each dose comprises a therapeutically effective amount of the at least one compound and the at least one agent.

[0023] In some embodiments, each dose of the at least one compound and the at least one agent are co-formulated. In other embodiments, each dose of the at least one compound and the at least one agent are co-packaged.

[0024] In some embodiments, the dosage forms can be formulated for oral administration.

[0025] In some embodiments, the at least one agent is a proton pump inhibitor, an antacid, or a histamine (H2)-receptor antagonist.

[0026] Also disclosed herein are various embodiments relating to use of at least one compound comprising sodium alginate, calcium, and bicarbonate in the manufacture of a medicament for the prevention or reduction of pulmonary aspiration of gastric contents in a mammal.

[0027] In some embodiments, the compositions described herein can be administered in conjunction with one or more agents, including proton pump inhibitors, antacids, and histamine (H2)-receptor antagonists, or pharmaceutically acceptable salts of any thereof.

[0028] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

[0029] BRIEF DESCRIPTION OF FIGURES FIG. 1 is a sonogram, upper abdominal longitudinal view, showing a liver, gastric antrum, and aorta in a patient in a supine position. The stomach is empty and small in size.

[0030] FIG. 2 is a sonogram taken immediately after the patient in FIG. 1 was administered a compound comprising sodium alginate, calcium, and bicarbonate. The gastric antram is in an expanded position. The component inside the stomach has a hazy appearance and distending stomach to a larger size.

[0031] 3

[0032] 45829115.1Docket No. MOF 24MB038 PCT FIG. 3 is a sonogram of the upper abdominal longitudinal view, again showing a distended stomach with an ingested compound.

[0033] FIG 4. Is a sonogram, showing beginning of solidification of the compound now with hyperechoic (or bright white) appearance where a raft is starting to form after administration of the compound.

[0034] FIG. 5 is a sonogram, upper abdominal longitudinal view, showing a hyperecoic (bright white) raft that forming a solid state resulting in obstructing any structures deep to it by blocking the ultrasound rays.

[0035] FIG. 6 is a sonogram in an upper abdominal longitudinal view showing the final stages of raft formation, causing the stomach contents to appear hazy deep to the raft due to acoustic shadowing. The hyperechoic (bright white) structure has disappeared due to solidification of the raft and floating to the top portion of the stomach.

[0036] FIG. 7 is a sonogram, upper abdominal longitudinal view, showing further and final solidification of the compound now with more significant and consistent shadowing effect because formation of a solid raft, obscuring structures deep to it.

[0037] FIG. 8 shows mechanism of alginate raft formation under acidic conditions. A dispersion containing sodium alginate, calcium carbonate (CaCCF), and bicarbonate ions is exposed to acidic conditions (HC1, 37 °C). Protonation of carbonate species generates CO2, producing gas bubbles that contribute to buoyancy. Simultaneously, dissolution of CaCOs releases Ca2+ions, which crosslink alginate chains to form a calcium-alginate hydrogel network. The combined effects of CO2 generation and ionic crosslinking result in the formation of a porous, buoyant alginate raft structure capable of entrapping components within the gel matrix.

[0038] FIG. 9 shows top-down visualization of the formation of the drafts. Comparative images showing the spreading behavior of investigational rafts. Formulations 3 and 7 demonstrate superior wall-to-wall coverage, ensuring a continuous barrier across the entire diameter of the vessel, while others show fragmentary gelling.

[0039] FIG. 10 shows comparison between 3, 5, 7, GA, and GD. Visual comparison of investigational preparations versus commercial benchmarks. The investigational biologic barriers (3, 5, 7) exhibit higher coherence and more uniform surface distribution than Gaviscon Advance (GA) and Gaviscon Double Action (GD).

[0040] FIG. 11 shows raft integrity under mechanical agitation. Preparation 7 remains intact as a single mass after 30 minutes of 100 rpm agitation, whereas Gaviscon products show significant fragmentation and barrier failure.

[0041] 4

[0042] 45829115.1Docket No. MOF 24MB038 PCT FIG. 12 shows relative viscosity of investigational formulations versus commercial benchmarks. Preparations 3 and 7 provide a low-viscosity liquid profile for ease of administration while forming the strongest rafts upon acid contact.

[0043] FIG. 13 shows inverted flask test demonstrating the solidity of the raft preventing of leakage out of the flask contents

[0044] FIG. 14 shows comparison of reflux prevention thresholds. The pressure in the bottle was increased until failure of GD raft. Preparation 7 withstands significantly higher internal gastric pressure compared to the commercial benchmark (GD) and the control, demonstrating its potential as a safety adjunct during airway management. DETAILED DESCRIPTION

[0045] Before the present disclosure is described in greater detail, it is to be understood that this disclosure is not limited to particular embodiments described, and as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

[0046] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0047] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described.

[0048] All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be constmed as an admission that the present disclosure is not

[0049] 5

[0050] 45829115.1Docket No. MOF 24MB038 PCT entitled to antedate such publication by virtue of prior disclosure. Further, the dates of publication provided could be different from the actual publication dates that may need to be independently confirmed.

[0051] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure. Any recited method can be carried out in the order of events recited or in any other order that is logically possible.

[0052] Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of chemistry, biology, and the like, which are within the skill of the art.

[0053] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to perform the methods and use the probes disclosed and claimed herein. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C, and pressure is at or near atmospheric. Standard temperature and pressure are defined as 20 °C and 1 atmosphere.

[0054] Before the embodiments of the present disclosure are described in detail, it is to be understood that, unless otherwise indicated, the present disclosure is not limited to particular materials, reagents, reaction materials, manufacturing processes, or the like, as such can vary. It is also to be understood that the terminology used herein is for purposes of describing particular embodiments only, and is not intended to be limiting. It is also possible in the present disclosure that steps can be executed in different sequence where this is logically possible.

[0055] It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.

[0056] As used herein, “comprising” is to be interpreted as specifying the presence of the stated features, integers, steps, or components as referred to, but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Moreover, each of the terms “by”, “comprising,” “comprises”, “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” are used in their open, non-limiting sense and may be used

[0057] 6

[0058] 45829115.1Docket No. MOF 24MB038 PCT interchangeably. Further, the term “comprising” is intended to include examples and aspects encompassed by the terms “consisting essentially of” and “consisting of.” Similarly, the term “consisting essentially of’ is intended to include examples encompassed by the term “consisting of.

[0059] As used herein, the term “and / or” includes any and all combinations of one or more of the associated listed items. Expressions such as “at least one of,” when preceding a list of elements, modify the entire list of elements and do not modify the individual elements of the list.

[0060] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent,” “a carrier,” or “a disorder,” include, but are not limited to, two or more such agents, earners, or disorders, including combinations of agents, carriers, or disorders, and the like.

[0061] Reference to "a / an" chemical compound refers to one or more molecules of the chemical compound rather than being limited to a single molecule of the chemical compound. Furthermore, the one or more molecules may or may not be identical, so long as they fall under the category of the chemical compound.

[0062] It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed.

[0063] Where a range is expressed, a further aspect includes from the one particular value and / or to the other particular value. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be

[0064] 7

[0065] 45829115.1Docket No. MOF 24MB038 PCT included in the smaller ranges and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g. the phrase “x to y” includes the range from ‘x’ to ‘y’ as well as the range greater than ‘x’ and less than ‘y’. The range can also be expressed as an upper limit, e.g. ‘about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘less than x’, less than y’, and ‘less than z’. Likewise, the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘greater than x’ , greater than y’, and ‘greater than z’. In addition, the phrase “about ‘x’ to ‘y’”, where ‘x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’”.

[0066] It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “about 0.1% to 5%’’ should be interpreted to include not only the explicitly recited values of about 0.1% to about 5%, but also include individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range.

[0067] As used herein, "about," "approximately," “substantially,” and the like, when used in connection with a numerical variable, can generally refers to the value of the variable and to all values of the variable that are within the experimental error (e.g., within the 95% confidence interval for the mean) or within + / - 10% of the indicated value, whichever is greater. As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” can mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those

[0068] 8

[0069] 45829115.1Docket No. MOF 24MB038 PCT of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about,” “approximate,” or “at or about” whether or not expressly stated to be such. It is understood that where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0070] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0071] As used herein, “administering” can refer to an administration that is oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, parenteral, intra-arteriole, intradermal, intraventricular, intraosseous, intraocular, intracranial, intraperitoneal, intralesional, intranasal, intracardiac, intraarticular, intracavemous, intrathecal, intravitreal, intracerebral, and intracerebroventricular, intratympanic, intracochlear, rectal, vaginal, by inhalation, by catheters, stents or via an implanted reservoir or other device that administers, either actively or passively (e.g. by diffusion) a composition the perivascular space and adventitia. For example a medical device such as a stent can contain a composition or formulation disposed on its surface, which can then dissolve or be otherwise distributed to the surrounding tissue and cells. The term “parenteral” can include subcutaneous, intravenous, intramuscular, intraarticular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injections or infusion techniques. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.

[0072] As used herein, “therapeutic agent” can refer to any substance, compound, molecule, and the like, which can be biologically active or otherwise can induce a pharmacologic, immunogenic, biologic and / or physiologic effect on a subject to which it is administered to by local and / or systemic action. A therapeutic agent can be a primary active agent, or in other words, the component(s) of a composition to which the whole or part of the effect of the composition is attributed. A therapeutic agent can be a secondary therapeutic agent, or in other words, the component(s) of a composition to which an

[0073] 9

[0074] 45829115.1Docket No. MOF 24MB038 PCT additional part and / or other effect of the composition is attributed. The term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like. Examples of therapeutic agents are described in well-known literature references such as the Merck Index (14th edition), the Physicians' Desk Reference (64th edition), and The Pharmacological Basis of Therapeutics (12th edition), and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment. For example, the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, antiepileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, beta-agonists and antiarrythmics), antihypertensives, diuretics, vasodilators; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressives; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including both double- and single-stranded molecules, gene constructs, expression vectors, antisense molecules and the like), small molecules (e.g., doxorubicin) and other biologically active macromolecules such as, for example, proteins and enzymes. The agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas. The term therapeutic agent also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis,

[0075] 10

[0076] 45829115.1Docket No. MOF 24MB038 PCT cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro- drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.

[0077] As used herein, “kit” means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose.

[0078] Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.

[0079] As used herein, “instruction(s)” means documents describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, troubleshooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. Instructions can comprise one or multiple documents, and are meant to include future updates.

[0080] As used herein, “attached” can refer to covalent or non-covalent interaction between two or more molecules. Non-covalent interactions can include ionic bonds, electrostatic interactions, van der Walls forces, dipole-dipole interactions, dipole-induced-dipole interactions, London dispersion forces, hydrogen bonding, halogen bonding, electromagnetic interactions, 7i-7t interactions, cation- interactions, anion-n interactions, polar 71-interactions, and hydrophobic effects.

[0081] As used herein, the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and juvenile subjects, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects.

[0082] 11

[0083] 45829115.1Docket No. MOF 24MB038 PCT As used herein, the terms "treating" and "treatment" can refer generally to obtaining a desired pharmacological and / or physiological effect. The effect can be, but does not necessarily have to be, prophylactic in terms of preventing or partially preventing a disease, symptom or condition thereof, such as a cancer, a disorder or disease associate with uncontrolled cellular proliferation, and / or a disorder or disease associated with increased risk of pulmonary aspiration of gastric contents. The effect can be therapeutic in terms of a partial or complete cure of a disease, condition, symptom or adverse effect attributed to the disease, disorder, or condition. The term "treatment" as used herein can include any treatment of a cancer, a disorder or disease associate with uncontrolled cellular proliferation, and / or a disorder or disease associated with increased risk of pulmonary aspiration of gastric contents in a subject, particularly a human and can include any one or more of the following: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., mitigating or ameliorating the disease and / or its symptoms or conditions. The term "treatment" as used herein can refer to both therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (subjects in need thereof) can include those already with the disorder and / or those in which the disorder is to be prevented. As used herein, the term "treating", can include inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and / or condition. Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, e.g., such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain.

[0084] As used herein, “dose,” “unit dose,” or “dosage” can refer to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of a disclosed compound and / or a pharmaceutical composition thereof calculated to produce the desired response or responses in association with its administration.

[0085] As used herein, “therapeutic” can refer to treating, healing, and / or ameliorating a disease, disorder, condition, or side effect, or to decreasing in the rate of advancement of a disease, disorder, condition, or side effect.

[0086] 12

[0087] 45829115.1Docket No. MOF 24MB038 PCT As used herein, “effective amount” can refer to the amount of a disclosed compound or pharmaceutical composition provided herein that is sufficient to effect beneficial or desired biological, emotional, medical, or clinical response of a cell, tissue, system, animal, or human. An effective amount can be administered in one or more administrations, applications, or dosages. The term can also include within its scope amounts effective to enhance or restore to substantially normal physiological function.

[0088] As used herein, the term “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors within the knowledge and expertise of the health practitioner and which may be well known in the medical arts. In the case of treating a particular disease or condition, in some instances, the desired response can be inhibiting the progression of the disease or condition. This may involve only slowing the progression of the disease temporarily. However, in other instances, it may be desirable to halt the progression of the disease permanently. This can be monitored by routine diagnostic methods known to one of ordinary skill in the art for any particular disease. The desired response to treatment of the disease or condition also can be delaying the onset or even preventing the onset of the disease or condition.

[0089] For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. It is generally preferred that a maximum dose of the pharmacological agents of the invention (alone or in combination with other therapeutic agents) be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art however, that a patient may insist

[0090] 13

[0091] 45829115.1Docket No. MOF 24MB038 PCT upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reasons.

[0092] A response to a therapeutically effective dose of a disclosed compound and / or pharmaceutical composition, for example, can be measured by determining the physiological effects of the treatment or medication, such as the decrease or lack of disease symptoms following administration of the treatment or pharmacological agent. Other assays will be known to one of ordinary skill in the art and can be employed for measuring the level of the response. The amount of a treatment may be varied for example by increasing or decreasing the amount of a disclosed compound and / or pharmaceutical composition, by changing the disclosed compound and / or pharmaceutical composition administered, by changing the route of administration, by changing the dosage timing and so on. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products.

[0093] As used herein, the term “prophylactically effective amount” refers to an amount effective for preventing onset or initiation of a disease or condition.

[0094] As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

[0095] The term “pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

[0096] The term “pharmaceutically acceptable salts”, as used herein, means salts of the active principal agents which are prepared with acids or bases that are tolerated by a biological system or tolerated by a subject or tolerated by a biological system and tolerated by a subject when administered in a therapeutically effective amount. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include, but are not limited to: sodium, potassium, calcium, ammonium, organic amino, magnesium salt, lithium salt, strontium salt or a similar salt. When compounds of the present disclosure contain

[0097] 14

[0098] 45829115.1Docket No. MOF 24MB038 PCT relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to; those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like.

[0099] As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.

[0100] The term “contacting” as used herein refers to bringing a disclosed compound or pharmaceutical composition in proximity to a cell, a target protein, or other biological entity together in such a manner that the disclosed compound or pharmaceutical composition can affect the activity of the a cell, target protein, or other biological entity, either directly; i.e., by interacting with the cell, target protein, or other biological entity itself, or indirectly; i.e., by interacting with another molecule, co-factor, factor, or protein on which the activity of the cell, target protein, or other biological entity itself is dependent.

[0101] As used herein, nomenclature for compounds, including organic compounds, can be given using common names, IUPAC, IUBMB, or CAS recommendations for nomenclature. When one or more stereochemical features are present, Cahn-Ingold-Prelog rules for stereochemistry can be employed to designate stereochemical priority, E / Z specification, and the like. One of skill in the art can readily ascertain the structure of a compound if given a name, either by systemic reduction of the compound structure

[0102] 15

[0103] 45829115.1Docket No. MOF 24MB038 PCT using naming conventions, or by commercially available software, such as CHEMDRAW™ (Cambridgesoft Corporation, U.S.A.).

[0104] It is understood, that unless otherwise specified, temperatures referred to herein are based on atmospheric pressure (i.e. one atmosphere).

[0105] Described herein are methods of administering compounds, or pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof, to a subject in need thereof. In some aspects, the subject can have a need for prevention of aspiration of gastric contents. In some embodiments, the subject in need thereof maintains a head-of-bed elevation of between 15 and 90 degrees following administration to support buoyancy and gravitational separation of gastric contents. Other compositions, compounds, methods, features, and advantages of the present disclosure will be or become apparent to one having ordinary skill in the art upon examination of the following drawings, detailed description, and examples. It is intended that all such additional compositions, compounds, methods, features, and advantages be included within this description, and be within the scope of the present disclosure.

[0106] In various aspects, the present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of at least one disclosed compound, at least one product of a disclosed method, or a pharmaceutically acceptable salt thereof. As used herein, “pharmaceutically-acceptable carriers” means one or more of a pharmaceutically acceptable diluents, preservatives, antioxidants, solubilizers, emulsifiers, coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, and adjuvants. The disclosed pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy and pharmaceutical sciences.

[0107] In a further aspect, the disclosed pharmaceutical compositions comprise a therapeutically effective amount of at least one disclosed compound, at least one product of a disclosed method, or a pharmaceutically acceptable salt thereof as an active ingredient, a pharmaceutically acceptable carrier, optionally one or more other therapeutic agent, and optionally one or more adjuvant. The disclosed pharmaceutical compositions include those suitable for oral, rectal, topical, pulmonary, nasal, and parenteral administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. In a further aspect, the disclosed pharmaceutical composition can be formulated to allow administration orally, nasally, via inhalation,

[0108] 16

[0109] 45829115.1Docket No. MOF 24MB038 PCT parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intradermally, subcutaneously, intraperitonealy, intraventricularly, intracranially and intratumorally.

[0110] As used herein, “parenteral administration” includes administration by bolus injection or infusion, as well as administration by intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular subarachnoid, intraspinal, epidural and intrastemal injection and infusion.

[0111] In various aspects, the present disclosure also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient, a therapeutically effective amount of a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, or a stereochemically isomeric form thereof. In a further aspect, a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, or a stereochemically isomeric form thereof, or any subgroup or combination thereof may be formulated into various pharmaceutical forms for administration purposes.

[0112] Pharmaceutically acceptable salts can be prepared from pharmaceutically acceptable non-toxic bases or acids. For therapeutic use, salts of the disclosed compounds are those wherein the counter ion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are contemplated by the present disclosure. Pharmaceutically acceptable acid and base addition salts are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the disclosed compounds are able to form.

[0113] In various aspects, a disclosed compound comprising an acidic group or moiety, e.g., a carboxylic acid group, can be used to prepare a pharmaceutically acceptable salt. For example, such a disclosed compound may comprise an isolation step comprising treatment with a suitable inorganic or organic base. In some cases, it may be desirable in practice to initially isolate a compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free acid compound by treatment with an acidic reagent, and subsequently convert the free acid to a

[0114] 17

[0115] 45829115.1Docket No. MOF 24MB038 PCT pharmaceutically acceptable base addition salt. These base addition salts can be readily prepared using conventional techniques, e.g., by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they also can be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before.

[0116] Bases which can be used to prepare the pharmaceutically acceptable baseaddition salts of the base compounds are those which can form non-toxic base-addition salts, i.e., salts containing pharmacologically acceptable cations such as, alkali metal cations (e.g., lithium, potassium and sodium), alkaline earth metal cations (e.g., calcium and magnesium), ammonium or other water-soluble amine addition salts such as N-methylglucamine-(meglumine), lower alkanolammonium and other such bases of organic amines. In a further aspect, derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. In various aspects, such pharmaceutically acceptable organic non-toxic bases include, but are not limited to, ammonia, methylamine, ethylamine, propylamine, isopropylamine, any of the four butylamine isomers, betaine, caffeine, choline, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, N,N'-dibenzylethylenediamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, tromethamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, quinuclidine, pyridine, quinoline and isoquinoline; benzathine, 7V-methyl-D-glucamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, hydrabamine salts, and salts with amino acids such as, for example, histidine, arginine, lysine and the like. The foregoing salt forms can be converted by treatment with acid back into the free acid form.

[0117] In various aspects, a disclosed compound comprising a protonatable group or moiety, e.g., an amino group, can be used to prepare a pharmaceutically acceptable salt. For example, such a disclosed compound may comprise an isolation step comprising treatment with a suitable inorganic or organic acid. In some cases, it may be desirable in

[0118] 18

[0119] 45829115.1Docket No. MOF 24MB038 PCT practice to initially isolate a compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an basic reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition salt. These acid addition salts can be readily prepared using conventional techniques, e.g., by treating the corresponding basic compounds with an aqueous solution containing the desired pharmacologically acceptable anions and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they also can be prepared by treating the free base form of the disclosed compound with a suitable pharmaceutically acceptable non-toxic inorganic or organic acid.

[0120] Acids which can be used to prepare the pharmaceutically acceptable acidaddition salts of the base compounds are those which can form non-toxic acid-addition salts, i.e., salts containing pharmacologically acceptable anions formed from their corresponding inorganic and organic acids. Exemplary, but non-limiting, inorganic acids include hydrochloric hydrobromic, sulfuric, nitric, phosphoric and the like. Exemplary, but non-limiting, organic acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, isethionic, lactic, maleic, malic, mandelicmethanesulfonic, mucic, pamoic, pantothenic, succinic, tartaric, p-toluenesulfonic acid and the like. In a further aspect, the acid-addition salt comprises an anion formed from hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

[0121] In practice, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, of the present disclosure can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present disclosure can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compounds of the present disclosure, and / or pharmaceutically acceptable salt(s) thereof, can also be administered by controlled release means and / or delivery devices.

[0122] 19

[0123] 45829115.1Docket No. MOF 24MB038 PCT The compositions can be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.

[0124] It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. The term “unit dosage form,” as used herein, refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. That is, a “unit dosage form” is taken to mean a single dose wherein all active and inactive ingredients are combined in a suitable system, such that the patient or person administering the drug to the patient can open a single container or package with the entire dose contained therein, and does not have to mix any components together from two or more containers or packages. Typical examples of unit dosage forms are tablets (including scored or coated tablets), capsules or pills for oral administration; single dose vials for injectable solutions or suspension; suppositories for rectal administration; powder packets; wafers: and segregated multiples thereof. This list of unit dosage forms is not intended to be limiting in any way, but merely to represent typical examples of unit dosage forms.

[0125] The pharmaceutical compositions disclosed herein comprise a compound of the present disclosure (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents. In various aspects, the disclosed pharmaceutical compositions can include a pharmaceutically acceptable carrier and a disclosed compound, or a pharmaceutically acceptable salt thereof. In a further aspect, a disclosed compound, or pharmaceutically acceptable salt thereof, can also be included in a pharmaceutical composition in combination with one or more other therapeutically active compounds. The instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The

[0126] 20

[0127] 45829115.1Docket No. MOF 24MB038 PCT pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0128] Techniques and compositions for making dosage forms useful for materials and methods described herein are described, for example, in the following references:

[0129] Modem Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979);

[0130] Pharmaceutical Dosage Fomrs: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.). The compounds described herein are typically to be administered in admixture with suitable pharmaceutical diluents, excipients, extenders, or carriers (termed herein as a pharmaceutically acceptable carrier, or a carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The deliverable compound will be in a form suitable for oral, rectal, topical, intravenous injection or parenteral administration. Carriers include solids or liquids, and the type of carrier is chosen based on the type of administration being used. The compounds may be administered as a dosage that has a known quantity of the compound.

[0131] Because of the ease in administration, oral administration can be a preferred dosage form, and tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed. However, other dosage forms may be suitable depending upon clinical population (e.g., age and severity of clinical condition), solubility properties of the specific disclosed compound used, and the like. Accordingly, the disclosed compounds can be used in oral dosage forms such as pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. In preparing the compositions for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols,

[0132] 21

[0133] 45829115.1Docket No. MOF 24MB038 PCT flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques.

[0134] The disclosed pharmaceutical compositions in an oral dosage form can comprise one or more pharmaceutical excipient and / or additive. Non-limiting examples of suitable excipients and additives include gelatin, natural sugars such as raw sugar or lactose, lecithin, pectin, starches (for example corn starch or amylose), dextran, polyvinyl pyrrolidone, polyvinyl acetate, gum arabic, alginic acid, tylose, talcum, lycopodium, silica gel (for example colloidal), cellulose, cellulose derivatives (for example cellulose ethers in which the cellulose hydroxy groups are partially etherified with lower saturated aliphatic alcohols and / or lower saturated, aliphatic oxyalcohols, for example methyl oxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate), fatty acids as well as magnesium, calcium or aluminum salts of fatty acids with 12 to 22 carbon atoms, in particular saturated (for example stearates), emulsifiers, oils and fats, in particular vegetable (for example, peanut oil, castor oil, olive oil, sesame oil, cottonseed oil, com oil, wheat germ oil, sunflower seed oil, cod liver oil, in each case also optionally hydrated); glycerol esters and polyglycerol esters of saturated fatty acids C12H24O2 to C18H36O2 and their mixtures, it being possible for the glycerol hydroxy groups to be totally or also only partly esterified (for example mono-, di- and triglycerides); pharmaceutically acceptable mono- or multivalent alcohols and polyglycols such as polyethylene glycol and derivatives thereof, esters of aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atoms, in particular 10-18 carbon atoms) with monovalent aliphatic alcohols (1 to 20 carbon atoms) or multivalent alcohols such as glycols, glycerol, diethylene glycol, pentacrythritol, sorbitol, mannitol and the like, which may optionally also be etherified, esters of citric acid with primary alcohols, acetic acid, urea, benzyl benzoate, dioxolanes, glyceroformals, tetrahydrofurfuryl alcohol, polyglycol ethers with Cl-C12-alcohols, dimethylacetamide, lactamides, lactates, ethylcarbonates, silicones (in particular medium-viscous polydimethyl

[0135] 22

[0136] 45829115.1Docket No. MOF 24MB038 PCT siloxanes), calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, magnesium carbonate and the like.

[0137] In some embodiments, sodium alginate in the compound is in a concentration from about 10 mg / mL to about 100 mg / mL, from about 15 mg / mL to about 90 mg / mL, from about 20 mg / mL to about 80 mg / mL, from about 25 mg / mL to about 70 mg / mL, from about 27 mg / mL to about 60 mg / mL, from about 30 mg / mL to about 50 mg / mL, the calcium carbonate is at a concentration from about 5 mg / mL to about 60 mg / mL, from about 7 mg / mL to about 50 mg / mL, from about 10 mg / mL to about 45 mg / mL, from about 12mg / mL to about 40 mg / mL, from about 15 mg / mL to about 35 mg / mL, and the concentration of sodium bicarbonate is at a concentration from about 5 mg / mL to about 50 mg / mL, from about 7 mg / mL to about 40 mg / mL, from about 9 mg / mL to about 30 mg / mL, from about 10 mg / mL to about 25 mg / mL.

[0138] Other auxiliary substances useful in preparing an oral dosage form are those which cause disintegration (so-called disintegrants), such as: cross-linked polyvinyl pyrrolidone, sodium carboxymethyl starch, sodium carboxymethyl cellulose or microcrystalline cellulose. Conventional coating substances may also be used to produce the oral dosage form. Those that may for example be considered are: polymerizates as well as copolymerizates of acrylic acid and / or methacrylic acid and / or their esters; copolymerizates of acrylic and methacrylic acid esters with a lower ammonium group content (for example EudragitR RS), copolymerizates of acrylic and methacrylic acid esters and trimethyl ammonium methacrylate (for example EudragitR RL); polyvinyl acetate; fats, oils, waxes, fatty alcohols; hydroxypropyl methyl cellulose phthalate or acetate succinate; cellulose acetate phthalate, starch acetate phthalate as well as polyvinyl acetate phthalate, carboxy methyl cellulose; methyl cellulose phthalate, methyl cellulose succinate, -phthalate succinate as well as methyl cellulose phthalic acid half ester; zein; ethyl cellulose as well as ethyl cellulose succinate; shellac, gluten; ethylcarboxyethyl cellulose; ethacrylate-maleic acid anhydride copolymer; maleic acid anhydride-vinyl methyl ether copolymer; styrol-maleic acid copolymerizate; 2-ethyl-hexyl- acrylate maleic acid anhydride; crotonic acid-vinyl acetate copolymer; glutaminic acid / glutamic acid ester copolymer; carboxymethylethylcellulose glycerol monooctanoate; cellulose acetate succinate; polyarginine.

[0139] Plasticizing agents that may be considered as coating substances in the disclosed oral dosage forms are: citric and tartaric acid esters (acetyl-triethyl citrate, acetyl tributyl-, tributyl-, triethyl-citrate); glycerol and glycerol esters (glycerol diacetate, -triacetate,

[0140] 23

[0141] 45829115.1Docket No. MOF 24MB038 PCT acetylated monoglycerides, castor oil); phthalic acid esters (dibutyl-, diamyl-, diethyl-, dimethyl-, dipropyl-phthalate), di-(2-methoxy- or 2-ethoxyethyl)-phthalate, ethylphthalyl glycolate, butylphthalylethyl glycolate and butylglycolate; alcohols (propylene glycol, polyethylene glycol of various chain lengths), adipates (diethyladipate, di-(2-methoxy- or 2-ethoxyethyl)-adipate; benzophenone; diethyl- and diburylsebacate, dibutylsuccinate, dibutyltartrate; diethylene glycol dipropionate; ethyleneglycol diacetate, -dibutyrate, -dipropionate; tributyl phosphate, tributyrin; polyethylene glycol sorbitan monooleate (polysorbates such as Polysorbar 50); sorbitan monooleate.

[0142] Moreover, suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents may be included as carriers. The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.

[0143] Examples of solid carriers include, but are not limited to, lactose, terra alba, sucrose, glucose, methylcellulose, dicalcium phosphate, calcium sulfate, mannitol, sorbitol talc, starch, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0144] In various aspects, a binder can include, for example, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. In a further aspect, a disintegrator can include, for example, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

[0145] In various aspects, an oral dosage form, such as a solid dosage form, can comprise a disclosed compound that is attached to polymers as targetable drug carriers or as a prodrug. Suitable biodegradable polymers useful in achieving controlled release of a drug include, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, caprolactones, polyhydroxy butyric acid, polyorthoesters, polyacetals, poly dihydropyrans, polycy anoacylates, and hydrogels, preferably covalently crosslinked hydrogels.

[0146] Tablets may contain the active ingredient in admixture with non- toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and

[0147] 24

[0148] 45829115.1Docket No. MOF 24MB038 PCT disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

[0149] A tablet containing a disclosed compound can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.

[0150] In various aspects, a solid oral dosage form, such as a tablet, can be coated with an enteric coating to prevent ready decomposition in the stomach. In various aspects, enteric coating agents include, but are not limited to, hydroxypropylmethylcellulose phthalate, methacrylic acid-methacrylic acid ester copolymer, polyvinyl acetate-phthalate and cellulose acetate phthalate. Akihiko Hasegawa “Application of solid dispersions of Nifedipine with enteric coating agent to prepare a sustained-release dosage form’’ Chem. Pharm. Bull. 33:1615-1619 (1985). Various enteric coating materials may be selected on the basis of testing to achieve an enteric coated dosage form designed ab initio to have a preferable combination of dissolution time, coating thicknesses and diametral crushing strength (e.g., see S. C. Porter et al. “The Properties of Enteric Tablet Coatings Made From Polyvinyl Acetate-phthalate and Cellulose acetate Phthalate”, J. Pharm. Pharmacol.

[0151] 22:42p (1970)). In a further aspect, the enteric coating may comprise hydroxypropylmethylcellulose phthalate, methacrylic acid-methacrylic acid ester copolymer, polyvinyl acetate-phthalate and cellulose acetate phthalate.

[0152] In various aspects, an oral dosage form can be a solid dispersion with a water soluble or a water insoluble carrier. Examples of water soluble or water insoluble carrier include, but are not limited to, polyethylene glycol, polyvinylpyrrolidone, hydroxypropylmethyl-cellulose, phosphatidylcholine, polyoxyethylene hydrogenated castor oil, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, or hydroxypropylmethylcellulose, ethyl cellulose, or stearic acid.

[0153] In various aspects, an oral dosage form can be in a liquid dosage form, including those that are ingested, or alternatively, administered as a mouth wash or gargle. For

[0154] 25

[0155] 45829115.1Docket No. MOF 24MB038 PCT example, a liquid dosage form can include aqueous suspensions, which contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. In addition, oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may also contain various excipients. The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions, which may also contain excipients such as sweetening and flavoring agents.

[0156] For the preparation of solutions or suspensions it is, for example, possible to use water, particularly sterile water, or physiologically acceptable organic solvents, such as alcohols (ethanol, propanol, isopropanol, 1,2-propylene glycol, polyglycols and their derivatives, fatty alcohols, partial esters of glycerol), oils (for example peanut oil, olive oil, sesame oil, almond oil, sunflower oil, soya bean oil, castor oil, bovine hoof oil), paraffins, dimethyl sulphoxide, triglycerides and the like.

[0157] In the case of a liquid dosage form such as a drinkable solutions, the following substances may be used as stabilizers or solubilizers: lower aliphatic mono- and multivalent alcohols with 2-4 carbon atoms, such as ethanol, n-propanol, glycerol, polyethylene glycols with molecular weights between 200-600 (for example 1 to 40% aqueous solution), diethylene glycol monoethyl ether, 1,2-propylene glycol, organic amides, for example amides of aliphatic Cl-C6-carboxylic acids with ammonia or primary, secondary or tertiary Cl-C4-amines or Cl-C4-hydroxy amines such as urea, urethane, acetamide, N-methyl acetamide, N,N-diethyl acetamide, N,N-dimethyl acetamide, lower aliphatic amines and diamines with 2-6 carbon atoms, such as ethylene diamine, hydroxyethyl theophylline, tromethamine (for example as 0.1 to 20% aqueous solution), aliphatic amino acids.

[0158] In preparing the disclosed liquid dosage form can comprise solubilizers and emulsifiers such as the following non-limiting examples can be used: polyvinyl pyrrolidone, sorbitan fatty acid esters such as sorbitan trioleate, phosphatides such as lecithin, acacia, tragacanth, polyoxyethylated sorbitan monooleate and other ethoxylated fatty acid esters of sorbitan, polyoxyethylated fats, polyoxyethylated oleotriglycerides, linolizated oleotriglycerides, polyethylene oxide condensation products of fatty alcohols, alkylphenols or fatty acids or also l-methyl-3-(2-hydroxyethyl)imidazolidone-(2). In this context, polyoxyethylated means that the substances in question contain polyoxyethylene chains, the degree of polymerization of which generally lies between 2 and 40 and in

[0159] 26

[0160] 45829115.1Docket No. MOF 24MB038 PCT particular between 10 and 20. Polyoxyethylated substances of this kind may for example be obtained by reaction of hydroxyl group-containing compounds (for example mono- or diglycerides or unsaturated compounds such as those containing oleic acid radicals) with ethylene oxide (for example 40 Mol ethylene oxide per 1 Mol glyceride). Examples of oleotriglycerides are olive oil, peanut oil, castor oil, sesame oil, cottonseed oil, com oil. See also Dr. H. P. Fiedler “Lexikon der Hillsstoffe fur Pharmazie, Kostnetik und angrenzende Gebiete” 1971, pages 191-195.

[0161] In various aspects, a liquid dosage form can further comprise preservali ves. stabilizers, buffer substances, flavor correcting agents, sweeteners, colorants, antioxidants and complex formers and the like. Complex formers which may be for example be considered are: chelate formers such as ethylene diamine tetraacetic acid, nitrilotri acetic acid, diethylene triamine pentaacetic acid and their salts.

[0162] It may optionally be necessary to stabilize a liquid dosage form with physiologically acceptable bases or buffers to a pH range of approximately 6 to 9.

[0163] Preference may be given to as neutral or weakly basic a pH value as possible (up to pH 8).

[0164] In order to enhance the solubility and / or the stability of a disclosed compound in a disclosed liquid dosage form, a parenteral injection form, or an intravenous injectable form, it can be advantageous to employ a-, 0- or y-cyclodextrins or their derivatives, in particular hydroxyalkyl substituted cyclodextrins, e.g. 2-hydroxypropyl-0-cyclodextrin or sulfobutyl-0-cyclodextrin. Also co-solvents such as alcohols may improve the solubility and / or the stability of the compounds according to the present disclosure in phamiaceutical compositions.

[0165] In various aspects, a disclosed liquid dosage form, a parenteral injection form, or an intravenous injectable form can further comprise liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.

[0166] Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

[0167] Pharmaceutical compositions of the present disclosure suitable injection, such as parenteral administration, such as intravenous, intramuscular, or subcutaneous administration. Pharmaceutical compositions for injection can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol,

[0168] 27

[0169] 45829115.1Docket No. MOF 24MB038 PCT liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

[0170] Pharmaceutical compositions of the present disclosure suitable for parenteral administration can include sterile aqueous or oleaginous solutions, suspensions, or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In some aspects, the final injectable form is sterile and must be effectively fluid for use in a syringe. The pharmaceutical compositions should be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0171] Injectable solutions, for example, can be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In some aspects, a disclosed parenteral formulation can comprise about 0.01-0.1 M, e.g. about 0.05 M, phosphate buffer. In a further aspect, a disclosed parenteral formulation can comprise about 0.9% saline.

[0172] In various aspects, a disclosed parenteral pharmaceutical composition can comprise pharmaceutically acceptable carriers such as aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include but not limited to water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles can include mannitol, normal serum albumin, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the like. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, collating agents, inert gases and the like. In a further aspect, a disclosed parenteral pharmaceutical composition can comprise may contain minor amounts of additives such as substances that enhance isotonicity and chemical stability, e.g., buffers and preservatives. Also contemplated for injectable pharmaceutical compositions are solid form preparations that are intended to

[0173] 28

[0174] 45829115.1Docket No. MOF 24MB038 PCT be converted, shortly before use, to liquid form preparations. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the subject or patient.

[0175] In addition to the pharmaceutical compositions described herein above, the disclosed compounds can also be formulated as a depot preparation. Such long acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.

[0176] Pharmaceutical compositions of the present disclosure can be in a form suitable for topical administration. As used herein, the phrase “topical application” means administration onto a biological surface, whereby the biological surface includes, for example, a skin area (e.g., hands, forearms, elbows, legs, face, nails, anus and genital areas) or a mucosal membrane. By selecting the appropriate carrier and optionally other ingredients that can be included in the composition, as is detailed herein below, the compositions of the present invention may be formulated into any form typically employed for topical application. A topical pharmaceutical composition can be in a form of a cream, an ointment, a paste, a gel, a lotion, milk, a suspension, an aerosol, a spray, foam, a dusting powder, a pad, and a patch. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared, utilizing a compound of the present disclosure, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.

[0177] In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and / or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and / or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.

[0178] Ointments are semisolid preparations, typically based on petrolatum or petroleum derivatives. The specific ointment base to be used is one that provides for optimum

[0179] 29

[0180] 45829115.1Docket No. MOF 24MB038 PCT delivery for the active agent chosen for a given formulation, and, preferably, provides for other desired characteristics as well (e.g., emollience). As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and nonsensitizing. As explained in Remington: The Science and Practice of Pharmacy, 19th Ed., Easton, Pa.: Mack Publishing Co. (1995), pp. 1399-1404, ointment bases may be grouped in four classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-soluble bases.

[0181] Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum. Emulsifiable ointment bases, also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum.

[0182] Emulsion ointment bases are either water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin and stearic acid. Preferred water-soluble ointment bases are prepared from polyethylene glycols of varying molecular weight.

[0183] Lotions are preparations that are to be applied to the skin surface without friction. Lotions are typically liquid or semiliquid preparations in which solid particles, including the active agent, are present in a water or alcohol base. Lotions are typically preferred for treating large body areas, due to the ease of applying a more fluid composition. Lotions are typically suspensions of solids, and oftentimes comprise a liquid oily emulsion of the oil-in-water type. It is generally necessary that the insoluble matter in a lotion be finely divided. Lotions typically contain suspending agents to produce better dispersions as well as compounds useful for localizing and holding the active agent in contact with the skin, such as methylcellulose, sodium carboxymethyl-cellulose, and the like.

[0184] Creams are viscous liquids or semisolid emulsions, either oil-in-water or water-in-oil. Cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also called the “internal” phase, is generally comprised of petrolatum and / or a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase typically, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. Reference may be made to Remington: The Science and Practice of Pharmacy, supra, for further information.

[0185] Pastes are semisolid dosage forms in which the bioactive agent is suspended in a suitable base. Depending on the nature of the base, pastes are divided between fatty pastes or those made from a single-phase aqueous gel. The base in a fatty paste is

[0186] 30

[0187] 45829115.1Docket No. MOF 24MB038 PCT generally petrolatum, hydrophilic petrolatum and the like. The pastes made from singlephase aqueous gels generally incorporate carboxymethylcellulose or the like as a base. Additional reference may be made to Remington: The Science and Practice of Pharmacy, for further information.

[0188] Gel formulations are semisolid, suspension- type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the carrier liquid, which is typically aqueous, but also, preferably, contain an alcohol and, optionally, an oil. Preferred organic macromolecules, i.e., gelling agents, are crosslinked acrylic acid polymers such as the family of carbomer polymers, e.g., carboxypolyalkylenes that may be obtained commercially under the trademark Carbopol™. Other types of preferred polymers in this context are hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers and polyvinylalcohol; modified cellulose, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methyl cellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin. In order to prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing or stirring, or combinations thereof.

[0189] Sprays generally provide the active agent in an aqueous and / or alcoholic solution which can be misted onto the skin for delivery. Such sprays include those formulated to provide for concentration of the active agent solution at the site of administration following delivery, e.g., the spray solution can be primarily composed of alcohol or other like volatile liquid in which the active agent can be dissolved. Upon delivery to the skin, the carrier evaporates, leaving concentrated active agent at the site of administration.

[0190] Foam compositions are typically formulated in a single or multiple phase liquid form and housed in a suitable container, optionally together with a propellant which facilitates the expulsion of the composition from the container, thus transforming it into a foam upon application. Other foam forming techniques include, for example the “Bag-in-a-can” formulation technique. Compositions thus formulated typically contain a low-boiling hydrocarbon, e.g., isopropane. Application and agitation of such a composition at the body temperature cause the isopropane to vaporize and generate the foam, in a manner similar to a pressurized aerosol foaming system. Foams can be water-based or aqueous alkanol, but are typically formulated with high alcohol content which, upon

[0191] 31

[0192] 45829115.1Docket No. MOF 24MB038 PCT application to the skin of a user, quickly evaporates, driving the active ingredient through the upper skin layers to the site of treatment.

[0193] Skin patches typically comprise a backing, to which a reservoir containing the active agent is attached. The reservoir can be, for example, a pad in which the active agent or composition is dispersed or soaked, or a liquid reservoir. Patches typically further include a frontal water permeable adhesive, which adheres and secures the device to the treated region. Silicone rubbers with self-adhesiveness can alternatively be used. In both cases, a protective permeable layer can be used to protect the adhesive side of the patch prior to its use. Skin patches may further comprise a removable cover, which serves for protecting it upon storage.

[0194] Examples of patch configuration which can be utilized with the present invention include a single-layer or multi-layer drug-in-adhesive systems which are characterized by the inclusion of the drug directly within the skin-contacting adhesive. In such a transdermal patch design, the adhesive not only serves to affix the patch to the skin, but also serves as the formulation foundation, containing the drug and all the excipients under a single backing film. In the multi-layer drug-in-adhesive patch a membrane is disposed between two distinct drug-in-adhesive layers or multiple drug-in-adhesive layers are incorporated under a single backing film.

[0195] Examples of pharmaceutically acceptable carriers that are suitable for pharmaceutical compositions for topical applications include carrier materials that are well-known for use in the cosmetic and medical arts as bases for e.g., emulsions, creams, aqueous solutions, oils, ointments, pastes, gels, lotions, milks, foams, suspensions, aerosols and the like, depending on the final form of the composition. Representative examples of suitable carriers according to the present invention therefore include, without limitation, water, liquid alcohols, liquid glycols, liquid polyalkylene glycols, liquid esters, liquid amides, liquid protein hydrolysates, liquid alkylated protein hydrolysates, liquid lanolin and lanolin derivatives, and like materials commonly employed in cosmetic and medicinal compositions. Other suitable carriers according to the present invention include, without limitation, alcohols, such as, for example, monohydric and polyhydric alcohols, e.g., ethanol, isopropanol, glycerol, sorbitol, 2-methoxyethanol, diethyleneglycol, ethylene glycol, hexyleneglycol, mannitol, and propylene glycol; ethers such as diethyl or dipropyl ether; polyethylene glycols and methoxypolyoxyethylenes (carbowaxes having molecular weight ranging from 200 to

[0196] 32

[0197] 45829115.1Docket No. MOF 24MB038 PCT 20,000); polyoxyethylene glycerols, polyoxyethylene sorbitols, stearoyl diacetin, and the like.

[0198] Topical compositions of the present disclosure can, if desired, be presented in a pack or dispenser device, such as an FDA-approved kit, which may contain one or more unit dosage forms containing the active ingredient. The dispenser device may, for example, comprise a tube. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser device may also be accompanied by a notice in a form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions for human or veterinary administration. Such notice, for example, may include labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert. Compositions comprising the topical composition of the invention formulated in a pharmaceutically acceptable carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0199] Another patch system configuration which can be used by the present invention is a reservoir transdermal system design which is characterized by the inclusion of a liquid compartment containing a drug solution or suspension separated from the release liner by a semi-permeable membrane and adhesive. The adhesive component of this patch system can either be incorporated as a continuous layer between the membrane and the release liner or in a concentric configuration around the membrane. Yet another patch system configuration which can be utilized by the present invention is a matrix system design which is characterized by the inclusion of a semisolid matrix containing a drug solution or suspension which is in direct contact with the release liner. The component responsible for skin adhesion is incorporated in an overlay and forms a concentric configuration around the semisolid matrix.

[0200] Pharmaceutical compositions of the present disclosure can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.

[0201] 33

[0202] 45829115.1Docket No. MOF 24MB038 PCT Pharmaceutical compositions containing a compound of the present disclosure, and / or pharmaceutically acceptable salts thereof, can also be prepared in powder or liquid concentrate form.

[0203] The pharmaceutical composition (or formulation) may be packaged in a variety of ways. Generally, an article for distribution includes a container that contains the pharmaceutical composition in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, foil blister packs, and the like. The container may also include a tamper proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container typically has deposited thereon a label that describes the contents of the container and any appropriate warnings or instructions.

[0204] The disclosed pharmaceutical compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Pharmaceutical compositions comprising a disclosed compound formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0205] The exact dosage and frequency of administration depends on the particular disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, solvate, or polymorph thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, or a stereochemically isomeric form thereof; the particular condition being treated and the severity of the condition being treated; various factors specific to the medical history of the subject to whom the dosage is administered such as the age; weight, sex, extent of disorder and general physical condition of the particular subject, as well as other medication the individual may be taking; as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or

[0206] 34

[0207] 45829115.1Docket No. MOF 24MB038 PCT increased depending on the response of the treated subject and / or depending on the evaluation of the physician prescribing the compounds of the present disclosure.

[0208] Depending on the mode of administration, the pharmaceutical composition will comprise from 0.05 to 99 % by weight, preferably from 0.1 to 70 % by weight, more preferably from 0.1 to 50 % by weight of the active ingredient, and, from 1 to 99.95 % by weight, preferably from 30 to 99.9 % by weight, more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.

[0209] In the treatment conditions which require prevention of aspiration of gastric contents an appropriate dosage level will generally be about 0.01 to 1000 mg per kg patient body weight per day and can be administered in single or multiple doses. In various aspects, the dosage level will be about 0.1 to about 500 mg / kg per day, about 0.1 to 250 mg / kg per day, or about 0.5 to 100 mg / kg per day. A suitable dosage level can be about 0.01 to 1000 mg / kg per day, about 0.01 to 500 mg / kg per day, about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range the dosage can be 0.05 to 0.5, 0.5 to 5.0 or 5.0 to 50 mg / kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 mg of the active ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50. 75, 100, 150, 200, 250, 300, 400, 500. 600, 750, 800, 900 and 1000 mg of the active ingredient for the symptomatic adjustment of the dosage of the patient to be treated. The compound can be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. This dosing regimen can be adjusted to provide the optimal therapeutic response.

[0210] Such unit doses as described hereinabove and hereinafter can be administered more than once a day, for example, 2, 3, 4, 5 or 6 times a day. In various aspects, such unit doses can be administered 1 or 2 times per day, so that the total dosage for a 70 kg adult is in the range of 0.001 to about 15 mg per kg weight of subject per administration. In a further aspect, dosage is 0.01 to about 1.5 mg per kg weight of subject per administration, and such therapy can extend for a number of weeks or months, and in some cases, years. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs that

[0211] 35

[0212] 45829115.1Docket No. MOF 24MB038 PCT have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those of skill in the area.

[0213] A typical dosage can be one 1 mg to about 100 mg of powder or 1 mg to about 300 mg taken once a day, or, multiple times per day, or one time-release capsule or tablet taken once a day and containing a proportionally higher content of active ingredient. The time-release effect can be obtained by capsule materials that dissolve at different pH values, by capsules that release slowly by osmotic pressure, or by any other known means of controlled release.

[0214] In some embodiments, the composition disclosed herein can be used for perioperative use. In some embodiments, the dosing paradigm is a single administration of approximately 10-50 mL (or equivalent dose) of the formulation, administered between 15 minutes and 1 hour prior to induction of anaesthesia, via oral ingestion, nasogastric tube, or orogastric tube to deliver the composition directly to its site of action in the stomach. In some embodiments, the formulation may take any ingestible fomr, including but not limited to a liquid, gel, suspension, emulsion, powder for reconstitution, capsule, tablet, chewable tablet, lozenge, or any combination thereof. In some embodiments, the intent is a single-dose, time-limited mechanical effect rather than chronic daily dosing.

[0215] It can be necessary to use dosages outside these ranges in some cases as will be apparent to those skilled in the art. Further, it is noted that the clinician or treating physician will know how and when to start, interrupt, adjust, or terminate therapy in conjunction with individual patient response.

[0216] The disclosed pharmaceutical compositions can further comprise other therapeutically active compounds, which are usually applied in the treatment of the above mentioned pathological or clinical conditions.

[0217] It is understood that the disclosed compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using.

[0218] As already mentioned, the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, and a pharmaceutically acceptable carrier. Additionally, the present disclosure relates to a process for preparing such a pharmaceutical composition, characterized in that a pharmaceutically acceptable earner

[0219] 36

[0220] 45829115.1Docket No. MOF 24MB038 PCT is intimately mixed with a therapeutically effective amount of a compound according to the present disclosure.

[0221] As already mentioned, the present disclosure also relates to a pharmaceutical composition comprising a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, and one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for a disclosed compound or the other drugs may have utility as well as to the use of such a composition for the manufacture of a medicament. The present disclosure also relates to a combination of disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, and a therapeutic agent known to prevent aspiration of gastric contents, treat a disorder associated with increased risk of pulmonary aspiration of gastric contents, or treat a disease or disorder having an increased risk of pulmonary aspiration of gastric contents, fhe present disclosure also relates to such a combination for use as a medicine. The present disclosure also relates to a product comprising (a) disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, and (b) an additional therapeutic agent, as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the modulatory effect of the disclosed compound and the additional therapeutic agent. The different drugs of such a combination or product may be combined in a single preparation together with pharmaceutically acceptable carriers or diluents, or they may each be present in a separate preparation together with pharmaceutically acceptable carriers or diluents.

[0222] In a further aspect, the present disclosure provides methods of treatment comprising administration of a therapeutically effective amount of a disclosed compound or pharmaceutical composition as disclosed herein above to a subject in need thereof. The disclosed compounds can be used as single agents or in combination with one or more other drugs in the treatment, prevention, control, amelioration or reduction of risk of the aforementioned diseases, disorders and conditions for which the compounds disclosed herein or the other drugs have utility, where the combination of drugs together are safer or more effective than either drug alone. The other drug(s) can be administered by a route and in an amount commonly used therefore, contemporaneously or

[0223] 37

[0224] 45829115.1Docket No. MOF 24MB038 PCT sequentially with a disclosed compound. When a disclosed compound is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such drugs and the disclosed compound is preferred. However, the combination therapy can also be administered on overlapping schedules. It is also envisioned that the combination of one or more active ingredients and a disclosed compound will be more efficacious than either as a single agent.

[0225] In one aspect, the compounds and pharmaceutical compositions disclosed herein are useful for treating, preventing, ameliorating, controlling, or reducing the risk of pulmonary aspiration of gastric contents in a subject. The method of preventing aspiration of gastric contents can include the step of administering to a subject a therapeutically effective amount of at least one compound disclosed herein or administering to a subject a pharmaceutical composition as disclosed herein. The subject can be a mammal, such as a human. In one aspect, the method of treatment can further comprise identifying a subject in need of treatment of a disorder having an increased risk of pulmonary aspiration of gastric contents. In another aspect, the subject can be diagnosed with a need for prevention of aspiration of gastric contents prior to the administering step.

[0226] In various aspects of the present disclosure, disclosed are methods for the prevention of pulmonary aspiration of gastric contents in a mammal involving the step of administering to the mammal a therapeutically effective amount of at least one compound comprising sodium alginate, calcium, and bicarbonate, or a pharmaceutically acceptable salt thereof.

[0227] In various embodiments of the present disclosure, the mammal is a human.

[0228] In some embodiments, the mammal has been diagnosed with a condition having increased risk of pulmonary aspiration of gastric contents prior to the administering step.

[0229] In some embodiments, the method further involves the step of identifying a mammal in need of prevention of pulmonary aspiration of gastric contents.

[0230] In some embodiments, the mammal has been diagnosed with a condition associated with increased risk of pulmonary aspiration of gastric contents. In some examples, the condition can be pregnancy, diabetes, gastroparesis, peripheral neuropathy, gastrointestinal obstruction, esophageal cancer, hiatal hernia, obesity, traumatic brain injury, gastroesophageal reflux disease, esophageal dysmotility, gas bloat, large paraesophageal hernia, or achalasia.

[0231] 38

[0232] 45829115.1Docket No. MOF 24MB038 PCT In some embodiments, the proposed use in pregnancy involves chronic or as-needed administration to reduce gastroesophageal reflux symptoms, particularly nocturnal reflux, in pregnant patients for whom OTC antacids and H2 blockers are either ineffective or undesirable. Given the well-established safety profile of the components, a modified formulation with a reduced concentration is envisioned for this population that is sufficient to form an effective raft while remaining appropriate for use during pregnancy-related reflux events.

[0233] In some embodiments, the compound can further comprises at least one of a proton pump inhibitor (PPI), an antacid, a histamine (H2)-receptor antagonist, or a combination of any thereof.

[0234] Also disclosed herein are various methods for physically restricting gastric contents from refluxing into an esophagus in a mammal involving the step of administering to the mammal a therapeutically effective amount of at least one compound comprising sodium alginate, calcium, and bicarbonate, or a pharmaceutically acceptable salt thereof.

[0235] In some embodiments, the mammal has been diagnosed with a condition having increased risk of gastric contents refluxing into the esophagus prior to the administering step.

[0236] In some embodiments, the method further involves identifying a mammal in need of physical restriction of gastric contents from refluxing into the esophagus.

[0237] In some embodiments, the mammal has been diagnosed with a condition associated with increased risk of gastric contents refluxing into the esophagus. In some examples, the condition can be pregnancy, diabetes, gastroparesis, peripheral neuropathy, gastrointestinal obstruction, esophageal cancer, hiatal hernia, obesity, traumatic brain injury, gastroesophageal reflux disease, esophageal dysmotility, gas bloat, large paraesophageal hernia, or achalasia.

[0238] Also disclosed herein are various embodiments of a kit having at least one compound comprising sodium alginate, calcium, and bicarbonate, or a pharmaceutically acceptable salt thereof; and one or more of: at least one agent known to increase gastrointestinal motility, at least one agent known to decrease stomach acid production, at least one agent known to treat a condition associated with pulmonary aspiration of gastric contents, at least one agent known to treat a condition having an increased risk of pulmonary aspiration of gastric contents, or instructions for preventing pulmonary aspiration of gastric contents.

[0239] 39

[0240] 45829115.1Docket No. MOF 24MB038 PCT In some embodiments, the at least one compound and the at least one agent are co-formulated. In other embodiments, the at least one compound and the at least one agent are co-packaged. In some embodiments, the kit can further have instructions to provide the compound in connection with intubation or administration of anesthesia.

[0241] In some embodiments, the instructions provide that intubation is performed or anesthesia is administered after the administering of at least one compound.

[0242] In some embodiments, the instructions provide that the administering of at least one compound is to effect prevention of pulmonary aspiration of gastric contents.

[0243] In some embodiments, the kit can further comprise a plurality of dosage forms, the plurality comprising one or more doses; wherein each dose comprises a therapeutically effective amount of the at least one compound and the at least one agent.

[0244] In some embodiments, each dose of the at least one compound and the at least one agent are co-formulated. In other embodiments, each dose of the at least one compound and the at least one agent are co-packaged.

[0245] In some embodiments, the dosage forms can be formulated for oral administration.

[0246] In some embodiments, the at least one agent is a proton pump inhibitor, an antacid, or a histamine (H2)-receptor antagonist.

[0247] Also disclosed herein are various embodiments relating to use of at least one compound comprising sodium alginate, calcium, and bicarbonate in the manufacture of a medicament for the prevention of pulmonary aspiration of gastric contents in a mammal.

[0248] In some embodiments, the compositions described herein can be administered in conjunction with one or more agents, including proton pump inhibitors, antacids, and histamine (H2)-receptor antagonists, or pharmaceutically acceptable salts of any thereof.

[0249] In various aspects, the disclosed kits can also comprise compounds and / or products co-packaged, co-formulated, and / or co-delivered with other components. For example, a drug manufacturer, a drug reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising a disclosed compound and / or product and another component for delivery to a patient.

[0250] In another aspect, the kit can comprise a plurality of dosage forms of the compound or pharmaceutical composition, such as an oral dosage form, a parenteral injection form, or an intravenous injectable form, as disclosed herein.

[0251] In a further aspect, the kit can comprise instructions for providing the compound or pharmaceutical composition in connection with surgery. The instructions can provide

[0252] 40

[0253] 45829115.1Docket No. MOF 24MB038 PCT that the surgery be performed prior to or after administering the compound or pharmaceutical composition. In another aspect, the instructions can provide that the surgery be performed at about the same time as the administering of the compound or pharmaceutical composition.

[0254] The disclosed compounds and / or pharmaceutical compositions comprising the disclosed compounds can conveniently be presented as a kit, whereby two or more components, which may be active or inactive ingredients, carriers, diluents, and the like, are provided with instructions for preparation of the actual dosage form by the patient or person administering the drug to the patient. Such kits may be provided with all necessary materials and ingredients contained therein, or they may contain instructions for using or making materials or components that must be obtained independently by the patient or person administering the drug to the patient. In further aspects, a kit can include optional components that aid in the administration of the unit dose to patients, such as vials for reconstituting powder forms, syringes for injection, customized IV delivery systems, inhalers, etc. Additionally, a kit can contain instructions for preparation and administration of the compositions. The kit can be manufactured as a single use unit dose for one patient, multiple uses for a particular patient (at a constant dose or in which the individual compounds may vary in potency as therapy progresses); or the kit may contain multiple doses suitable for administration to multiple patients (“bulk packaging”). The kit components may be assembled in cartons, blister packs, bottles, tubes, and the like.

[0255] In a further aspect, the disclosed kits can be packaged in a daily dosing regimen (e.g., packaged on cards, packaged with dosing cards, packaged on blisters or blow-molded plastics, etc.). Such packaging promotes products and increases patient compliance with drug regimens. Such packaging can also reduce patient confusion. The present invention also features such kits further containing instructions for use.

[0256] In a further aspect, the present disclosure also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

[0257] 41

[0258] 45829115.1Docket No. MOF 24MB038 PCT It is contemplated that the disclosed kits can be used in connection with the disclosed methods of making, the disclosed methods of using or treating, and / or the disclosed compositions.

[0259] In one aspect, the invention relates to a method for the manufacture of a medicament for prevention of aspiration of gastric contents in a mammal. The method can include combining a therapeutically effective amount of a disclosed compound or product of a disclosed method of making with a pharmaceutically acceptable carrier or diluent.

[0260] In various embodiments, the disclosure relates to methods for preventing pulmonary aspiration of gastric contents in a patient comprising administering a therapeutically effective amount of a compound comprising sodium alginate, calcium, and bicarbonate, or pharmaceutically acceptable salts thereof. The present disclosure therefore provides prevention of pulmonary aspiration in patients at risk of aspirating gastric contents due to impaired gastrointestinal emptying and / or gastroparesis. A patient at risk of aspirating gastric contents includes patients with conditions having increased risk of gastric reflux, such as one who has gastrointestinal obstruction or another acute intra- abdominal process.

[0261] Alginates are naturally derived compounds made from brown seaweed. They work as a thickening agent to form a buoyant alginate raft that acts as a physical barrier against gastric contents refluxing into the esophagus. Alginates have a long-track record of safety, biocompatibility, with minimal side effects, and now have been shown to be as effective in the treatment of acid reflux as proton pump inhibitors (PPIs).

[0262] Alginate-based formulations act primarily by a unique non-systemic mechanism of action. When exposed to stomach acid, alginates rapidly undergo gelation and form a gel-like structure known as a “raft.” Alginate rafts can protect the esophageal mucosa by limiting gastric reflux of gastric contents into the esophagus, often by floating to the top of the stomach and blocking contents from reflux. Alginate rafts, according to the methods described herein, can be used to prevent pulmonary aspiration of gastric contents. In some examples, the alginate-based formulations can be administered to a patient during the peri-intubation time period after the patient is placed under general anesthesia but before an endotracheal tube is placed. The alginate -based formulations described herein can serve as a barrier between the stomach and esophagus to physically prevent stomach contents from coming up into the esophagus.

[0263] 42

[0264] 45829115.1Docket No. MOF 24MB038 PCT As described herein, alginate rafts can comprise algae (sodium alginate), calcium, and bicarbonate. Current commercially available formulations of alginate-based formulations and compounds may not be strong enough to block active vomiting.

[0265] Therefore, in some embodiments, a higher proportion of calcium is present.

[0266] In some embodiments, the alginate-based formulations can be a commercially available formulation. In some examples, the commercially available formulation can be Gaviscon®, Algicon®, Gastrocoat®, or Magnatol®.

[0267] In some embodiments, the alginate -based formulation can be polysaccharides and polysaccharide derivatives. Such polymers may include, without limitation, alginates (including sodium alginate, potassium alginate, and calcium alginate), chitosan, chitin, carrageenan, agar, agarose, hyaluronic acid, dextran, pullulan, pectin, gellan gum, xanthan gum, guar gum, cellulose and cellulose derivatives (including methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, and carboxymethyl cellulose), starch and modified starches, and combinations thereof.

[0268] In various embodiments, the compounds and formulations used in the methods described herein can comprise alginates or an alginic acid or a salt or ester thereof and a source of divalent calcium which act as cross-linking agents. In some examples, suitable sources of calcium ions are those derived from the carbonate, lactate, chloride, gluconate, phosphate, hydrogen phosphate, sulphate, tartrate or citrate salts. In some embodiments, the compounds and formulations used in the methods described herein can comprise carbonate or bicarbonate salts. In some examples, suitable carbonate or bicarbonate salts are potassium carbonate or bicarbonate, sodium carbonate or bicarbonate, calcium carbonate, sodium glycine carbonate, magnesium carbonate or aluminum carbonate. The carbonate or bicarbonate salt can be present in an amount so as to provide an adequate volume of gas, or carbon dioxide, to float the alginate gel produced when the compound or formulation contacts gastric acid in the stomach.

[0269] Suitable alginates can be isolated from various species, in particular from algae belonging to the order Phaeophyceae and soil bacteria such as Azotobacter vinelandii and Azotobacter crococcum and from several strains of Pseudomonas bacteria. Sources of alginates can include Laminaria digitata, Ecklonia maxima, Macrocystis pyrifera, Lessonia nigrescens, Ascophyllum nodosum, Laminaria japonica, Durvillea antartica, Durvillea potatorum and Laminaria hyperborea.

[0270] 43

[0271] 45829115.1Docket No. MOF 24MB038 PCT The alginate-based formulations and compounds described herein can also comprise a proton pump inhibitor (PPI). In some examples, the PPI can be dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, or rabeprazole.

[0272] In some embodiments, the alginate-based formulations and compounds can comprise a histamine (H2)-antagonist. In some examples, the histamine antagonist can be cimetidine, famotidine, nizatidine, or ranitidine.

[0273] In some embodiments, the alginate-based formulations and compounds can comprise an additional agent. In some examples, the agent can be a prokinetic, such as domperidone, metoclopramide, erythromycin, or renzapride, to promote gastric emptying and reduce risk of aspiration.

[0274] In some embodiments, methods for preventing aspiration of gastric contents can include administration of a therapeutically effective amount of any of the previously described compounds or formulations which are capable of forming a floating gelatinous raft when contacted with stomach acid sufficient to block stomach contents from entering the esophagus.

[0275] In some embodiments, pulmonary aspiration may occur in association with one or more reflux events involving retrograde movement of gastrointestinal contents toward the upper aerodigestive tract. Such reflux events may include, but are not limited to, Gastroesophageal Reflux Disease (GERD), Laryngopharyngeal Reflux (LPR), bile reflux, Duodenog astric Reflux (DGR), vomiting, dysphagia, and conditions associated with recurrent regurgitation, including Rumination Syndrome.

[0276] In some embodiments, adjustment of the relative ratios of the components of the compositions disclosed herein may provide therapeutic flexibility for the treatment of patients experiencing different reflux-related events. In certain embodiments, compositions comprising modified component ratios may be administered sequentially or co-administered.

[0277] In some embodiments, sequential administration comprises administering a first composition disclosed herein, followed by administration of a second composition disclosed herein, optionally comprising an additional pharmaceutically acceptable salt. A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

[0278] 44

[0279] 45829115.1Docket No. MOF 24MB038 PCT EMBODIMENTS

[0280] Embodiment 1. A method for the prevention of pulmonary aspiration of gastric contents in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one compound comprising sodium alginate, calcium carbonate, and sodium bicarbonate, or a pharmaceutically acceptable salt thereof.

[0281] Embodiment 2. The method of embodiment 1 , wherein the mammal is a human. Embodiment 3. The method of any one of embodiments 1 or 2, wherein the mammal has been diagnosed with a condition having increased risk of pulmonary aspiration of gastric contents prior to the administering step.

[0282] Embodiment 4. The method of any one of embodiments 1 to 3, further comprising the step of identifying a mammal in need of prevention of pulmonary aspiration of gastric contents.

[0283] Embodiment 5. The method of any one of embodiments 1 to 4, wherein the mammal has been diagnosed with a condition associated with increased risk of pulmonary aspiration of gastric contents.

[0284] Embodiment 6. The method of any one of embodiments 1 to 5, wherein the condition is pregnancy, diabetes, gastroparesis, peripheral neuropathy, gastrointestinal obstruction, esophageal cancer, surgical absence of lower esophageal sphincter (and / or portions of esophagus), hiatal hernia, obesity, traumatic brain injury, altered mental status, stroke, gastroesophageal reflux disease, esophageal dysmotility, gas bloat, large paraesophageal hernia, critical illness, dysphagia, or achalasia.

[0285] Embodiment 7. The method of any one of embodiments 1 to 6, wherein the compound further comprises at least one of a proton pump inhibitor (PPI), an antacid, a histamine (thj-receptor antagonist, or a combination of any thereof.

[0286] Embodiment 8. The method of any one of embodiments 1 to 7, wherein the composition is administered in conjunction with one or more agents selected from the group consisting of proton pump inhibitors, antacids, and histamine (thj-receptor antagonists, or pharmaceutically acceptable salts of any thereof.

[0287] Embodiment 9. A method for physically restricting gastric contents from refluxing into an esophagus in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one compound comprising sodium alginate, calcium, and bicarbonate, or a pharmaceutically acceptable salt thereof.

[0288] Embodiment 10. The method of embodiment 9, wherein the mammal is a human.

[0289] 45

[0290] 45829115.1Docket No. MOF 24MB038 PCT Embodiment 11. The method of any one of embodiment 9 or 10, wherein the mammal has been diagnosed with a condition having increased risk of gastric contents refluxing into the esophagus prior to the administering step.

[0291] Embodiment 12. The method of any one of embodiments 9 to 11, further comprising the step of identifying a mammal in need of physical restriction of gastric contents from refluxing into the esophagus.

[0292] Embodiment 13. The method of any one of embodiments 9 to 12, wherein the mammal has been diagnosed with a condition associated with increased risk of gastric contents refluxing into the esophagus.

[0293] Embodiment 14. The method of any one of embodiments 9 to 13, wherein the condition is pregnancy, diabetes, gastroparesis, peripheral neuropathy, gastrointestinal obstruction, esophageal cancer, hiatal hernia, obesity, traumatic brain injury, gastroesophageal reflux disease, esophageal dysmotility, gas bloat, large paraesophageal hernia, or achalasia.

[0294] Embodiment 15. The method of any one of embodiments 9 to 14, wherein the compound further comprises at least one of a proton pump inhibitor (PPI), an antacid, a histamine (ITj-receptor antagonist, or a combination of any thereof.

[0295] Embodiment 16. The method of any one of embodiments 9 to 15, wherein the composition is administered in conjunction with one or more agents selected from the group consisting of proton pump inhibitors, antacids, and histamine (H2)-receptor antagonists, or pharmaceutically acceptable salts of any thereof.

[0296] Embodiment 17. A kit comprising at least one compound comprising sodium alginate, calcium, and bicarbonate, or a pharmaceutically acceptable salt thereof; and one or more of:

[0297] a) at least one agent known to increase gastrointestinal motility;

[0298] b) at least one agent known to decrease stomach acid production;

[0299] c) at least one agent known to treat a condition associated with pulmonary aspiration of gastric contents;

[0300] d) at least one agent known to treat a condition having an increased risk of pulmonary aspiration of gastric contents; or

[0301] e) instructions for preventing pulmonary aspiration of gastric contents. Embodiment 18. The kit of embodiment 17, wherein the at least one compound and the at least one agent are co-formulated.

[0302] 46

[0303] 45829115.1Docket No. MOF 24MB038 PCT Embodiment 19. The kit of any one of embodiment 17 or 18, wherein the at least one compound and the at least one agent are co-packaged.

[0304] Embodiment 20. The kit of any one of embodiments 17 to 19, further comprising instructions to provide the compound in connection with intubation or administration of anesthesia.

[0305] Embodiment 21. The kit of any one of embodiments 17 to 20, wherein the instructions provide that intubation is performed or anesthesia is administered after the administering of at least one compound.

[0306] Embodiment 22. The kit of any one of embodiments 17 to 21, wherein the instructions provide that the administering of at least one compound is to effect prevention of pulmonary aspiration of gastric contents.

[0307] Embodiment 23. The kit of any one of embodiments 17 to 22, further comprising a plurality of dosage forms, the plurality comprising one or more doses; wherein each dose comprises a therapeutically effective amount of the at least one compound and the at least one agent.

[0308] Embodiment 24. The kit of any one of embodiments 17 to 23, wherein each dose of the at least one compound and the at least one agent are co-formulated.

[0309] Embodiment 25. The kit of any one of embodiments 17 to 24. wherein each dose of the at least one compound and the at least one agent are co-packaged.

[0310] Embodiment 26. The kit of any one of embodiments 17 to 25, wherein the dosage forms are formulated for oral administration.

[0311] Embodiment 27. The kit of any one of embodiments 17 to 26, wherein the at least one agent is a proton pump inhibitor, an antacid, or a histamine (H2)-receptor antagonist.

[0312] Embodiment 28. Use of a compound of at least one compound of comprising sodium alginate, calcium, and bicarbonate in the manufacture of a medicament for the prevention of pulmonary aspiration of gastric contents in a mammal.

[0313] Embodiment 29. The method of embodiment 1, wherein the sodium alginate in the first compound is a concentration from about 10 mg / mL to about 100 mg / mL, the calcium carbonate is at a concentration from about 5 mg / mL to about 60 mg / mL, and the concentration of sodium bicarbonate is at a concentration from about 5 mg / mL to about 50 mg / mL.

[0314] Embodiment 30. The method of embodiment 29, further comprising administering a second compound comprising sodium alginate, calcium carbonate, and

[0315] 47

[0316] 45829115.1Docket No. MOF 24MB038 PCT sodium bicarbonate, wherein the second compound has a higher concentration of sodium alginate than the first compound.

[0317] Embodiment 31. The method of embodiment 30, wherein the second compound is administered sequentially or simultaneously with the first compound.

[0318] Embodiment 32. A pharmaceutical composition for the prevention or reduction of pulmonary aspiration of gastric contents in a mammal, comprising:

[0319] a. a polysaccharide or polysaccharide derivative,

[0320] b. a carbonate or bicarbonate salt,

[0321] c. an ionic salt, and

[0322] d. a pharmaceutically acceptable carrier,

[0323] wherein the pharmaceutical composition forms a raft atop gastric contents; and wherein the raft maintains an intact mass for at least 20 minutes after agitation at 100 rpm, wherein the raft has an elastic modulus of at least 1 kPa to 100 kPa, wherein the raft has a density of at least 0.5 to at least 0.95 g / cm3, or any combination thereof.

[0324] Embodiment 33. The pharmaceutical composition of embodiment 32, wherein the polysaccharide or polysaccharide derivative comprises an alginate.

[0325] Embodiment 34. The pharmaceutical composition of any one of embodiments 32 or 33, wherein the alginate is from about 10 mg / mL to about 100 mg / mL sodium alginate.

[0326] Embodiment 35. The pharmaceutical composition of any one of embodiments 32 to 34, wherein the carbonate or bicarbonate salt comprises sodium bicarbonate is from about 5 mg / mL to about 60 mg / mL.

[0327] Embodiment 36. The pharmaceutical composition of any one of embodiments 32 to 35, wherein the ionic salt comprises calcium carbonate is from about 5 mg / mL to about 50 mg / mL.

[0328] EXAMPLES

[0329] Example 1: Administration of an Alginate to Prevent Pulmonary Aspiration of Enteric Contents

[0330] Pulmonary aspiration of gastric contents remains an important issue in anesthesiology, with significant implications for patient safety and outcomes due to morbidity, mortality, and potential medico-legal consequences. Pulmonary aspiration of gastric contents accounts for 5% of claims in the American Society of Anesthesiologists Closed Claims Project, with 57% of these events resulting in death. Of those patients who aspirated, 61% had either gastrointestinal obstruction or another acute intra- 48

[0331] 45829115.1Docket No. MOF 24MB038 PCT abdominal process. Other studies have shown rates of pulmonary aspiration ranging from as rare as 1 in 10,000 to as common as 1 in every 2,000 anesthetics. The majority of these events occur, as would be expected, when the patient’s consciousness and airway reflexes are impaired such as during monitored anesthesia care and induction of general anesthesia both before and during airway instrumentation, but can occur anytime in the peri-anesthetic period.

[0332] Identified risk factors (Table 1) for aspiration include but are not limited to emergent procedures, gastrointestinal obstruction or other acute abdominal process, morbid obesity, recent oral intake, neurologic disease, recent traumatic injury, pregnancy, history of gastric bypass, medications or conditions that affect lower esophageal sphincter(LES) tone, recent opioid administration, or medical comorbidities such as diabetes mellitus or gastroesophageal reflux disease (GERD). The number of surgical procedures performed worldwide continues to rise each year, coinciding with an increasing prevalence of aspiration risk factors such as obesity and diabetes mellitus. Even further, this risk is exacerbated by the increasing use of glucagon-like peptide- 1 (GLP-1) receptor agonists, which slow gastric emptying, rising rates of diabetes and gastroparesis, and contributing to the growing volume of surgical procedures globally. Additionally, emergent surgeries, such as those related to trauma or childbirth, present challenges in risk mitigation when NPO guidelines cannot be strictly observed.

[0333] Table 1. Risk Factors for Pulmonary Aspiration of Gastric Contents

[0334]

[0335] Category Risk Factor Mechanism

[0336] Increases intra-abdominal pressure and reflux Obesity

[0337] risk.

[0338] Diabetes mellitus Gastroparesis leads to delayed gastric emptying. Gastroesophageal

[0339] Weak lower esophageal sphincter (LES) allows reflux disease

[0340] retrograde flow.

[0341] (GERD)

[0342] Neurologic

[0343] disorders (e.g., Impaired swallowing and cough reflexes reduce stroke, airway protection.

[0344] Patient-related Parkinson’ s)

[0345] Altered mental

[0346] status (e.g.,

[0347] Depressed consciousness impairs protective trauma,

[0348] intoxication, airway reflexes.

[0349] sedation)

[0350] Hormonal and mechanical factors delay Pregnancy

[0351] emptying and weaken LES tone.

[0352] Hiatal hernia Alters anatomy and weakens LES bam er.

[0353]

[0354] Advanced age Reduces gastric motility and reflex sensitivity.

[0355] 49

[0356] 45829115.1Docket No. MOF 24MB038 PCT

[0357] Recent food or

[0358] fluid intake (<6— 8 Increases residual gastric volume and acidity. hours NPO)

[0359] Emergency

[0360] Stomach assumed to be full; no fasting period. surgery

[0361] Upper GI or Direct manipulation increases risk of esophageal surgery regurgitation.

[0362] Proximal accumulation of gastric contents and Bowel obstruction

[0363] gas.

[0364] S urgical / Procedural Increased intraabdominal

[0365] Mechanically impairs gastric emptying and pressure (e.g.,

[0366] promotes reflux.

[0367] laparoscopy,

[0368] ascites)

[0369] Trendelenburg or

[0370] Facilitates retrograde flow of gastric contents lithotomy

[0371] toward the oropharynx.

[0372] positioning

[0373] Inadequate NPO Residual stomach contents increase aspiration duration risk at induction.

[0374] Positive pressure

[0375] mask ventilation Insufflation of stomach increases likelihood of before airway regurgitation.

[0376] secured

[0377] Prolonged or

[0378] Extends time with unprotected airway; increases difficult airway

[0379] aspiration risk.

[0380] management

[0381] Anesthetic Inadequate depth

[0382] technique-related of anesthesia May trigger vomiting or coughing during during airway laryngoscopy.

[0383] manipulation

[0384] Improper airway

[0385] protection (e.g., Allows refluxed contents to bypass airway unsealed cuff, defenses.

[0386] wrong placement)

[0387] Use of supraglottic

[0388] Provides less protection than endotracheal airway devices in

[0389] tubes.

[0390] high-risk patients

[0391] GLP-1 receptor

[0392] Significantly delay gastric emptying and agonists (e.g.,

[0393] increase residual volume.

[0394] semaglutide)

[0395] Slows gastric motility and increases residual Medication-related Opioid use

[0396] content.

[0397] Anticholinergics Reduce GI motility and lower LES tone.

[0398] Sedatives and Impair consciousness and suppress airway benzodiazepines reflexes.

[0399] Nasogastric or

[0400] Disrupts LES function and may serve as a Other orogastric tube

[0401] conduit for reflux.

[0402]

[0403] presence

[0404] 50

[0405] 45829115.1Docket No. MOF 24MB038 PCT

[0406] Current Strategies for Aspiration Prevention

[0407] Pulmonary aspiration of gastric contents first requires gastric regurgitation via either lower esophageal sphincter relaxation and / or increased intragastric pressure then is followed by pulmonary aspiration. This is distinct from other routes of pulmonary aspiration which may originate in the oral or nasal cavity such as when food finds it way into the tracheobronchial tree rather than the esophagus. This distinction is important because the methods to prevent pulmonary aspiration of gastric contents lend themselves mostly to the prevention of gastric regurgitation, either by preventing any gastric contents from existing, limiting their ability to enter the trachea or as a last resort, minimizing the damage they will cause if they do enter the lungs.

[0408] Current strategies to prevent or mitigate the sequelae of pulmonary aspiration utilize both pharmacologic and non-pharmacologic approaches including adequate preoperative fasting, avoidance of medications that delay gastric emptying or reduce lower esophageal sphincter tone, placement of pre-induction nasogastric tube (NGT) and the use of rapid sequence induction (RSI) (fable 2). Pharmacologic methods primarily involve the use of non-particulate antacids and prokinetics, while non-pharmacologic strategies encompass NPO guidelines, head elevation, pre -induction NGT placement, cricoid pressure, rapid sequence induction to minimize gastric insufflation, and ensuring timely airway securement. Additional preventive measures include awake fiberoptic intubation and pharmacologic approaches such as non-particulate antacids and prokinetic agents. However, these strategies have important limitations: their effectiveness varies, and their implementation may be impractical in certain clinical scenarios, such as facial trauma, patient non-cooperation, or cervical spine instability. The combination of rising surgical volume, increasing prevalence of aspiration risk factors, and the absence of a universally effective prophylactic method to prevent pulmonary aspiration, underscores the urgent need for a more reliable intervention. Despite their widespread use, the effectiveness of these interventions remains uncertain. Multiple studies have demonstrated inconsistent results in preventing pulmonary aspiration, and to date, no pharmacologic agent has received stronger than a "may be used" or "no routine use" recommendation in the American Society of Anesthesiologists (ASA) guidelines.

[0409] Table 2. Non-pharmacologic anc Pharmacologic Aspiration Prevention Strategies Strategy Type Mechanism Benefit Limitation Not feasible in Non- Minimizes gastric Reduces

[0410] emergencies; does NPO Guidelines volume by gastric content pharmacologic not address delayed restricting oral volume:

[0411]

[0412] gastric emptying 51

[0413] 45829115.1Docket No. MOF 24MB038 PCT

[0414] Table 2. Non-pharmacologic anc Pharmacologic Aspiration Prevention Strategies Strategy Type Mechanism Benefit Limitation intake standard of

[0415] preoperatively care

[0416] Efficacy is Applies pressure to controversial; may Aims to

[0417] Non- occlude the distort airway Cricoid Pressure prevent passive pharmacologic esophagus during anatomy and regurgitation

[0418] intubation complicate intubation Positions patient Effectiveness is May reduce

[0419] Head-Up Non- with head elevated position-dependent;

[0420] reflux risk

[0421] Positioning pharmacologic to reduce reflux by through gravity may not be feasible gravity in all patients Combines rapid

[0422] sedation and Standard of

[0423] intubation with care in high- Risk of inadequate cricoid pressure to risk patients; preoxygenation; occlude the minimizes cricoid pressure esophagus, head-up unprotected efficacy is Rapid Sequence Non- positioning to airway time, controversial and Induction (RSI) pharmacologic reduce reflux by reduces may distort airway gravity, and passive anatomy; head-up avoidance of regurgitation, positioning positive pressure and limits effectiveness is ventilation to gastric position-dependent prevent gastric distension

[0424] insufflation

[0425] Maintains

[0426] Useful in

[0427] spontaneous

[0428] difficult airway Cannot be ventilation while

[0429] scenarios; performed in Awake securing airway

[0430] Non- avoids positive emergencies or Video / Fiberoptic under direct

[0431] pharmacologic pressure uncooperative Intubation visualization,

[0432] ventilation and patients; highly reducing risk of

[0433] preserves operator dependent gastric content

[0434] airway reflexes

[0435] aspiration

[0436] Reduces May not be Nasogastric Decompresses

[0437] Non- volume of tolerated in awake Tube (prestomach contents

[0438] pharmacologic gastric patients; potential induction) before induction

[0439] contents mucosal trauma Not feasible for all Avoids sedation by Eliminates

[0440] surgeries;

[0441] Regional, using regional risks

[0442] contraindicated in Neuraxial, or Non- nerve blocks, associated with

[0443] some patients due Local pharmacologic neuraxial (e.g., airway

[0444] to coagulation Anesthesia spinal / epidural), or manipulation

[0445] status or other local anesthesia and aspiration

[0446]

[0447] factors

[0448] 52

[0449] 45829115.1Docket No. MOF 24MB038 PCT

[0450] Table 2. Non-pharmacologic anc Pharmacologic Aspiration Prevention Strategies Strategy Type Mechanism Benefit Limitation Reduces Does not reduce Non-Particulate Neutralize gastric

[0451] Pharmacologic acidity of volume or prevent Antacids acid

[0452] aspirate reflux

[0453] Does not reduce Acid-Reducers Reduces volume or prevent Reduce acid

[0454] (e.g., PPI’s and Pharmacologic acidity of reflux; take secretion

[0455] H2 blockers) aspirate prolonged time to work

[0456] May reduce Limited efficacy in Prokinetic

[0457] Enhances gastric gastric volume diabetic Agents (e.g., Pharmacologic

[0458] emptying in select gastroparesis; not metoclopramide)

[0459] patients immediate acting Non-systemic;

[0460] immediate

[0461] Not yet studied for Form a buoyant onset;

[0462] aspiration gel-like “raft” that physically

[0463] prevention floats on gastric prevents reflux perioperatively; Alginates Pharmacologic contents, physically of all stomach

[0464] commercial blocking reflux and contents

[0465] formulations not neutralizing gastric including acid,

[0466] optimized for this acid pepsin, and

[0467] purpose solid / liquid

[0468]

[0469] contents

[0470] Alginate Strategy

[0471] Alginates are a family of naturally occurring linear copolymers consisting of (l,4)-linked P-D-mannuronic acid (M) and a-L-guluronic acid (G) residues, that are typically extracted from various species of brown algae (Phaeophyceae), with Laminaria hyperborea representing the most important source for anti-reflux alginates owing to its physiochemical properties. Alginates offer a unique mechanism by forming a physical barrier in the stomach that may prevent the aspiration of gastric contents. In the presence of acid, bicarbonate and calcium ions, alginates rapidly form a strong, flexible, buoyant, viscous gel that floats atop the gastric contents — creating a barrier known as a "raft." The raft prevents the entirety of the stomach contents - acid, pepsin and food products - from refluxing into the esophagus with varying efficacy depending on the ratio of constituent ingredients and volume ingested. Unlike traditional approaches that rely on modifying gastric acidity or motility, alginates provide a direct, physical barrier against reflux. Alginates can be administered immediately prior to surgery, offering a practical solution in situations where traditional methods like NPO guidelines are not feasible. Further, alginates are widely used in the pharmaceutical, food, biomedical industries due to being 53

[0472] 45829115.1Docket No. MOF 24MB038 PCT biocompatible, nonimmunogenic, nontoxic, easily dissolvable for excretion, safe for ingestion by children and pregnant women and recently Generally Recognized as Safe by the Food and Drug Administration.

[0473] Commercially available alginate formulations are used worldwide for the management of GERD, but they were not specifically designed to prevent pulmonary aspiration of gastric contents. Nevertheless, these formulations exhibit physiochemical properties — such as buoyancy, raft strength, raft formation time, and raft duration — that suggest potential utility in this context. Benchtop testing of several widely available alginate products has demonstrated that one of the most commonly used formulations withstood over 350 mmHg of pressure before extruding through a 20 mm orifice — a finding of particular relevance, as the maximum diameter of the human gastroesophageal junction (GEJ) is approximately 20 mm, and while most aspiration during anesthetic induction is passive, peak intragastric pressures rarely exceed 290 mmHg in patients with induced vomiting. To further enhance effectiveness for aspiration prophylaxis, these formulations could be optimized by adjusting the ratios of existing components or incorporating additional agents to improve performance characteristics, including faster raft formation, prolonged structural stability, increased mechanical strength, expanded surface area, and enhanced acid-neutralizing capacity.

[0474] The use of a physical barrier to prevent gastric content regurgitation is not a new concept; however, employing alginates to serve this function represents a novel and promising approach. In one study, a balloon affixed to the distal end of a nasogastric tube was used to occlude the gastric cardia in 26 awake human volunteers who had ingested 1 liter of water. Vomiting was then induced while subjects were positioned in the lateral decubitus position. A similar experimental protocol was conducted in 12 animal subjects. These findings highlight the feasibility of mechanically blocking the gastroesophageal junction to reduce aspiration risk — supporting the conceptual foundation for using alginate-based rafts as a non-invasive, pharmacologic alternative. In addition to eliminating the need for foreign objects or procedural manipulation, alginate compounds offer several other advantages: they have a well-established safety record, are biocompatible and non-immunogenic, neutralize acid in the stomach and naturally degrade over a relatively short period of time, allowing for easy excretion. These characteristics make alginates an attractive candidate for aspiration prophylaxis, particularly in settings where invasiveness and tolerability are important considerations.

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[0476] 45829115.1Docket No. MOF 24MB038 PCT A wide range of studies — including magnetic resonance imaging (MRI), X-ray, scintigraphy, ex vivo models, and in vivo pH-manometry — have demonstrated that alginate-based formulations do indeed form a floating raft that consistently localizes above gastric contents. This raft occupies the anatomically correct position at the GEJ, effectively separating the stomach from the esophagus in both fasting and postprandial states.

[0477] Mechanism of Aspiration and Pulmonary Sequela

[0478] Pulmonary aspiration of gastric contents involves a complex inteiplay between the stomach( volume, acidity), the LES(tone, hiatal hernia presence, foreign object presence), the upper esophageal sphincter(UES)(pharyngo-UES and laryngo-UES contractile reflexes), patient positioning, external forces(laparoscopy, obesity), loss of volitional actions (voluntary swallowing, coughing or throat clearing) and reflexive actions(gagging, coughing, vomiting, esophago-glottal closure reflex). Importantly, for pulmonary aspiration of gastric contents to occur, the patient must both regurgitate and aspirate - necessitating multiple points of failure within this ecosystem.

[0479] Gastric contents include hydrochloric acid, pepsin, mucus, water, electrolytes, and any foreign material such as medications or food that a patient has ingested. The acidity and volume of gastric contents have long been held as the most important factors influencing the sequela of aspirated gastric contents and thus are the targets of most interventions. An oft cited minimum gastric volume of 0.4mL / kg and pH <2.5 has been called into question as this was derived from one experiment on one Rhesus monkey with application of 0.4mL / kg of acid directly on the right main stem bronchus. In fact, more recent studies have demonstrated a normal fasting gastric fluid volume as up to 1.5 mL / kg- representing the upper limit of normal gastric secretions - and thus placing a significant number of patients above the classic 0.4mL / kg threshold as at risk for aspiration. Further studies have shown that severe lung injury also occurs with non-acidic aspirate such as food particles and bile (pH 7.5-8.0), however extreme acidity and high volume aspiration appear to portend the worst lung injury.

[0480] During the peri-anesthetic state - which we will define here as receiving consciousness-altering medications to include monitored anesthesia care, moderate sedation, deep sedation, and all the phases of general anesthesia including pre-operative anxiolysis, pre-induction, peri-induction, peri-extubation, and ultimately until baseline sensorium has been achieved - multiple points of failure are often present and can predispose to the conditions necessary for both regurgitation and pulmonary aspiration.

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[0482] 45829115.1Docket No. MOF 24MB038 PCT Regurgitation during the peri-anesthetic state is primarily a passive process, resulting from lower esophageal sphincter (LES) relaxation and attenuation of protective airway reflexes, rather than from active retching or emesis, but this can also occur. Further, patient’ s can have baseline encephalopathy or altered neurologic functions that predispose and contribute to both silent aspiration and symptomatic aspiration of gastric contents on an on-going basis. As a result of acute or on-going aspiration of gastric contents, patient’s may develop aspiration pneumonitis, aspiration pneumonia, and most severely, acute respiratory distress syndrome, resulting in mechanical ventilation, prolonged hospital stays and ultimately increased morbidity and mortality.

[0483] Example 2: Mechanism of Action and Material Science of Alginate Rafts When an oral suspension of sodium alginate reaches the gastric lumen (pH approx 1-2), three chemical reactions acid-induced precipitation, carbon-dioxidc entrapment, and divalent ion cross-linking, must occur simultaneously to generate an effective barrier. Soluble sodium alginate is protonated by gastric hydrochloric acid (HC1), converting it into insoluble alginic acid. This creates the initial gel matrix.

[0484] Meanwhile, sodium bicarbonate in the formulation reacts with HC1 to produce carbon dioxide gas. The microbubbles become trapped within the viscous alginic acid gel, lowering the overall density of the mass and causing it to float like a raft on top of the gastric chyme. Simultaneously, calcium carbonate serves as a reservoir of Ca2+ions. In the acidic environment, CaCCL dissolves, releasing Ca2+which coordinates with the carboxylate groups on the G-blocks of adjacent alginate chains. This follows the "eggbox" model, where the calcium ion sits in a pocket created by the zig-zag structure of the guluronic acid units, providing mechanical strength and structural integrity to the raft.

[0485] Experimental Framework and Design of Mixtures

[0486] To optimize the biologic product for perioperative use — where the barrier must spread across the entire gastric surface and resist high pressures during anesthetic induction — a systematic Design of Experiments (DOE) was implemented. The investigation explored eight primary combinations of alginate viscosity, Nal ICO? levels, and CaCOa loading.

[0487] Factorial Experimental Design

[0488] The design focused on identifying the optimal concentrations to maximize two competing objectives: spreading efficiency (to ensure no gaps in coverage) and raft strength (to prevent rupture).

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[0490] 45829115.1Docket No. MOF 24MB038 PCT

[0491] Table 3. Factorial d esign of alginate raft formulations and component levels.

[0492] Alginate

[0493] Run NaHCCL CaCCh (g / lOOmL) Formulation Code (g / lOOmL) (g / lOOmL)

[0494] 1 2.50 (Low) 1.07 (Low) 1.63 (Low) L-L-L 2 5.00 (High) 1.07 (Ix>w) 1.63 (Low) H-L-L 3 2.50 (Low) 2.13 (High) 1.63 (Low) L-H-L 4 2.50 (Low) 1.07 (Low) 3.25 (High) L-L-H 5 5.00 (High) 2.13 (High) 1.63 (Low) H-H-L 6 5.00 (High) 1.07 (Low) 3.25 (High) ILL-II 7 2.50 (Low) 2.13 (High) 3.25 (High) L-H-H

[0495]

[0496] 8 5.00 (High) 2.13 (High) 3.25 (High) H-H-H

[0497] Standardized Preparation Protocol

[0498] The transition from raw materials to a functional biologic mixture requires

[0499] precise hydration to ensure structural homogeneity. The following protocol was established for each 100 mL of formulation: Hydration: Alginate powder was sprinkled into approximately 80 mL of DI water under high-shear stirring. This process continued for 1-2 hours at room temperature, or overnight in a refrigerator, until a smooth, lump-free solution was formed. This step has proven to be important as incomplete hydration leads to polymer aggregates that weaken the final raft. Powder Integration: Once smooth, NaHCOs was stirred in, followed by CaCOs. The total volume was then brought to 100 mL. Quality Control: Strong vacuum degassing was strictly avoided to prevent the removal of dissolved gases that assist in initial buoyancy. Suspensions were tested within 24 hours. Because the insoluble carbonates tend to settle, containers were inverted and gently mixed immediately before dosing.

[0500] Raft Formation and Spreading Dynamics

[0501] The spreading capacity of the raft determines its ability to "cap" the gastric contents wall-to-wall. In a 250 mL beaker containing 150 mL of 0.1 M HC1 at 37 °C, a

[0502] 10 mL dose was administered. Visual documentation from the top revealed that Formulations 3 and 7 achieved near 100% surface coverage. Other formulations, particularly those with higher alginate concentrations but lower bicarbonate levels,

[0503] formed localized "islands" or dense polymer accumulations that left significant portions of the acidic surface exposed.

[0504] Further analysis indicated that raft strength increased significantly during the first 15 minutes, driven by the dissolution kinetics of CaCO_3 in the acidic medium. Further, the resulting rafts remained stable and buoyant in the pH approx. 1 environment for at least 3 hours, covering the duration of most surgical procedures. We also found that a 2%

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[0506] 45829115.1Docket No. MOF 24MB038 PCT NaHCCh concentration was found to be an important threshold for providing sufficient effervescence to drive lateral spreading. The 3.25% CaCCh loading (Formulations 7 and 8) appeared to increase raft toughness, providing a more robust physical mass to resist mechanical breach.

[0507] Preparations 3, 5, and 7 were selected for direct comparison with commercial standards. The beaker spreading tests showed that these investigational formulations covered the surface more uniformly than Gaviscon Double Action, which often showed limited lateral expansion.

[0508] The human stomach is a dynamic environment characterized by peristaltic waves and hydrostatic shifts. To test the durability of the barrier, rafts were subjected to high-intensity mechanical agitation (100 rpm for 30 minutes). While GA and GD rafts began to fragment into smaller particles after 10-15 minutes, Preparations 3, 5, and 7

[0509] maintained their integrity throughout the entire 30-minute stress test. This suggests that the investigational cross-linking density is more effective at absorbing shear stress than existing formulations.

[0510] Viscosity was measured using a cup viscometer to ensure the liquid preparations were compatible with oral administration in patients who may already be fasted or experiencing nausea.

[0511] fable 4. Viscosity and swallowing safety.

[0512] Sample Relative Viscosity (Relative to Clinical Implication

[0513] S3)

[0514] S3 1.0 Optimal swallowing / spreading balance

[0515] S7 1.0 Low liquid viscosity; high raft strength

[0516] S5 7.9 Thicker suspension; slower gelling kinetics

[0517] GA 13.9 High suspension viscosity;

[0518] potential palatability issues GD 2.0 Moderate viscosity; comparable to investigational range

[0519]

[0520] One of the innovations of this work is the decoupling of iquid suspension viscosity from final raft strength. By selecting specific alginate grades and optimizing the

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[0522] 45829115.1Docket No. MOF 24MB038 PCT Ca2+release pathway, Preparations 3 and 7 remain easy to ingest but transform into a superior mechanical barrier in situ.

[0523] Reflux Simulation and Pressure Breakthrough

[0524] An important test for any aspiration-prevention system is its ability to withstand a simulated reflux event. Traditional medications focus on acid neutralization or symptom relief, but for perioperative safety, the barrier must be physically unbreachable under pressure.

[0525] The "Inverted Flask" test provided a macroscopic visualization of the seal. When a 250 mL Erlenmeyer flask containing a formed raft was inverted, Preparations 3, 5, and 7 were able to hold the entire volume of HO without any liquid escaping past the barrier. This indicates a complete circumferential seal and adhesion to the glass surface, mimicking the desired behavior at the esophageal orifice.

[0526] To provide a quantitative assessment of the breakthrough threshold, a custom reflux simulator was designed. A flexible vessel containing the acid and raft was compressed by an inflatable pneumatic bag (sphygmomanometer cuff). The vessel had a 3 cm exit orifice, representing the relaxed LOS in a patient under deep sedation or general anesthesia.

[0527] Pressure was increased until the raft was either broken (rupture failure) or forced through the orifice (extrusion failure). The results demonstrated that Preparation 7 was significantly more resistant than Gaviscon Double Action, withstanding higher pneumatic loads before failure.

[0528] The results of this investigation represent a significant advance in perioperative safety engineering. By reformulating over-the-counter ingredients into a specific clinical biologic product, we have addressed the dual requirement of rapid lateral spreading and high mechanical breakthrough resistance.

[0529] The present disclosure aims to refine clinical practice by integrating alginates into preventive protocols for pulmonary aspiration. The approaches described herein can challenge current practices by introducing a new, effective tool for mitigating aspiration risk, particularly for patients undergoing urgent procedures or those with compromised gastric motility. The present disclosure can provide: enhanced efficacy by providing an additional preventive measure for high-risk patients, thereby improving patient safety during anesthesia and reducing the incidence of aspiration-related complications: broader applicability by offering a viable solution in emergency situations where adherence to traditional NPO guidelines is not possible or effective; increased clinical options by

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[0531] 45829115.1Docket No. MOF 24MB038 PCT expanding the toolkit available to clinicians for managing and preventing aspiration, ultimately leading to improved patient outcomes and potentially reducing healthcare costs associated with aspiration-related complications.

[0532] In summary, the introduction of alginates as a preventive measure for pulmonary aspiration can address a significant gap in current practices, offering a novel, safe, and effective solution with the potential for immediate and broad clinical impact.

[0533] Alginates have the unique ability to interact with stomach acid to form a viscous, buoyant barrier that sits atop gastric contents to physically prevent gastric contents from entering the esophagus. The present disclosure contrasts with traditional pharmacologic interventions that either neutralize stomach acid (i.e. antacids), reduce acid production (i.e. PPIs), or attempt to empty stomach contents in an antegrade fashion, none of which directly address the mechanical movement of gastric contents into the esophagus and airway.

[0534] The introduction of alginates represents a refinement and improvement over current approaches to preventing aspiration in several key ways:

[0535] 1. Novel Modality in High-Risk Patients: Traditional methods for preventing aspiration, such as NPO fasting guidelines, cricoid pressure application antacids, or Histamine H2-receptor antagonists (H2 blockers), are often either not effective in urgent or emergent situations or are limited in their ability to prevent aspiration in patients with full stomachs, or delayed gastric emptying due to gastroparesis, or GLP-1 receptor agonists. Alginate formulations can be administered in these high-risk scenarios to form a near immediate protective barrier, providing an additional safety measure that existing approaches often lack.

[0536] 2. Innovative Application of a Known Compound: While alginates have long been used to manage GERD symptoms, the methods described herein represent a new use of the compound in the perioperative and critical care contexts. By demonstrating their ability to prevent reflux and specifically pulmonary aspiration in an in-vitro model, the present disclosure aims to expand the clinical utility of alginates beyond their current application in managing heartbum and mild reflux symptoms.

[0537] 3. Functional Model Creation: The present disclosure can incorporate various concentrations of bicarbonate and calcium into alginate formulations to enhance their physical properties and create an optimal barrier. In contrast, traditional antacids often only neutralize acid without providing any mechanical protection. The present disclosure could transform clinical practice by introducing alginates as a standard preventive

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[0539] 45829115.1Docket No. MOF 24MB038 PCT measure for pulmonary aspiration in critical care and surgical settings. The present disclosure can allow the focus to shift from purely pharmacologic or time-consuming non-pharmacologic interventions, like fasting or airway management techniques, to an easily administered, cost-effective, and low-risk solution. By integrating alginates into perioperative protocols, clinicians can have an additional tool to mitigate aspiration risk, particularly in cases where current methods are insufficient or impractical.

[0540] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of skill in the art to which the disclosed invention belongs. Publications cited herein and the materials for which they are cited are specifically incorporated by reference.

[0541] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

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[0543] 45829115.1

Claims

Docket No. MOF 24MB038 PCTCLAIMS1. A method for the prevention or reduction of pulmonary aspiration of gastric contents in a mammal comprising the step of administering to the mammal a therapeutically effective amount of a first compound comprising sodium alginate, calcium carbonate, and sodium bicarbonate, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the mammal is a human.

3. The method of claim 1 , wherein the mammal has been diagnosed with a condition having increased risk of pulmonary aspiration of gastric contents prior to the administering step.

4. The method of claim 1, further comprising the step of identifying a mammal in need of prevention or reduction of pulmonary aspiration of gastric contents.

5. The method of claim 1, wherein the mammal has been diagnosed with a condition associated with increased risk of pulmonary aspiration of gastric contents.

6. The method of claim 5, wherein the condition is pregnancy, diabetes, gastroparesis, peripheral neuropathy, gastrointestinal obstruction, esophageal cancer, hiatal hernia, obesity, traumatic brain injury, gastroesophageal reflux disease, esophageal dysmotility, gas bloat, large paraesophageal hernia, or achalasia.

7. The method of claim 1, wherein the first compound further comprises at least one of a proton pump inhibitor (PPI), an antacid, a histamine (ID-receptor antagonist, or a combination of any thereof.

8. The method of claim 1, wherein the sodium alginate in the first compound is a concentration from about 10 mg / mL to about 100 mg / mL, the calcium carbonate is at a concentration from about 5 mg / mL to about 60 mg / mL, and the concentration of sodium bicarbonate is at a concentration from about 5 mg / mL to about 50 mg / mL.

9. The method of claim 8, further comprising administering a second compound comprising sodium alginate, calcium carbonate, and sodium bicarbonate, wherein the second compound has a higher concentration of sodium alginate than the first compound.

10. The method of claim 9, wherein the second compound is administered sequentially or simultaneously with the first compound.

11. A pharmaceutical composition for the prevention or reduction of pulmonary aspiration of gastric contents in a mammal, comprising:a. a polysaccharide or polysaccharide derivative,b. a carbonate or bicarbonate salt,c. an ionic salt, and6245829115.1Docket No. MOF 24MB038 PCT d. a pharmaceutically acceptable carrier,wherein the pharmaceutical composition forms a raft atop gastric contents; and wherein the raft maintains an intact mass for at least 20 minutes after agitation at 100 rpm, wherein the raft has an elastic modulus of at least 1 kPa to 100 kPa, wherein the raft has a density of at least 0.5 to at least 0.95 g / cm3, or any combination thereof.

12. The pharmaceutical composition of claim 11, wherein the polysaccharide or polysaccharide derivative comprises an alginate.

13. The pharmaceutical composition of claim 12, wherein the alginate is from about 10 mg / mL to about 100 mg / mL sodium alginate.

14. The pharmaceutical composition of claim 11 , wherein the carbonate or bicarbonate salt comprises sodium bicarbonate is from about 5 mg / mL to about 60 mg / mL.

15. The pharmaceutical composition of claim 11, wherein the ionic salt comprises calcium carbonate is from about 5 mg / mL to about 50 mg / mL.6345829115.1

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