Oral preparations containing porous silica particles and their medical uses

Abstract

The present invention provides an oral formulation comprising (a) water, (b) porous silica particles having pores in the mesoporous range, and (c) a thickener, wherein the mesoporous range pores have an average pore size of about 7.0 to about 25.0 nm, and the thickener is selected from xanthan gum and microcrystalline cellulose, or a mixture thereof. Uses of such formulations are also provided.

Description

[Technical Field]

[0001] The present invention relates to novel formulations and their uses, particularly in medicine.

[0002] In particular, the present invention relates to novel aqueous formulations for oral administration comprising silica particles and a thickening agent, and the use of such formulations in methods for treating or preventing metabolic diseases and disorders such as prediabetes, type 2 diabetes, dyslipidemia, obesity, etc. The present invention also relates to the use of such formulations in methods for slowing food digestion and reducing the uptake of biomolecules into the body from the digestive system. [Background technology]

[0003] The listing or discussion of any prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

[0004] Metabolism is the sum of all energy processes in the body, and metabolic disorders interfere with normal metabolism, including the process of converting food into energy. Metabolic disorders occur when abnormal chemical reactions in the body interfere with metabolic processes. There are different groups of disorders. Some affect the breakdown of amino acids, carbohydrates, or lipids. Another group, mitochondrial diseases, affect the part of the cell that produces energy. Metabolic disorders can be classified as primary (genetic) or secondary (related to, among other things, lifestyle or environment).

[0005] Metabolic syndrome is a medical term that defines the simultaneous occurrence of at least three of five medical conditions: abdominal obesity, high blood pressure, high blood sugar, hypertriglyceridemia, and low HDL (high-density lipoprotein) levels. Metabolic syndrome indicates an increased risk of cardiovascular disease and type 2 diabetes.

[0006] Diabetes is the most common metabolic disease. There are two main types of diabetes: type 1 and type 2. Both types of diabetes are chronic diseases that affect how the body regulates blood sugar (glucose). There is a strong genetic (hereditary) factor in the development of type 1 diabetes. There are several causes of type 2 diabetes, including genetics and lifestyle choices.

[0007] Before developing type 2 diabetes, patients suffer from a condition called prediabetes. Prediabetes is characterized by high blood sugar (glucose) levels above what is considered normal but not high enough to be classified as type 2 diabetes. Prediabetes is a high-risk state for developing type 2 diabetes. If left untreated, 15–30% of people with prediabetes will develop type 2 diabetes within five years (U.S. Department of Health and Human Services, Centers for Disease Control and Prevention (2014)). The number of people with prediabetes is expected to increase significantly, affecting an estimated 482 million people worldwide by 2040.

[0008] Currently, there are no guideline-approved medical treatments for prediabetes. The standard of care for prediabetes management is lifestyle intervention. Patients with prediabetes are managed by primary care, and exercise and a healthy diet are recommended. Adherence to lifestyle interventions is low, with only 10-20% of patients successfully implementing a new lifestyle. Thus, there is currently a large unmet clinical need for the treatment of prediabetes, with only 3.7% of prediabetic patients considered suitable for treatment with metformin (see Moin, T. et al., Ann. Intern. Med., 162, 542 (2015)).

[0009] According to the U.S. Centers for Disease Control and Prevention, the incidence of type 2 diabetes has tripled over the past 30 years. This is driven by the global epidemic of obesity, a major risk factor for developing type 2 diabetes and prediabetes. Obesity is defined as the accumulation of abnormal or excessive fat that can compromise health. Essentially, obesity occurs when the body consumes more calories than it uses over time. Obesity increases the risk of developing various chronic diseases, including insulin resistance, type 2 diabetes, high blood pressure, high cholesterol, stroke, heart attack, sleep apnea, congestive heart failure, osteoarthritis, and cancer. In particular, high levels of cholesterol and lipids (dyslipidemia) are associated with cardiovascular disease and atherosclerosis.

[0010] Dyslipidemia is considered a metabolic disease and is defined as abnormal levels of lipids (e.g., cholesterol and fats) in the blood. It is often caused by diet and lifestyle. Cardiovascular disease is often grouped together with metabolic disorders because it frequently occurs as a consequence of diabetes and dyslipidemia.

[0011] Statins are the most widely used lipid-lowering drugs for preventing coronary artery disease in high-risk patients. However, there is controversy regarding their positive effects on preventing death and cardiovascular disease in low-risk and medium-risk patients (Tonelli, M., CMAJ, 183, 1189-1202 (2011); Ward, S., Health Technol Assess., 1-160 (2007)). Furthermore, there are many intolerant patients who experience adverse events such as liver damage, neurological effects, and muscle pain (see, for example, Silva MA et al., Clin Ther., 28 (1), 26-35 (2006) and Beatrice AG, et al., American Journal of Cardiovascular Drugs, 8 (6), 373-418 (2008)). The latter is a major side effect that limits the use of statins (Martini, J. et al., Canadian Journal of Cardiology, 27, 635-662 (2011)). Therefore, new and more efficient lipid-lowering therapeutic alternatives, with or without concomitant lipid-lowering drugs, are needed.

[0012] Considering the above, it is clear that there is a great impetus for the development of new initiatives, medicines and medical technologies that will provide effective, rapid and safe methods for the prevention and treatment of pre-diabetes, diabetes and their related diseases.

[0013] Silica particles with specific porosity have previously been shown to reduce adipose tissue in animal model systems (see WO 2014 / 072363 and Kupferschmidt, N. et al., Nanomedicine, 9(9), 1353-1362 (2014)). Animals receiving large-pore mesoporous silica along with a high-fat diet showed significant reductions in body weight and body fat composition, with no observable adverse effects. In particular, the authors suggest the use of such silica for the reduction of body weight and body fat composition as a means of treating obesity.

[0014] Such silica materials have been reported to have the potential to reduce levels of HbA1c, a biomarker corresponding to long-term plasma glucose levels (see Baek, J. et al., Nanomedicine, 17:1, 9-22 (2022)).

[0015] Furthermore, it has been shown that the porosity of such silica particles can be tuned to achieve different physicochemical properties (see WO2019 / 166656).

[0016] Porous silica particles are thermally and chemically stable and consist entirely of pure silicon dioxide. They have controllable pore size, providing high surface area and a large total pore volume. These properties, along with other properties such as stability and biocompatibility, make them suitable for biomedical applications (Wang, Y. et al., Nanomedicine Nanotechnology, Biol. Med. 11, 313-327 (2015)). Furthermore, a similar substance has previously been approved as a food additive (European Center for Ecotoxicology and Toxicology of Chemicals Synthetic Amorphous Silica (CAS No. 7631-86-9), JACC No. 51, page 14 (ECETOC, 2006)).

[0017] However, the use of such silica particles in methods of medical treatment poses significant challenges, particularly since these particles are typically administered orally.

[0018] The dosage of silica material required to achieve a therapeutic effect is relatively large, typically in the range of several grams, which makes it inconvenient to provide such material in tablet or capsule form, as multiple dosage units would need to be consumed due to limitations on the size and shape of individual tablets or capsules suitable for oral administration.

[0019] To address this issue, silica materials may be provided in the form of orally ingestible liquids, but such liquid formulations are unstable and can result in uneven distribution of the silica material from the formulation, as well as poor taste, such as a gritty texture and dry mouth after consumption.

[0020] Therefore, there is a need for oral formulations of silica materials suitable for uses such as those described herein that are stable and do not interfere with the function of the silica materials. Ideally, such formulations would have a pleasant texture and be more easily ingested. DETAILED DESCRIPTION OF THE INVENTION

[0021] It has been unexpectedly discovered that improved oral formulations of therapeutically active silica materials can be prepared by adding certain thickening agents, and such formulations may find use as dietary supplements, pharmaceuticals, and medical devices that may be useful in treating the diseases and disorders described herein.

[0022] New formulations In a first aspect of the present invention, (a) water; (b) porous silica particles having pores in the mesoporous range; (c) a thickener; Including, The average pore size of the pores in the mesoporous range is about 7.0 to about 25.0 nm, the thickener is selected from xanthan gum and microcrystalline cellulose or a mixture thereof; An oral formulation is provided.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the common meaning as understood by one of ordinary skill in the art to which this invention pertains.

[0024] For the avoidance of doubt, a formulation as defined in the first aspect of the invention (including all embodiments and features thereof) may also be referred to as a "formulation of the invention (or formulation of the first aspect of the invention)" etc. Such a formulation may also be referred to as a composition, and these terms may be used interchangeably. Similarly, a silica particle as defined in the first aspect of the invention (including all embodiments and features thereof) may also be referred to as a "silica (or silica material or silica particle) of the invention (or of the first aspect of the invention)" etc.

[0025] When used herein in connection with a specific value (such as an amount), the term "about" (or similar terms such as "approximately") is understood to indicate that such value may vary by up to 10% (specifically, up to 5%, for example, up to 4%, 3%, 2%, or 1%) of the defined value. In each instance, it is contemplated that such terms may be replaced with notations such as "±10%" (or by indicating a variation of a specific amount calculated based on the relevant value). In connection with percentage amounts referred to herein, the term "about" (or similar terms such as "approximately") is understood to indicate that such value may vary by up to 10% (specifically, up to 5%, for example, up to 4%, 3%, 2%, or 1%) of the defined percentage value. It is also contemplated that at each point, the term "about" may be omitted.

[0026] For the avoidance of doubt, reference to a formulation comprising particular ingredients includes the possibility that the formulation consists (or consists mainly) of those ingredients.

[0027] For the avoidance of doubt, those skilled in the art will understand that when the percentages of certain ingredients are defined as belonging to different (i.e., non-overlapping) groups, the sum of those percentages cannot exceed 100%. Thus, if the maximum value for one or more non-overlapping groups of ingredients exceeds 100%, those skilled in the art will understand that one or more of those ingredients must be present in an amount less than the maximum. Similarly, the sum of the specified ingredients need not equal 100% if other ingredients may be present in the formulation.

[0028] Those skilled in the art will understand that reference to an oral formulation refers to a formulation intended for (e.g., suitable for) oral ingestion by humans or animals (e.g., mammals such as domestic pets or recreational animals, such as cats, dogs, horses, rabbits, etc., or livestock, such as cows, pigs, sheep, goats, chickens, turkeys, etc.). In certain circumstances, reference to ingestion by such a human or animal subject (which may also be referred to as a patient in the context of methods of medical treatment) refers specifically to the treatment of adult (e.g., full-grown) subjects.

[0029] In particular, reference to an oral formulation refers to a formulation intended for (eg suitable for) oral ingestion by a human, such as an adult (eg a human aged 18 years or older).

[0030] Those skilled in the art will understand that references herein to oral ingestion refer to formulations that are swallowed by the subject in one or more movements, and therefore, those skilled in the art will understand that the formulations of the present invention may be in the form of a liquid, a gel, or a soft solid, such that the formulation can be easily swallowed.

[0031] Those skilled in the art will appreciate that it may be advantageous for the formulation to be provided in the form of a flowable liquid, so that it can be consumed by the subject like a drink.

[0032] Thus, in a specific embodiment, the formulation is a liquid (in which case it may be referred to as a liquid formulation).

[0033] Those skilled in the art will understand that the term liquid generally refers to a substance that is free-flowing, has a definite volume, and generally has a consistency similar to water or liquid oil.

[0034] In a further embodiment, the formulation may be provided in the form of a soft solid / gel that may have a consistency similar to yogurt (e.g., solid yogurt that may have a spoonable consistency).

[0035] Those skilled in the art will appreciate that the amount of each component included in the formulation can be adjusted to achieve the required viscosity and flow properties.

[0036] In specific embodiments, the formulation may be provided in a form classified as low to medium viscosity, with a viscosity and / or flowability similar to that of a milkshake or similar beverage / food item.

[0037] In a further embodiment, the formulation may be provided in a form that is classified as thickened, with a viscosity and / or flow similar to that of set yogurt or similar food items.

[0038] As described herein, the formulations of the present invention comprise water. In particular, the formulations typically comprise water as a significant component, being the predominant (i.e., largest) component by weight. Thus, the formulations can be described as aqueous (or substantially aqueous) formulations.

[0039] One skilled in the art will appreciate that the amount of water included in the formulation may be selected to achieve desired properties of the formulation, such as a desired viscosity and / or flowability.

[0040] In a specific embodiment, the formulation comprises: at least about 70.0% (e.g., at least about 71.0, 72.0, 73.0, 74.0, 75.0, 76.0, 77.0, 78.0, 79.0%) by weight (wt%) of water, and / or (e.g., and At least about 80.0% by weight water (e.g., at least about 81.0, 82.0, 83.0, 84.0, or 85.0% by weight).

[0041] In specific embodiments, the formulation comprises up to about 95.0% water by weight (eg, up to about 94.0, 93.0, 92.0, or 91.0% by weight).

[0042] In more specific embodiments, the formulation comprises up to about 90.0% water by weight (eg, up to about 89.0, 88.0, 87.0, 86.0, or 85.0% by weight).

[0043] For example, in specific embodiments, the formulation comprises about 70.0 to about 95.0% water by weight.

[0044] In a more specific embodiment, the formulation comprises about 75.0 to about 95.0% water by weight.

[0045] In a more specific embodiment, the formulation comprises about 80.0 to about 95.0% water by weight.

[0046] In a more specific embodiment, the formulation comprises about 75.0 to about 90.0% water by weight.

[0047] In a more specific embodiment, the formulation comprises about 80.0 to about 90.0% water by weight.

[0048] In a more specific embodiment, the formulation comprises from about 82.0 to about 88.0% water by weight.

[0049] In a more specific embodiment, the formulation comprises about 83.0 to about 87.0% water by weight.

[0050] In a more specific embodiment, the formulation comprises about 84.0 to about 86.0% water by weight.

[0051] In certain embodiments, the formulation comprises about 84.0 to about 91.0% water by weight.

[0052] In certain embodiments, the formulation comprises about 84.0 to about 90.0% water by weight.

[0053] In a specific embodiment, the formulation comprises about 85 to about 86% water by weight, for example, about 85.6% water by weight.

[0054] In a specific embodiment, the formulation comprises about 89 to about 90% water by weight, for example, about 89.0 to about 90.0% water by weight.

[0055] In certain embodiments, when amounts of other ingredients are specified, it may be understood that the remainder of the ingredients (eg, by weight) is water.

[0056] As described herein, the formulations of the present invention comprise porous silica particles having pores in the mesoporous range, the average pore size of the pores in the mesoporous range being in the range of about 7.0 to about 25.0 nm.

[0057] One skilled in the art will understand that the amount of such porous silica particles in the formulation may be selected to provide an appropriate loading such that administration of an appropriate amount of the formulation provides a desired dosage of silica material (such as the dosage required to achieve a desired biological effect, such as the therapeutic and non-therapeutic effects described herein).

[0058] In a specific embodiment, the formulation comprises: at least about 5.0 wt. % (e.g., at least about 6.0, 7.0, 8.0, or 9.0 wt. %) porous silica particles, and / or (e.g., and) up to about 15.0 wt. % (e.g., at least about 14.0, 13.0, 12.0, or 11.0 wt. %) porous silica particles Includes:

[0059] In a specific embodiment, the formulation comprises about 5.0 to about 15.0% by weight of porous silica particles.

[0060] In a more specific embodiment, the formulation comprises about 6.0 to about 14.0% by weight of porous silica particles.

[0061] In a more specific embodiment, the formulation comprises about 7.0 to about 13.0% by weight of porous silica particles.

[0062] In a more specific embodiment, the formulation comprises about 8.0 to about 12.0% by weight of porous silica particles.

[0063] In a more specific embodiment, the formulation comprises about 9.0 to about 11.0% by weight of porous silica particles.

[0064] In a more specific embodiment, the formulation comprises about 9.0 to about 10.5% by weight of porous silica particles.

[0065] In specific embodiments, the formulation comprises about 9.0 to about 10.0 wt.% porous silica particles, such as about 10.0 wt.% or about 9.4 wt.% porous silica particles.

[0066] As described herein, the formulations of the present invention include a thickening agent, which is selected from xanthan gum and microcrystalline cellulose (MCC) or mixtures thereof.

[0067] In a specific embodiment, the thickening agent is selected from (ie, selected from the group consisting of) xanthan gum and microcrystalline cellulose.

[0068] As described herein, these thickening agents have been found to allow for the preparation of formulations that offer improved properties in terms of stability and taste (e.g., as a result of their texture) without interfering with the biological activity of the silica material, in contrast to other such agents.

[0069] Those skilled in the art will appreciate that the microcrystalline cellulose may also be colloidal microcrystalline cellulose.

[0070] Those skilled in the art will be able to select the appropriate amounts of various thickening agents to achieve the desired properties of the formulation, such as viscosity and flowability.

[0071] In a specific embodiment, the formulation comprises: at least about 0.1 wt. % (e.g., at least about 0.2, 0.3, 0.4, or 0.5 wt. %) of a thickening agent, and / or (e.g., and) up to about 1.5% by weight (e.g., up to about 1.4, 1.3, 1.2, or 1.1% by weight) of a thickening agent Includes:

[0072] In a specific embodiment, the formulation comprises from about 0.1% to about 1.5% by weight of a thickening agent.

[0073] In a specific embodiment, the formulation comprises from about 0.2% to about 1.4% by weight of a thickening agent.

[0074] In a specific embodiment, the formulation comprises from about 0.3% to about 1.3% by weight of a thickening agent.

[0075] In a specific embodiment, the formulation comprises from about 0.4% to about 1.2% by weight of a thickening agent.

[0076] In a specific embodiment, the formulation comprises from about 0.5% to about 1.1% by weight of a thickening agent.

[0077] In certain embodiments, the thickening agent is microcrystalline cellulose.

[0078] In such embodiments (ie, when the thickening agent is microcrystalline cellulose), the formulation comprises from about 0.8% to about 1.2% by weight of the thickening agent.

[0079] In further such embodiments (ie, where the thickening agent is microcrystalline cellulose), the formulation comprises from about 0.9% to about 1.1% by weight of the thickening agent.

[0080] In particular in such embodiments (ie, where the thickening agent is microcrystalline cellulose), the formulation comprises about 1% by weight of the thickening agent, for example about 1.0% by weight of the thickening agent.

[0081] Additionally, as described herein, it has been found that the use of xanthan gum as a thickening agent results in formulations with further improved texture and further improved taste.

[0082] In a specific embodiment, the thickening agent is xanthan gum.

[0083] In such embodiments (ie, when the thickening agent is xanthan gum), the formulation comprises from about 0.3% to about 0.9% by weight of the thickening agent.

[0084] In further such embodiments (ie, where the thickening agent is xanthan gum), the formulation comprises from about 0.4% to about 0.8% by weight of the thickening agent.

[0085] In still further such embodiments (ie, where the thickening agent is xanthan gum), the formulation comprises from about 0.5% to about 0.7% by weight of the thickening agent.

[0086] In particular such embodiments (ie, where the thickening agent is xanthan gum), the formulation comprises about 0.6% v by weight, such as about 0.63% by weight of thickening agent.

[0087] Those skilled in the art will appreciate that the formulations of the present invention may contain additional ingredients to adjust and / or maintain properties such as freshness / food safety (i.e., freedom from contaminants such as bacterial or mold growth), taste, aroma, and / or color of the formulation.

[0088] Thus, in a specific embodiment, the formulation comprises: (d) optionally, one or more preservatives, sweeteners, flavorings, fragrances, and / or coloring agents Further includes:

[0089] In specific embodiments, the amount of optional ingredient (d) present in the formulation is up to about 10.0% by weight (eg, up to about 9.0, 8.0, 7.0, or 6.0% by weight) of the formulation.

[0090] In more specific embodiments, the amount of optional ingredient (d) present in the formulation is up to about 5.0% by weight (eg, up to about 4.9, 4.8, 4.7, 4.6, 4.5, or 4.4% by weight) of the formulation.

[0091] For example, the formulation may further include one or more preservatives, such as food preservatives suitable for human consumption known to those skilled in the art.

[0092] For example, suitable preservatives include lactic acid, benzoic acid and its pharmaceutically acceptable salts (e.g., sodium benzoate), sorbic acid and its pharmaceutically acceptable salts (e.g., potassium sorbate), and citric acid, and mixtures thereof.

[0093] Preservatives that may especially be mentioned include citric acid and potassium sorbate, and mixtures thereof.

[0094] For the avoidance of doubt, preservatives as described herein may also be referred to as acidity regulators.

[0095] In a specific embodiment, the formulation further comprises one or more preservatives.

[0096] For example, in specific embodiments, the formulation includes the preservatives citric acid (e.g., in an amount of about 0.1 to about 0.3% by weight of the formulation, e.g., about 0.2% by weight of the formulation, e.g., about 0.22% by weight of the formulation) and potassium sorbate (e.g., in an amount of about 0.05 to about 0.15% by weight of the formulation, e.g., about 0.1% by weight of the formulation, e.g., about 0.09% by weight of the formulation).

[0097] The formulations may also include one or more flavorings and / or sweetening agents, including flavorings and / or sweetening agents suitable for human consumption known to those of skill in the art.

[0098] For example, suitable sweeteners may include sugars (sucrose, tagatose, alulose, etc.), sugar alcohols (erythritol, xylitol, sorbitol, mannitol, etc.), artificial sweeteners (sucralose, saccharin, acesulfame K, aspartame, etc.), plant extracts (steviol glycosides, monk fruit extracts, etc.) Sweeteners that may be mentioned in particular include non-caloric sweeteners, especially sugar alcohols (erythritol, etc.) and plant extracts (steviol glycosides, etc.).

[0099] In a specific embodiment, the formulation comprises one or more sweeteners.

[0100] One skilled in the art can select the appropriate sweetener and the amount thereof to achieve the desired taste profile of the formulation.

[0101] In a specific embodiment, the sweetener is present in an amount of about 0.01 to about 10.0% by weight of the formulation.

[0102] In more specific embodiments, the sweetener is present in an amount of from about 0.05 to about 10.0% by weight of the formulation.

[0103] In an even more specific embodiment, the sweetener is present in an amount of from about 0.1 to about 10.0% by weight of the formulation.

[0104] In an even more specific embodiment, the sweetener is present in an amount of from about 0.5 to about 10.0% by weight of the formulation.

[0105] In an even more specific embodiment, the sweetener is present in an amount of from about 1.0 to about 10.0% by weight of the formulation.

[0106] In an even more specific embodiment, the sweetener is present in an amount of from about 2.0 to about 9.0% by weight of the formulation.

[0107] In an even more specific embodiment, the sweetener is present in an amount of from about 2.0 to about 8.0% by weight of the formulation.

[0108] In an even more specific embodiment, the sweetener is present in an amount of from about 2.0 to about 7.0% by weight of the formulation.

[0109] In an even more specific embodiment, the sweetener is present in an amount of from about 2.0 to about 6.0% by weight of the formulation.

[0110] In an even more specific embodiment, the sweetener is present in an amount of about 3.0 to about 5.0% by weight of the formulation.

[0111] In an even more specific embodiment, the sweetener is present in an amount of about 3.0 to about 4.0% by weight of the formulation.

[0112] In an even more specific embodiment, the sweetener is present in an amount of about 3.5 to about 3.9% by weight of the formulation.

[0113] In an even more specific embodiment, the sweetener is present in an amount of about 3.6 to about 3.9% by weight of the formulation.

[0114] In a specific embodiment, the sweetener is present in an amount of about 4% by weight of the formulation, such as about 3.8% by weight of the formulation.

[0115] In more specific embodiments, the sweetener is erythritol or a mixture of erythritol and steviol glycosides.

[0116] In particular such embodiments (i.e., where the sweeteners are erythritol and steviol glycosides), the sweeteners are present in an amount of about 4% by weight of the formulation, e.g., about 3.8% by weight of the formulation, e.g., erythritol is present in an amount of about 3.7 to about 3.8% by weight of the formulation, e.g., about 3.75% by weight of the formulation, and steviol glycosides are present in an amount of about 0.01% by weight of the formulation.

[0117] As described herein, the formulations may additionally include flavorings (e.g., vanilla and / or fruit flavorings), which may be derived from extracts and / or artificial agents.

[0118] Such flavorings may be present in an amount of from about 0.01 to about 0.50% by weight of the formulation, such as from about 0.01 to about 0.30% by weight of the formulation, for example about 0.25% by weight of the formulation.

[0119] In certain embodiments, the formulation further comprises: (e) optionally, one or more additional active agents Includes:

[0120] As used herein, the term active agent may refer to a component that imparts a biological effect to a subject, and may be referred to as a biologically active agent.

[0121] For example, such additional active agents may include soluble fiber (such as inulin or dextrin), pharmaceuticals, vitamins, minerals, natural (eg, plant) extracts, and the like.

[0122] In a specific embodiment, the formulation is free (or substantially free) of additional active agents (ie, active agents other than the silica material of the present invention).

[0123] For the avoidance of doubt, the formulation may also contain further additional ingredients which may be selected to enhance and / or complement its properties.

[0124] For example, one skilled in the art will understand that other additional ingredients, such as dyes and fragrances, may be selected to provide a formulation that is appealing to the subject. If present, such ingredients may be present in essentially negligible amounts compared to the other ingredients.

[0125] In specific embodiments, the amount of the ingredients specified herein (i.e., components (a)-(c), or (a)-(d), or (a)-(e), as appropriate) equals 100% (in such embodiments, the formulation may be said to consist of, or consist essentially of, the ingredients specified herein).

[0126] In other embodiments, other ingredients may be added to the formulations of the present invention in amounts additional to the ingredients and their relative amounts specified above without altering the properties of the formulation. In such embodiments, the formulation comprises the ingredients specified herein (i.e., components (a)-(c), or (a)-(d), or (a)-(e), as appropriate) (relative amounts equal to 100%), and optionally further comprises other ingredients.

[0127] Those skilled in the art will appreciate that the formulations of the present invention comprise mixtures of each component, particularly since such mixtures contain each component evenly distributed throughout the formulation, these formulations may be described as homogeneous (or substantially homogeneous).

[0128] As described herein, the formulations of the present invention are stable, which may indicate that the components of the formulation and the distribution of components therein do not change over an extended period of time of at least 42 days (e.g., at least 1 year (365 days)).

[0129] In specific embodiments, the formulation is stable for at least 42 days (e.g., at least 1 year (365 days)), e.g., the formulation remains homogeneous (or substantially homogeneous) during storage for at least 42 days (e.g., at least 1 year (365 days)), e.g., when protected from moisture and sunlight, at room temperature and pressure.

[0130] Porous Silica Particles Those skilled in the art will appreciate that the porous silica particles provided in the formulation of the first aspect of the invention may be referred to as a plurality thereof, which may in turn be referred to as a porous silica material.

[0131] For the avoidance of doubt, porous silica particles having pores in the mesoporous range may also be referred to as mesoporous silica particles, and vice versa.

[0132] Those skilled in the art will understand that, herein, references to pores being of a certain size refer to the average diameter of the relevant pores (i.e., the average diameter of the individual pores taking into account the pore dimensions). For the avoidance of doubt, those skilled in the art will understand that references to the average pore size may particularly refer to the average size of each pore opening (or, in the case of pores where the pore channels traverse the particle body internally, the average size of all openings to the pore(s)), which may be referred to as the pore window(s) (or pore window(s)).

[0133] For the avoidance of doubt, unless otherwise stated, averages referred to herein are calculated as arithmetic means.

[0134] Unless otherwise specified, the pore size described herein is measured by nitrogen adsorption and calculated using density functional theory (DFT) methods (see, for example, the method described in Landers, J. et al., Colloids and Surfaces A: Physicochem. Engineering Aspects, 437, 3-32 (2013)). Therefore, unless otherwise specified, reference to average pore size herein refers to the pore size measured by nitrogen adsorption and calculated using density functional theory (DFT).

[0135] Those skilled in the art will understand that reference to a percentage of pores present in a particular range can be understood to refer to the pore size distribution (PSD) of such particles, and thus a reference to a percentage of pores present in a particular range refers to the total volume of pores present in each range as a percentage of the total pore volume of the relevant pore group(s) (e.g., pores in the mesoporous range).

[0136] For the avoidance of doubt, reference to particles having a particular average pore size may, in certain cases, include reference to pores that are functionally equivalent to particles having such average pore size (e.g., as used in the methods described herein).

[0137] Those skilled in the art will understand that the pore size distribution of silica materials can be measured using DFT pore size distribution curves, a technique well understood by those skilled in the art (see, for example, Olivier, JP, Conklin, WB and Szombathely, MV, Studies in Surface Science and Catalysis, 87, 81-89 (1994)). The percentage of pores is calculated from the DFT cumulative pore size distribution curve.

[0138] Those skilled in the art will understand that reference to porous silica particles having pores in the mesoporous range is intended to refer to porous silica particles in the usual sense in the art, i.e., having (or containing / comprising) pores with diameters in the range of 2 to 50 nm, and that the material may be referred to as mesoporous and the pores may be referred to as mesopores.

[0139] For the avoidance of doubt, those skilled in the art will understand that the porous silica material referred to in the first aspect of the present invention may also have (i.e. further contain / comprise) pores with diameters outside the mesoporous range, such as having micropores (i.e. pores with a diameter of less than 2 nm) and / or macropores (i.e. pores with a diameter of more than 50 nm).

[0140] For the avoidance of doubt, unless otherwise stated, references to pore percentage as used herein refer to volume percentage.

[0141] In a specific embodiment, at least about 40% (ie, 40% by volume) of the pores present in the silica material of the present invention are in the mesoporous range.

[0142] In more specific embodiments, at least about 50%, such as at least about 60%, and especially at least about 70% of the pores present in the silica material of the present invention are in the mesoporous range.

[0143] Those skilled in the art will understand that for pores within a certain range, the average (i.e., arithmetic mean) pore size can also be calculated.As described herein, this average pore size is measured by nitrogen adsorption technology and calculated using density functional theory (DFT) known to those skilled in the art (see Olivier, JP, Conklin, WB and Szombathely, MV, Studies in Surface Science and Catalysis, 87, 81-89 (1994); Landers, J., et al., Colloids and Surfaces A: Physicochem. Eng. Aspects, 437, 3-32 (2013)).Therefore, unless otherwise specified, the average pore size herein refers to the average pore size measured by nitrogen adsorption and calculated using DFT.

[0144] In a specific embodiment, the pores in the mesoporous range have an average pore size of about 7.0 to about 24.0 nm.

[0145] In a more specific embodiment, the pores in the mesoporous range have an average pore size of about 7.0 to about 23.0 nm.

[0146] In an even more specific embodiment, the pores in the mesoporous range have an average pore size of from about 7.0 to about 22.0 nm.

[0147] In an even more specific embodiment, the pores in the mesoporous range have an average pore size of from about 7.0 to about 21.0 nm.

[0148] In an even more specific embodiment, the pores in the mesoporous range have an average pore size of from about 7.0 to about 20.0 nm.

[0149] For example, in certain embodiments, the average pore size of the pores in the mesoporous range is Approximately 7.0~19.0nm, Approximately 7.0~18.0nm, Approximately 7.0~17.0nm, Approximately 7.0~16.0nm, Approximately 7.0~15.0nm, Approximately 7.0~14.0nm, about 7.0 to about 13.0 nm, or Approximately 7.0~12.0nm is.

[0150] In certain embodiments, the pores in the mesoporous range have an average pore size of about 8.0 to about 13.0 nm.

[0151] In a more specific embodiment, the pores in the mesoporous range have an average pore size of about 8.0 to about 12.0 nm.

[0152] In a more specific embodiment, the average pore size of the pores in the mesoporous range is from about 8.0 to about 11.0 nm.

[0153] In an alternative embodiment, the average pore size of the pores in the mesoporous range is from about 9.0 to about 11.0 nm.

[0154] In an even more specific embodiment, the pores in the mesoporous range have an average pore size of from about 9.2 to about 11.0 nm.

[0155] In an even more specific embodiment, the pores in the mesoporous range have an average pore size of from about 9.4 to about 10.8 nm.

[0156] In an even more specific embodiment, the pores in the mesoporous range have an average pore size of from about 9.5 to about 10.7 nm.

[0157] In an even more specific embodiment, the pores in the mesoporous range have an average pore size of from about 9.6 to about 10.7 nm.

[0158] In an even more specific embodiment, the pores in the mesoporous range have an average pore size of from about 9.5 to about 10.6 nm.

[0159] In a most specific embodiment, the pores in the mesoporous range have an average pore size of about 9.6 to about 10.6 nm.

[0160] In a further embodiment, the pores in the mesoporous range have an average pore size of from about 8.0 to about 22.0 nm.

[0161] In yet another embodiment, the average pore size of the pores in the mesoporous range is from about 9.0 to about 22.0 nm.

[0162] In yet another embodiment, the pores in the mesoporous range have an average pore size of from about 10.0 to about 22.0 nm.

[0163] In yet another embodiment, the average pore size of the pores in the mesoporous range is from about 10.0 to about 21.0 nm.

[0164] In yet another embodiment, the average pore size of the pores in the mesoporous range is from about 10.0 to about 20.0 nm.

[0165] In yet another embodiment, the average pore size of the pores in the mesoporous range is from about 9.0 to about 21.0 nm.

[0166] In yet another embodiment, the average pore size of the pores in the mesoporous range is from about 10.0 to about 21.0 nm.

[0167] In yet another embodiment, the average pore size of the pores in the mesoporous range is from about 11.0 to about 21.0 nm.

[0168] In yet another embodiment, the average pore size of the pores in the mesoporous range is from about 12.0 to about 21.0 nm.

[0169] In yet another embodiment, the average pore size of the pores in the mesoporous range is from about 13.0 to about 21.0 nm.

[0170] In yet another embodiment, the average pore size of the pores in the mesoporous range is from about 14.0 to about 21.0 nm.

[0171] In yet another embodiment, the average pore size of the pores in the mesoporous range is from about 15.0 to about 21.0 nm.

[0172] In yet another embodiment, the average pore size of the pores in the mesoporous range is from about 16.0 to about 21.0 nm.

[0173] In yet another embodiment, the average pore size of the pores in the mesoporous range is from about 16.0 to about 20.0 nm.

[0174] In yet another embodiment, the average pore size of the pores in the mesoporous range is from about 17.0 to about 20.0 nm.

[0175] In yet another embodiment, the average pore size of the pores in the mesoporous range is from about 17.0 to about 19.0 nm.

[0176] In yet another embodiment, the average pore size of the pores in the mesoporous range is from about 17.0 to about 18.0 nm.

[0177] In yet another embodiment, the average pore size of the pores in the mesoporous range is about 22 nm (eg, about 22.0 nm).

[0178] Those skilled in the art will appreciate that in addition to reference to an (arithmetic) average pore size as described herein, the silica materials of the present invention may also be defined with reference to a distribution of pore sizes, such as the distribution of pore sizes for pores in the mesoporous range.

[0179] In specific embodiments of the first aspect of the present invention, at least 21% (e.g., at least at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, or at least 29%) of the pores within the mesoporous range (by volume) have a diameter within the specified range of average pore size (i.e., the specified range for the average pore size).

[0180] In a more specific embodiment of the first aspect of the present invention, at least about 30% of the pores in the mesoporous range have diameters within the range of the average pore size.

[0181] In even more specific embodiments of the first aspect of the present invention, at least about 35% (at least 40% or at least 45%) of the pores in the mesoporous range have diameters within the average pore size range.

[0182] Furthermore, in more specific embodiments of the first aspect of the present invention, at least about 50% (e.g., at least 55%, at least 60%, at least about 65%, at least about 70%, or particularly at least about 72%) of the pores in the mesoporous range have diameters within the average pore size range (i.e., the range given for the average pore size of the pores in the mesoporous range defined herein).

[0183] For example, in certain embodiments, at least about 50% (e.g., at least 55%, at least 60%, at least about 65%, at least about 70%, or particularly at least about 72%) of the pores in the mesoporous range have diameters within the range of about 7.0 to about 25.0 nm.

[0184] In certain embodiments, up to about 100% (or up to about 99%, about 95%, or about 90%) of the pores in the mesoporous range have diameters within the average pore size range.

[0185] In certain embodiments, about 21% to about 100% (or particularly about 25% to about 99% or 100%) of the pores in the mesoporous range have diameters within the average pore size range.

[0186] In even more specific embodiments of the first aspect of the present invention, at least about 30% (eg, from about 30% to about 99% or 100%) of the pores in the mesoporous range have diameters within the average pore size range.

[0187] In even more specific embodiments of the first aspect of the present invention, at least about 35% (eg, about 35% to about 99%) of the pores in the mesoporous range have diameters within the average pore size range.

[0188] In even more specific embodiments of the first aspect of the present invention, about 40% to about 90% (or about 99% or 100%) of the pores in the mesoporous range have diameters within the average pore size range.

[0189] For example, in specific embodiments (i.e., specific embodiments of the first aspect of the present invention), at least about 25% (e.g., about 25% to about 99%, about 50% to about 99%, or 100%) of the pores of the silica particles are mesopores with sizes ranging from about 7.0 to about 25.0 nm (e.g., about 7.0 to about 18.0 nm, or about 7.0 to about 13.0 nm).

[0190] Similarly, in specific embodiments, at least about 50% (e.g., about 50% to about 99%, about 50% to about 90%, etc.) of the pores in the silica particles are mesopores with sizes ranging from about 7.0 to about 25.0 nm (e.g., about 7.0 to about 18.0 nm, or about 7.0 to about 13.0 nm).

[0191] In specific embodiments (i.e., specific embodiments of the first aspect of the present invention), at least about 50% (e.g., about 50% to about 99%) of the pores of the silica particles are mesopores having a size ranging from about 9.0 to about 12.0 nm.

[0192] In a further embodiment, at least about 25% (eg, at least about 50%, about 60%, or about 70%) of the pores of the silica particles are mesopores in the size range of about 9.0 to about 10.2 nm.

[0193] In a further embodiment, at least about 25% (eg, at least about 50%, about 60%, or about 70%) of the pores of the silica particles are mesopores in the size range of about 9.0 to about 11.0 nm.

[0194] In more specific embodiments, at least about 25% (eg, about 25% to about 99%) of the pores of the silica particles are mesopores having a size ranging from about 9.0 to about 11.0 nm.

[0195] In even more specific embodiments, at least about 25% (eg, about 25% to about 99%) of the pores of the silica particles are mesopores ranging in size from about 9.0 to about 10.2 nm.

[0196] Those skilled in the art will understand that reference to porous silica particles having pores in the mesoporous range necessarily requires that such particles be porous, and this includes particles that exhibit porous behavior. Thus, porous silica particles refer to particles that have significant porosity, and in certain embodiments may be defined with reference to characteristics such as the pore volume and / or surface area of the particle, for example, with reference to parameters defined herein (the characteristics described herein, as well as other characteristics described herein, may be used alone or in combination).

[0197] Those skilled in the art will also appreciate that the total volume of pores within each particle can affect the surface area of the particle.

[0198] Those skilled in the art will appreciate that the surface area of a particle (or a sample of particles) can be calculated using Brunauer-Emmett-Teller (BET) theory, a technique known to those skilled in the art (e.g., Brunauer, S., Emmett, P.H., and Teller, E., J. Am. Chem. Soc., 60(2), 309-319 (1938)).

[0199] In a specific embodiment, the silica particles have a particle size of at least about 150 μm. 2 / g BET surface area.

[0200] In a more specific embodiment, the silica particles have a particle size of at least about 200 mm 2 / g BET surface area.

[0201] In an even more specific embodiment, the silica particles have a particle size of at least about 300 m 2 / g (e.g., at least about 350 m 2 / g) BET surface area.

[0202] In an even more specific embodiment, the silica particles have a particle size of at least about 400 m 2 / g (e.g., at least about 450 m 2 / g) BET surface area.

[0203] In a specific embodiment, the silica particles have a particle size of at least about 500 m 2 / g BET surface area.

[0204] In a specific embodiment, the BET surface area is up to about 1500 m 2 / g(maximum approx. 1200m 2 / g or 1000m 2 / g, etc.).

[0205] For example, in a specific embodiment, the silica particles have a particle size of about 200 to about 1500 m 2 / g BET surface area.

[0206] In a further embodiment, the silica particles have a particle size of from about 500 to about 1200 m 2 / g BET surface area.

[0207] In an even more specific embodiment, the silica particles have a viscosity of from about 600 to about 1200 m 2 / g BET surface area.

[0208] In an alternative embodiment, the silica particles are from about 600 to about 1000 m 2 / g BET surface area.

[0209] In a further alternative embodiment, the silica particles have a particle size of from about 500 to about 900 μm. 2 / g, for example, about 550 to about 900 m 2 / g BET surface area.

[0210] In yet a further alternative embodiment, the silica particles have a viscosity of from about 600 to about 850 μm. 2 / g BET surface area.

[0211] Those skilled in the art will appreciate that the porous silica particles can be provided in a variety of shapes.

[0212] In a specific embodiment, the silica particles have a substantially non-spherical morphology (ie, an aspect ratio greater than 1:1, eg, greater than 1.1:1).

[0213] In more specific embodiments, the aspect ratio of the silica particles is greater than 1.5:1, such as greater than 1.8:1.

[0214] In an even more specific embodiment, the aspect ratio of the silica particles is 2:1 or greater.

[0215] As used herein, the term "aspect ratio" is understood to refer to the ratio between the largest and smallest cross-sectional diameters of a silica particle.

[0216] Alternatively, such particles (i.e., particles having a substantially non-spherical morphology) may be described as having at least one asymmetric (i.e., the morphology of the particle differs about the plane) plane (i.e., a plane that divides the particle equally in half).

[0217] In more specific embodiments, the silica particles have an essentially rod-like morphology. Thus, in specific embodiments, the porous silica particles can be characterized by having an essentially rod-like morphology as observed by electron microscopy (e.g., using techniques known to those skilled in the art, such as scanning electron microscopy (SEM) or transmission electron microscopy (TEM)), e.g., rod lengths of about 0.5 to about 5.0 μm.

[0218] As used herein, the term essentially rod-shaped is understood to refer to particles that are elongated in shape, resembling rods, which may be straight or curved (e.g., such rod-shaped particles may be substantially straight).

[0219] In an alternative embodiment, the silica particles of the present invention can be substantially spherical (or can be referred to as spherical). Thus, in a specific embodiment, the silica particles of the present invention can have an aspect ratio (or average aspect ratio) of about 1:1.

[0220] In a further embodiment, the silica particles of the present invention may be in amorphous form.

[0221] Those skilled in the art will understand that the term average particle size, as used herein, refers to the average diameter of the particle at its largest point (e.g., its length in the case of a rod-shaped particle, or its diameter in the case of a spherical particle), which can be measured using techniques known to those skilled in the art, such as electron microscopy techniques (e.g., by scanning electron microscopy (SEM) or transmission electron microscopy (TEM) techniques known to those skilled in the art). In a specific embodiment, particle size is determined using electron microscopy (e.g., SEM).

[0222] In specific embodiments, particle size may be defined in terms of its diameter, such as when the particle is spherical.

[0223] In specific such embodiments, the silica particles have an average particle size of from about 0.1 to about 20.0 μm.

[0224] In a more specific embodiment, the silica particles have an average particle size of from about 0.1 to about 15.0 μm.

[0225] In an even more specific embodiment, the silica particles have an average particle size of from about 0.1 to about 10.0 μm.

[0226] In an even more specific embodiment, the silica particles have an average particle size of from about 0.5 to about 10.0 μm.

[0227] In an even more specific embodiment, the silica particles have an average particle size of from about 0.5 to about 5.0 μm.

[0228] In one particular embodiment, the silica particles have an average particle size of about 0.5 to about 4.5 μm.

[0229] In a specific embodiment, the silica particles have an average particle size of about 1.0 to about 10.0 μm.

[0230] In a specific embodiment, the silica particles have an average particle size of about 1.0 to about 5.0 μm.

[0231] In a more specific embodiment, the silica particles have an average particle size of about 1.0 to about 4.0 μm.

[0232] In a more specific embodiment, the silica particles have an average particle size of about 1.0 to about 4.0 μm.

[0233] In an even more specific embodiment, the silica particles have an average particle size of from about 2.0 to about 4.0 μm.

[0234] In an even more specific embodiment, the silica particles have an average particle size of about 3.0 to about 4.0 μm.

[0235] In further embodiments, such as where the particle is rod-shaped, particle size may (or may also) be defined in terms of its width (referring to the diameter at its narrowest point).

[0236] In specific such embodiments, the silica particles have an average width of from about 0.05 to about 0.6 μm.

[0237] In a more specific embodiment, the silica particles have an average width of from about 0.1 to about 0.6 μm.

[0238] In an even more specific embodiment, the silica particles have an average width of from about 0.1 to about 0.4 μm.

[0239] In an even more specific embodiment, the silica particles have an average width of from about 0.2 to about 0.4 μm.

[0240] Those skilled in the art will understand that porous silica materials of the type described in this invention are typically amorphous. Thus, in certain embodiments, the porous silica particles may be described as substantially amorphous porous silica particles (and materials formed of a plurality of such particles may similarly be described). Thus, the porous silica particles may be described as amorphous porous silica particles.

[0241] In alternative embodiments, the silica material present in the particles according to the first aspect of the invention may be described as amorphous. In such embodiments, the term amorphous will be understood to indicate that the structure of the silica material (excluding any pores present therein) does not possess substantial order such as may be present in crystalline materials (i.e., the porous silica particles, or silica material, may be referred to as non-crystalline).

[0242] As described herein, those skilled in the art will understand that the silica materials of the present invention are porous. Thus, the silica particles of the present invention can be said to have a certain minimum total pore volume, or range of such volumes, as measured using nitrogen adsorption (e.g., taken as the volume adsorbed at the highest P / P value, e.g., P / P=0.995).

[0243] In a specific embodiment, the total pore volume is at least about 0.2 cm 3 / g (e.g., at least about 0.3, 0.4, 0.5, 0.6, or 0.7 cm 3 / g).

[0244] In a specific embodiment, the total pore volume is from about 0.2 to about 2.5 cm 3 / g.

[0245] In more specific embodiments, the total pore volume is from about 0.2 to about 2.0 cm 3 / g.

[0246] In a more specific embodiment, the total pore volume is from about 0.5 to about 1.5 cm 3 / g.

[0247] In an even more specific embodiment, the total pore volume is from about 0.6 to about 1.4 cm 3 / g.

[0248] For example, in certain embodiments, the total pore volume is from about 0.7 to about 1.3 cm 3 / g.

[0249] Medical and non-medical uses As described herein, the formulations of the present invention may be useful for treating certain diseases and disorders and may therefore be provided in a form suitable for such use. Accordingly, the formulations of the present invention may be described as pharmaceutical formulations (e.g., oral pharmaceutical formulations).

[0250] In a second aspect of the invention, there is provided a formulation as defined in the first aspect of the invention (including all embodiments and features thereof) for pharmaceutical use (or medical use or medicinal use).

[0251] In an alternative second aspect of the present invention there is provided the use of a formulation defined in the first aspect of the present invention (including all embodiments and features thereof) as a medical device.

[0252] As described herein, the onset of metabolic disorders such as type 2 diabetes and obesity is usually preceded by an increase in certain risk factors that can lead to metabolic or cardiovascular events. Reduction of these risk factors can lead to prevention or delay of the onset of actual disease. The formulations described in the present invention may be particularly suitable for use in reducing these risk factors and treating resulting conditions (e.g., obesity, prediabetes, type 2 diabetes, dyslipidemia, etc.).

[0253] Furthermore, treatment with the formulations of the present invention may provide an effective means for treating obesity and reducing body fat (i.e., body fat in the form of adipose tissue), and therefore may also be suitable for use in treating related conditions.

[0254] In a third aspect of the invention, there is provided a method for the treatment or prevention of a metabolic disease or disorder, comprising administering to a patient in need of treatment or prevention of a metabolic disease or disorder a therapeutically effective amount of a formulation as defined in the first aspect of the invention.

[0255] In a fourth aspect of the invention, there is provided a formulation as defined in the first aspect of the invention for use in the treatment or prevention of a metabolic disease or disorder.

[0256] In an alternative fourth aspect of the invention there is provided a formulation as defined in the first aspect of the invention for use in the treatment or prevention of a metabolic disease or disorder.

[0257] As used herein, those skilled in the art will understand that reference to a metabolic disease or disorder refers to a disease or disorder that interferes with normal metabolism, i.e., the process of converting food into energy. As such, such diseases and disorders include those that would be expected to benefit from modulation of food intake, such as regulating the uptake of dietary components (e.g., carbohydrates such as sugars, proteins, and lipids).

[0258] Those skilled in the art will also appreciate that metabolic diseases and disorders can in turn lead to cardiovascular diseases and disorders, which may also be treated (or prevented) as part of the present invention.

[0259] In a specific embodiment of the fourth aspect of the invention, the treatment or prevention of a metabolic disease or disorder comprises: (a) Reduction of metabolic risk factors for type 2 diabetes, (b) the treatment or prevention of type 2 diabetes; (c) treating or preventing prediabetes; (d) treatment or prevention of metabolic syndrome; (e) the treatment or prevention of obesity; (f) reducing or preventing an increase in body fat levels in the form of adipose tissue; (g) reducing or preventing an increase in triglyceride and / or cholesterol levels; and (h) Treatment or prevention of dyslipidemia Refers to...

[0260] For the avoidance of doubt, those skilled in the art will understand that references in the fourth aspect of the invention to reducing or preventing an increase in the level of a particular substance (i.e. the level of a particular substance in the body of a patient) may refer to such reducing in a therapeutic manner or preventing an increase in a prophylactic manner, and may therefore be made to a patient in need thereof.

[0261] Alternatively, references in the fourth aspect of the invention to reducing or preventing an increase in the level of a particular substance (i.e., the level of a particular substance in a patient's body) may refer to such reduction or prevention of an increase being achieved in a non-therapeutic (e.g., cosmetic) manner.

[0262] Thus, in a further alternative fourth aspect of the invention, a formulation as defined in the first aspect of the invention is - non-therapeutic reduction or prevention of an increase in body fat levels in the form of adipose tissue, and - Non-therapeutic reduction or prevention of an increase in triglyceride and / or cholesterol levels It is provided to be used.

[0263] Those skilled in the art will understand that references to the treatment of a particular condition (or, equivalently, treating the condition) have their usual meaning in the medical field. In particular, these terms may refer to achieving a reduction in the severity and / or frequency of occurrence of one or more clinical symptoms associated with the condition, as determined by a physician examining a patient with or susceptible to the condition. For example, in the case of treating type 2 diabetes, the term may refer to achieving a reduction in blood glucose levels experienced by the patient (e.g., postprandial blood glucose levels, i.e., those experienced after eating a meal).

[0264] As used herein, the term prevention includes the prevention of (and, similarly, preventing) a disease or disorder. Thus, a reference to prevention can also be a reference to a preventative measure, and vice versa. In particular, such a term refers to achieving a reduction (e.g., at least a 10% reduction, e.g., at least a 20%, 30%, or 40% reduction, e.g., at least a 50% reduction) in the likelihood that a patient (or healthy subject) will develop a condition (which may be understood to mean that the patient's condition changes and that a physician diagnoses them as having the relevant disease or disorder and, e.g., as needing treatment) or experiencing the associated effects.

[0265] Similarly, reference to achieving a reduction in a risk factor can refer to achieving a clinically significant reduction in the level of at least one biomarker for such risk factor. For example, in certain circumstances, such a reduction can be at least a 1% reduction (e.g., at least a 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, or 40% reduction, e.g., at least a 50% reduction) in the level of the risk factor above normal values (the range of values expected in a healthy patient), as known to those skilled in the art.

[0266] As used herein, reference to a patient(s) refers to a living organism that is the subject of treatment, including a mammalian (e.g., human or animal) patient.

[0267] In specific embodiments, reference to a patient refers to a human patient.

[0268] In alternative embodiments, reference to a patient may refer to other mammals such as farm animals (e.g., cows, pigs, sheep, goats, horses, chickens, turkeys, etc.) and / or household pets (e.g., cats, dogs, rabbits, etc.).

[0269] Thus, in certain alternative embodiments, the formulation of the first aspect of the invention may be referred to as a veterinary composition.

[0270] For the avoidance of doubt, those skilled in the art will understand that such treatment or prevention is administered to a patient (or subject) in need thereof. The need of a patient (or subject) for such treatment or prevention may be assessed by one skilled in the art.

[0271] As used herein, the terms disease and disorder (and similarly terms condition, illness, medical problem, etc.) may be used interchangeably.

[0272] As used herein, the term "effective amount" refers to that amount of a formulation that confers a therapeutic effect on a treated patient. Such an effect may be observed objectively (i.e., measurable by some test or marker) or subjectively (i.e., the subject gives an indication of and / or feels an effect). In particular, the effect may be observed (e.g., measured) objectively using a suitable test known to one skilled in the art.

[0273] For the avoidance of doubt, those skilled in the art (e.g., physicians) will be able to determine the actual dosage which will be most suitable for an individual patient, which may vary depending on the route of administration, the type and severity of the condition being treated, and the species, age, weight, sex, renal function, hepatic function, and response of the particular patient being treated.

[0274] For example, particularly when administered orally to a human patient, the formulations described in the first aspect of the present invention may be administered in doses comprising about 0.1 to about 20.0 g (e.g., about 0.5 to about 15.0 g, such as about 1.0 to about 5.0 g, e.g., about 1.0 g, about 2.0 g, or about 3.0 g) of porous silica material, and these doses may be administered one or more times per day (i.e., during a 24 hour period).

[0275] In particular, those skilled in the art will appreciate that doses of silica material may be administered at appropriate intervals to correspond with the patient's ingestion of food (e.g., at mealtimes), and therefore, doses referred to herein may be understood to be doses timed to be administered simultaneously with food (i.e., timed to coincide with the time at which the patient consumes food, e.g., mealtimes).

[0276] As used herein, references to diseases and disorders shall be understood by those skilled in the art, including references to definitions provided in international classifications of such disorders (see, e.g., the International Classification of Diseases (ICD) provided by the World Health Organization (WHO), updated as of January 1, 2017).

[0277] For example, the disorder called metabolic syndrome, which may also be known by other names, may refer to a cluster of at least three of the following five medical conditions: abdominal obesity, high blood pressure, hyperglycemia (glucose), hypertriglyceridemia, and low high-density lipoprotein (HDL) levels (e.g., as defined by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III)).

[0278] As described herein, the formulations of the present invention are capable of exerting therapeutic effects themselves, and thus treatment with such particles and compositions may be therapeutically effective without the use of other therapeutic agent(s).

[0279] In a specific embodiment of the fourth aspect of the invention, the method or use does not include co-administration with other therapeutic agents used in a similar method or use (i.e. the formulation of the first aspect of the invention may be used / administered as monotherapy).

[0280] In a more specific embodiment of the fourth aspect of the invention, the method or use does not include co-administration with other therapeutic agents.

[0281] In a further embodiment of the fourth aspect of the invention, the method comprises administering a formulation defined in the first aspect of the invention as monotherapy.

[0282] As described herein, the present invention relates to the use of the formulations described herein as active therapeutic agents, such as in methods for reducing metabolic risk factors for type 2 diabetes. The present invention also relates to such uses in the treatment of prediabetes, which may refer to the prevention of prediabetes progressing to the clinical state diagnosed as type 2 diabetes.

[0283] For the avoidance of doubt, metabolic risk factors for type 2 diabetes and methods for measuring the same are well known to those skilled in the art. Non-limiting examples of biomarkers of such risk factors include abnormal (i.e., shifted) levels of low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, cholesterol, apoA1 and / or apoB, and / or abnormal ratios between apoA1 and apoB, between LDL and HDL (reference to an "abnormal" level refers to a value that is shifted by a clinically significant amount from normal values for the patient, as determined by one of skill in the art), and / or identification of high blood pressure, elevated insulin resistance, high blood glucose levels, elevated HbA1c, and any combination thereof (reference to an "elevated" or "high" level may refer to a value that is higher by a clinically significant amount from normal values for the patient, as determined by one of skill in the art).

[0284] In a specific embodiment, the metabolic risk factors for type 2 diabetes are based on an analysis of the levels of one or more biomarkers selected from the group consisting of LDL, HDL, triglycerides, cholesterol, ApoA1 and ApoB; the ratio of ApoA1 to ApoB, the ratio of LDL to HDL cholesterol; blood pressure, insulin resistance, glucose levels, and HbA1c levels.

[0285] In a specific embodiment, a metabolic risk factor for type 2 diabetes may be the identification of an elevated level of HbA1c. Similarly, a patient may be identified as having prediabetes based on the identification of an elevated level of HbA1c if the patient has not been diagnosed with diabetes (e.g., type 2 diabetes).

[0286] For the avoidance of doubt, those skilled in the art will understand that reference to elevated levels of HbA1c refers to levels that are above the range expected to be observed in such patients (i.e., patients of the same type), but in a healthy state.

[0287] For example, according to the American Diabetes Association, an HbA1c level may be considered high if it is 39.0 mmol / mol or higher (corresponding to a DCCT of 5.7%). Specifically, a patient may be diagnosed with prediabetes if their HbA1c level is in the range of 39.0 mmol / mol to 46.0 mmol / mol (DCCT of 5.7% to 6.4%). However, patients with HbA1c levels above 46.0 mmol / mol may be diagnosed with prediabetes if they do not meet the clinical diagnostic criteria for diabetes; a diagnosis of diabetes typically requires an HbA1c level of 47.0 mmol / mol or higher.

[0288] Those skilled in the art will also be aware that prediabetes may be diagnosed based on other indications known to those skilled in the art, such as measuring fasting blood glucose levels (e.g., by identifying a fasting blood glucose level of 100-125 mg / dl) or using an oral glucose tolerance test (OGTT) (e.g., based on patients having a 2-hour OGTT blood glucose result of 140 mg / dl-199 mg / dl).

[0289] Those skilled in the art will appreciate that the condition dyslipidemia may be understood to mean elevated levels of lipids (cholesterol, triglycerides, or both) carried by lipoproteins in the blood. This term may include hypolipoproteinemia (hyperlipidemia), which refers to abnormally high levels of total cholesterol, low-density lipoprotein (LDL), or triglycerides, and abnormally low high-density lipoprotein (HDL). Thus, for the avoidance of doubt, dyslipidemia includes hyperlipidemia.

[0290] As described herein, the formulations of the present invention act to reduce metabolic risk factors for diabetes independent of treatment of underlying causative factors such as obesity.

[0291] Thus, in a specific embodiment of the fourth aspect of the invention, (a) Reduction of metabolic risk factors for type 2 diabetes, (b) the treatment or prevention of type 2 diabetes; (c) treatment of prediabetes, and / or (e.g., and) (d) Treatment or prevention of metabolic syndrome is performed in non-obese patients (i.e., patients with a BMI of less than 30), particularly non-overweight patients (i.e., patients with a BMI of less than 25), such as patients of a healthy weight (e.g., patients with a BMI of 18.5 to 24.9).

[0292] As described herein, the formulations of the present invention may be useful in medical treatments performed without other therapeutic agents (ie, as monotherapy).

[0293] In a further embodiment of the fourth aspect of the invention, - Treatment or prevention of type 2 diabetes, - Treating prediabetes, - treatment or prevention of metabolic syndrome, and / or (e.g., and) - Treatment of dyslipidemia is performed in patients who are not receiving (i.e., not taking) other therapeutic agents for the treatment or prevention of these conditions.

[0294] In specific embodiments, reference to cholesterol levels may include reference to ApoA1, ApoB and / or non-HDL cholesterol, and / or LDL cholesterol, and the LDL / HDL cholesterol ratio.

[0295] As described herein, the silica materials of the present invention can function as molecular sieves by physically separating small molecules from larger molecules through their custom porosity. This physicochemical separation results in a delay and reduction in food digestion and biomolecule uptake, thereby reducing energy intake and lowering and delaying postprandial blood lipid and glucose peaks in animal model systems, as well as lowering biomarkers such as HbA1c and LDL cholesterol blood levels in human subjects.

[0296] As used herein, by referring to specific biological markers, reference to a reduction in risk factors can refer to a reduction in these risk factors from elevated levels to levels that are close to (or within) the range expected for a patient in a healthy state. For example, in relation to a reduction in HbA1c levels, the reduction can refer to a reduction of at least 0.1 mmol / mol, e.g., from about 0.1 mmol / mol to about 20.0 mmol / mol. Those skilled in the art will understand that such a reduction can occur after long-term treatment.

[0297] In particular, the formulations of the present invention may be used as pharmaceutical treatments or active dietary supplements to improve metabolic health by reducing food efficiency, and may be used in subject (or patient) populations at risk of developing pre-diabetes, as well as those already diagnosed with metabolic disorders such as, but not limited to, type 2 diabetes, obesity, weight-related disorders, abnormal blood glucose homeostasis, and metabolic syndrome.

[0298] In specific embodiments, ingestion of the formulation may affect total carbohydrate absorption from the digestive system. The term carbohydrate absorption refers to the process that occurs in the digestive system that involves the breakdown of food components containing complex carbohydrates, i.e., sugar polymers longer than dimers, so that they can be taken up or absorbed by an organism.

[0299] In another embodiment, the formulation may affect HbA1c levels when used for a long period of time (e.g., at least one month). The term "HbA1c" refers to glycosylated hemoglobin, a laboratory measurement of glycemic control over the past two to three months (Bennett, C. M. et al., Diabet. Med., 24(4), 333-43 (2007)). As those skilled in the art know, this biological marker is well established and used to diagnose type 2 diabetes and assess the risk of complications (Lind, M. et al., Diabetes & Metabolic Syndrome: Clinical Research and Reviews, 2(4), 282-293 (2008)).

[0300] Thus, in specific embodiments, the treatment of prediabetes, or treatment or prevention of diabetes and / or metabolic syndrome described herein is characterized (i.e., identified) by a reduction in, or prevention of an increase in, HbA1c levels in the patient. Furthermore, methods of treating such conditions may also be referred to as methods of lowering HbA1c levels in a patient in need thereof.

[0301] In particular embodiments, the uses or methods described herein may require that the silica material or composition be administered with food or drink (eg, with food).

[0302] Use as a dietary supplement As described herein, the formulations of the present invention may be useful as dietary supplements and may therefore be provided in a form suitable for such use. Accordingly, the formulations of the present invention may be described as dietary supplement formulations (e.g., oral dietary supplement formulations).

[0303] In a fifth aspect of the present invention, there is provided a formulation as defined in the first aspect of the present invention (including all embodiments and features thereof) for use as a dietary supplement.

[0304] For the avoidance of doubt, a formulation referred to as a nutraceutical formulation may also be suitable for use as a pharmaceutical formulation (and therefore referred to as a pharmaceutical formulation), and vice versa. Accordingly, the formulations of the present invention may be referred to as oral pharmaceutical or nutraceutical formulations, etc.

[0305] Those skilled in the art will appreciate that the formulations of the present invention may be ingested (ie, administered) simultaneously with or as part of a food (eg, meal) or beverage.

[0306] Those skilled in the art will understand that references herein to administration with food (or, equivalently, administration with a meal) or with a beverage can refer to administration at the same time as the food or beverage is consumed, or immediately before or after consumption of the food or beverage (e.g., up to 2 hours, e.g., up to 1 hour, or particularly up to 30 minutes before or after ingestion of food).

[0307] Those skilled in the art will also understand that the formulations of the present invention, when used, for example, as dietary supplements, may induce the biological effects described herein. Accordingly, the dietary supplement formulations described herein may also be referred to as active dietary supplement formulations.

[0308] Those skilled in the art will appreciate that administering the formulations of the present invention with food or drink (i.e., oral administration) may reduce their efficiency, meaning that less energy will be absorbed from a given amount of nutrient.

[0309] Thus, in a sixth aspect of the present invention there is provided a method of reducing the efficacy of a food or drink item, comprising administering a formulation as defined in the first aspect of the present invention (including all embodiments and features thereof) together with said food or drink.

[0310] In an alternative sixth aspect of the invention there is provided the use of a formulation as defined in the first aspect of the invention in a method of reducing the efficacy of a food or drink item, said use comprising administering the silica particles or composition together with said food or drink item.

[0311] In particular embodiments, the food or drink item is a food item, such as a meal.

[0312] In a specific embodiment, the reduced efficacy of the food or drink item comprises a reduced glycemic response resulting from the ingestion of the food or drink item.

[0313] In yet another embodiment, the formulation may reduce postprandial carbohydrate uptake in the blood. As used herein, the term postprandial may refer to the levels observed immediately after ingesting a meal, as measured over time.

[0314] In one embodiment, the formulation can simultaneously affect carbohydrate and lipid absorption from the digestive system upon ingestion, hi another embodiment, the particles can affect blood lipid levels upon ingestion.

[0315] In yet another embodiment, the formulation can affect the overall postprandial absorption of carbohydrates and lipids in the blood upon ingestion.

[0316] Those skilled in the art will understand that reference to the glycemic response of a food or beverage item has its ordinary meaning in the art, such as referring to the plasma glucose levels experienced by a patient immediately after (and therefore resulting from) ingestion of the food or beverage item. This is sometimes referred to as the postprandial glycemic response (change in concentration) caused when a carbohydrate-containing food or meal is ingested. Thus, reference to reducing the glycemic response can refer to the reduction in glucose levels experienced by a patient when ingesting a food or beverage item in conjunction with administration of the silica particles or composition compared to what would be experienced if ingested without administration of the silica particles or composition.

[0317] Similarly, in specific embodiments, reducing the efficacy of a food or drink item comprises reducing plasma triglyceride levels after consuming the food or drink item.

[0318] In such cases, reference to a reduction in plasma glucose or triglyceride levels may refer to a reduction of at least 1% (e.g., at least 2%, 3%, 5%, 7%, 10%, 15% or especially at least 20%).

[0319] Those skilled in the art will appreciate that plasma levels of a particular substance (such as blood glucose levels) can be measured using techniques known to those skilled in the art, such as by periodic analysis of blood samples taken from the patient at appropriate times.

[0320] Packaging and Manufacturing Those skilled in the art will recognize that the formulations of the present invention will be packaged (eg, for distribution and sale) in a manner appropriate for a pharmaceutical or food supplement, depending on their intended use.

[0321] For example, the formulations of the present invention may be packaged in single-portion containers, such as containers from which the formulation can be consumed directly (eg, disposable bottles or pouches, or stick packs, etc.).

[0322] The formulations of the present invention can be prepared using techniques known to those skilled in the art, for example, by mixing the components of the composition (sequentially in one process or a subset thereof) to obtain a substantially homogeneous mixture thereof.

[0323] Thus, in a further aspect of the present invention there is provided a process for preparing a formulation according to the first aspect of the present invention (including all embodiments and features thereof), comprising the steps of mixing the ingredients of the formulation together to form a mixture and homogenising the mixture.

[0324] Without being bound by theory, porous silica particles having many well-defined pores restricting the internal volume according to the present invention and compositions containing the same may function through their ability to function as molecular sieves and provide this function in vivo, for example, in the digestive system. This effect is thought to occur through the action of pores present in particles of a specific size. After ingestion, the porous silica particles mix with food in the digestive system. In the digestive system, digestive enzymes break down large food molecules into small biomolecules that can be absorbed by the body. Thus, the digestive system contains both large and small biomolecules.

[0325] The silica material of the present invention is believed to function as a molecular sieve through its custom-designed porosity, physically separating small biomolecules from larger ones. Only small molecules diffuse into the pores of the silica material (i.e., small molecules are molecules that can diffuse into the pores of the silica material, while large molecules are molecules that cannot diffuse into the pores but may interact with the surface of the silica material). This physically separates some of the small biomolecules, such as digestive enzymes and metabolites, dietary lipid complexes, and carbohydrates, from undigested food in the digestive system. The main digestive enzymes that break down sugars and fats are amylase and lipase, respectively. When functioning as a molecular sieve, it is believed that these digestive enzymes, among other biomolecules, may enter the pores of the silica through a facilitated diffusion effect resulting from the claimed combination of pore sizes. This physically separates the trapped enzymes from undigested food, slowing digestion and nutrient absorption from the digestive system.

[0326] It is believed that the formulations of the present invention can provide porous silica material in a stable form that can be easily ingested by a subject without affecting its functionality. In particular, such formulations allow the porous silica material to be presented in a form that does not have the unpleasant mouthfeel (i.e., gritty or dry aftertaste) associated with other formulations, thus improving the palatability of the formulation. [Brief explanation of the drawings]

[0327] [Figure 1] Effect of different formulations on silica amylase adsorption efficiency (A)–(D). Mesoporous silica particles (MSP) suspended in various formulations were tested for their ability to adsorb porcine pancreatic amylase. The kinetics of amylase adsorption by silica in the formulations can be seen in the area under the curve (AUC) analysis in the time course graphs (A–C) and (D), respectively. Formulations 3, 6, and 9 reduced the effectiveness of silica to adsorb amylase by 25%, 40%, and 11%, respectively, compared to unformulated MSP. Data are presented as mean ± standard error (SE) (n=2). [Figure 2] The results of Example 6 are presented. [Example]

[0328] The present invention is further described with reference to the following examples, which are not intended to limit the scope of the invention.

[0329] Example 1: Preparation / Characterization of Mesoporous Silica Particle (MSP) Materials material Mesoporous silica particles (MSPs) were prepared according to a previously described process (see Baek, J. et al., Nanomedicine 17:1, 9-22 (2022), in particular the experimental procedures described therein, the contents of which are incorporated herein by reference). Briefly, a mesostructured templating agent (P123, average molecular weight = 5800 gmol) was added. -1 triblock copolymer, PEO 20 PPO 70 PEO 20 ) was dissolved in aqueous hydrochloric acid (HCl) at an acid concentration equivalent to 1.6 M. After complete dissolution of P123, tetraethyl orthosilicate (TEOS) was added with vigorous stirring at 40 °C. The final molar ratio of P123:TEOS in the solution was 0.02:1.00, and the molar ratio of TEOS:HCl:HO was 1:7:230. The synthesis was left at 40 °C for 20 h, followed by a hydrothermal treatment at 100 °C for 10 h.

[0330] Nitrogen Adsorption Analysis Brunauer-Emmett-Teller (BET) surface areas were calculated from adsorption isotherms at relative pressures (p / p°) < 0.2. Total pore volumes were recorded at relative pressures (p / p°) = 0.995. Average pore size and pore size distribution were derived from adsorption curves using density functional theory (DFT) methods. Measurements were performed at liquid nitrogen temperature (-196 °C) using a TriStar II volumetric adsorption analyzer, and data analysis was performed using MicroActive software for TriStar II version 2.03 (Micromeritics Instrument Corp., GA, USA).

[0331] Particle size Scanning electron microscopy using a JSM-7401F (JEOL Ltd., Tokyo, Japan) was used to characterize particle size and morphology from SEM micrographs. Average particle size (length and width) was analyzed from ≥50 particles using ImageJ (see Schindelin J, Arganda-Carreras I, Frise E et al., Fiji: an open-source platform for biological image analysis., Nat. Methods, 9(7), 676-682 (2012)).

[0332] [Table 1]

[0333] Example 2: Preparation of formulations The following ingredients were purchased from Sigma-Aldrich: potassium sorbate (1.05119.1000), citric acid (27109), xanthan gum (G1253), sodium carboxymethylcellulose (419303), tragacanth gum (G1128), colloidal microcrystalline cellulose (435244), and guar gum (G4129). Peach flavor was obtained from Einar Willumsen (12101). Erythritol was purchased from Amazon (ASIN B01MFCXDZA). Formulations were homogenized using a Witeg HG-15A homogenizer equipped with an HT1018 dispersing tool.

[0334] Preparation of control (unformulated) MSP suspension MSP (5 g) was added to 45 g of MilliQ water (MQ H2O) and homogenized at low speed for 3 minutes.

[0335] Preparation of stock solutions Solution 1: Potassium sorbate was dissolved in MQ HO. Citric acid was then added to the same solution and stirred until dissolved. The concentration of potassium sorbate was 0.125% by weight, and the concentration of citric acid was 0.250% by weight.

[0336] Solution 2: Peach flavor (0.3 g) was diluted in 3.7 g of MQ H2O.

[0337] Preparation 1: MSP (5 g) was added to 40.15 g of Solution 1 and 4.75 g of MQ H2O and homogenized on low speed for 3 minutes.

[0338] Formulations 2-10: The thickening agent (concentration according to Table 2; sometimes referred to as thickener) was slowly added to 40.15 g of Solution 1 and MQ HO (amount adjusted to a total weight of 50 g) while homogenizing. The homogenization speed was gradually increased from low to medium as the formulation thickened. After adding the thickening agent, the gel was homogenized at medium speed for an additional 3 minutes, or until the thickening agent was completely dispersed (no lumps were visible). Finally, 5 g of MSP was added to the formulation and homogenized at medium speed for 3 minutes.

[0339] Formula 11: Erythritol (2 g) was added to 40.15 g of Solution 1, 0.67 g of Solution 2, and 1.88 g of MQ HO. The mixture was stirred until the erythritol was dissolved. Xanthan gum (0.3 g) was slowly added to the solution while homogenizing. The homogenization speed was gradually increased from low to medium as the formulation thickened. After the xanthan gum was added, the formulation was homogenized at medium speed for an additional 3 minutes, or until the xanthan gum was completely dispersed (no lumps were visible). Finally, 5 g of MSP was added to the formulation and homogenized at medium speed for 3 minutes.

[0340] [Table 2]

[0341] Example 3: Evaluation of suspension stability The day after preparation, approximately 20 mL of each formulation was transferred to a glass vial and stored in the dark at room temperature. After 6 weeks (42 days), the samples were visually inspected. If separation was observed (clear liquid on top), the suspension was not stable. If no separation was observed after 4 weeks, the suspension was considered stable under the conditions of this experiment. The results are shown in Table 3.

[0342] [Table 3]

[0343] Example 4: Evaluation of suspension stability after 1 year storage at room temperature Some of the samples that appeared stable after 6 weeks of storage in the dark at room temperature (Example 3) were stored under the same conditions. After one year, the samples were visually inspected again. If separation was observed (clear liquid on top), the suspension was not stable. If no separation was observed after one year, the suspension was considered stable under the conditions of this experiment. The results are shown in Table 4.

[0344] [Table 4]

[0345] Example 5: Amylase adsorption assay Preparation of working solutions and standard curve samples Prior to the assay, several working solutions were prepared. 2x PBS was prepared by dissolving one PBS tablet (Medicago, 09-2052-100) in 100 mL of MQ HO. After dissolution, the pH was adjusted to 5.4. A working solution (312 μg / mL) of porcine pancreatic amylase (Sigma-Aldrich, A4268) was freshly prepared by diluting the required amount of stock solution with 2x PBS (pH 5.4) on the day of the experiment. A working solution of bicinchoninic acid (BCA) was freshly prepared on the day of the experiment according to the manufacturer's instructions. Amylase standard curve samples (45 μL each) were prepared by serial dilution with 2x PBS (pH 5.4) in a 96-well PCR plate (VWR, 732-2387). After serial dilution, 45 μL of MQ HO was added to each standard curve sample. The concentrations of the standard curve samples were 156, 78, 39, 19.5, 9.8, 4.9, and 0 μg / mL.

[0346] Preparation of test formulations Test formulations were prepared by weighing approximately 1 g of formulation and diluting it into approximately 4 mL of MQ HO (1:5 dilution to obtain 20 mg / mL silica). Samples were sonicated to obtain a homogenous suspension. Briefly, a 2 mm microtip (VibrasCell) was attached to the ultrasonicator (VibrasCell) and the silica suspension was sonicated for 3 minutes at 40% amplitude without pulsing.

[0347] Adsorption of porcine pancreatic amylase onto silica Test formulations were incubated with porcine pancreatic amylase at 37°C for 15, 30, and 60 minutes for enzyme adsorption / capture. Different silica concentrations (1000, 500, 250, and 125 μg / mL, 45 μL each) were prepared by serial dilution with MQ HO in a 96-well PCR plate containing an amylase standard curve. 45 μL of porcine pancreatic amylase working solution (312 μg / mL, final amylase concentration = 156 μg / mL) was dispensed into each well. The plate was sealed (VWR, 391-1254) and incubated at 37°C for 15, 30, and 60 minutes with vertical rotation using a rotator (Harvard Apparatus, 74-2302). After incubation, the plate was centrifuged at 2000 × g for 5 minutes at room temperature. The supernatant (60 μL) from each well was transferred to a new 96-well plate (Corning, CLS3370).

[0348] Colorimetric determination of unbound porcine pancreatic amylase The amount of unbound porcine pancreatic amylase in the supernatant was measured using a BCA assay. 60 μL of BCA working solution was added to each well containing the supernatant, and the plate was sealed (Bio-Rad, MSB1001) and incubated at 60°C for 1 hour. The plate was then cooled to room temperature for 15 minutes, and the absorbance was measured at 562 nm.

[0349] Calculation of the Loading Capacity of Porcine Pancreatic Amylase on Silica The amount of unbound porcine pancreatic amylase was used to calculate the silica loading capacity (µg amylase / mg silica) over time. The concentration of free amylase in each sample was estimated from the slope and intercept of the amylase standard curve. The amount of amylase adsorbed / trapped by silica (µg / mL) was calculated by subtracting the protein concentration of free amylase from the initial amylase concentration of 156 µg / mL. Using GraphPad software, the calculated amylase removal (µg / mL) was plotted against the silica concentration (125–1000 µg / mL) at each time point (amylase removal graph).

[0350] The effectiveness of MSP was determined by the amount of amylase (µg) adsorbed by 1 mg of silica. This was called the loading capacity (µg amylase / mg silica) and was calculated using the amylase removal graph. For each time point (15, 30, and 60 min), the silica concentration required to remove approximately 50% of the maximum amylase removal was calculated using the "nonlinear regression (curve fit)" and "standard curve for interpolation" analyses in GraphPad software. The calculated amount of silica (mg / mL) required to remove 50% of the amylase (µg / mL) after 15, 30, and 60 min was used to calculate the loading capacity (µg amylase / mg silica) for each time point. The loading capacity was plotted as a time course graph, with the y-axis representing the loading capacity (µg amylase / mg silica) and the x-axis representing time (15–60 min). From this time course graph, the area under the curve (AUC) for each sample was calculated using the analysis tool in GraphPad Prism. The AUC for each sample was compared to a control unprepared MSP sample.

[0351] The results are presented in Figure 1. Formulas 3, 6, and 9 reduced the effectiveness of silica to adsorb amylase by 25%, 40%, and 11%, respectively, compared to unformulated MSP. Data are presented as mean ± SE (n=2).

[0352] Example 6: Amylase adsorption capacity after 1 year storage at room temperature Samples that appeared stable after 6 weeks of storage in the dark at room temperature (Example 3) were stored under the same conditions. After 1 year, samples that showed no decrease in efficacy compared to freshly prepared unformulated MSP in the amylase adsorption assay (Example 5) were reanalyzed using the method described in Example 5. The results are presented in Figure 2. All formulations tested showed acceptable efficacy compared to unformulated MSP. Data are presented as mean ± SE (n = 2).

Claims

1. An oral formulation comprising: (a) water; (b) porous silica particles having pores in the mesoporous range; (c) a thickener; Including, the average pore size of the pores in the mesoporous range is about 7.0 to about 25.0 nm; An oral formulation wherein the thickening agent is selected from xanthan gum and microcrystalline cellulose or a mixture thereof.

2. 10. The formulation of claim 1, wherein the formulation comprises from about 70.0 to about 95.0% by weight of water.

3. 3. The formulation of claim 1 or claim 2, wherein the formulation comprises about 5.0 to about 15.0% by weight of the porous silica particles.

4. The formulation according to any one of claims 1 to 3, wherein the thickening agent is xanthan gum.

5. 5. The formulation of any one of claims 1 to 4, wherein the formulation comprises from about 0.3% to about 0.9% by weight of the thickening agent.

6. The formulation (d) one or more preservatives, sweeteners, flavorings, fragrances, and / or coloring agents The formulation of any one of claims 1 to 5, further comprising:

7. 7. The formulation of any one of claims 1 to 6, wherein the average pore size of the pores in the mesoporous range is from about 7.0 to about 22.0 nm.

8. 8. The formulation of any one of claims 1 to 7, wherein the average pore size of the pores in the mesoporous range is from about 10.0 to about 21.0 nm.

9. 9. The formulation of any one of claims 1 to 8, wherein the average pore size of the pores in the mesoporous range is from about 10.0 to about 20.0 nm.

10. 10. The formulation of any one of claims 1 to 9, wherein at least about 40% by volume of the pores are in the mesoporous range.

11. The silica particles are at least about 200 m ２ 11. The formulation according to any one of claims 1 to 10, having a BET surface area of 1 / g.

12. 12. The formulation of any one of claims 1 to 11, wherein the silica particles have an average particle size of about 0.1 to about 20.0 μm.

13. 13. The formulation of any one of claims 1 to 12, wherein the silica particles have an average particle size of about 1.0 to about 5.0 μm.

14. The silica particles are about 0.7 to about 1.3 cm ３ The formulation according to any one of claims 1 to 13, having a total pore volume of 1 / g.

15. A formulation according to any one of claims 1 to 14 for use as a pharmaceutical.

16. A method for treating or preventing a metabolic disease or disorder, comprising administering a therapeutically effective amount of the formulation of any one of claims 1 to 14 to a patient in need of such treatment or prevention.

17. A formulation according to any one of claims 1 to 14 for use in the treatment or prevention of a metabolic disease or disorder.

18. 18. The method according to claim 16 or the composition for use according to claim 17, wherein the treatment or prevention of a metabolic disease or disorder comprises: (a) reducing metabolic risk factors for type 2 diabetes; (b) the treatment or prevention of type 2 diabetes; (c) treating or preventing prediabetes; (d) treatment or prevention of metabolic syndrome; (e) the treatment or prevention of obesity; (f) reducing or preventing an increase in body fat levels in the form of adipose tissue; (g) reducing or preventing an increase in triglyceride and / or cholesterol levels; and (h) Treatment or prevention of dyslipidemia A method or composition comprising:

19. 15. A method of reducing the efficacy of a food or drink item, comprising administering a formulation according to any one of claims 1 to 14 together with said food or drink item.

20. Use of a formulation according to any one of claims 1 to 14 as a dietary supplement.

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