Oral formulations comprising porous silica particles and medical uses thereof

Abstract

Provided herein is an oral formulation comprising: (a) water; (b) porous silica particles having pores in the mesopore range; and (c) a thickener, wherein the average pore size of the pores within the range of the mesopores is from 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 uses of such formulations, such as their use in medicine.

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

[0003] The listing or discussion of any previously published document in this specification should not necessarily be taken as an admission 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 disrupt normal metabolism, including the process of converting food into energy. Metabolic disorders occur when abnormal chemical reactions in the body disrupt the metabolic process. There are different groups of disorders. Some affect the breakdown of amino acids, carbohydrates or lipids. Another group, mitochondrial diseases, affects the part of the cell that produces energy. Metabolic disorders can be classified as primary (inherited) or secondary (related to lifestyle, environment, etc.).

[0005] Metabolic syndrome is a medical term that defines the clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low high-density lipoprotein (HDL) levels, such that these conditions occur together. 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 the way the body regulates blood sugar (glucose). There is a strong genetic (hereditary) factor involved 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, the patient suffers from a medical condition known as prediabetes. Prediabetes is characterized by elevated blood sugar (glucose) levels that are higher than those considered normal but not enough to be classified as type 2 diabetes. Prediabetes is a high-risk state for developing type 2 diabetes. If left untreated, 15% to 30% of people with prediabetes will develop type 2 diabetes within five years (USDepartment of Health and Human Services, Centersfor Disease Control and Prevention (2014)). The number of individuals with prediabetes is expected to increase significantly, and by 2040, it is estimated that 482 million people will be affected worldwide.

[0008] There are currently no approved drug treatments in the guidelines for prediabetes. The standard of care for prediabetes management is lifestyle intervention. Prediabetic patients are managed by primary care, where they are advised to exercise and eat a healthy diet. Lifestyle interventions have low compliance rates, with only 10% to 20% of patients being able to implement a new lifestyle. Therefore, there is currently a major unmet clinical need for treating prediabetes, with only 3.7% of prediabetic patients currently considered suitable for treatment with metformin (see Moin, T. et al., Ann. Intern. Med., 162, 542 (2015)).

[0009] According to the Centers for Disease Control and Prevention, the incidence of type 2 diabetes has tripled in the past 30 years. This is primarily due to the global epidemic of obesity, which is a major risk factor for developing type 2 diabetes and prediabetes. Obesity is defined as abnormal or excessive fat accumulation that can impair health. Basically, obesity occurs when the body takes in more calories than it burns over time. Obesity increases the risk of developing a variety of 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 (lipid disorders) are associated with cardiovascular disease and atherosclerosis.

[0010] Dyslipidemia is considered a metabolic disease and is defined as abnormal levels of lipids (such as cholesterol and / or fats) in the blood. This is often due to diet and lifestyle. Cardiovascular disease is often grouped with metabolic disorders because it is often a result of diabetes and dyslipidemia.

[0011] Statins are the most widely used lipid-lowering drugs for preventing coronary heart disease in high-risk patients. However, there is controversy about 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)). In addition, there are a large number of 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 A. G., et al., American Journal of Cardiovascular Drugs, 8 (6), 373-418 (2008)). The latter is the main side effect that limits the use of statins (Martini, J. et al., Canadian J of Cardiology, 27, 635-662 (2011)). Therefore, there is a need for new and more effective lipid-lowering treatment alternatives with and without combinations of lipid-lowering drugs.

[0012] In view of the above, it is evident that there is a major impetus to develop new approaches, drugs and medical technologies that provide effective, rapid-acting and safer prevention and treatment approaches to delay and treat prediabetes, diabetes and its related conditions.

[0013] It has been previously shown that silica particles with a specific porosity can reduce adipose tissue in animal model systems (see: WO 2014 / 072363 and Kupferschmidt, N. et al., Nanomedicine, 9(9), 1353-1362 (2014)). Animals receiving macroporous mesoporous silica and a high-fat diet showed a significant reduction in body weight and body fat composition with no observable negative effects. In particular, the authors proposed using such silica to reduce body weight and body fat composition as a means for treating obesity.

[0014] It has been reported that such silica materials can also reduce levels of HbA1c, a biomarker whose levels correspond 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 WO 2019 / 166656).

[0016] Porous silica particles are thermally and chemically stable and consist only of pure silica. They have a controllable pore size, which can provide a high surface area and a large total pore volume. These properties, especially stability and biocompatibility, make them suitable for biomedical applications (Wang, Y. et al., Nanomedicine Nanotechnology, Biol. Med., 11, 313–327 (2015)). In addition, similar materials have previously been approved as food additives (European Chemical Synthetic Amorphous Silica Ecotoxicology and Toxicology Center (CAS No. 7631-86-9), JACC No. 51, p. 14 (ECETOC, 2006)).

[0017] However, the use of such silica particles in medical treatment approaches presents significant challenges, particularly because such particles are typically administered orally.

[0018] To achieve a therapeutic effect, the dose of silica material required is usually relatively large, typically in the range of several grams, which makes it inconvenient to provide such materials in tablet or capsule form because restrictions on the size and shape of individual tablets and capsules suitable for oral administration may result in the need to consume multiple dosage units.

[0019] To address this problem, silica materials may be present in the form of liquids that can be consumed orally. However, such liquid formulations are instability-prone because the silica material may separate from the formulation, causing it to become unevenly distributed and have a poor mouthfeel profile, such as having a gritty texture and causing a feeling of dry mouth after consumption.

[0020] Therefore, there is a need for oral formulations of silica materials that are stable and do not inhibit the function of the silica materials, making them suitable for uses such as those described herein. Ideally, such formulations would also have a pleasant texture, making them easier to consume. DETAILED DESCRIPTION

[0021] It has been unexpectedly discovered that improved oral formulations of therapeutically active silica materials can be prepared by adding certain thickening agents. Such formulations can be used as dietary supplements and as pharmaceutical agents or medical devices, which can be used to treat diseases and disorders as described herein.

[0022] New formulations

[0023] In a first aspect of the present invention, there is provided an oral preparation comprising:

[0024] (a) water;

[0025] (b) porous silica particles having pores in the mesoporous range; and

[0026] (c) a thickener,

[0027] in:

[0028] The average pore size of pores in the mesopore range is from about 7.0 to about 25.0 nm; and

[0029] The thickener is selected from xanthan gum and microcrystalline cellulose or a mixture thereof.

[0030] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0031] For the avoidance of doubt, a formulation as defined in the first aspect of the present invention (including all embodiments and features thereof) may also be referred to as "a formulation of the present invention (or the first aspect of the present 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 present invention (including all embodiments and features thereof) may also be referred to as "silicon dioxide (or silica material or silica particles) of the present invention (or the first aspect of the present invention)" etc.

[0032] When used herein with respect to a particular value (such as an amount), the term "about" (or similar terms, such as "approximately") will be understood to indicate that such value may vary within at most 10% (specifically, at most 5%, such as at most 4%, 3%, 2% or 1%) of the defined value. It is contemplated that such terms may be replaced with the notation "±10%" or the like in each case (or by indicating the variance of a particular amount calculated based on the relevant value). With respect to percentage amounts mentioned herein, the term "about" (or similar terms, such as "approximately") will be understood to indicate that such value may vary within at most 10% (specifically, at most 5%, such as at most 4%, 3%, 2% or 1%) of the defined percentage value. It is also contemplated that the term "about" may be deleted in each case.

[0033] For the avoidance of doubt, reference to a formulation comprising certain ingredients will include the possibility that such formulation may consist of (or consist essentially of) those ingredients.

[0034] For the avoidance of doubt, the skilled person will understand that where percentages of a component are defined as belonging to different (i.e., non-overlapping) groups, the sum of these percentages cannot exceed 100%. Thus, where the maximum value of a component of one or more non-overlapping groups exceeds 100%, the skilled person will understand that one or more of those components must be present in an amount less than the maximum value. Similarly, where other components may be present in the formulation, it is not required that the sum of the specified components equal 100%.

[0035] The skilled artisan will understand that reference to an oral formulation will refer to a formulation intended for (e.g., suitable for) oral consumption, such as a formulation for oral consumption by a human or animal (e.g., a mammal, such as a household pet or recreational animal, such as a cat, dog, horse, rabbit, etc., or livestock, such as cattle, pigs, sheep, goats, chickens, turkeys, etc.). In certain instances, reference to consumption by such a human or animal subject (who may also be referred to as a patient in connection with medical treatment methods) will specifically refer to treatment of an adult (e.g., full-grown) subject.

[0036] In particular, reference to an oral formulation will refer to a formulation intended for (eg suitable for) oral consumption by a human, such as an adult (eg a human who is at least 18 years of age).

[0037] The skilled person will understand that references herein to oral consumption will refer to a formulation that is swallowed by a subject in one action or in several actions. Thus, the skilled person will understand that the formulation of the present invention may be in the form of a liquid, gel or soft solid such that the formulation can be easily swallowed.

[0038] The skilled person will appreciate that it may be advantageous to provide the formulation in the form of a readily flowable liquid so that it can be consumed by the subject as a drink.

[0039] Thus, in particular embodiments, the formulation is a liquid (in which case it may be referred to as a liquid formulation).

[0040] The skilled person will understand that the term liquid will typically refer to a substance that is free flowing but has a constant volume, typically having a consistency similar to that of water or liquid oil.

[0041] In further embodiments, the formulation may be provided in the form of a soft solid / gel, which may have a consistency similar to that of yogurt (eg, set yogurt, which may be described as having a spoonable consistency).

[0042] The skilled artisan will appreciate that the amount of each component present in the formulation can be adjusted in order to achieve the desired viscosity and flowability.

[0043] In particular embodiments, the formulation may be provided in a form having a viscosity classified as low to medium, such as having a viscosity and / or fluidity similar to that of a milkshake or similar drink / food.

[0044] In further embodiments, the formulation may be provided in a form having a viscosity that is classified as high, such as having a viscosity and / or fluidity similar to that of set yogurt or a similar food product.

[0045] As described herein, the formulations of the present invention include water. In particular, the formulations typically include water as an important component, such as the main (i.e., largest) component by weight. Therefore, the formulations can be described as aqueous (or substantially aqueous) formulations.

[0046] The skilled artisan will appreciate that the amount of water included in the formulation may be selected so as to achieve desired characteristics of the formulation, such as a desired viscosity and / or flowability.

[0047] In a specific embodiment, the formulation comprises:

[0048] At least about 70.0% (such as at least about 71.0%, 72.0%, 73.0%, 74.0%, 75.0%, 76.0%, 77.0%, 78.0%, 79.0%) water by weight (wt %); and / or (e.g., and)

[0049] At least about 80.0 wt % (such as at least about 81.0 wt %, 82.0 wt %, 83.0 wt %, 84.0 wt % or 85.0 wt %) water.

[0050] In specific embodiments, the formulation comprises up to about 95.0 wt % (such as up to about 94.0 wt %, 93.0 wt %, 92.0 wt % or 91.0 wt %) water.

[0051] In more specific embodiments, the formulation comprises up to about 90.0 wt % (such as up to about 89.0 wt %, 88.0 wt %, 87.0 wt %, 86.0 wt % or 85.0 wt %) water.

[0052] For example, in particular embodiments, the formulation comprises from about 70.0 to about 95.0 wt % water.

[0053] In more specific embodiments, the formulation comprises about 75.0 to about 95.0 wt % water.

[0054] In more specific embodiments, the formulation comprises about 80.0 to about 95.0 wt % water.

[0055] In more specific embodiments, the formulation comprises about 75.0 to about 90.0 wt % water.

[0056] In more specific embodiments, the formulation comprises about 80.0 to about 90.0 wt % water.

[0057] In more specific embodiments, the formulation comprises about 82.0 to about 88.0 wt % water.

[0058] In more specific embodiments, the formulation comprises about 83.0 to about 87.0 wt % water.

[0059] In more specific embodiments, the formulation comprises about 84.0 to about 86.0 wt % water.

[0060] In certain embodiments, the formulation comprises about 84.0 to about 91.0 wt % water.

[0061] In certain embodiments, the formulation comprises about 84.0 to about 90.0 wt % water.

[0062] In specific embodiments, the formulation comprises about 85 to about 86 wt % water, such as about 85.6 wt % water.

[0063] In specific embodiments, the formulation comprises about 89 to about 90% wt % water, such as about 89.0 to about 90.0% wt % water.

[0064] In particular embodiments, it is understood that where amounts of other ingredients are specified, the remainder of the composition (eg, by weight) is water.

[0065] As described herein, the formulations of the present invention comprise porous silica particles having pores in the mesopore range, wherein the average pore size of the pores in the mesopore range is from about 7.0 to about 25.0 nm.

[0066] One skilled in the art will appreciate that the amount of such porous silica particles in a formulation can be selected to provide an appropriate loading amount such that administration of an appropriate amount of the formulation is capable of delivering a desired dose of the silica material (e.g., a dose required to achieve a desired biological effect, such as the therapeutic and non-therapeutic effects described herein).

[0067] In a specific embodiment, the formulation comprises:

[0068] At least about 5.0 wt % (such as at least about 6.0 wt %, 7.0 wt %, 8.0 wt % or 9.0 wt %) of porous silica particles; and / or (e.g., and)

[0069] Up to about 15.0 wt %, such as at least about 14.0 wt %, 13.0 wt %, 12.0 wt %, or 11.0 wt % porous silica particles.

[0070] In specific embodiments, the formulation comprises about 5.0 to about 15.0 wt % of the porous silica particles.

[0071] In more specific embodiments, the formulation comprises about 6.0 to about 14.0 wt % of the porous silica particles.

[0072] In more specific embodiments, the formulation comprises about 7.0 to about 13.0 wt % of the porous silica particles.

[0073] In more specific embodiments, the formulation comprises about 8.0 to about 12.0 wt % of the porous silica particles.

[0074] In more specific embodiments, the formulation comprises about 9.0 to about 11.0 wt % of the porous silica particles.

[0075] In more specific embodiments, the formulation comprises about 9.0 to about 10.5 wt % of the porous silica particles.

[0076] 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.

[0077] As described herein, the formulation of the present invention comprises a thickener, wherein the thickener is selected from xanthan gum and microcrystalline cellulose (MCC) or a mixture thereof.

[0078] In a specific embodiment, the thickening agent is selected from (ie, selected from the group consisting of) xanthan gum and microcrystalline cellulose.

[0079] As described herein, it has been discovered that these thickening agents, in contrast to other such agents, allow for the preparation of formulations that offer improved properties in terms of stability and palatability (due to, for example, their texture) without inhibiting the biological activity of the silica material.

[0080] The skilled person will appreciate that the microcrystalline cellulose may be colloidal microcrystalline cellulose.

[0081] Those skilled in the art will be able to select appropriate amounts of each such thickening agent in order to achieve the desired characteristics of the formulation, such as its viscosity and flowability.

[0082] In a specific embodiment, the formulation comprises:

[0083] At least about 0.1 wt % (such as at least about 0.2 wt %, 0.3 wt %, 0.4 wt % or 0.5 wt %) of a thickener; and / or (e.g., and)

[0084] Up to about 1.5 wt %, such as up to about 1.4 wt %, 1.3 wt %, 1.2 wt % or 1.1 wt % thickener.

[0085] In specific embodiments, the formulation comprises from about 0.1 wt % to about 1.5 wt % of a thickener.

[0086] In specific embodiments, the formulation comprises from about 0.2 wt % to about 1.4 wt % of a thickener.

[0087] In specific embodiments, the formulation comprises from about 0.3 wt % to about 1.3 wt % of a thickener.

[0088] In specific embodiments, the formulation comprises from about 0.4 wt % to about 1.2 wt % of a thickener.

[0089] In specific embodiments, the formulation comprises from about 0.5 wt % to about 1.1 wt % of a thickener.

[0090] In certain embodiments, the thickening agent is microcrystalline cellulose.

[0091] In such embodiments (ie, where the thickening agent is microcrystalline cellulose), the formulation comprises from about 0.8 wt % to about 1.2 wt % of the thickening agent.

[0092] In further such embodiments (ie, where the thickening agent is microcrystalline cellulose), the formulation comprises from about 0.9 wt % to about 1.1 wt % of the thickening agent.

[0093] In specific such embodiments (ie, where the thickening agent is microcrystalline cellulose), the formulation comprises about 1 wt % of the thickening agent, such as about 1.0 wt % of the thickening agent.

[0094] As also described herein, it has been discovered that the use of xanthan gum as a thickening agent provides formulations with yet further improved texture, which results in yet further improved palatability.

[0095] In a specific embodiment, the thickening agent is xanthan gum.

[0096] In such embodiments (ie, where the thickener is xanthan gum), the formulation comprises from about 0.3 wt % to about 0.9 wt % of the thickener.

[0097] In further such embodiments (ie, where the thickener is xanthan gum), the formulation comprises from about 0.4 wt % to about 0.8 wt % of the thickener.

[0098] In yet further such embodiments (ie, where the thickener is xanthan gum), the formulation comprises from about 0.5 wt % to about 0.7 wt % of the thickener.

[0099] In specific such embodiments (ie, where the thickener is xanthan gum), the formulation comprises about 0.6 wt % of the thickener, such as about 0.63 wt % of the thickener.

[0100] Those skilled in the art will appreciate that the formulations of the present invention may include additional components in order to adjust and / or maintain properties such as freshness / food safety (i.e., freedom from contaminants such as bacteria and mold growth), taste, aroma and / or color of the formulation.

[0101] Therefore, in a specific embodiment, the formulation further comprises:

[0102] (d) optionally, one or more preservatives, sweeteners, flavoring agents, fragrances and / or coloring agents.

[0103] In specific embodiments, optional component (d) is present in the formulation in an amount up to about 10.0 wt % (such as up to about 9.0 wt %, 8.0 wt %, 7.0 wt % or 6.0 wt %) of the formulation.

[0104] In more particular embodiments, optional component (d) is present in the formulation in an amount up to about 5.0 wt % (such as up to about 4.9 wt %, 4.8 wt %, 4.7 wt %, 4.6 wt %, 4.5 wt % or 4.4 wt %) of the formulation.

[0105] For example, the formulation may further comprise one or more preservatives, such as those food preservatives suitable for human consumption as known to those skilled in the art.

[0106] For example, suitable preservatives would include lactic acid, benzoic acid and pharmaceutically acceptable salts thereof (eg sodium benzoate), sorbic acid and pharmaceutically acceptable salts thereof (eg potassium sorbate) and citric acid, including mixtures thereof.

[0107] Specific preservatives that may be mentioned include citric acid and potassium sorbate, including mixtures thereof.

[0108] For the avoidance of doubt, preservatives, such as those described herein, may also be referred to as acidity regulators.

[0109] In specific embodiments, the formulations further comprise one or more preservatives.

[0110] For example, in specific embodiments, the formulation comprises the preservatives citric acid (e.g., in an amount of about 0.1 to about 0.3 wt % of the formulation, such as about 0.2 wt % of the formulation, e.g., about 0.22 wt % of the formulation) and potassium sorbate (e.g., in an amount of about 0.05 to about 0.15 wt % of the formulation, such as about 0.1 wt % of the formulation, e.g., about 0.09 wt % of the formulation).

[0111] The formulations may also contain one or more flavoring and / or sweetening agents, such as those known to those skilled in the art to be suitable for human consumption.

[0112] For example, suitable sweeteners can include sugars (such as sucrose, tagatose and psicose), sugar alcohols (such as erythritol, xylitol, sorbitol and mannitol), artificial sweeteners (such as sucralose, saccharin, acesulfame potassium and aspartame) and plant extracts (such as steviol glycosides and monk fruit extracts). Specific sweeteners that can be mentioned include non-caloric sweeteners, particularly sugar alcohols (such as erythritol) and plant extracts (such as steviol glycosides).

[0113] In specific embodiments, the formulations comprise one or more sweeteners.

[0114] The skilled artisan will be able to select suitable sweeteners and amounts thereof in order to achieve the desired taste profile for the formulation.

[0115] In particular embodiments, the sweetener is present in an amount of about 0.01 to about 10.0 wt % of the formulation.

[0116] In more specific embodiments, the sweetener is present in an amount of about 0.05 to about 10.0 wt % of the formulation.

[0117] In yet more specific embodiments, the sweetener is present in an amount of about 0.1 to about 10.0 wt % of the formulation.

[0118] In yet more specific embodiments, the sweetener is present in an amount of about 0.5 to about 10.0 wt % of the formulation.

[0119] In yet more specific embodiments, the sweetener is present in an amount of about 1.0 to about 10.0 wt % of the formulation.

[0120] In yet more specific embodiments, the sweetener is present in an amount of about 2.0 to about 9.0 wt % of the formulation.

[0121] In yet more specific embodiments, the sweetener is present in an amount of about 2.0 to about 8.0 wt % of the formulation.

[0122] In yet more specific embodiments, the sweetener is present in an amount of about 2.0 to about 7.0 wt % of the formulation.

[0123] In yet more specific embodiments, the sweetener is present in an amount of about 2.0 to about 6.0 wt % of the formulation.

[0124] In yet more specific embodiments, the sweetener is present in an amount of about 3.0 to about 5.0 wt % of the formulation.

[0125] In yet more specific embodiments, the sweetener is present in an amount of about 3.0 to about 4.0 wt % of the formulation.

[0126] In yet more specific embodiments, the sweetener is present in an amount of about 3.5 to about 3.9 wt % of the formulation.

[0127] In yet more specific embodiments, the sweetener is present in an amount of about 3.6 to about 3.9 wt % of the formulation.

[0128] In particular embodiments, the sweetener is present in an amount of about 4 wt % of the formulation, such as about 3.8 wt % of the formulation.

[0129] In more specific embodiments, the sweetener is erythritol or a mixture of erythritol and steviol glycosides.

[0130] In specific such embodiments (i.e., where the sweeteners are erythritol and steviol glycosides), the sweeteners are present in an amount of about 4 wt % of the formulation, such as about 3.8 wt % of the formulation, for example wherein erythritol is present in an amount of about 3.7 to about 3.8 wt % of the formulation, such as about 3.75 wt % of the formulation, and steviol glycosides are present in an amount of about 0.01 wt % of the formulation.

[0131] As described herein, the formulations may additionally contain flavoring agents (eg, vanilla and / or fruit flavorings), which may be derived from extracts and / or artificial agents.

[0132] Such flavoring agents may be present in an amount of about 0.01 to about 0.50 wt % of the formulation, for example, about 0.01 to about 0.30 wt % of the formulation, such as about 0.25 wt % of the formulation.

[0133] In certain embodiments, the formulation further comprises:

[0134] (e) optionally, one or more additional active agents.

[0135] As used herein, the term active agent may refer to a component that has a biological effect on a subject, which component may be referred to as a bioactive agent.

[0136] For example, such additional active agents may include soluble fibers (such as inulin and dextrin), pharmaceutical agents, vitamins, minerals, natural (eg, plant) extracts, and the like.

[0137] In specific embodiments, the formulation contains no (or is substantially free of) additional active agents (ie, active agents other than the silica materials of the present invention).

[0138] For the avoidance of doubt, the formulation may comprise further additional components which may be selected so as to enhance and / or supplement the properties of the formulation.

[0139] For example, the skilled artisan will appreciate that other such additional components, such as colorants and flavors, may be selected in order to provide an attractive formulation to a subject. Where present, such components may be present in substantially negligible amounts when compared to the other components.

[0140] In specific embodiments, the amount of a component as specified herein (i.e., components (a) to (c), or (a) to (d), or (a) to (e) as appropriate) is equal to 100% (in these embodiments, the formulation can be said to consist of, or consist essentially of, the components as specified herein).

[0141] In other embodiments, other components may be added to the formulations of the present invention in amounts other than the components and their relative amounts as specified above without changing the properties of the formulation. In such embodiments, the formulation comprises the components as specified herein (i.e., components (a) to (c), or (a) to (d), or (a) to (e) as required) (wherein their relative amounts are equal to 100%), optionally comprising additional components.

[0142] The skilled person will appreciate that the formulations of the present invention will contain each component as a mixture thereof. In particular, such a mixture will contain each component such that it is evenly distributed throughout the formulation, which formulation can be described as homogeneous (or substantially homogeneous).

[0143] As described herein, the formulations of the invention will be stable, which may indicate that the composition of the formulation and the distribution of such compositions therein will not change over an extended period of time, such as a period of at least 42 days, such as at least 1 year (365 days).

[0144] In specific embodiments, the formulation will be stable for at least 42 days, such as at least 1 year (365 days), such as where the formulation will remain homogeneous (or substantially homogeneous) after storage for a period of at least 42 days, such as at least 1 year (365 days); e.g., at room temperature and pressure, when protected from moisture and sunlight.

[0145] Porous silica particles

[0146] The skilled person will appreciate that the porous silica particles as provided in the formulation of the first aspect of the invention may be referred to as a plurality of porous silica particles, and the plurality may be referred to as a porous silica material.

[0147] 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.

[0148] The skilled person will appreciate that reference herein to a pore of a certain size will refer to the average diameter of the relevant pores (i.e. the average diameter of each individual pore taking into account its size). For the avoidance of doubt, the skilled person will appreciate that reference to the average pore size may specifically refer to the average size of the opening of each pore (or, in the case of pores whose passages traverse the body of the particle internally, to the average size of all openings of the pores), which may be referred to as the pore window (or window of the pore).

[0149] For the avoidance of doubt, averages referred to herein are calculated as median averages unless otherwise stated.

[0150] Unless otherwise stated, the pore sizes as described herein are measured by nitrogen adsorption and calculated using density functional theory (DFT) methods (see, e.g., methods described in Landers, J. et al., Colloids and Surfaces A: Physicochem. Engineering Aspects, 437, 3–32 (2013)). Therefore, unless otherwise stated, references herein to average pore size will refer to pore size as measured by nitrogen adsorption and calculated using density functional theory (DFT).

[0151] The skilled person will understand that reference to the percentage of pores present in a particular range can be understood as a reference to the pore size distribution (PSD) of such particles. Thus, reference to the percentage of pores present in a particular range will refer to the combined volume of pores present in each range as a percentage of the total pore volume of the relevant group of pores (e.g., pores in the mesopore range).

[0152] For the avoidance of doubt, reference to particles having a particular average pore size may in some cases include reference to pores that are functionally equivalent (eg, when used in the manner described herein) to particles having such average pore size.

[0153] The skilled person will understand that the pore size distribution of the silica material can be measured using a DFT pore size distribution curve, a technique well understood by those skilled in the art (see, e.g., 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.

[0154] The skilled person will understand that reference to porous silica particles having pores in the mesoporous range will take its ordinary meaning in the art, i.e. to porous silica particles having (or containing / including) pores having diameters in the range of 2 to 50 nm, these materials may be referred to as mesoporous and the pores may be referred to as mesopores.

[0155] For the avoidance of doubt, the skilled person will appreciate that the porous silica material referred to in the first aspect of the invention may also have (i.e. further contain / include) pores having diameters outside the mesopore range, such as by having micropores (i.e. pores having a diameter less than 2 nm) and / or macropores (i.e. pores having a diameter greater than 50 nm).

[0156] For the avoidance of doubt, references to percentages of pores as used herein will refer to percentages by volume unless otherwise stated.

[0157] In specific embodiments, at least about 40% (ie, 40% by volume) of the pores present in the silica materials of the present invention are in the mesopore range.

[0158] 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 materials of the present invention are in the mesopore range.

[0159] The skilled person will appreciate that, for holes within a given range, the average (i.e., median average) pore size can also be calculated. As described herein, such average pore size can be measured by nitrogen adsorption techniques and calculated using density functional theory (DFT), which is well 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 stated, reference to average pore size herein will refer to the average pore size as measured by nitrogen adsorption and calculated using DFT.

[0160] In specific embodiments, the average pore size of pores in the mesopore range is from about 7.0 to about 24.0 nm.

[0161] In more specific embodiments, the average pore size of the pores in the mesopore range is from about 7.0 to about 23.0 nm.

[0162] In yet more specific embodiments, the average pore size of the pores in the mesopore range is from about 7.0 to about 22.0 nm.

[0163] In yet more specific embodiments, the average pore size of the pores in the mesopore range is from about 7.0 to about 21.0 nm.

[0164] In yet more specific embodiments, the average pore size of the pores in the mesopore range is from about 7.0 to about 20.0 nm.

[0165] For example, in certain embodiments, the average pore size of pores in the mesopore range is:

[0166] about 7.0 to about 19.0 nm;

[0167] about 7.0 to about 18.0 nm;

[0168] about 7.0 to about 17.0 nm;

[0169] about 7.0 to about 16.0 nm;

[0170] about 7.0 to about 15.0 nm;

[0171] about 7.0 to about 14.0 nm;

[0172] about 7.0 to about 13.0 nm; or

[0173] About 7.0 to about 12.0 nm.

[0174] In certain embodiments, the average pore size of pores in the mesopore range is from about 8.0 to about 13.0 nm.

[0175] In more specific embodiments, the average pore size of the pores in the mesopore range is from about 8.0 to about 12.0 nm.

[0176] In more specific embodiments, the average pore size of the pores in the mesopore range is from about 8.0 to about 11.0 nm.

[0177] In alternative embodiments, the average pore size of pores in the mesopore range is from about 9.0 to about 11.0 nm.

[0178] In yet more specific embodiments, the average pore size of the pores in the mesopore range is from about 9.2 to about 11.0 nm.

[0179] In yet more specific embodiments, the average pore size of the pores in the mesopore range is from about 9.4 to about 10.8 nm.

[0180] In yet more specific embodiments, the average pore size of the pores in the mesopore range is from about 9.5 to about 10.7 nm.

[0181] In yet more specific embodiments, the average pore size of the pores in the mesopore range is from about 9.6 to about 10.7 nm.

[0182] In yet more specific embodiments, the average pore size of the pores in the mesopore range is from about 9.5 to about 10.6 nm.

[0183] In a most specific embodiment, the average pore size of the pores in the mesopore range is from about 9.6 to about 10.6 nm.

[0184] In further embodiments, the average pore size of the pores in the mesopore range is from about 8.0 to about 22.0 nm.

[0185] In yet further embodiments, the average pore size of pores in the mesopore range is from about 9.0 to about 22.0 nm.

[0186] In yet further embodiments, the average pore size of pores in the mesopore range is from about 10.0 to about 22.0 nm.

[0187] In yet further embodiments, the average pore size of the pores in the mesopore range is from about 10.0 to about 21.0 nm.

[0188] In yet further embodiments, the average pore size of pores in the mesopore range is from about 10.0 to about 20.0 nm.

[0189] In yet further embodiments, the average pore size of pores in the mesopore range is from about 9.0 to about 21.0 nm.

[0190] In yet further embodiments, the average pore size of the pores in the mesopore range is from about 10.0 to about 21.0 nm.

[0191] In yet further embodiments, the average pore size of pores in the mesopore range is from about 11.0 to about 21.0 nm.

[0192] In yet further embodiments, the average pore size of the pores in the mesopore range is from about 12.0 to about 21.0 nm.

[0193] In yet further embodiments, the average pore size of pores in the mesopore range is from about 13.0 to about 21.0 nm.

[0194] In yet further embodiments, the average pore size of the pores in the mesopore range is from about 14.0 to about 21.0 nm.

[0195] In yet further embodiments, the average pore size of the pores in the mesopore range is from about 15.0 to about 21.0 nm.

[0196] In yet further embodiments, the average pore size of the pores in the mesopore range is from about 16.0 to about 21.0 nm.

[0197] In yet further embodiments, the average pore size of the pores in the mesopore range is from about 16.0 to about 20.0 nm.

[0198] In yet further embodiments, the average pore size of pores in the mesopore range is from about 17.0 to about 20.0 nm.

[0199] In yet further embodiments, the average pore size of the pores in the mesopore range is from about 17.0 to about 19.0 nm.

[0200] In yet further embodiments, the average pore size of pores in the mesopore range is from about 17.0 to about 18.0 nm.

[0201] In yet further embodiments, the average pore size of pores in the mesopore range is about 22 nm (eg, about 22.0 nm).

[0202] The skilled person will appreciate that in addition to referring to the (median) average pore size as described herein, the silica materials of the present invention may also be defined by referring to the pore size distribution, such as the pore size distribution of pores in the mesopore range.

[0203] In a particular embodiment of the first aspect of the invention, at least 21% (such as 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 mesopore range (by volume) have a diameter within the range specified for the average pore diameter (i.e., as specified for the average pore diameter).

[0204] In a more specific embodiment of the first aspect of the invention, at least about 30% of the pores in the mesopore range have a diameter within the average pore size range.

[0205] In yet more specific embodiments of the first aspect of the invention, at least about 35%, such as at least 40% or at least 45%, of the pores in the mesopore range have diameters in the average pore size range.

[0206] In a still more specific embodiment of the first aspect of the invention, at least about 50% (such as at least 55%, at least 60%, at least about 65%, at least about 70% or in particular at least about 72%) of the pores in the mesopore range have a diameter within the average pore size range (i.e. the range given for the average pore size of pores in the mesopore range as defined herein).

[0207] For example, in certain embodiments, at least about 50% (such as at least 55%, at least 60%, at least about 65%, at least about 70%, or in particular at least about 72%) of the pores in the mesopore range have diameters in the range of about 7.0 to about 25.0 nm.

[0208] In certain embodiments, up to about 100% (or up to about 99%, about 95%, or about 90%) of the pores in the mesopore range have diameters within the average pore size range.

[0209] In certain embodiments, about 21% to about 100% (or particularly about 25% to about 99% or 100%) of the pores in the mesopore range have diameters within the average pore size range.

[0210] In yet more specific embodiments of the first aspect of the invention, at least about 30% (eg, about 30% to about 99% or 100%) of the pores in the mesopore range have diameters within the average pore size range.

[0211] In yet more specific embodiments of the first aspect of the invention, at least about 35% (e.g., about 35% to about 99%) of the pores in the mesopore range have diameters within the average pore size range.

[0212] In yet more specific embodiments of the first aspect of the invention, about 40% to about 90% (or to about 99% or 100%) of the pores in the mesopore range have diameters within the average pore size range.

[0213] For example, in specific embodiments (i.e., specific embodiments of the first aspect of the invention), at least about 25% (e.g., about 25% to about 99%, such as about 50% to about 99% or 100%) of the pores of the silica particles are mesopores having a size ranging from about 7.0 to about 25.0 nm (such as about 7.0 to about 18.0 nm, or about 7.0 to about 13.0 nm).

[0214] Similarly, in specific embodiments, at least about 50% (e.g., about 50% to about 99%, such as about 50% to about 90%) of the pores of the silica particles are mesopores having a size ranging from about 7.0 to about 25.0 nm (such as about 7.0 to about 18.0 nm, or about 7.0 to about 13.0 nm).

[0215] In specific embodiments (ie, specific embodiments of the first aspect of the invention), at least about 50% (eg, 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.

[0216] In further embodiments, at least about 25% (eg, at least about 50%, about 60%, or about 70%) of the pores of the silica particles are mesopores having a size ranging from about 9.0 to about 10.2 nm.

[0217] In further embodiments, at least about 25% (eg, at least about 50%, about 60%, or about 70%) of the pores of the silica particles are mesopores having a size ranging from about 9.0 to about 11.0 nm.

[0218] 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.

[0219] In yet 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 10.2 nm.

[0220] The skilled person will understand that reference to porous silica particles having pores in the mesoporous range will necessarily require that such particles are porous, which will include particles that behave in a porous manner. Thus, porous silica particles will refer to particles having a significant degree of porosity, which in certain embodiments may be defined by reference to features such as the pore volume and / or surface area of ​​the particles, such as by reference to those parameters as defined herein (the features described herein may be employed alone or in combination with other features described herein).

[0221] The skilled artisan will also appreciate that the total volume of pores in each particle may affect the surface area of ​​the particle.

[0222] The skilled artisan will appreciate that the surface area of ​​a particle (or a sample of particles) can be calculated using the Brunauer Emmett Teller (BET) theory, which is a technique well known to those skilled in the art (see, e.g., Brunauer, S., Emmett, PH and Teller, E., J. Am. Chem. Soc., 60(2), 309-319 (1938)).

[0223] In specific embodiments, the silica particles have a diameter of at least about 150 m 2 / g of BET surface area.

[0224] In more specific embodiments, the silica particles have a particle size of at least about 200 m 2 / g of BET surface area.

[0225] In yet more specific embodiments, the silica particles have a particle size of at least about 300 m 2 / g (such as at least about 350m 2 / g) of BET surface area.

[0226] In still more specific embodiments, the silica particles have a particle size of at least about 400 m 2 / g (such as at least about 450m 2 / g) of BET surface area.

[0227] In a specific embodiment, the silica particles have a diameter of at least about 500 m2 / g of BET surface area.

[0228] In specific embodiments, the BET surface area is at most about 1500 m 2 / g (such as up to about 1200m 2 / g or 1000m 2 / g).

[0229] For example, in specific embodiments, the silica particles have a diameter of about 200 to about 1500 m 2 / g of BET surface area.

[0230] In other embodiments, the silica particles have a diameter of about 500 to about 1200 m 2 / g of BET surface area.

[0231] In yet more specific embodiments, the silica particles have a diameter of about 600 to about 1200 m 2 / g of BET surface area.

[0232] In alternative embodiments, the silica particles have a diameter of about 600 to about 1000 m 2 / g of BET surface area.

[0233] In further alternative embodiments, the silica particles have a particle size of about 500 to about 900 m 2 / g, such as about 550 to about 900 m 2 / g of BET surface area.

[0234] In yet another alternative embodiment, the silica particles have a diameter of about 600 to about 850 m 2 / g of BET surface area.

[0235] The skilled artisan will appreciate that the porous silica particles may be provided in a variety of shapes.

[0236] In specific embodiments, the silica particles have a substantially non-spherical morphology (ie, an aspect ratio greater than 1:1, such as greater than 1.1:1).

[0237] In more specific embodiments, the silica particles have an aspect ratio greater than 1.5:1, such as greater than 1.8:1.

[0238] In yet more specific embodiments, the silica particles have an aspect ratio equal to or greater than 2:1.

[0239] As used herein, the term "aspect ratio" will be understood to refer to the ratio between the largest cross-sectional diameter and the smallest cross-sectional diameter of a silica particle.

[0240] Alternatively, such particles (ie, particles having a substantially non-spherical morphology) may be described as having at least one plane (ie, a bisector plane that bisects the particle) that is asymmetric (ie, such that the morphology of the particle differs about that plane).

[0241] In more specific embodiments, the silica particles have a substantially rod-shaped morphology. Thus, in specific embodiments, the porous silica particles can be characterized as having a substantially rod-shaped morphology, as observed by electron microscopy (such as by scanning electron microscopy (SEM) or transmission electron microscopy (TEM), using techniques known to those skilled in the art), such as having a rod length of about 0.5 to about 5.0 μm.

[0242] As used herein, the term "substantially rod-shaped" will be understood to refer to particles that are in an elongated form resembling a rod, wherein the rod may be straight or curved (eg such rod-shaped particles may be substantially straight).

[0243] In alternative embodiments, the silica particles of the present invention may be substantially spherical (or referred to as spherical). Thus, in specific embodiments, the silica particles of the present invention may have an aspect ratio (or average aspect ratio) of about 1:1.

[0244] In further embodiments, the silica particles of the present invention may be amorphous in shape.

[0245] The skilled person will understand that the term average particle size as used herein will refer to the average diameter of the particles at their largest point (e.g., their length in the case of rod-shaped particles; or their diameter in the case of spherical particles), which can be measured using techniques well known to those skilled in the art, for example, using electron microscopy techniques (such as by scanning electron microscopy (SEM) or transmission electron microscopy (TEM) techniques known to those skilled in the art). In specific embodiments, the particle size is determined using electron microscopy (e.g., using SEM).

[0246] In specific embodiments, such as those in which the particle is spherical, the size of the particle can be defined by reference to its diameter.

[0247] In specific such embodiments, the silica particles have an average particle size of about 0.1 to about 20.0 μm.

[0248] In more specific embodiments, the silica particles have an average particle size of about 0.1 to about 15.0 μm.

[0249] In yet more specific embodiments, the silica particles have an average particle size of about 0.1 to about 10.0 μm.

[0250] In yet another more specific embodiment, the silica particles have an average particle size of about 0.5 to about 10.0 μm.

[0251] In still more specific embodiments, the silica particles have an average particle size of about 0.5 to about 5.0 μm.

[0252] In certain embodiments, the silica particles have an average particle size of about 0.5 to about 4.5 μm.

[0253] In specific embodiments, the silica particles have an average particle size of about 1.0 to about 10.0 μm.

[0254] In specific embodiments, the silica particles have an average particle size of about 1.0 to about 5.0 μm.

[0255] In more specific embodiments, the silica particles have an average particle size of about 1.0 to about 4.0 μm.

[0256] In more specific embodiments, the silica particles have an average particle size of about 1.0 to about 4.0 μm.

[0257] In yet more specific embodiments, the silica particles have an average particle size of about 2.0 to about 4.0 μm.

[0258] In yet more specific embodiments, the silica particles have an average particle size of about 3.0 to about 4.0 μm.

[0259] In other embodiments, such as those in which the particle is rod-shaped, the size of the particle may be defined by (or also be defined by) reference to its width (which would be the diameter at the narrowest point).

[0260] In specific such embodiments, the silica particles have an average width of about 0.05 to about 0.6 μm.

[0261] In more specific embodiments, the silica particles have an average width of about 0.1 to about 0.6 μm.

[0262] In yet more specific embodiments, the silica particles have an average width of about 0.1 to about 0.4 μm.

[0263] In yet a more specific embodiment, the silica particles have an average width of about 0.2 to about 0.4 μm.

[0264] The skilled person will appreciate that porous silica materials of the type described in the present invention are typically non-crystalline. Thus, in certain embodiments, porous silica particles may be described as substantially non-crystalline porous silica particles (and materials formed from a plurality of such particles may be described in the same manner). Thus, porous silica particles may be described as non-crystalline porous silica particles.

[0265] In alternative embodiments, the silica material present in the particles as described in the first aspect of the invention may be described as amorphous. In such embodiments, it will be understood that the term amorphous will indicate that the structure of the silica material (excluding the pores present therein) has no substantial order, such as may be present in a crystalline material (i.e., a porous silica particle or silica material may be referred to as non-crystalline).

[0266] As described herein, the skilled artisan will appreciate that the silica materials of the present invention are porous. Thus, the silica particles of the present invention may be referred to as having a certain minimum total pore volume, as measured using nitrogen adsorption (e.g., taken as the volume adsorbed at the highest value of P / P0, e.g., P / P0=0.995), or a range of such volumes.

[0267] In particular embodiments, the total pore volume is at least about 0.2 cm 3 / g (such as at least about 0.3, 0.4, 0.5, 0.6 or 0.7 cm 3 / g).

[0268] In specific embodiments, the total pore volume is from about 0.2 to about 2.5 cm 3 / g.

[0269] In more specific embodiments, the total pore volume is from about 0.2 to about 2.0 cm 3 / g.

[0270] In yet more specific embodiments, the total pore volume is from about 0.5 to about 1.5 cm 3 / g.

[0271] In still more specific embodiments, the total pore volume is from about 0.6 to about 1.4 cm 3 / g.

[0272] For example, in certain embodiments, the total pore volume is from about 0.7 to about 1.3 cm 3 / g.

[0273] Medical and non-medical uses

[0274] As described herein, the formulations of the invention can be used to treat certain diseases and conditions, and thus can be provided in a form suitable for such use.Thus, the formulations of the invention can be described as pharmaceutical formulations (eg, oral pharmaceutical formulations).

[0275] In a second 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 medicament (or for use in medicine or as a medicament).

[0276] In an alternative second aspect of the invention there is provided use of a formulation as defined in the first aspect of the invention (including all embodiments and features thereof) as a medical device.

[0277] As described herein, the development of metabolic disorders such as type 2 diabetes and obesity typically precedes an increase in certain risk factors that may lead to metabolic or cardiovascular events. Reducing such risk factors may lead to the prevention or delayed onset of the actual disease. Formulations as described in the present invention may be particularly suitable for reducing such risk factors, and for treating the resulting conditions (such as obesity, prediabetes, type 2 diabetes, and dyslipidemia).

[0278] Furthermore, treatment with the formulations of the invention may provide an effective means for treating obesity and reducing body fat (ie, body fat in the form of adipose tissue), and thus may also be useful in treating related conditions.

[0279] In a third aspect of the invention there is provided a method for treating or preventing a metabolic disease or disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount of a formulation as defined in the first aspect of the invention.

[0280] In a fourth aspect of the present invention there is provided a formulation as defined in the first aspect of the present invention for use in the treatment or prevention of a metabolic disease or disorder.

[0281] 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.

[0282] As used herein, the skilled artisan will understand that reference to a metabolic disease or disorder will refer to a disease or disorder that disrupts normal metabolism (i.e., the process of converting food into energy). Thus, such diseases and disorders will include diseases and disorders that would be expected to benefit from modification of dietary intake, such as by regulating the intake of dietary components (e.g., carbohydrates, such as sugars, proteins, and lipids).

[0283] The skilled artisan will also appreciate that metabolic diseases and disorders may in turn give rise to cardiovascular diseases and disorders, which may also be treated (or their prevention may be effected) as part of the present invention.

[0284] In particular embodiments of the fourth aspect of the invention, treating or preventing a metabolic disease or disorder will refer to:

[0285] (a) reduce metabolic risk factors for type 2 diabetes;

[0286] (b) treating or preventing type 2 diabetes;

[0287] (c) treating or preventing prediabetes;

[0288] (d) treatment or prevention of metabolic syndrome;

[0289] (e) treating or preventing obesity;

[0290] (f) reducing the level of body fat in the form of adipose tissue or preventing an increase in the level of body fat in the form of adipose tissue;

[0291] (g) reducing triglyceride and / or cholesterol levels or preventing an increase in triglyceride and / or cholesterol levels; and

[0292] (h) Treating or preventing dyslipidemia.

[0293] For the avoidance of doubt, the skilled person will appreciate that references in the fourth aspect of the invention to reduction in the level of a certain substance (i.e. the level of a certain substance in a patient's body) or prevention of an increase in that level may refer to such reduction in a therapeutic manner, or to prevention of an increase in a prophylactic manner, and may therefore be carried out in a patient in need thereof.

[0294] Alternatively, references in the fourth aspect of the invention to reducing the level of a substance (ie the level of a substance in a patient) or preventing an increase in that level may refer to such reducing or preventing an increase in a non-therapeutic (eg cosmetic) manner.

[0295] Therefore, in a further alternative fourth aspect of the present invention, there is provided the use of a formulation as defined in the first aspect of the present invention in:

[0296] - Non-therapeutic reduction of body fat levels in the form of adipose tissue or prevention of

[0297] Increased fat levels; and

[0298] - Non-therapeutic reduction of triglyceride and / or cholesterol levels or prevention of an increase in triglyceride and / or cholesterol levels.

[0299] The skilled person will understand that the reference to the treatment of a particular condition (or similarly, the treatment of the condition) will adopt its normal meaning in the medical field. In particular, these terms can refer to achieving a reduction in the severity and / or frequency of one or more clinical symptoms associated with the condition, as judged by a doctor treating a patient with or susceptible to such symptoms. For example, in the case of treating type 2 diabetes, the term can refer to achieving a reduction in the blood glucose level (e.g., postprandial blood glucose level, i.e., the blood glucose level experienced after consuming food) experienced by the patient.

[0300] As used herein, the term prevention will include reference to prevention (and similarly, the act of preventing) of a disease or disorder (and vice versa). Thus, reference to prevention may also be reference to prevention, and vice versa. In particular, such terms may refer to achieving a reduction (e.g., at least a 10% reduction, such as 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 a change in the patient's condition such that the patient is diagnosed by a physician as having the relevant disease or disorder, e.g., requiring treatment of the relevant disease or disorder) or experience a relevant effect.

[0301] 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 of such a risk factor. For example, in some cases, as known to those skilled in the art, such a reduction can be a reduction of at least 1% (e.g., at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30% or 40%, such as a reduction of at least 50%) in the level of such a risk factor over its normal value (i.e., the range of values ​​expected in such a patient in a healthy state).

[0302] As used herein, reference to a patient (or patients) will refer to the living subject being treated, including a mammalian (eg, human or animal) patient.

[0303] In specific embodiments, reference to a patient will refer to a human patient.

[0304] In alternative embodiments, references to patients may refer to other mammals, such as livestock (e.g., cows, pigs, sheep, goats, horses, chickens, turkeys, etc.) and / or household pets (e.g., cats, dogs, rabbits, etc.).

[0305] Therefore, in certain alternative embodiments, the formulation of the first aspect of the invention is alternatively referred to as a veterinary composition.

[0306] For the avoidance of doubt, the skilled person will understand that such treatment or prevention will be carried out in a patient (or subject) in need thereof. The need for such treatment or prevention in a patient (or subject) can be assessed by a skilled person.

[0307] As used herein, the terms disease and disorder (and similarly, the terms disorder, disease, medical problem, etc.) are used interchangeably.

[0308] As used herein, the term effective amount will refer to the amount of the formulation that imparts a therapeutic effect to the patient being treated. The effect can be observed in an objective manner (i.e., measurable by some test or marker) or in a subjective manner (i.e., the subject gives an indication of the effect and / or feels the effect). In particular, the effect can be observed (e.g., measured) in an objective manner using appropriate tests as known to those skilled in the art.

[0309] For the avoidance of doubt, the skilled artisan (e.g., a physician) will be able to determine the actual dosage most suitable for an individual patient which may vary with 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 specific patient being treated.

[0310] For example, particularly when administered orally to a human patient, a formulation as described in the first aspect of the invention may be administered in a dose 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, for example about 1.0 g, about 2.0 g or about 3.0 g) of porous silica material, which dose may be administered once or more per day (i.e., during a 24-hour period).

[0311] In particular, the skilled person will appreciate that the dose of the silica material may be administered at suitable intervals, such as intervals corresponding to the patient's consumption of food (e.g., meals). Thus, the dose referred to herein may be understood as a timed dose to be administered with food (i.e., timed to coincide with the time the patient consumes food (e.g., meals)).

[0312] As used herein, references to diseases and disorders will be understood by those skilled in the art, such as by reference to definitions provided in international classifications of such disorders (see, e.g., the International Classification of Disease (ICD) as provided by the World Health Organization (WHO), such as the classification updated as of January 1, 2017).

[0313] For example, the condition known as metabolic syndrome (which is sometimes known by other names) may refer to the clustering of at least three of the five following medical conditions: abdominal obesity, high blood pressure, high blood sugar (glucose), high serum triglycerides, and low high-density lipoprotein (HDL) levels (e.g., as defined by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATPIII)).

[0314] As described herein, the formulations of the present invention are capable of delivering a therapeutic effect themselves. Thus, treatment using such particles and compositions can be therapeutically effective even in the absence of any other therapeutic agent for treatment.

[0315] In particular embodiments of the fourth aspect of the invention, the method or use does not comprise administration in combination with other therapeutic agents used in the same such method or use (ie, the formulation of the first aspect of the invention may be used / administered as a monotherapy).

[0316] In a more specific embodiment of the fourth aspect of the invention, the method or use does not comprise administration in combination with other therapeutic agents.

[0317] In a further embodiment of the fourth aspect of the invention, the method comprises administering the formulation as defined in the first aspect of the invention as monotherapy.

[0318] As described herein, the present invention relates to the use of a formulation as described herein as an active therapeutic agent, such as in a method for reducing metabolic risk factors for type 2 diabetes. The present invention also relates to such use in the treatment of prediabetes, which may refer to preventing the progression of prediabetes to a clinical state diagnosed as type 2 diabetes.

[0319] For the avoidance of doubt, metabolic risk factors for type 2 diabetes and methods of measuring them will be well known to those skilled in the art. Non-limiting examples of biomarkers of such risk factors may include: identification of: disturbed (i.e., shifted) levels of low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, cholesterol, Apo A1, and / or Apo B; and / or disturbed ratios between Apo A1 and Apo B, and / or between LDL and HDL (wherein reference to "disturbed" levels may refer to values ​​that deviate from the normal values ​​of the patient in question by a clinically significant amount, as determined by those skilled in the art); and / or hypertension, elevated insulin resistance, high glucose levels, elevated HbA1c, and any combination thereof (wherein reference to "elevated" or "high" levels may refer to values ​​that are higher than the normal values ​​of the patient in question by a clinically significant amount, as determined by those skilled in the art).

[0320] In a specific embodiment, the metabolic risk factors for type 2 diabetes are based on analysis of: the levels of one or more biomarkers selected from the group consisting of: LDL, HDL, triglycerides, cholesterol, Apo A1 and Apo B; the ratio between Apo A1 and Apo B and the ratio between LDL and HDL cholesterol; and blood pressure, insulin resistance and blood glucose levels, and the levels of HbA1c.

[0321] In a specific embodiment, a metabolic risk factor for type 2 diabetes may be identification of elevated levels of HbA1c. Similarly, based on identification of elevated levels of HbA1c in a patient not diagnosed as having diabetes (eg, type 2 diabetes), the patient may be identified as having prediabetes.

[0322] For the avoidance of doubt, the skilled person will appreciate that references to elevated levels of HbAIc will refer to levels above that within the range expected to be observed in such patients (ie patients of the same type) but in a healthy state.

[0323] For example, according to the American Diabetes Association, HbA1c levels can be identified as elevated when at or above 39.0 mmol / mol (equal to 5.7% DCCT). In particular, a patient can be identified as having prediabetes when having an HbA1c level within the range of 39.0 mmol / mol to 46.0 mmol / mol (5.7% to 6.4% DCCT; although if a patient with an HbA1c level greater than 46.0 mmol / mol does not meet the clinical diagnostic criteria for diabetes (which typically requires an HbA1c level greater than or equal to 47.0 mmol / mol), such a patient may be diagnosed with prediabetes).

[0324] The skilled artisan will also appreciate that prediabetes can be diagnosed based on other indicator factors as known to those skilled in the art, such as based on measurement of fasting blood glucose levels (e.g., by identifying a fasting blood glucose of 100 to 125 mg / dl) or by use of an oral glucose tolerance test (OGTT) (e.g., based on a patient having an OGTT 2-hour blood glucose result of from 140 mg / dl to 199 mg / dl).

[0325] It will be appreciated by the skilled artisan that dyslipidemia conditions may be understood as high levels of lipids (cholesterol, triglycerides, or both) carried by lipoproteins in the blood. The term may include hypolipoproteinemia (hyperlipidemia), which refers to abnormally high levels of total cholesterol, low-density lipoprotein (LDL), or triglycerides, and abnormally low levels of high-density lipoprotein (HDL). Thus, for the avoidance of doubt, dyslipidemia includes hyperlipidemia.

[0326] As described herein, the formulations of the invention may act to reduce metabolic risk factors for diabetes in a manner independent of the treatment of underlying causative factors, such as obesity.

[0327] Therefore, in a specific embodiment of the fourth aspect of the present invention, said:

[0328] (a) reduce metabolic risk factors for type 2 diabetes,

[0329] (b) treating or preventing type 2 diabetes,

[0330] (c) treating prediabetes, and / or (e.g., and)

[0331] (d) treating or preventing metabolic syndrome in non-obese patients (i.e. patients with a BMI less than 30), particularly in non-overweight patients (i.e. patients with a BMI less than 25), such as in patients of healthy weight (e.g. patients with a BMI of 18.5 to 24.9).

[0332] As described herein, the formulations of the invention can be used in medical treatments performed without the use of other therapeutic agents (ie, as monotherapy).

[0333] In another embodiment of the fourth aspect of the present invention, said:

[0334] - Treat or prevent type 2 diabetes;

[0335] -Treatment of prediabetes;

[0336] - Treating or preventing metabolic syndrome; and / or (e.g., and)

[0337] -Treatment of dyslipidemia

[0338] This is in patients who are not administered (ie, not taking) another therapeutic agent to treat or prevent such a condition.

[0339] In specific examples, reference to cholesterol levels may include reference to Apo Al, Apo B and / or non-HDL cholesterol and / or LDL cholesterol and the LDL / HDL cholesterol ratio.

[0340] As described herein, the silica materials of the present invention can act as molecular sieves by physically separating smaller molecules from larger molecules via their tailored porosity. This physicochemical separation results in a delay and reduction in food digestion and biomolecule uptake into the body, thereby reducing energy intake, thereby reducing and delaying postprandial lipid and blood glucose peaks in animal model systems, and reducing biomarkers in human subjects, such as blood levels of HbA1c and LDL cholesterol.

[0341] As used herein, reference to reducing risk factors by reference to specific biomarkers may refer to reducing these risk factors from elevated levels to levels closer to (or even within) the range expected in such patients in a healthy state. For example, with respect to a reduction in HbA1c levels, such a reduction may refer to a reduction of at least 0.1 mmol / mol, such as a reduction of about 0.1 mmol / mol to about 20.0 mmol / mol. The skilled artisan will understand that such a reduction may occur after treatment over an extended period of time.

[0342] In particular, the formulations of the present invention can be used as drug treatments or as active dietary supplements to increase metabolic health by reducing food efficacy, which can be used in groups of subjects (or patients) who are at risk of developing prediabetes or have been diagnosed with metabolic diseases such as but not limited to type 2 diabetes, obesity, weight-related diseases, abnormal blood glucose homeostasis and metabolic syndrome.

[0343] In particular embodiments, ingestion of the formulation can affect total carbohydrate absorption from the digestive system. The term "carbohydrate absorption" refers to the process occurring 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 ingested or absorbed by an organism.

[0344] In another embodiment, the formulation can affect the level of HbA1c after use over an extended period of time (e.g., at least one month). The term "HbA1c" means glycosylated hemoglobin and is a laboratory measurement of blood sugar control during the first 2 to 3 months (Bennett, CM et al., Diabet. Med., 24(4), 333-43 (2007)). As will be known to those skilled in the art, this biomarker is well established and used for type 2 diabetes diagnosis and risk assessment of complications (Lind, M. et al., Diabetes & Metabolic Syndrome: Clinical Research and Reviews, 2(4), 282-293 (2008)).

[0345] Thus, in specific embodiments, treating prediabetes or treating or preventing diabetes and / or metabolic syndrome as described herein may be characterized (i.e., identified) by reducing HbA1c levels in a patient or preventing an increase in HbA1c levels in a patient. Additionally, methods of treating such conditions may be referred to as methods of reducing HbA1c levels in a patient in need thereof.

[0346] In particular embodiments, the uses or methods described herein may require administering a silica material or composition with a food or drink (eg, administering with a food).

[0347] Use as a dietary supplement

[0348] As described herein, the formulations of the present invention can be used as dietary supplements and thus can be provided in a form suitable for such use.Thus, the formulations of the present invention can be described as dietary supplement formulations (eg, oral dietary supplement formulations).

[0349] 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.

[0350] For the avoidance of doubt, a formulation referred to as a dietary supplement formulation may also be suitable for use as a pharmaceutical formulation (and therefore referred to as a pharmaceutical formulation), and vice versa. Thus, the formulation of the present invention may be referred to as an oral medicament or dietary supplement formulation, etc.

[0351] The skilled person will appreciate that the formulation of the invention may be taken (ie administered) simultaneously with, or as part of, a food (eg a meal) or a drink.

[0352] The skilled person will understand that references herein to administration with food (or similarly, administration with a meal) or administration with a drink may refer to administration simultaneously with consumption of the food or drink, or administration shortly before or after consumption of the food or drink (e.g. up to 2 hours, such as up to 1 hour, or in particular up to 30 minutes before or after consumption of the food).

[0353] The skilled artisan will also appreciate that the formulations of the present invention, for example, when used as dietary supplements, can induce the biological effects described herein. Therefore, the dietary supplement formulations as described herein can also be referred to as active dietary supplement formulations.

[0354] The skilled person will appreciate that administration of the formulations of the invention with food or drink (ie oral administration) may reduce their efficacy, meaning that less energy is absorbed from a given amount of nutrients.

[0355] Thus, in a sixth aspect of the invention there is provided a method of reducing the efficacy of a food or beverage comprising administering a formulation as defined in the first aspect of the invention (including all embodiments and features thereof) together with the food or beverage.

[0356] In an alternative sixth aspect of the invention there is provided use of a formulation as defined in the first aspect of the invention in a method of reducing the efficacy of a food or beverage, wherein the use comprises administering the silica particles or composition together with the food or beverage.

[0357] In particular embodiments, the food or beverage is a food, such as a meal.

[0358] In specific embodiments, the reduction in the efficacy of a food or beverage comprises a reduction in the glycemic response resulting from consumption of the food or beverage.

[0359] In yet another embodiment, the formulation can reduce postprandial carbohydrate uptake in the blood.As used herein, the term postprandial can refer to levels observed immediately after a meal has been consumed, as measured over time.

[0360] In one embodiment, the formulation can affect both the absorption of carbohydrates and lipids from the digestive system after ingestion. In another embodiment, the particles can affect the level of blood lipids after ingestion.

[0361] In another embodiment, the formulation can affect the total postprandial absorption of carbohydrate and lipid uptake into the blood following ingestion.

[0362] The skilled artisan will understand that reference to the glycemic response of a food or beverage will take its normal meaning in the art, such as by referring to the plasma glucose level experienced by a patient immediately following (and therefore attributable to) the consumption of a food or beverage, which may be referred to as the postprandial glycemic response (change in concentration) elicited when a food or meal containing carbohydrates is ingested. Thus, reference to lowering the glycemic response may refer to a patient experiencing a lower glucose level after consuming a food or beverage than would be experienced if such consumption occurred without the administration of the silica particles or composition, when such consumption occurs with the administration of the silica particles or composition.

[0363] Similarly, in particular embodiments, the reduction in the efficacy of a food or beverage comprises a reduction in plasma triglyceride levels after consumption of the food or beverage.

[0364] In such cases, reference to a reduction in plasma glucose or triglyceride levels may refer to a reduction of at least 1%, such as at least 2%, 3%, 5%, 7%, 10%, 15% or in particular at least 20%.

[0365] The skilled artisan will appreciate that plasma levels of a particular substance, such as blood glucose levels, may be measured in a patient using techniques well known to those skilled in the art, such as by routine analysis of blood samples taken from the patient at appropriate times.

[0366] Packaging and manufacturing

[0367] The skilled artisan will appreciate that the formulations of the present invention may be packaged (eg, for distribution and sale) in any manner suitable for a pharmaceutical or food supplement, as long as it is suitable for the intended use.

[0368] For example, the formulations of the invention may be packaged in a single-portion container, such as a container from which the formulation may be consumed directly (eg, a single-use bottle or pouch, or a stick pack).

[0369] The formulations of the present invention can be prepared using techniques known to those skilled in the art, such as by mixing the components of the composition (either in one process or sequentially in subgroups thereof) to obtain a substantially homogeneous mixture thereof.

[0370] Therefore, in a further aspect of the invention, there is provided a method of preparing a formulation according to the first aspect of the invention (including all embodiments and features thereof), comprising the steps of bringing the components of the formulation together to form a mixture thereof and homogenising the mixture.

[0371] Without wishing to be bound by theory, it is believed that the porous silica particles with well-defined internal volume limited pores according to the present invention and the compositions comprising the same can function through their ability to act as molecular sieves and their ability to deliver this function in vivo (such as in the digestive system). This effect is believed to be produced by the action of the pores present in the particles of a certain size. After ingestion, the porous silica particles mix with food in the digestive system. In the digestive system, larger food molecules are broken down by digestive enzymes into sufficiently small biomolecules for body absorption. Therefore, the digestive system contains large biomolecules and small biomolecules.

[0372] It is believed that the silica material of the present invention acts as a molecular sieve through its customized porosity, whereby smaller biomolecules are physically separated from larger biomolecules. Only small molecules will diffuse into the pores of the silica material (that is, small molecules are molecules that can diffuse into the pores of the silica material, and macromolecules are molecules that will not diffuse into the pores but can interact with the surface of the silica material). This can physically separate a portion of smaller biomolecules such as digestive enzymes and metabolites from undigested food in the digestive system, including dietary lipid complexes and carbohydrates. The main digestive enzymes responsible for decomposing sugars and fats are amylase and lipase, respectively. When acting as a molecular sieve, it is believed that these digestive enzymes and other biomolecules can enter the pores of silica through the promoted diffusion effect produced by the combination of the claimed pore size. This physically separates the captured enzymes from the undigested food, resulting in slower digestion and absorption of nutrients from the digestive system.

[0373] It is believed that the formulations of the present invention allow the porous silica material to be provided in a form that is stable and easily consumed by a subject without affecting its functionality. In particular, such formulations allow the porous silica material to be present in a form that does not have the unpleasant mouthfeel (i.e., grit and dry aftertaste) associated with other formulations, thereby increasing the palatability of the formulation.

[0374] BRIEF DESCRIPTION OF THE DRAWINGS

[0375] Figure 1: Effect of different formulations on the efficacy of silica amylase adsorption (A) to (D). The ability of mesoporous silica particles (MSP) suspended in various formulations to adsorb porcine pancreatic amylase was tested. The dynamics of amylase adsorption by silica in the formulations can be seen in the time course graphs (A to C) and their corresponding area under the curve (AUC) analysis in (D). Compared with unformulated MSP, formulations 3, 6 and 9 reduced the efficacy of silica adsorption of amylase by 25%, 40% and 11%, respectively. Data are presented as mean ± standard error (SE) (n = 2).

[0376] Examples

[0377] The present invention will be further described by reference to the following examples, which are not intended to limit the scope of the present invention. Example 1: Preparation / Characterization of Mesoporous Silica Particle (MSP) Materials

[0378] Material

[0379] Mesoporous silica particles (MSP) were prepared according to previously described methods (see Baek, J. et al., Nanomedicine 17:1, 9-22 (2022), in particular the experimental procedures described therein, the contents of which are hereby incorporated by reference). Briefly, a mesostructured template (P123, average molecular weight = 5800 g mol -1 ,PEO 20 PPO 70 PEO 20 The triblock polymer of P123 (a) was dissolved in an aqueous hydrochloric acid (HCl) solution, wherein the acid concentration was equivalent to 1.6 M. After complete dissolution of P123, tetraethyl orthosilicate (TEOS) was added at 40°C with vigorous stirring. The final molar ratio of P123:TEOS in the solution was 0.02:1.00, and the molar ratio of TEOS:HCl:H2O was 1:7:230. The synthesis was kept static at 40°C for 20 hours and further hydrothermally treated at 100°C for 10 hours.

[0380] Nitrogen adsorption analysis

[0381] Brunauer-Emmett-Teller (BET) surface area is calculated from the adsorption isotherm at relative pressure (p / p°) <0.2. Total pore volume is recorded at relative pressure (p / p°) = 0.995. Average pore size and pore size distribution are derived from adsorption curves using density functional theory (DFT) methods. Measurements were performed using a TriStar II volumetric adsorption analyzer at liquid nitrogen temperature (-196°C), and data analysis was performed using TriStar II software MicroActive 2.03 version (Micromeritics Instrument Corp., Georgia, USA).

[0382] Particle size

[0383] A scanning electron microscope using JSM-7401F (JEOL Ltd., Tokyo, Japan) was used to characterize the particle size and morphology from SEM micrographs. The average particle size (length and width) was analyzed from ≥50 particles using ImageJ (Fiji; 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)).

[0384] Table 1: Material properties

[0385] Various properties of the investigated MSP materials were measured using the techniques and operating conditions listed above. The identified characteristics are described in Table 1 below.

[0386] <![CDATA[BET surface area (m 2 / g)]]> 925 <![CDATA[Total pore volume (cm 3 / g)]]> 1.19 <![CDATA[Average pore diameter – all pores 1 (nm)]]> 5.2 <![CDATA[Average pore diameter within the mesopore range - DFT (nm) 2 > 10.2 Average particle size (μm) 1.1(length)0.3(width) <![CDATA[Percentage of pores within the mesopore range 3 > 80 <![CDATA[Percentage of mesopores in the range of 7 to 25 nm 4 > 73 <![CDATA[Percentage of mesopores in the range of 7 to 18 nm 5 > 71

[0387] 1 [4x total pore volume (cm 3 / g) / BET surface area (m 2 / g)]x 1000

[0388] 2 Calculated from adsorption curves using the DFT model and assuming cylindrical pore geometry

[0389] 3 Calculated based on DFT pore size distribution and total pore volume: [(pore volume at 50 nm – pore volume at 2 nm) / total pore volume] x 100

[0390] 4 Calculated based on DFT pore size distribution: [(pore volume at 25 nm – pore volume at 7 nm) / (pore volume at 50 nm – pore volume at 2 nm)] x 100

[0391] 5 Calculated based on DFT pore size distribution: [(pore volume at 18 nm – pore volume at 7 nm) / (pore volume at 50 nm – pore volume at 2 nm)] x 100

[0392] Example 2: Preparation of formulations

[0393] 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 (ASINB01MFCXDZA). The formulation was homogenized using a Witeg HG-15A homogenizer equipped with a HT1018 dispersion tool.

[0394] Preparation of control (unformulated) MSP suspension

[0395] MSP (5 g) was added to 45 g of MilliQ water (MQ H2O) and homogenized at low speed for 3 minutes.

[0396] Preparation of stock solutions

[0397] Solution 1: Potassium sorbate was dissolved in MQ H2O. Then citric acid was added to the same solution and stirred until dissolved. The concentration of potassium sorbate was 0.125 wt% and the concentration of citric acid was 0.250 wt%.

[0398] Solution 2: Peach flavor (0.3 g) was diluted in 3.7 g MQ H2O.

[0399] Formulation 1: MSP (5 g) was added to 40.15 g of Solution 1 and 4.75 g of MQ H2O and homogenized at low speed for 3 minutes.

[0400] Formulations 2 to 10: Thickener (concentration according to Table 2; it is also referred to as thickener) was slowly added to 40.15 g of Solution 1 and MQ H2O (the amount was adjusted to have a total weight of 50 g) while homogenizing. As the formulation thickened, the homogenization speed was slowly increased from low to medium. After the addition of the thickener, the gel was homogenized at medium speed for another 3 minutes or until the thickener seemed to be completely dispersed (lumps were no longer visible). Finally, 5 g of MSP was added to the formulation and homogenized at medium speed for 3 minutes.

[0401] Formulation 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 H2O. The mixture was stirred until the erythritol was dissolved. Xanthan gum (0.3 g) was slowly added to the solution while homogenizing. As the formulation thickened, the homogenization speed was slowly increased from a low speed to a medium speed. After the xanthan gum was added, the formulation was homogenized at a medium speed for another 3 minutes or until the xanthan gum seemed to be completely dispersed (lumps were no longer visible). Finally, 5 g of MSP was added to the formulation and homogenized at a medium speed for 3 minutes.

[0402] Table 2: Preparation

[0403]

[0404]

[0405] *Xanthan gum in formulations 2, 3, and 11; sodium carboxymethylcellulose in formulation 4; tragacanth gum in formulations 5 and 6; colloidal microcrystalline cellulose in formulations 7 and 8; guar gum in formulations 9 and 10

[0406] Example 3: Evaluation of suspension stability

[0407] On the second day after production, approximately 20 mL of each formulation was transferred to a glass bottle and stored in the dark at room temperature. After six weeks (42 days), the samples were visually observed. If separation was observed (clear liquid on top), the suspension was unstable. If separation was not observed after four weeks, the suspension was considered to be stable under the conditions of the experiment. The results are presented in Table 3.

[0408] Table 3. Results of suspension stability evaluation

[0409] preparation Thickener Suspension stability Preparation 1 - Unstable Preparation 2 Xanthan gum 0.6wt% Stable Preparation 3 Xanthan gum 1.0wt% Stable Preparation 4 Sodium carboxymethyl cellulose 1.0wt% Unstable Preparation 5 Tragacanth gum 1.0wt% Unstable Preparation 6 Tragacanth gum 2.0wt% Stable Preparation 7 Colloidal microcrystalline cellulose 1.0wt% Unstable Preparation 8 Colloidal microcrystalline cellulose 2.0wt% Stable Preparation 9 Guar gum 1.0wt% Unstable Preparation 10 Guar gum 2.0wt% Not assessed* Preparation 11 Xanthan gum 0.6wt% Stable

[0410] *This formulation formed a very thick paste and the MSP could not be mixed evenly, so manufacturing was discontinued

[0411] Example 4: Evaluation of the stability of the suspension after 1 year of storage at room temperature

[0412] Some samples that appeared stable after six weeks of storage in the dark at room temperature (Example 3) were kept under the same conditions. After 1 year, the samples were visually observed again. If separation was observed (clear liquid on top), the suspension was unstable. If no separation was observed after 1 year, the suspension was considered stable under the experimental conditions. The results are presented in Table 4.

[0413] Table 4. Results of the suspension stability evaluation after 1 year at room temperature

[0414] preparation Thickener Suspension stability Preparation 2 Xanthan gum 0.6wt% Stable Preparation 3 Xanthan gum 1.0wt% Stable Preparation 8 Colloidal microcrystalline cellulose 2.0wt% Stable Preparation 11 Xanthan gum 0.6wt% Stable

[0415] Example 5: Amylase adsorption assay

[0416] Preparation of working solutions and standard curve samples

[0417] Before measuring, several working solutions were prepared. 1 PBS tablet (Medicago, 09-2052-100) was dissolved in 100mL MQ H2O to prepare 2x PBS. Once dissolved, pH was adjusted to 5.4. On the same day of the experiment, a working solution of porcine pancreatic amylase (Sigma-Aldrich, A4268) (312 μg / mL) was freshly prepared by diluting the required amount of stock solution with 2xPBS (pH 5.4). According to the manufacturer's instructions, a working solution of bicinchoninic acid (BCA) was freshly prepared on the same day of the experiment. Amylase standard curve samples (each 45 μL) were prepared by serial dilution using 2x PBS (pH 5.4) in 96-well PCR plates (VWR, 732-2387). After serial dilution, 45 μL of MQ H2O 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.

[0418] Preparation of test formulations

[0419] The test formulations were prepared by weighing approximately 1 g of the formulation and diluting it in approximately 4 mL of MQ H2O (1:5 dilution to obtain 20 mg / mL of silica). The samples were then sonicated to obtain a homogenous suspension. Briefly, a 2 mm microtip (Vibra cell) was loaded into a sonicator (Vibra cell) and the silica suspension was sonicated at 40% amplitude for 3 minutes without pulsing.

[0420] Adsorption of porcine pancreatic amylase by silicon dioxide

[0421] The test preparation was incubated with porcine pancreatic amylase at 37°C for 15, 30 and 60 minutes for enzyme adsorption / retention. Silica (1000, 500, 250 and 125 μg / mL, 45 μL each) was prepared by serial dilution using MQ H2O 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 aliquoted 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). When the incubation was complete, the plate was centrifuged at room temperature for 5 minutes at 2000 x g. The supernatant (60 μL) from each well was transferred to a new 96-well plate (Corning, CLS3370).

[0422] Colorimetric determination of unbound porcine pancreatic amylase

[0423] The amount of unbound porcine pancreatic amylase in the supernatant was determined via the BCA assay. 60 μL of BCA working solution was added to each well containing the supernatant, 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 read at 562 nm.

[0424] Calculation of the loading capacity of silicon dioxide for porcine pancreatic amylase

[0425] The amount of unbound porcine pancreatic amylase was used to calculate the loading capacity of silica over time (μg amylase / mg silica). The concentration of unbound amylase in each sample was inferred from the slope and intercept of the amylase standard curve. The amount of amylase adsorbed / retained by silica (in μg / mL) was calculated by subtracting the protein concentration of unbound amylase from the starting amylase concentration (which was 156 μg / mL). Using GraphPad software, the calculated removed amylase (μg / mL) was plotted against the silica concentration (125 to 1000 μg / mL) at each time point (amylase removal graph).

[0426] The efficacy of MSP is determined by how much amylase (μg) is adsorbed by 1mg of silica. This is called load capacity (μg amylase / mg silica) and is calculated by using the amylase removal graph. For each time point (15, 30, 60 minutes), the silica concentration required for removing approximately 50% of the maximum amylase removal amount is calculated by using the "nonlinear regression (curve fitting)" and "interpolation standard curve" analysis in GraphPad software. The load capacity (μg amylase / mg silica) at each time point is then calculated using the amount (mg / mL) of silica calculated to remove 50% of the amylase (in μg / mL) after 15, 30 and 60 minutes. The load capacity is plotted as a time course diagram, wherein the y-axis is the load capacity (μg amylase / mg silica), and the x-axis is time (15 to 60 minutes). According to the time course diagram, the area under the curve (AUC) of each sample is calculated using the analysis tool in GraphPadPrism. The AUC of each sample was then compared to an unformulated MSP sample control.

[0427] The results are Figure 1 Compared to unformulated MSP, Formulations 3, 6, and 9 reduced the efficacy of silica adsorption of amylase by 25%, 40%, and 11%, respectively. Data are presented as mean ± SE (n=2).

[0428] Example 6: Amylase adsorption capacity after 1 year storage at room temperature

[0429] The samples that appeared stable after six weeks of storage in the dark at room temperature (Example 3) were kept under the same conditions. After 1 year, the samples that did not have reduced efficacy when compared to unformulated MSP in the amylase adsorption assay when freshly prepared (Example 5) were analyzed again using the method described in Example 5. Figure 2 All formulations tested had acceptable efficacy compared to unformulated MSP. Data are presented as mean ± SE (n=2).

Claims

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

2. The formulation of claim 1, wherein the formulation comprises about 70.0 to about 95.0 wt% water.

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

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

5. The formulation of any one of claims 1 to 4, wherein the formulation comprises from about 0.3 wt% to about 0.9 wt% of the thickener.

6. The formulation according to any one of claims 1 to 5, wherein the formulation further comprises: (d) one or more preservatives, sweeteners, flavoring agents, fragrances and / or coloring agents.

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

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

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

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

11. The formulation of any one of claims 1 to 10, wherein the silica particles have a diameter of at least about 200 m 2 / g of BET surface area.

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

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

14. The formulation of any one of claims 1 to 13, wherein the silica particles have a diameter of from about 0.7 to about 1.3 cm 3 / g total pore volume.

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

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

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

19. A method of reducing the efficacy of a food or beverage, the method comprising administering the formulation of any one of claims 1 to 14 together with the food or beverage.

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

Images