WO2016171571A1 - Compositions and kits for the treatment and prevention of blood glucose disorders - Google Patents

Compositions and kits for the treatment and prevention of blood glucose disorders Download PDF

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Publication number
WO2016171571A1
WO2016171571A1 PCT/NZ2016/050065 NZ2016050065W WO2016171571A1 WO 2016171571 A1 WO2016171571 A1 WO 2016171571A1 NZ 2016050065 W NZ2016050065 W NZ 2016050065W WO 2016171571 A1 WO2016171571 A1 WO 2016171571A1
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WIPO (PCT)
Prior art keywords
glucose
biscuit
beverage
complex carbohydrate
kit
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PCT/NZ2016/050065
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French (fr)
Inventor
Lindsay Donald MCTAVISH
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Ajw Enterprises Limited
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Publication date
Application filed by Ajw Enterprises Limited filed Critical Ajw Enterprises Limited
Priority to AU2016250936A priority Critical patent/AU2016250936A1/en
Publication of WO2016171571A1 publication Critical patent/WO2016171571A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
    • A—HUMAN NECESSITIES
    • A21—BAKING; EDIBLE DOUGHS
    • A21D—TREATMENT, e.g. PRESERVATION, OF FLOUR OR DOUGH, e.g. BY ADDITION OF MATERIALS; BAKING; BAKERY PRODUCTS; PRESERVATION THEREOF
    • A21D13/00—Finished or partly finished bakery products
    • A21D13/06—Products with modified nutritive value, e.g. with modified starch content
    • A21D13/062—Products with modified nutritive value, e.g. with modified starch content with modified sugar content; Sugar-free products
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A23L2/60—Sweeteners
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present disclosure relates to compositions, including a glucose beverage and a complex carbohydrate biscuit, which may be used in conjunction to treat or prevent blood glucose disorders, including hypoglycaemia and hyperglycaemia.
  • the disclosed glucose beverage and a complex carbohydrate biscuit may be employed to treat or prevent hypoglycaemia, and to prevent subsequent occurrence of rebound hyperglycaemia.
  • kits comprising these compositions, as well as methods of making and using such kits. Also related are methods of using the composition and kits to address various blood glucose disorders and any symptoms thereof.
  • hypoglycaemia is the most common acute metabolic complication in type 1 diabetes, and is a major impediment to the goal of improving metabolic control (Diabetes Control and Complications Trial Research Group, 1993; Davis et al., 1998). Severe hypoglycaemia, which is associated with seizures or coma, has become more common with general improvements in metabolic control in some reports in the paediatric diabetes clinic (Davis et al., 1998).
  • Hypoglycaemia is of particular concern in children. The symptoms of hypoglycaemia are particularly distressing for children and their families, and it influences early brain development, especially with early onset of diabetes (Ryan and Becker, 1999).
  • Glucose and other carbohydrates have been used with varying efficacy (American Diabetes Association, 2005; Husband et al., 2009; Brodows et al., 1984; Slama et al., 1990; McTavish et al., 2011).
  • Brodows et al. (1984) found glucose tablets to be more effective than milk or orange juice in resolving hypoglycaemia in adults, using a euglycemic clamp.
  • Slama et al. (1990) found carbohydrate in a gel form was significantly less effective in resolving hypoglycaemia, whereas glucose tablets, sucrose tablets and a preparation containing mixed mono- and oligo- saccharides were most effective.
  • hypoglycaemia there are treatments for hypoglycaemia that have substandard efficacy. There are also treatments that are limited in use by low palatability and/or low patient compliance. It also is widely acknowledged that standard treatments for hypoglycaemia often result in under-treatment, or over-treatment, i.e., rebound hyperglycaemia. Moreover, it is known that hypoglycaemia may arise in the absence of diabetic disorders, such as from overtraining, fasting, or excessive alcohol consumption. Thus, there is a significant need for compositions, including packaged compositions and kits, which are effective for treating and preventing blood glucose disorders, including hypoglycaemia/hyperglycaemia.
  • the invention comprises a kit comprising: a glucose beverage that includes at least 15 g glucose and a complex carbohydrate biscuit that includes at least 10 g carbohydrate.
  • the glucose beverage includes about 15 g or about 30 g glucose.
  • the glucose beverage comprises 50 ml to 100 ml in volume.
  • the glucose beverage comprises 80 ml in volume, and includes 15 g of glucose.
  • the glucose beverage comprises 100 ml in volume, and includes 30 g of glucose.
  • the glucose beverage is provided in a sachet.
  • the complex carbohydrate biscuit includes 10 g to 20 g carbohydrate.
  • the complex carbohydrate biscuit comprises about 20 g or about 30 g in weight. [0017] The complex carbohydrate biscuit comprises 12 g carbohydrate and 20 g in weight.
  • the complex carbohydrate biscuit is one or more of: gluten free, egg free, or dairy free.
  • the complex carbohydrate biscuit is provided in a packet.
  • the glucose beverage and complex carbohydrate biscuit are provided together in a bag.
  • the kit further includes an additional glucose beverage.
  • the kit further includes instructions for use.
  • the kit further includes a means for testing blood glucose levels.
  • the means for testing blood glucose levels is a glucose test strip.
  • the kit further includes an antiseptic.
  • the invention comprises a method of treating hypoglycaemia in a subject, which comprises: providing to a subject a kit comprising a glucose beverage that includes at least 15 g glucose and a complex carbohydrate biscuit that includes at least 10 g carbohydrate, the subject ingesting the glucose beverage and then ingesting the complex carbohydrate biscuit, thereby treating the hypoglycaemia.
  • the glucose beverage includes about 15 g or about 30 g glucose.
  • the glucose beverage comprises 50 ml to 100 ml in volume.
  • the glucose beverage comprises 80 ml in volume, and includes 15 g of glucose.
  • the glucose beverage comprises 100 ml in volume, and includes 30 g of glucose. [0032] The glucose beverage is provided in a sachet.
  • the complex carbohydrate biscuit includes 10 g to 20 g carbohydrate.
  • the complex carbohydrate biscuit comprises 20 g or 30 g in weight.
  • the complex carbohydrate biscuit comprises 12 g carbohydrate and 20 g in weight.
  • the complex carbohydrate biscuit is one or more of: gluten free, egg free, or dairy free.
  • the complex carbohydrate biscuit is provided in a packet.
  • the glucose beverage and complex carbohydrate biscuit are provided together in a bag.
  • the kit further includes an additional glucose beverage.
  • the kit further includes instructions for use.
  • the kit further includes a means for testing blood glucose levels.
  • the means for testing blood glucose levels is a glucose test strip.
  • the kit further includes an antiseptic.
  • the hypoglycaemia is associated with type 1 or type 2 diabetes, or gestational diabetes.
  • hypoglycaemia is associated excessive exercise or fasting.
  • the method further comprises the subject ingesting an additional glucose beverage prior to ingestion of the biscuit.
  • the method further comprises a waiting period between ingestion of the glucose beverage and ingestion of the complex carbohydrate biscuit.
  • the waiting period is from 10 minutes to 15 minutes.
  • the method further comprises testing blood glucose levels at any one or more of the periods: prior to ingestion of the beverage, prior to ingestion of the biscuit, following ingestion of the biscuit.
  • Figure 1 Diagram of clinical treatment protocol.
  • Figure 2 Diagram of alternative treatment method.
  • Figure 3 Diagram of a further alternative treatment method.
  • hypoglycaemia means having one or more symptom of low blood glucose, for example, one or more of: low levels of blood glucose, e.g., based on serum or whole blood glucose levels, polyphagia, nausea, hunger, lightheadedness, dizziness, sweating, chills, clamminess, paleness, irritability, impatience, shakiness (e.g., shaky hands), nervousness, anxiety, confusion including delirium, dysphoria, sadness, blurred or otherwise impaired vision, tingling or numbness in the lips or tongue, headaches, weakness (e.g., weak knees), fatigue or sleepiness, lack of coordination, nightmares or crying out during sleep, neuroglycopenia, rapid/fast heartbeat, seizures, unconsciousness, and brain damage.
  • low levels of blood glucose e.g., based on serum or whole blood glucose levels
  • polyphagia e.g., nausea, hunger, lightheadedness, dizziness, sweating, chills, clamminess, paleness,
  • Symptoms of hypoglycaemia may appear when the blood glucose falls below 4 mmol/1, although it is also possible for symptoms to arise at higher glucose levels.
  • Whipple's triad may be used to determine a diagnosis of hypoglycaemia: 1) symptoms known to be caused by hypoglycaemia; 2) low blood glucose at the time the symptoms occur; and 3) reversal or improvement of symptoms or problems when glucose levels are restored. See J Internat Chir 3:237-276 (1938).
  • a “hypoglycaemic event” refers to an acute condition of hypoglycaemia.
  • Hyperglycaemia means having one or more symptom of high blood glucose, for example, one or more of: high levels of serum glucose, e.g., based on serum or whole blood glucose levels, elevated levels of glucose in the urine, polyphagia, polydipsia, polyuria, blurred vision, fatigue or sleepiness, weight loss, slower wound healing, dry mouth, dry or itchy skin, tingling in feet or heels, erectile dysfunction, recurrent infections, external ear infections, cardiac arrhythmia, stupor, coma, seizures, diabetic ketoacidosis (DKA), and hyperglycaemic hyperosmolar nonketotic syndrome (HHNS).
  • high levels of serum glucose e.g., based on serum or whole blood glucose levels, elevated levels of glucose in the urine, polyphagia, polydipsia, polyuria, blurred vision, fatigue or sleepiness, weight loss, slower wound healing, dry mouth, dry or itchy skin, tingling in feet or heels, erectile dysfunction, recurrent
  • Symptoms of hyperglycaemia may appear when serum glucose rises above 11.1 mmol/1 (200 mg/dl). However, it is possible for symptoms to arise at lower glucose levels, and in some circumstances symptoms may not be apparent until even higher values such as 15-20 mmol/1 (-250-300 mg/dl).
  • a blood glucose “disorder” refers to disorder associated with abnormal levels of glucose in the blood (e.g., outside the range of 3.6 to 7.8 mmol/1). This includes hypoglycaemia or hyperglycaemia, as described in detail herein, and includes a hypoglycaemic event.
  • a "subject” may be a human or non-human animal.
  • Treating as used herein is meant as reducing, ameliorating, or resolving a disorder, for example a blood glucose disorder, such as hypoglycaemia.
  • a treatment will result in the reduction, amelioration, or elimination of one or more symptoms of the disorder.
  • Treatment may involve increasing serum glucose levels, as well as the stabilisation of blood glucose levels. Short term and long term increases may be achieved.
  • Prevention as used herein is meant as stopping or delaying the onset of a disorder, for example a blood glucose disorder, such hypo- or hyperglycaemia.
  • a preventative measure will result in the stoppage or delay of one or more symptoms of the disorder, or a lessening of symptoms if such do arise.
  • Prevention may involve increasing or maintaining serum glucose levels, as well as the stabilisation of blood glucose levels. Short term increases and long term increases may be achieved.
  • compositions and kits for treating or preventing blood glucose disorders are provided.
  • ingestion of glucose included as part of a glucose beverage can be used to achieve short term treatment of a hypoglycaemic event.
  • ingestion of a complex carbohydrate biscuit longer term treatment of hypoglycaemia is possible, while avoiding the potential for rebound hyperglycaemia. Therefore, a kit that combines in the correct proportions both the glucose beverage and the complex carbohydrate biscuit is considered highly advantageous for control of blood glucose levels, and the avoidance of both under- and over-treatment of hypoglycaemia.
  • the glucose beverage is formulated to allow for rapid ingestion, such that hypoglycaemia events are quickly addressed.
  • the volume of the beverage may be about 100 ml, or may be about 50 ml, about 60 ml, about 70 ml, about 80 ml, or about 90 ml.
  • the volume of the beverage may be greater at about 200 ml, or about 110 ml, about 120 ml, about 130 ml, about 140 ml, about 150 ml, about 160 ml, about 170 ml, about 180 ml, or about 190 ml.
  • the volume may range from 50 ml to 100 ml, from 50 ml to 150 ml, or from 100 ml to 200 ml.
  • the main liquid component of the beverage is preferably water, although other liquid components may also be used.
  • the glucose beverage may include a total of about 15 g or about 30 g glucose, or may include at least or about 15 g, at least or about 20 g, at least or about 23 g, at least or about 25 g, at least or about 28 g, at least or about 32 g, at least or about 35 g, at least or about 40 g, or at least or about 45 g glucose.
  • the total glucose content may range from 15 g to 30 g, from 20 g to 30 g, from 25 g to 30 g, or from 30 g to 35 g.
  • the glucose beverage includes a total of 30 g glucose, in a total volume of 100 ml.
  • D-glucose is utilised for the beverage of the invention. This may be provided in the form of dextrose monohydrate.
  • the glucose beverage may include additional additives, including one or more stabilisers, preservatives, antioxidants, sweeteners, flavouring agents, and colouring agents.
  • the glucose beverage includes a food acid such as citric acid.
  • it may be useful to include other components in the glucose beverage for example, sodium or other forms of salt (e.g., one or more electrolytes), or vegetable or fruit extracts or juice.
  • the glucose beverage is prepared without any colouring, sweetening, or flavouring.
  • the glucose beverage is packaged to be readily transported, and easily accessed.
  • the glucose beverage may be packaged into a sachet, or any other means, including a pouch, tube, juice box, can, or bottle.
  • the beverage packaging may be flexible, and may be comprised of plastic and/or foil components.
  • the packaging may include a nozzle or other means for drinking and/or pouring the liquid contained therein.
  • the packaging may include cap, zipper seal, or other means for resealing after use. For sachet packaging, tear strips or tear lines may be included.
  • the complex carbohydrate biscuit is prepared to counteract hunger and other symptoms of hypoglycaemia, but to avoid rebound hyperglycaemia.
  • the biscuit may include flour, oil, and sugar components. It is noted that ⁇ 4% of people with type 1 diabetes have coeliac disease and cannot consume gluten. There is also a large proportion of the general population that is gluten intolerant. Therefore, the flour may be gluten free flour, selected from one or more of: maize, corn flour, rice flour, and starch components. In various aspects, the biscuit may be gluten free, dairy free, egg free, or any combination of these.
  • the biscuit may also be a lower fat biscuit, for example, with less than 25% total fat content.
  • the biscuit may have a lower glycaemic index, for example, less than 25% sugar content.
  • a savoury biscuit i.e., a low sugar or sugar free biscuit
  • the biscuit may include additional additives, including one or more stabilisers, preservatives, antioxidants, emulsifiers, further sweeteners (e.g., sugar free sweeteners), flavouring agents, and colouring agents.
  • it may be useful to include other components in the biscuit for example, fibre, protein, and/or fruit.
  • the complex carbohydrate biscuit may be about 20 g or about 30 g total weight, or may be at least or about 15 g, at least or about 20 g, at least or about 25 g, at least or about 35 g, at least or about 40 g, at least or about 45 g, at least or about 50 g.
  • the weight of the complex carbohydrate biscuit may range from 15 g to 45 g, from 20 g to 30 g, from 25 g to 30 g, or from 30 g to 50 g.
  • the sugar content of the biscuit may be about less than 10%, less than 20%, less than 25%, less than 30%, or less than 40%.
  • the total carbohydrate content of the biscuit may be about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70 %, about 75%, or about 80%; or may range from 30% to 80%, from 40% to 60%, or from 50% to 70%.
  • the carbohydrate component may be about 10 g or about 14 g, in each biscuit, or at least or about 8 g, at least or about 10 g, at least or about 12 g, at least or about 14 g, at least or about 16 g, at least or about 18 g, at least or about 20 g.
  • the carbohydrate component may range from 8 g to 14 g, from 10 g to 20 g, or from 12 g to 18 g, in each biscuit.
  • the complex carbohydrate biscuit is packaged so that it is readily transported, and easily accessed.
  • the biscuit may be placed into biscuit packet, or any other means, including a pouch, a box, or a canister.
  • the biscuit packaging may be flexible, and may be comprised of paper, plastic, or foil components, or any combination thereof.
  • the biscuit packaging may include a zipper seal, or other means for resealing after use.
  • it may be useful to include tear strips, tear lines, or perforation to expedite opening.
  • kits for an adult subject may include 1 x glucose beverage, 100 ml (30 g glucose), plus 1 x complex carbohydrate biscuit, 20 g.
  • a kit for a child subject ( ⁇ 50 kg) may include 1 x glucose beverage, 80 ml (15 g glucose), plus 1 x complex carbohydrate biscuit 20 g.
  • a kit for an overweight adult (> 100 kg) may include 2 x glucose beverages, 100 ml, each (30 g glucose, each), plus 1 x complex carbohydrate biscuit, 30 g, or, alternatively, 2 x complex carbohydrate biscuits, 20 g, each.
  • the kit comprising the glucose beverage and complex carbohydrate biscuit may be packaged in a bag, or in any other suitable packaging, including a pouch, sack, satchel, canister, or box. Any packaging material may be used, for example, plastic, paper, or foil components, or any combination thereof.
  • the kit may be sealed closed by plastic wrap or other means. It may be beneficial to combine several kits (e.g., single use kits) in one larger package, such as a larger bag or a box. Each of the individually packaged kits may include written instructions for the subject to follow.
  • the kit is made to be transportable and easily stored for use in various situations, for example, at schools, hospitals, prisons, airlines, sporting events, at home, or in the car.
  • the kit of the invention may include further components to provide ease of use.
  • the kit may include a set of glucose test strips for the subject to employ.
  • the kit may include other components, such as one or more of: antiseptics (e.g., wipe, spray, or gel), hand sanitiser, timers, serviettes, beverage straws, or other easily transportable items.
  • antiseptics e.g., wipe, spray, or gel
  • hand sanitiser e.g., hand sanitiser
  • timers e.g., timers, serviettes, beverage straws, or other easily transportable items.
  • the present invention provides a glucose beverage that can be used to achieve short term treatment of a hypoglycaemic event. Also provided is a complex carbohydrate biscuit that can be used to achieve longer term treatment of hypoglycaemia, while at the same time avoiding the triggers for hyperglycaemia.
  • the kit is provided to combine both the glucose beverage and the complex carbohydrate biscuit in the correct proportions. Such kit is considered highly beneficial for controlling blood glucose levels, and avoiding both the under-treatment and over-treatment of hypoglycaemia.
  • compositions and kits of the invention find use in treating and preventing blood glucose disorders, including hypoglycaemia and hyperglycaemia. While the compositions and kits of the invention may be used specifically as treatments for hypoglycaemia that is associated with type 1 or type 2 diabetes, or gestational diabetes, the invention is not limited to such specific use.
  • hypoglycaemia may be associated with one or more of: pre-diabetes, overmedication with insulin or antidiabetic pills (e.g., sulfonylurea drugs), use of medications such as beta blockers, pentamidine, salicylates, sulfa drugs, quinine, and trimethoprim (e.g., Bactrim®, Septra®), over-exercise or over-exertion, alcohol consumption including binge drinking, fasting, severe infections, cancer causing poor oral intake, cancer involving the liver, adrenal insufficiency, kidney failure, liver failure, stomach surgery that causes food to pass too quickly into the small intestine, low levels of certain hormones, such as Cortisol, growth hormone, glucagon, or epinephrine, congenital/genetic defects in the regulation of insulin release (e.g., congenital hyperinsulinism), congenital conditions associated with increased insulin release (e.g., infant born to a diabetic mother,
  • the glucose beverage and complex carbohydrate biscuit are provided to a subject having hypoglycaemia, such as a type 1 diabetes patient having a hypoglycaemia event.
  • the hypoglycaemia may be confirmed by a glucose blood test (e.g., levels less than 4 mmol/1).
  • the subject then ingests the glucose beverage, and then tests blood glucose levels. There may be a waiting period after consumption of the beverage and before testing, for example, about 15 minutes of waiting. If the glucose blood test appears normal (e.g., levels equal to or greater than 4 mmol/1), the subject ingests the complex carbohydrate biscuit.
  • the subject ingests a further glucose beverage, re-tests (e.g., after a waiting period) to confirm normal glucose levels, and then consumes the biscuit.
  • a waiting period after consumption of the beverage and before testing for example, about 15 minutes of waiting.
  • the subject may carry out a final test to confirm blood glucose levels.
  • a waiting period after consumption of the biscuit and before testing such as about 15 minutes or about 20 minutes of waiting. It is noted that the various waiting times may be altered to suit a particular situation or a particular subject being treated. In certain circumstances, shorter waiting times between 10 and 15 minutes, or longer waiting times of more than 20 minutes may be useful.
  • an adult subject ( ⁇ 100 kg) is provided with a kit that includes 1 x glucose beverage sachet, 100 ml (30 g glucose), plus 1 x complex carbohydrate biscuit, 20 g.
  • the subject On experiencing one or more symptoms of hypoglycaemia, the subject follows the particular treatment method of:
  • step (2) Test blood glucose. If below 4.0 mmol/1, then go to step (2). If equal to or greater than 4.0 mmol/1, then go to step (3);
  • a child subject ( ⁇ 50 kg) is provided with a kit that includes 1 x 80 ml glucose beverage (15 g glucose), plus 1 x complex carbohydrate biscuit 20 g.
  • the same treatment steps are followed as above.
  • an overweight adult (> 100 kg) is provided with a kit that includes 2 x glucose beverages, 100 ml, each (30 g glucose, each), plus 1 x complex carbohydrate biscuit, 30 g.
  • the subject On experiencing on or more symptoms of hypoglycaemia, the subject follows the particular treatment method of:
  • step (2) Test blood glucose. If below 4.0 mmol/1, then go to step (2). If equal to or greater than 4.0 mmol/1, then go to step (3);
  • the methods of the invention may be modified based on the particular bodyweight of the subject being treated.
  • an adult subject is provided with a kit that includes 1 x glucose beverage sachet, 100 ml (30 g glucose), plus 1 x complex carbohydrate biscuit, 20 g.
  • the subject On experiencing on or more symptoms of hypoglycaemia, the subject follows the particular treatment method of:
  • step (2) Test blood glucose. If below 4.0 mmol/1, then go to step (2). If above or equal to 4.0 mmol/1, then go to step (3);
  • kits that each include 1 x glucose beverage sachet, 100 ml (30 g glucose), plus 1 x complex carbohydrate biscuit, 20 g.
  • Test blood glucose If below 4.0 mmol/1, then go to step (2). If above or equal to 4.0 mmol/1, then go to step (3);
  • step (3) Consume glucose beverage in an amount of 0.3 g glucose per kilogram bodyweight (see, e.g., McTavish et al., 2015) or consume entire 30 g glucose beverage. Wait 15 minutes before re-testing. If equal to or greater than 4.0 mmol/1, go to step (3). If less than 4.0 mmol/1, consume a further 0.3 g glucose per kilogram bodyweight (see, e.g., McTavish et al., 2015) or a further 30 g glucose beverage. Wait another 15 minutes before re-testing. If needed, continue to repeat beverage consumption/re-testing until blood glucose is equal to or greater than 4.0 mmol/1, then go to step (3);
  • the subject's blood glucose testing can be recorded at steps (1), (2), and (3), as noted above.
  • the methods of the invention may be adapted to treat hypoglycaemia that is not associated with diabetes.
  • the glucose beverage and complex carbohydrate biscuit can be provided to a subject experiencing one or more symptoms of hypoglycaemia (e.g., shakiness and/or dizziness), from excessive exercise, fasting, or other causes unrelated to diabetes.
  • the subject ingests the glucose beverage, and then ingests the gluten free biscuit.
  • There may be a waiting period after consumption of the beverage and before consumption of the biscuit for example, about 15 minutes of waiting.
  • There may be a further waiting period after consumption of the biscuit for example, about 15 minutes or about 30 minutes of waiting to see if the symptoms have abated. If symptoms have not lessened in severity, then ingestion of a further beverage and biscuit may be initiated.
  • the various waiting times may be altered to suit a particular situation or a particular subject being treated.
  • the methods of the invention may be used to preclude the onset of hypoglycaemia.
  • the glucose beverage and/or complex carbohydrate biscuit may be consumed following a fasting period or a period of excessive exercise, before symptoms of hypoglycaemia are noted.
  • ingestion of the glucose beverage increases blood glucose levels by 1.5 to 2 mmol/1, for an adult subject ( ⁇ 100 kg) ingesting 1 x glucose beverage, 100 ml (30 g glucose). This is sufficient to prevent or mitigate a hypoglycaemia event for the adult subject under most circumstances.
  • ingestion of the complex carbohydrate biscuit provides further increase in blood glucose levels, and also stabilisation of blood glucose for the subject.
  • consumption of the glucose beverage and complex carbohydrate biscuit is used to address the significant hunger symptoms of hypoglycaemia, without providing over-treatment and occurrence of hyperglycaemia. It will be understood, however, that in certain circumstances the compositions may be used, separately. For example, for very mild symptoms of hypoglycaemia, particularly for non- diabetic hypoglycaemia, it may be preferable to use only the glucose beverage or only the complex carbohydrate biscuit to allay such symptoms.
  • Example 1 Glucose beverage and biscuit preparation for an adult subject
  • a glucose beverage was prepared for an adult subject to include:
  • the nutritional information for the glucose beverage is set out below:
  • Cent-tins no artificial colours or flavours.
  • the glucose beverage was poured into a sachet packet. The sachet was sealed. A 20 g gluten free biscuit was then obtained and combined with the glucose sachet in a bag. Instructions for use were also included on the rear of the bag.
  • the gluten free biscuit included the ingredients of: gluten free flour (maize, corn flour, rice flour, pregel starch), vegetable margarine ((oils: sunflower, canola, palm, coconut), emulsifiers E471, E322, antioxidant E307, food acid (330), acidity regulator (500), food colouring agent E160a, flavour, water, salt), caster sugar, bicarbonate of soda, vanilla, and water.
  • the nutritional information for the biscuit is set out below.
  • Example 2 Glucose beverage and biscuit preparation for a child subject [0093]
  • a glucose beverage is prepared for a child subject to include:
  • the glucose beverage is poured into a sachet packet.
  • the sachet is sealed.
  • a 20 g gluten free biscuit is then obtained and combined with the glucose sachet in a bag. Instructions for use are also included in the bag.
  • Example 3 Clinical study to investigate compositions and kits for treating hypoglycaemia
  • a randomized crossover study is used to assess the protocols for treating hypoglycaemia in people with type 1 diabetes.
  • the study is approved by the Central Ethics Committee and registered with the Australian and New Zealand Clinical Trials Register.
  • the study aims to recruit at least 30 people aged > 18 years with type 1 diabetes, with a history of recent, recurrent episodes of hypoglycaemia.
  • Exclusion criteria include adrenal insufficiency, uncompensated hypothyroidism, clinical autonomic neuropathy, coeliac disease, and living alone.
  • Participants provide written informed consent.
  • a questionnaire is used to gather relevant clinical information, including duration of diabetes, most recent HbAlc value, a list of current medications and medical history.
  • the test treatment includes: consumption of 100 ml glucose beverage (30 g glucose), optionally followed by a further 100 ml glucose beverage (30 g glucose), followed by 20 g gluten free biscuit, as described in Example 1, above. See protocol outlined in Figure 1. Control treatments such as orange juice are carried out in parallel. Each treatment is written on capillary glucose record forms, with each form placed into an envelope and sealed.
  • the research trial coordinator uses a previously generated randomization sequence downloaded from sealedenvelop.com to assign a number to each envelope and writes the assigned number on the outside. This enables a crossover study with each participant planned to have, in random order, several treatments per treatment protocol.
  • the participants are also given an Accu-chek® Performa (Nano; Roche Diagnostics, Mannheim, Germany) capillary glucose meter, 150 Accu-chek® Performa blood test strips (Roche Diagnostics), a bag containing the 100 ml glucose beverage and 20 g biscuit, or the control treatment, a stopwatch, stamped envelopes and capillary glucose recording forms to mail back to the principal investigator.
  • a participant identifies a symptomatic hypoglycaemic event, defined as a capillary glucose value of ⁇ 4.0 mmol/1 (Endocrine Society, 2013), they are instructed to open the next envelope in consecutive ascending order to determine the treatment protocol for that episode. Time zero is defined as the time of ingesting the nominated treatment.
  • the participant follows the instructions to consume the glucose beverage (100 ml), and wait 15 minutes before completing a second capillary glucose recording. If the second capillary glucose is > 4.0 mmol/1, then the participant follows the guidelines of consuming the 20 g gluten free biscuit. If the recording remains ⁇ 4.0 mmol/1, then the participant consumes a further glucose beverage (100 ml).
  • a final blood test is taken at 5 minutes after the resolution of the hypoglycaemic event to investigate whether immediate rebound hyperglycaemia has occurred.
  • Each blood test time and level is recorded by participants on the respective data sheet, along with actual number of grams of glucose beverage consumed, together with any symptoms. The participant mails this back to the lead investigator.
  • the primary outcome is the capillary glucose after 15 minutes adjusted for baseline capillary glucose.
  • the main secondary outcomes are the proportion of participants with capillary glucose > 8 mmol/1 after 15 minutes and the proportion needing more than one treatment.
  • a post hoc analysis is also carried out to examine if there is an interaction between the response to treatment and the gender of participant.
  • ISPAD Institute for Pediatric and Adolescent Diabetes
  • TJ Longitudinal relationship of asymptomatic hypoglycaemia to cognitive function in IDDM. Diabetes Care 1989;12:89-93.
  • Husband AC Crawford S, McCoy LA, Pacaud D. The effectiveness of glucose, sucrose, and fructose in treating hypoglycaemia in children with type 1 diabetes. Pediatr Diabetes 2009; 11: 154-158.
  • Adolescents with Type 1 Diabetes A Statement of the American Diabetes Association. Diabetes Care 2005;28: 186-212. [00133] Slama G, Traynard P-Y, Desplanque N, et al. The Search for an optimized treatment of hypoglycemia: carbohydrates in tablets, solution, or gel for the correction of insulin reactions. Arch Intern Med 1990;150:589-93.

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Abstract

The present disclosure encompasses compositions for treating and preventing blood glucose disorders, kits comprising these compositions, and methods of utilising these kits and compositions. Particularly encompassed are the compositions of a glucose beverage and a complex carbohydrate biscuit, which are provided in correct proportions, and which may be used together treat or prevent hypoglycaemia, and to prevent the subsequent onset of rebound hyperglycaemia.

Description

COMPOSITIONS AND KITS FOR THE TREATMENT AND PREVENTION OF BLOOD GLUCOSE DISORDERS
RELATED APPLICATION
[0001] This application claims the benefit of New Zealand provisional patent application number 707238, filed 21 April 2015, the contents of which are hereby incorporated herein in their entirety.
FIELD OF THE INVENTION
[0002] The present disclosure relates to compositions, including a glucose beverage and a complex carbohydrate biscuit, which may be used in conjunction to treat or prevent blood glucose disorders, including hypoglycaemia and hyperglycaemia. In particular, the disclosed glucose beverage and a complex carbohydrate biscuit may be employed to treat or prevent hypoglycaemia, and to prevent subsequent occurrence of rebound hyperglycaemia. The present disclosure relates also to kits comprising these compositions, as well as methods of making and using such kits. Also related are methods of using the composition and kits to address various blood glucose disorders and any symptoms thereof.
BACKGROUND OF THE INVENTION
[0003] The importance of improved metabolic control in preventing the long- term vascular complications associated with diabetes is well established (Diabetes Control and Complications Trial Research Group, 1993; White et al., 2001). Tight glycaemic control in type 1 diabetes reduces rates of long-term vascular complications, and has become the standard of treatment (Diabetes Control and Complications Trial Research Group, 1993 and 1994; Davis et al., 1998; EDIC Research Group, 2001). However, increased frequency of hypoglycaemia is a consequence of aiming for normo- glycaemia (Cryer et al., 2002). As a result, hypoglycaemia is the most common acute metabolic complication in type 1 diabetes, and is a major impediment to the goal of improving metabolic control (Diabetes Control and Complications Trial Research Group, 1993; Davis et al., 1998). Severe hypoglycaemia, which is associated with seizures or coma, has become more common with general improvements in metabolic control in some reports in the paediatric diabetes clinic (Davis et al., 1998). [0004] Hypoglycaemia is of particular concern in children. The symptoms of hypoglycaemia are particularly distressing for children and their families, and it influences early brain development, especially with early onset of diabetes (Ryan and Becker, 1999). Cognitive deficits have been identified both in children with severe hypoglycaemia (Bjorgaas et al., 1997; Northam et al., 2001) and with recurrent asymptomatic hypoglycaemia (Golden et al. 1989). In fact, both hyper- and hypoglycaemia have been shown to be relevant to cognitive development (Schoenle et al., 2002; Perantie et al., 2008; Gondor-Frederick et al., 2009). Thus, prevention and treatment of hypoglycaemia, as well as hyperglycaemia, are major aims in the management of children with type 1 diabetes.
[0005] Although mild to moderate hypoglycaemia is a significant health care problem, there are surprisingly few clinical studies assessing its most effective management. The National Institute for Clinical Excellence UK, the Canadian Diabetes Association, Diabetes Australia, and the Australasian Pediatric Endocrine Group all recommend immediate oral, rapidly absorbed carbohydrate, 10-20 g, for the management of a hypoglycaemic event (NICE, 2004; Canadian Diabetes Association, 2001; Diabetes Australia, 2010; Australasian Pediatric Endocrine Group, 2005). While these recommendations are widely cited for clinical management of hypoglycaemic events, they have little evidence base.
[0006] Different results are seen with different treatments for hypoglycaemia.
Glucose and other carbohydrates have been used with varying efficacy (American Diabetes Association, 2005; Husband et al., 2009; Brodows et al., 1984; Slama et al., 1990; McTavish et al., 2011). Brodows et al. (1984) found glucose tablets to be more effective than milk or orange juice in resolving hypoglycaemia in adults, using a euglycemic clamp. Slama et al. (1990) found carbohydrate in a gel form was significantly less effective in resolving hypoglycaemia, whereas glucose tablets, sucrose tablets and a preparation containing mixed mono- and oligo- saccharides were most effective. McTavish and Wiltshire (2011) found that jellybeans were significantly less effective than orange juice or glucose tablets in resolution of hypoglycaemia in children, whereas orange juice and glucose tablets showed similar efficacy. The Guidelines from CCDHB Diabetes Service in New Zealand recommend a range of different fast acting carbohydrates for hypoglycaemia, including orange juice, sugar sweetened soft drinks, Mentos® fruit candies, and dextrose tablets. However, it is apparent from available research that these different consumables can have widely differing effects.
[0007] Thus, there are treatments for hypoglycaemia that have substandard efficacy. There are also treatments that are limited in use by low palatability and/or low patient compliance. It also is widely acknowledged that standard treatments for hypoglycaemia often result in under-treatment, or over-treatment, i.e., rebound hyperglycaemia. Moreover, it is known that hypoglycaemia may arise in the absence of diabetic disorders, such as from overtraining, fasting, or excessive alcohol consumption. Thus, there is a significant need for compositions, including packaged compositions and kits, which are effective for treating and preventing blood glucose disorders, including hypoglycaemia/hyperglycaemia.
SUMMARY OF THE INVENTION
[0008] In one aspect, the invention comprises a kit comprising: a glucose beverage that includes at least 15 g glucose and a complex carbohydrate biscuit that includes at least 10 g carbohydrate.
[0009] In various aspects:
[0010] The glucose beverage includes about 15 g or about 30 g glucose.
[0011] The glucose beverage comprises 50 ml to 100 ml in volume.
[0012] The glucose beverage comprises 80 ml in volume, and includes 15 g of glucose.
[0013] The glucose beverage comprises 100 ml in volume, and includes 30 g of glucose.
[0014] The glucose beverage is provided in a sachet.
[0015] The complex carbohydrate biscuit includes 10 g to 20 g carbohydrate.
[0016] The complex carbohydrate biscuit comprises about 20 g or about 30 g in weight. [0017] The complex carbohydrate biscuit comprises 12 g carbohydrate and 20 g in weight.
[0018] The complex carbohydrate biscuit is one or more of: gluten free, egg free, or dairy free.
[0019] The complex carbohydrate biscuit is provided in a packet.
[0020] The glucose beverage and complex carbohydrate biscuit are provided together in a bag.
[0021] The kit further includes an additional glucose beverage.
[0022] The kit further includes instructions for use.
[0023] The kit further includes a means for testing blood glucose levels.
[0024] The means for testing blood glucose levels is a glucose test strip.
[0025] The kit further includes an antiseptic.
[0026] In one other aspect, the invention comprises a method of treating hypoglycaemia in a subject, which comprises: providing to a subject a kit comprising a glucose beverage that includes at least 15 g glucose and a complex carbohydrate biscuit that includes at least 10 g carbohydrate, the subject ingesting the glucose beverage and then ingesting the complex carbohydrate biscuit, thereby treating the hypoglycaemia.
[0027] In various aspects:
[0028] The glucose beverage includes about 15 g or about 30 g glucose.
[0029] The glucose beverage comprises 50 ml to 100 ml in volume.
[0030] The glucose beverage comprises 80 ml in volume, and includes 15 g of glucose.
[0031] The glucose beverage comprises 100 ml in volume, and includes 30 g of glucose. [0032] The glucose beverage is provided in a sachet.
[0033] The complex carbohydrate biscuit includes 10 g to 20 g carbohydrate.
[0034] The complex carbohydrate biscuit comprises 20 g or 30 g in weight.
[0035] The complex carbohydrate biscuit comprises 12 g carbohydrate and 20 g in weight.
[0036] The complex carbohydrate biscuit is one or more of: gluten free, egg free, or dairy free.
[0037] The complex carbohydrate biscuit is provided in a packet.
[0038] The glucose beverage and complex carbohydrate biscuit are provided together in a bag.
[0039] The kit further includes an additional glucose beverage.
[0040] The kit further includes instructions for use.
[0041] The kit further includes a means for testing blood glucose levels.
[0042] The means for testing blood glucose levels is a glucose test strip.
[0043] The kit further includes an antiseptic.
[0044] The hypoglycaemia is associated with type 1 or type 2 diabetes, or gestational diabetes.
[0045] The hypoglycaemia is associated excessive exercise or fasting.
[0046] The method further comprises the subject ingesting an additional glucose beverage prior to ingestion of the biscuit.
[0047] The method further comprises a waiting period between ingestion of the glucose beverage and ingestion of the complex carbohydrate biscuit.
[0048] The waiting period is from 10 minutes to 15 minutes. [0049] The method further comprises testing blood glucose levels at any one or more of the periods: prior to ingestion of the beverage, prior to ingestion of the biscuit, following ingestion of the biscuit.
[0050] The foregoing brief summary broadly describes the features and technical advantages of certain embodiments of the present invention. Further technical advantages will be described in the detailed description of the invention and examples that follows.
[0051] Novel features that are believed to be characteristic of the invention will be better understood from the detailed description of the invention when considered in connection with any accompanying figures and examples. However, the figures and examples provided herein are intended to help illustrate the invention or assist with developing an understanding of the invention, and are not intended to limit the invention's scope.
BRIEF DESCRIPTION OF THE DRAWINGS
[0052] Figure 1 : Diagram of clinical treatment protocol.
[0053] Figure 2: Diagram of alternative treatment method.
[0054] Figure 3: Diagram of a further alternative treatment method.
DETAILED DESCRIPTION OF THE INVENTION
[0055] The following description sets forth numerous exemplary configurations, parameters, and the like. It should be recognised, however, that such description is not intended as a limitation on the scope of the present invention, but is instead provided as a description of exemplary embodiments.
[0056] All references, including patents and patent applications, cited in this specification are hereby incorporated by reference. No admission is made that any reference constitutes prior art. Nor does discussion of any reference constitute an admission that such reference forms part of the common general knowledge in the art, in New Zealand or in any other country. Definitions
[0057] In each instance herein, in descriptions, embodiments, and examples of the present invention, the terms "comprising", "including", etc., are to be read expansively, without limitation. Thus, unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise", "comprising", and the like are to be construed in an inclusive sense as to opposed to an exclusive sense, that is to say in the sense of "including but not limited to".
[0058] As used herein "hypoglycaemia" means having one or more symptom of low blood glucose, for example, one or more of: low levels of blood glucose, e.g., based on serum or whole blood glucose levels, polyphagia, nausea, hunger, lightheadedness, dizziness, sweating, chills, clamminess, paleness, irritability, impatience, shakiness (e.g., shaky hands), nervousness, anxiety, confusion including delirium, dysphoria, sadness, blurred or otherwise impaired vision, tingling or numbness in the lips or tongue, headaches, weakness (e.g., weak knees), fatigue or sleepiness, lack of coordination, nightmares or crying out during sleep, neuroglycopenia, rapid/fast heartbeat, seizures, unconsciousness, and brain damage. Symptoms of hypoglycaemia may appear when the blood glucose falls below 4 mmol/1, although it is also possible for symptoms to arise at higher glucose levels. In certain circumstances, Whipple's triad may be used to determine a diagnosis of hypoglycaemia: 1) symptoms known to be caused by hypoglycaemia; 2) low blood glucose at the time the symptoms occur; and 3) reversal or improvement of symptoms or problems when glucose levels are restored. See J Internat Chir 3:237-276 (1938).
[0059] A "hypoglycaemic event" refers to an acute condition of hypoglycaemia.
[0060] "Hyperglycaemia" means having one or more symptom of high blood glucose, for example, one or more of: high levels of serum glucose, e.g., based on serum or whole blood glucose levels, elevated levels of glucose in the urine, polyphagia, polydipsia, polyuria, blurred vision, fatigue or sleepiness, weight loss, slower wound healing, dry mouth, dry or itchy skin, tingling in feet or heels, erectile dysfunction, recurrent infections, external ear infections, cardiac arrhythmia, stupor, coma, seizures, diabetic ketoacidosis (DKA), and hyperglycaemic hyperosmolar nonketotic syndrome (HHNS). Symptoms of hyperglycaemia may appear when serum glucose rises above 11.1 mmol/1 (200 mg/dl). However, it is possible for symptoms to arise at lower glucose levels, and in some circumstances symptoms may not be apparent until even higher values such as 15-20 mmol/1 (-250-300 mg/dl).
[0061] A blood glucose "disorder" refers to disorder associated with abnormal levels of glucose in the blood (e.g., outside the range of 3.6 to 7.8 mmol/1). This includes hypoglycaemia or hyperglycaemia, as described in detail herein, and includes a hypoglycaemic event.
[0062] As used herein, a "subject" may be a human or non-human animal.
[0063] "Treating" as used herein is meant as reducing, ameliorating, or resolving a disorder, for example a blood glucose disorder, such as hypoglycaemia. A treatment will result in the reduction, amelioration, or elimination of one or more symptoms of the disorder. Treatment may involve increasing serum glucose levels, as well as the stabilisation of blood glucose levels. Short term and long term increases may be achieved.
[0064] "Preventing" as used herein is meant as stopping or delaying the onset of a disorder, for example a blood glucose disorder, such hypo- or hyperglycaemia. A preventative measure will result in the stoppage or delay of one or more symptoms of the disorder, or a lessening of symptoms if such do arise. Prevention may involve increasing or maintaining serum glucose levels, as well as the stabilisation of blood glucose levels. Short term increases and long term increases may be achieved.
Compositions and kits for treating or preventing blood glucose disorders
[0065] Conventional therapy for diabetes involved administration of one or more injections per day of various forms of insulin while monitoring blood glucose levels. However, near normal blood glucose levels are difficult if not impossible to achieve using conventional therapy. There remains an ongoing need for adjunct treatments for diabetes to control serum glucose levels, and to prevent or treat blood glucose disorders, such as hypo- and hyperglycaemia.
[0066] In accordance with the present invention, it is proposed that ingestion of glucose included as part of a glucose beverage can be used to achieve short term treatment of a hypoglycaemic event. When followed by ingestion of a complex carbohydrate biscuit, longer term treatment of hypoglycaemia is possible, while avoiding the potential for rebound hyperglycaemia. Therefore, a kit that combines in the correct proportions both the glucose beverage and the complex carbohydrate biscuit is considered highly advantageous for control of blood glucose levels, and the avoidance of both under- and over-treatment of hypoglycaemia.
[0067] The glucose beverage is formulated to allow for rapid ingestion, such that hypoglycaemia events are quickly addressed. The volume of the beverage may be about 100 ml, or may be about 50 ml, about 60 ml, about 70 ml, about 80 ml, or about 90 ml. Alternatively, the volume of the beverage may be greater at about 200 ml, or about 110 ml, about 120 ml, about 130 ml, about 140 ml, about 150 ml, about 160 ml, about 170 ml, about 180 ml, or about 190 ml. In various aspects, the volume may range from 50 ml to 100 ml, from 50 ml to 150 ml, or from 100 ml to 200 ml. The main liquid component of the beverage is preferably water, although other liquid components may also be used.
[0068] The glucose beverage may include a total of about 15 g or about 30 g glucose, or may include at least or about 15 g, at least or about 20 g, at least or about 23 g, at least or about 25 g, at least or about 28 g, at least or about 32 g, at least or about 35 g, at least or about 40 g, or at least or about 45 g glucose. In various aspects, the total glucose content may range from 15 g to 30 g, from 20 g to 30 g, from 25 g to 30 g, or from 30 g to 35 g. In one preferred aspect, the glucose beverage includes a total of 30 g glucose, in a total volume of 100 ml. In a particular aspect, D-glucose is utilised for the beverage of the invention. This may be provided in the form of dextrose monohydrate.
[0069] The glucose beverage may include additional additives, including one or more stabilisers, preservatives, antioxidants, sweeteners, flavouring agents, and colouring agents. In a particular aspect, the glucose beverage includes a food acid such as citric acid. In some circumstances, it may be useful to include other components in the glucose beverage, for example, sodium or other forms of salt (e.g., one or more electrolytes), or vegetable or fruit extracts or juice. In a specific aspect, the glucose beverage is prepared without any colouring, sweetening, or flavouring.
[0070] The glucose beverage is packaged to be readily transported, and easily accessed. The glucose beverage may be packaged into a sachet, or any other means, including a pouch, tube, juice box, can, or bottle. In various aspects, the beverage packaging may be flexible, and may be comprised of plastic and/or foil components. The packaging may include a nozzle or other means for drinking and/or pouring the liquid contained therein. The packaging may include cap, zipper seal, or other means for resealing after use. For sachet packaging, tear strips or tear lines may be included.
[0071] The complex carbohydrate biscuit is prepared to counteract hunger and other symptoms of hypoglycaemia, but to avoid rebound hyperglycaemia. The biscuit may include flour, oil, and sugar components. It is noted that ~ 4% of people with type 1 diabetes have coeliac disease and cannot consume gluten. There is also a large proportion of the general population that is gluten intolerant. Therefore, the flour may be gluten free flour, selected from one or more of: maize, corn flour, rice flour, and starch components. In various aspects, the biscuit may be gluten free, dairy free, egg free, or any combination of these.
[0072] In general, dietitians recommend keeping both fat and simple sugar to below 10%. Also, excessive fats and sugars from biscuits can lead to poor diabetes control if consumed frequently. Therefore, the biscuit may also be a lower fat biscuit, for example, with less than 25% total fat content. The biscuit may have a lower glycaemic index, for example, less than 25% sugar content. Thus, a savoury biscuit (i.e., a low sugar or sugar free biscuit), similar to a scone or cracker, is also encompassed. The biscuit may include additional additives, including one or more stabilisers, preservatives, antioxidants, emulsifiers, further sweeteners (e.g., sugar free sweeteners), flavouring agents, and colouring agents. In some circumstances, it may be useful to include other components in the biscuit, for example, fibre, protein, and/or fruit.
[0073] The complex carbohydrate biscuit may be about 20 g or about 30 g total weight, or may be at least or about 15 g, at least or about 20 g, at least or about 25 g, at least or about 35 g, at least or about 40 g, at least or about 45 g, at least or about 50 g. In various aspects, the weight of the complex carbohydrate biscuit may range from 15 g to 45 g, from 20 g to 30 g, from 25 g to 30 g, or from 30 g to 50 g. The sugar content of the biscuit may be about less than 10%, less than 20%, less than 25%, less than 30%, or less than 40%. The total carbohydrate content of the biscuit may be about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70 %, about 75%, or about 80%; or may range from 30% to 80%, from 40% to 60%, or from 50% to 70%. Thus, the carbohydrate component may be about 10 g or about 14 g, in each biscuit, or at least or about 8 g, at least or about 10 g, at least or about 12 g, at least or about 14 g, at least or about 16 g, at least or about 18 g, at least or about 20 g. The carbohydrate component may range from 8 g to 14 g, from 10 g to 20 g, or from 12 g to 18 g, in each biscuit.
[0074] The complex carbohydrate biscuit is packaged so that it is readily transported, and easily accessed. The biscuit may be placed into biscuit packet, or any other means, including a pouch, a box, or a canister. The biscuit packaging may be flexible, and may be comprised of paper, plastic, or foil components, or any combination thereof. The biscuit packaging may include a zipper seal, or other means for resealing after use. For the biscuit packaging, it may be useful to include tear strips, tear lines, or perforation to expedite opening.
[0075] In particular aspects, the glucose beverage and complex carbohydrate biscuit are combined together as components for a kit. For example, a kit for an adult subject may include 1 x glucose beverage, 100 ml (30 g glucose), plus 1 x complex carbohydrate biscuit, 20 g. A kit for a child subject (< 50 kg) may include 1 x glucose beverage, 80 ml (15 g glucose), plus 1 x complex carbohydrate biscuit 20 g. A kit for an overweight adult (> 100 kg) may include 2 x glucose beverages, 100 ml, each (30 g glucose, each), plus 1 x complex carbohydrate biscuit, 30 g, or, alternatively, 2 x complex carbohydrate biscuits, 20 g, each.
[0076] The kit comprising the glucose beverage and complex carbohydrate biscuit may be packaged in a bag, or in any other suitable packaging, including a pouch, sack, satchel, canister, or box. Any packaging material may be used, for example, plastic, paper, or foil components, or any combination thereof. The kit may be sealed closed by plastic wrap or other means. It may be beneficial to combine several kits (e.g., single use kits) in one larger package, such as a larger bag or a box. Each of the individually packaged kits may include written instructions for the subject to follow. Advantageously, the kit is made to be transportable and easily stored for use in various situations, for example, at schools, hospitals, prisons, airlines, sporting events, at home, or in the car.
[0077] Optionally, the kit of the invention may include further components to provide ease of use. For example, the kit may include a set of glucose test strips for the subject to employ. The kit may include other components, such as one or more of: antiseptics (e.g., wipe, spray, or gel), hand sanitiser, timers, serviettes, beverage straws, or other easily transportable items. Methods of using the compositions and kits for treating and preventing blood glucose disorders
[0078] The present invention provides a glucose beverage that can be used to achieve short term treatment of a hypoglycaemic event. Also provided is a complex carbohydrate biscuit that can be used to achieve longer term treatment of hypoglycaemia, while at the same time avoiding the triggers for hyperglycaemia. In particular aspects, the kit is provided to combine both the glucose beverage and the complex carbohydrate biscuit in the correct proportions. Such kit is considered highly beneficial for controlling blood glucose levels, and avoiding both the under-treatment and over-treatment of hypoglycaemia.
[0079] The compositions and kits of the invention find use in treating and preventing blood glucose disorders, including hypoglycaemia and hyperglycaemia. While the compositions and kits of the invention may be used specifically as treatments for hypoglycaemia that is associated with type 1 or type 2 diabetes, or gestational diabetes, the invention is not limited to such specific use. It is noted that hypoglycaemia may be associated with one or more of: pre-diabetes, overmedication with insulin or antidiabetic pills (e.g., sulfonylurea drugs), use of medications such as beta blockers, pentamidine, salicylates, sulfa drugs, quinine, and trimethoprim (e.g., Bactrim®, Septra®), over-exercise or over-exertion, alcohol consumption including binge drinking, fasting, severe infections, cancer causing poor oral intake, cancer involving the liver, adrenal insufficiency, kidney failure, liver failure, stomach surgery that causes food to pass too quickly into the small intestine, low levels of certain hormones, such as Cortisol, growth hormone, glucagon, or epinephrine, congenital/genetic defects in the regulation of insulin release (e.g., congenital hyperinsulinism), congenital conditions associated with increased insulin release (e.g., infant born to a diabetic mother, birth trauma, reduced oxygen delivery during birth, major birth stress, Beckwith-Wiedemann syndrome, and other genetic conditions), insulinoma or insulin -producing tumour, other tumours like hepatoma, mesothelioma, and fibrosarcoma, which produce insulin-like factors.
[0080] In accordance with the present invention, the glucose beverage and complex carbohydrate biscuit are provided to a subject having hypoglycaemia, such as a type 1 diabetes patient having a hypoglycaemia event. The hypoglycaemia may be confirmed by a glucose blood test (e.g., levels less than 4 mmol/1). The subject then ingests the glucose beverage, and then tests blood glucose levels. There may be a waiting period after consumption of the beverage and before testing, for example, about 15 minutes of waiting. If the glucose blood test appears normal (e.g., levels equal to or greater than 4 mmol/1), the subject ingests the complex carbohydrate biscuit. If the glucose blood test appears low (e.g., levels less than 4 mmol/1), the subject ingests a further glucose beverage, re-tests (e.g., after a waiting period) to confirm normal glucose levels, and then consumes the biscuit. As before, there may be a waiting period after consumption of the beverage and before testing, for example, about 15 minutes of waiting. After biscuit ingestion, the subject may carry out a final test to confirm blood glucose levels. Again, there may be a waiting period after consumption of the biscuit and before testing, such as about 15 minutes or about 20 minutes of waiting. It is noted that the various waiting times may be altered to suit a particular situation or a particular subject being treated. In certain circumstances, shorter waiting times between 10 and 15 minutes, or longer waiting times of more than 20 minutes may be useful.
[0081] As an exemplary method, an adult subject (< 100 kg) is provided with a kit that includes 1 x glucose beverage sachet, 100 ml (30 g glucose), plus 1 x complex carbohydrate biscuit, 20 g. On experiencing one or more symptoms of hypoglycaemia, the subject follows the particular treatment method of:
1) Test blood glucose. If below 4.0 mmol/1, then go to step (2). If equal to or greater than 4.0 mmol/1, then go to step (3);
2) Consume glucose beverage. Wait 15 minutes before re-testing. If equal to or greater than 4.0 mmol/1, go to step (3). If less than 4.0 mmol/1, open a new kit and follow instructions;
3) Consume biscuit and re-test in 15 to 30 minutes.
[0082] As another example, a child subject (< 50 kg) is provided with a kit that includes 1 x 80 ml glucose beverage (15 g glucose), plus 1 x complex carbohydrate biscuit 20 g. The same treatment steps are followed as above.
[0083] As a further example, an overweight adult (> 100 kg) is provided with a kit that includes 2 x glucose beverages, 100 ml, each (30 g glucose, each), plus 1 x complex carbohydrate biscuit, 30 g. On experiencing on or more symptoms of hypoglycaemia, the subject follows the particular treatment method of:
1) Test blood glucose. If below 4.0 mmol/1, then go to step (2). If equal to or greater than 4.0 mmol/1, then go to step (3);
2) Consume first glucose beverage. Wait 15 minutes before re-testing. If equal to or greater than 4.0 mmol/1, go to step (3). If less than 4.0 mmol/1, consume second beverage. Wait 15 minutes before re-testing. If equal to or greater than 4.0 mmol/1, go to step (3). If less than 4.0 mmol/1, open a new kit and follow instructions;
3) Consume biscuit and re-test in 15 to 30 minutes.
[0084] In alternate aspects, the methods of the invention may be modified based on the particular bodyweight of the subject being treated. For example, an adult subject is provided with a kit that includes 1 x glucose beverage sachet, 100 ml (30 g glucose), plus 1 x complex carbohydrate biscuit, 20 g. On experiencing on or more symptoms of hypoglycaemia, the subject follows the particular treatment method of:
1) Test blood glucose. If below 4.0 mmol/1, then go to step (2). If above or equal to 4.0 mmol/1, then go to step (3);
2) Consume glucose beverage in an amount of 0.3 g glucose per kilogram bodyweight (see, e.g., McTavish et al., 2015). Wait 15 minutes before re-testing. If equal to or greater than 4.0 mmol/1, go to step (3). If less than 4.0 mmol/1, consume a further 0.3 g glucose per kilogram bodyweight (see, e.g., McTavish et al., 2015);
3) Consume at least 10 g of biscuit and re-test in 15 to 30 minutes.
[0085] An exemplification of this method is outlined in Figure 2.
[0086] In other aspects, the methods of the invention may be further modified as follows. An adult subject is provided with at least two kits that each include 1 x glucose beverage sachet, 100 ml (30 g glucose), plus 1 x complex carbohydrate biscuit, 20 g. On experiencing on or more symptoms of hypoglycaemia, the subject follows the particular treatment method of: 1) Test blood glucose. If below 4.0 mmol/1, then go to step (2). If above or equal to 4.0 mmol/1, then go to step (3);
2) Consume glucose beverage in an amount of 0.3 g glucose per kilogram bodyweight (see, e.g., McTavish et al., 2015) or consume entire 30 g glucose beverage. Wait 15 minutes before re-testing. If equal to or greater than 4.0 mmol/1, go to step (3). If less than 4.0 mmol/1, consume a further 0.3 g glucose per kilogram bodyweight (see, e.g., McTavish et al., 2015) or a further 30 g glucose beverage. Wait another 15 minutes before re-testing. If needed, continue to repeat beverage consumption/re-testing until blood glucose is equal to or greater than 4.0 mmol/1, then go to step (3);
3) Consume the 20 g biscuit and re -test in 30 minutes. Optionally, the subject's blood glucose testing can be recorded at steps (1), (2), and (3), as noted above.
[0087] An exemplification of this method is outlined in Figure 3.
[0088] In other aspects, the methods of the invention may be adapted to treat hypoglycaemia that is not associated with diabetes. For example, the glucose beverage and complex carbohydrate biscuit can be provided to a subject experiencing one or more symptoms of hypoglycaemia (e.g., shakiness and/or dizziness), from excessive exercise, fasting, or other causes unrelated to diabetes. The subject ingests the glucose beverage, and then ingests the gluten free biscuit. There may be a waiting period after consumption of the beverage and before consumption of the biscuit, for example, about 15 minutes of waiting. There may be a further waiting period after consumption of the biscuit, for example, about 15 minutes or about 30 minutes of waiting to see if the symptoms have abated. If symptoms have not lessened in severity, then ingestion of a further beverage and biscuit may be initiated. As before, the various waiting times may be altered to suit a particular situation or a particular subject being treated.
[0089] In further aspects, the methods of the invention may be used to preclude the onset of hypoglycaemia. For example, the glucose beverage and/or complex carbohydrate biscuit may be consumed following a fasting period or a period of excessive exercise, before symptoms of hypoglycaemia are noted.
[0090] In accordance with the disclosed methods, it is proposed that ingestion of the glucose beverage increases blood glucose levels by 1.5 to 2 mmol/1, for an adult subject (< 100 kg) ingesting 1 x glucose beverage, 100 ml (30 g glucose). This is sufficient to prevent or mitigate a hypoglycaemia event for the adult subject under most circumstances. Following the beverage, ingestion of the complex carbohydrate biscuit provides further increase in blood glucose levels, and also stabilisation of blood glucose for the subject. Employed together, consumption of the glucose beverage and complex carbohydrate biscuit is used to address the significant hunger symptoms of hypoglycaemia, without providing over-treatment and occurrence of hyperglycaemia. It will be understood, however, that in certain circumstances the compositions may be used, separately. For example, for very mild symptoms of hypoglycaemia, particularly for non- diabetic hypoglycaemia, it may be preferable to use only the glucose beverage or only the complex carbohydrate biscuit to allay such symptoms.
EXAMPLES
[0091] The examples described herein are provided for the purpose of illustrating specific embodiments of the invention and are not intended to limit the invention in any way.
Example 1: Glucose beverage and biscuit preparation for an adult subject
[0092] A glucose beverage was prepared for an adult subject to include:
80.5 g (80.5 ml) water
30 g dextrose monohydrate
0.03-0.05 g acidity regulator (food acid 330)
Total fluid volume: 100 ml
The nutritional information for the glucose beverage is set out below:
Figure imgf000017_0001
Cent-tins no artificial colours or flavours. The glucose beverage was poured into a sachet packet. The sachet was sealed. A 20 g gluten free biscuit was then obtained and combined with the glucose sachet in a bag. Instructions for use were also included on the rear of the bag. The gluten free biscuit included the ingredients of: gluten free flour (maize, corn flour, rice flour, pregel starch), vegetable margarine ((oils: sunflower, canola, palm, coconut), emulsifiers E471, E322, antioxidant E307, food acid (330), acidity regulator (500), food colouring agent E160a, flavour, water, salt), caster sugar, bicarbonate of soda, vanilla, and water. The nutritional information for the biscuit is set out below.
Figure imgf000018_0001
Example 2: Glucose beverage and biscuit preparation for a child subject [0093] A glucose beverage is prepared for a child subject to include:
70.2 g (70.2 ml) water
15 g dextrose monohydrate
0.03-0.05 g acidity regulator (food acid 330)
Total fluid volume: 80 ml
[0094] The glucose beverage is poured into a sachet packet. The sachet is sealed.
A 20 g gluten free biscuit is then obtained and combined with the glucose sachet in a bag. Instructions for use are also included in the bag.
Example 3: Clinical study to investigate compositions and kits for treating hypoglycaemia
[0095] A randomized crossover study is used to assess the protocols for treating hypoglycaemia in people with type 1 diabetes. The study is approved by the Central Ethics Committee and registered with the Australian and New Zealand Clinical Trials Register. The study aims to recruit at least 30 people aged > 18 years with type 1 diabetes, with a history of recent, recurrent episodes of hypoglycaemia. Exclusion criteria include adrenal insufficiency, uncompensated hypothyroidism, clinical autonomic neuropathy, coeliac disease, and living alone.
[0096] Participants provide written informed consent. A questionnaire is used to gather relevant clinical information, including duration of diabetes, most recent HbAlc value, a list of current medications and medical history. The test treatment includes: consumption of 100 ml glucose beverage (30 g glucose), optionally followed by a further 100 ml glucose beverage (30 g glucose), followed by 20 g gluten free biscuit, as described in Example 1, above. See protocol outlined in Figure 1. Control treatments such as orange juice are carried out in parallel. Each treatment is written on capillary glucose record forms, with each form placed into an envelope and sealed.
[0097] Using a previously generated randomization sequence downloaded from sealedenvelop.com, the research trial coordinator then assigns a number to each envelope and writes the assigned number on the outside. This enables a crossover study with each participant planned to have, in random order, several treatments per treatment protocol. The participants are also given an Accu-chek® Performa (Nano; Roche Diagnostics, Mannheim, Germany) capillary glucose meter, 150 Accu-chek® Performa blood test strips (Roche Diagnostics), a bag containing the 100 ml glucose beverage and 20 g biscuit, or the control treatment, a stopwatch, stamped envelopes and capillary glucose recording forms to mail back to the principal investigator.
[0098] Once a participant identifies a symptomatic hypoglycaemic event, defined as a capillary glucose value of < 4.0 mmol/1 (Endocrine Society, 2013), they are instructed to open the next envelope in consecutive ascending order to determine the treatment protocol for that episode. Time zero is defined as the time of ingesting the nominated treatment. For the test treatment, the participant follows the instructions to consume the glucose beverage (100 ml), and wait 15 minutes before completing a second capillary glucose recording. If the second capillary glucose is > 4.0 mmol/1, then the participant follows the guidelines of consuming the 20 g gluten free biscuit. If the recording remains < 4.0 mmol/1, then the participant consumes a further glucose beverage (100 ml). A final blood test is taken at 5 minutes after the resolution of the hypoglycaemic event to investigate whether immediate rebound hyperglycaemia has occurred. [0099] Each blood test time and level is recorded by participants on the respective data sheet, along with actual number of grams of glucose beverage consumed, together with any symptoms. The participant mails this back to the lead investigator. The primary outcome is the capillary glucose after 15 minutes adjusted for baseline capillary glucose. The main secondary outcomes are the proportion of participants with capillary glucose > 8 mmol/1 after 15 minutes and the proportion needing more than one treatment. A post hoc analysis is also carried out to examine if there is an interaction between the response to treatment and the gender of participant.
[00100] Persons of ordinary skill can utilise the disclosures and teachings herein to produce other embodiments and variations without undue experimentation. All such embodiments and variations are considered to be part of this invention.
[00101] Accordingly, one of ordinary skill in the art will readily appreciate from the disclosure that later modifications, substitutions, and/or variations performing substantially the same function or achieving substantially the same result as embodiments described herein may be utilised according to such related embodiments of the present invention. Thus, the invention is intended to encompass, within its scope, the modifications, substitutions, and variations to processes, manufactures, compositions of matter, compounds, means, methods, and/or steps disclosed herein.
References
[00102] American Diabetes Association. Evidence-based nutritional principles and recommendations for the treatment and prevention of diabetes and related complications. Diabetes Care 2002;25: 148-198.
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[00104] Australasian Pediatric Endocrine Group - for the Department of Health and Aging. Clinical Practice Guidelines: Typel diabetes in children and adolescents. 2005. Available from http://www.nhmrc.gov.au/publications/synopses/cpl02syn.htm.
[00105] Bjorgaas M, Gimse R, Vik T, Sand T. Cognitive function in type 1 diabetic children with and without episodes of severe hypoglycaemia. Acta Paediatr 1997;86: 148-153. [00106] Brodows RG, Williams C, Amatruda M. Treatment of insulin reactions in diabetics. JAMA 1984;252:3378-81.
[00107] Bryden KS, Neil A, Mayou RA, Peveler RC, Fairburn CG, Dunger DB.
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Claims

WHAT IS CLAIMED IS:
1. A kit comprising: a glucose beverage that includes at least 15 g glucose and a complex carbohydrate biscuit that includes at least 10 g carbohydrate.
2. The kit according to claim 1, wherein the glucose beverage includes about 15 g or about 30 g glucose.
3. The kit according to claim 1 or claim 2, wherein the glucose beverage comprises 50 ml to 100 ml in volume.
4. The kit according to any one of claims 1 to 3, wherein the glucose beverage comprises 80 ml in volume, and includes 15 g of glucose.
5. The kit according to any one of claims 1 to 3, wherein the glucose beverage comprises 100 ml in volume, and includes 30 g of glucose.
6. The kit according to any one of claims 1 to 5, wherein the glucose beverage is provided in a sachet.
7. The kit according to any one of claims 1 to 6, wherein the complex carbohydrate biscuit includes 10 g to 20 g carbohydrate.
8. The kit according to any one of claims 1 to 7, wherein the complex carbohydrate biscuit comprises about 20 g or about 30 g in weight.
9. The kit according to any one of claims 1 to 8, wherein the complex carbohydrate biscuit comprises 12 g carbohydrate and 20 g in weight.
10. The kit according to any one of claims 1 to 9, wherein the complex carbohydrate biscuit is one or more of: gluten free, dairy free, or egg free.
11. The kit according to any one of claims 1 to 10, wherein the complex carbohydrate biscuit is provided in a packet.
12. The kit according to any one of claims 1 to 11, wherein the glucose beverage and complex carbohydrate biscuit are provided together in a bag.
13. The kit according to any one of claims 1 to 12, which further includes an additional glucose beverage.
14. The kit according to any one of claims 1 to 13, which further includes instructions for use.
15. The kit according to any one of claims 1 to 14, which optionally includes a means for testing blood glucose levels and/or an antiseptic.
16. The kit according to claim 15, wherein the means for testing blood glucose levels comprises a glucose test strip.
17. A method of treating hypoglycaemia in a subject, which comprises: providing to a subject a kit comprising a glucose beverage that includes at least 15 g glucose and a complex carbohydrate biscuit that includes at least 10 g carbohydrate, the subject ingesting the glucose beverage, or ingesting 0.3 g glucose/kg based on the subject's weight, and then ingesting the complex carbohydrate biscuit, thereby treating the hypoglycaemia.
18. The method according to claim 17, which further comprises the subject ingesting an additional glucose beverage prior to ingestion of the biscuit.
19. The method according to claim 17 or claim 18, which further comprises a waiting period between ingestion of the glucose beverage and ingestion of the complex carbohydrate biscuit.
20. The method according to claim 19, wherein the waiting period is from 10 minutes to 15 minutes.
21. The method according to any one of claims 17 to 20, which further comprises testing blood glucose levels at one or more of the periods: prior to ingestion of the beverage, prior to ingestion of the biscuit, following ingestion of the biscuit.
22. The method according to any one of claims 17 to 21, wherein the glucose beverage includes about 15 g or about 30 g glucose.
23. The method according to any one of claims 17 to 22, wherein the glucose beverage comprises 50 ml to 100 ml in volume.
24. The method according to any one of claims 17 to 23, wherein the glucose beverage comprises 80 ml in volume, and includes 15 g of glucose.
25. The method according to any one of claims 17 to 23, wherein the glucose beverage comprises 100 ml in volume, and includes 30 g of glucose.
26. The method according to any one of claims 17 to 25, wherein the glucose beverage is provided in a sachet.
27. The method according to any one of claims 17 to 26, wherein the complex carbohydrate biscuit includes 10 g to 20 g carbohydrate.
28. The method according to any one of claims 17 to 27, wherein the complex carbohydrate biscuit comprises about 20 g or about 30 g in weight.
29. The method according to any one of claims 17 to 28, wherein the complex carbohydrate biscuit comprises 12 g carbohydrate and 20 g in weight.
30. The method according to any one of claims 17 to 29, wherein the complex carbohydrate biscuit is one or more of: gluten free, dairy free, or egg free.
31. The method according to any one of claims 17 to 30, wherein the complex carbohydrate biscuit is provided in a packet.
32. The method according to any one of claims 17 to 31, wherein the glucose beverage and the complex carbohydrate biscuit are provided together in a bag.
33. The method according to any one of claims 17 to 32, wherein the kit further includes an additional glucose beverage.
34. The method according to any one of claims 17 to 33, wherein the kit further includes instructions for use.
35. The method according to any one of claims 17 to 34, wherein the kit optionally includes a means for testing blood glucose levels and/or an antiseptic.
36. The method according to claim 34, wherein the means for testing blood glucose levels comprises a glucose test strip.
37. The method according to any one of claims 17 to 36, wherein the hypoglycaemia is associated with type 1 or type 2 diabetes, or gestational diabetes.
38. The method according to any one of claims 17 to 36, wherein the hypoglycaemia is associated excessive exercise or fasting.
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