RU2389493C2 - Composition and method for increasing blood glucose level - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to pharmaceutical industry and concerns a composition for glucose delivery through an oral mucosa for increasing of glucose (sugar) blood level of an individual. The composition contains: a. effective amount of glucose, b. effective amount of sodium glycocholate, c. effective amount of a pharmaceutically acceptable carrier; the composition it is free from additional active pharmaceutical agents.

EFFECT: development of the effective method for increasing glucose (sugar) blood level.

13 cl, 9 ex, 4 tbl, 7 dwg

Description

FIELD OF THE INVENTION

The present invention relates to compositions and methods for increasing blood glucose levels, as well as to devices containing the compositions, and their use.

BACKGROUND

Hypoglycemia, or low blood glucose (sugar), is a drug condition that affects humans and other mammals. Hypoglycemia exists when blood glucose levels are or become lower than normal (usually below 70 mg / dl and sometimes below 50 mg / dl). Hypoglycemia can occur when plasma insulin levels rise to levels that are higher than normal, which leads to lowering blood glucose levels to levels not sufficient to provide enough energy for normal functioning of the body. Hypoglycemia can be exacerbated due to physical activity or other activities when higher blood glucose levels are required. Hypoglycemia is a well-studied side effect of drugs used in the treatment of diabetes, but it can also be a side effect of other drugs or the result of other diseases, hormonal or enzyme deficiency or tumor. Hypoglycemia can also be caused by exacerbations in individuals who are otherwise healthy.

Mild to moderate hypoglycemia can lead to symptoms that include one or more of the following symptoms: hunger, irritability, trembling, sweating, dizziness caused by light, dizziness, anxiety, weakness, difficulty speaking or concentrating, nightmares, irritability , slurred speech, confusion, activity contrary to common sense, headache, pale skin color, slowness or convulsive twitching, tingling sensation around the mouth, fatigue and even epil ptichesky fit. If a mild or moderate form of hypoglycemia is not immediately treated, it can turn into a severe form of hypoglycemia. Severe hypoglycemia occurs when blood glucose levels drop and remain low for too long. Severe hypoglycemia can cause the brain to become deprived of enough energy to function properly, which can lead to loss of consciousness, an epileptic seizure, coma, or death. Other consequences include slurred speech, confusion, or irrational activity.

Hypoglycemia is also quite common in newborn babies. Symptoms may include tremors, cyanosis, apnea, hypothermia, low tone of the body (body), poor feeding, lethargy, and an epileptic seizure.

The most common causes of hypoglycemia include inadequate, with long intervals or skipping meals or snacks, excessive doses of insulin or another diabetes drug, such as sulfonylurea and meglitinides, increased activity or physical activity, and excessive alcohol consumption.

Individuals with recurring or recurring hypoglycemia can adapt to it without showing mild to moderate symptoms of hypoglycemia. This adaptation is especially dangerous since these individuals may be in a state of anxiety and may not detect any symptoms of hypoglycemia immediately prior to a coma. A common treatment for such individuals is to perform a frequent blood test to determine blood glucose levels and to increase blood glucose levels when they become too low. Hypoglycemia can usually be treated relatively quickly and simply by bringing the blood glucose levels of individuals to normal levels.

Hypoglycemia treatment courses are well developed. A common method is to ingest some form of sugar, such as fruit juice, glucose tablets, milk, sugar, honey or hard candies, followed by waiting for 15 minutes to observe how the symptoms subside or blood glucose levels rise to an acceptable level. If symptoms persist or blood glucose levels continue to be below acceptable levels, the individual repeats the ingestion of the sugar-containing substance and waits again, observing the effect on the blood sugar level.

This generally accepted method is effective only if time is not wasted and the affected individual is capable of joint action and can chew and swallow. Accordingly, there remains a need for therapeutic compositions and methods of administration that can be conveniently applied by third parties or independently administered with little or no training.

SUMMARY OF THE INVENTION

According to a first aspect, the invention provides a glucose composition for delivering glucose through the oral mucosa to increase the level of glucose in an individual’s blood, the composition comprising:

effective amount of glucose

effective amount of at least one absorption enhancer selected from lecithin, hyaluronic acid, glycolic acid, lactic acid, chamomile extract, cucumber extract, oleic acid, linoleic acid, linolenic acid, monoolein, monooleates, monolaurates, borage oil, evening primrose oil, menthol , trihydroxyoxycholanylglycine, glycerol, polyglycerol, lysine, polylysine, triolein, polyoxyethylene ethers, polydananolalkyl ethers, chenodeoxycholate, deoxycholate, alkaline salicylate o metal, a pharmaceutically acceptable edetate and their pharmaceutically acceptable salts and analogues, and

an effective amount of a pharmaceutically acceptable carrier, wherein the composition does not contain any additional active pharmaceutical agents.

The mucous membrane of the mouth may be the mucous membrane of the cheek.

The composition may contain glucose in a concentration of from 10 to 80% w / w, from 20 to 70% w / w. or from 30 to 60% wt./wt.

The absorption enhancer may be present in a concentration of from 0.01 to 5% w / w, from 0.01 to 3% w / w. or from 0.01 to 1% wt./wt. The total concentration of the absorption enhancer may be less than 10% w / w. or less than 5% w / w.

The composition may include sodium glycocholate, glycerin, sodium lauryl sulfate and / or polyoxyethylene sorbitan monooleate.

The carrier may be an aqueous solvent, such as purified water. Alternatively, the carrier may be a chewing gum base.

The composition may further include at least one additional ingredient selected from flavoring agents, coloring agents, preservatives and antimicrobial agents. In addition, the composition may include sodium benzoate as a preservative or antimicrobial agent.

According to a second aspect, the invention provides a non-aerosol metering device comprising a composition according to the first aspect. The dispensing device may be a dispenser with a measured dose, which can be adapted to deliver the composition in the form of droplets having a size of from 1 to 200 μm or from 1 to 20 μm, and can be adapted for dispensing from 0.05 to 0.5 ml, from 0.05 to 0.3 ml or 0.05 to 0.1 ml of the glucose composition per act of spraying.

According to a third aspect, the invention provides a method for increasing an individual’s blood glucose level, comprising administering an effective amount of a composition according to a first aspect to an individual’s oral mucosa (eg, gums). Administration may include spraying the composition into the mouth of an individual using a non-aerosol metering device (eg, a dose-measuring device).

The method may include administering from 30 to 50 mg of glucose in an atomization act from the metering device, and may include administering a total dose of 150 to 300 mg or 175 to 200 mg of glucose in a single dosing session. In addition, the method may include introducing from three to eight acts of spraying in a dosing session.

The amount of glucose composition sprayed in the spraying act can be from 0.05 to 0.5 ml, from 0.05 to 0.3 ml, or 0.05 to 0.1 ml.

According to a fourth aspect, the invention provides the use of a composition according to a first aspect in increasing an individual’s blood glucose level or in treating an individual’s hypoglycemia.

Finally, according to a fourth aspect, the invention provides the use of a composition according to the first aspect in the manufacture of a product for the treatment of hypoglycemia or low blood sugar.

The present invention provides a glucose composition in which glucose is at least partially encapsulated in micelles formed by one or more of the proposed absorption enhancing agents or enhancers. Glucose may be present in the form of small monolamellar vesicles, large monolamellar vesicles, polylamellar vesicles, or oligolamellar vesicles. An absorption enhancer enables glucose to be transported rapidly through the membranes of the mouth to increase blood glucose levels in an individual who needs treatment. Membranes or mucous membranes of the mouth consist of gingival, pharyngeal, lingual, sublingual or palatine mucous membranes. The sublingual mucous membrane includes the membrane of the ventral surface of the tongue and the base of the mouth; the gingival mucosa is the lining or mucous membrane of the cheek. The sublingual, buccal, or other oral mucosa is relatively permeable, allowing rapid absorption of the composition of the present invention. Therefore, the present method of increasing the level of glucose in the blood of an individual is effective, non-invasive and convenient.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the effect of the oral administration of the glucose composition according to the invention on the blood glucose level in non-resistant individuals with type II diabetes.

Figure 2 shows the effect of the oral administration of a glucose composition on blood glucose levels in resistant individuals with type II diabetes.

Figure 3 shows the effect of the oral administration of a glucose composition on blood glucose in non-resistant, healthy individuals.

Figure 4 shows the effect of the oral administration of a glucose composition on blood glucose levels in resistant, healthy individuals.

Figure 5 shows the effects of the oral administration of a glucose composition containing 4 g of glucose on blood glucose in resistant healthy individuals who were administered insulin in an amount of 0.11 IU / kg body weight. The results of placebo treatment and treatment showing the ingestion of a glucose tablet containing 4 g of glucose are presented for comparison purposes.

6 shows the effect of oral administration of a glucose composition containing 8 g of glucose on blood glucose levels in resistant healthy individuals. The results of placebo treatment and treatment showing the ingestion of two glucose tablets containing 8 g of glucose are presented for comparison purposes.

7 shows the effect of oral administration of a glucose composition containing 4 g of glucose on blood glucose levels in resistant healthy individuals. The results of placebo treatment and treatment showing oral administration of 4 g of glucose are presented for comparison purposes.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “including” includes “including without limitation.” Thus, a preparation or group comprising a number of ingredients may also include additional ingredients without special listing. As used herein, the term "consisting essentially of" includes the listed ingredients and those additional ingredients that do not actually affect the basic and new features of the invention. The main and new features of the invention are the characteristics of the absorption of glucose present in the present composition through the mucous membranes of the mouth (for example, through the buccal, pharyngeal, lingual, sublingual and palatine mucous membranes) and penetration into the bloodstream of an individual. As used herein, the term “consisting of” means “including only the listed ingredients and any impurities normally present in them”. Thus, a preparation or group consists of a number of ingredients that cannot include additional ingredients not specifically listed separately from impurities typically present in the listed ingredients.

As used herein, the term “effective amount” means that the amount is necessary to achieve the desired result, i.e. to obtain a given increase in the level of glucose in the blood of the individual at the desired rate of absorption of glucose through the membrane of the mouth. Such an amount should be understood as having a therapeutic effect in the body of the individual.

It will be understood that the effective amount will vary depending on the glucose composition, the nature and severity of the hypoglycemia being treated, and the individual being treated. The determination of which constituents are in the “effective amount” of the glucose composition for a particular individual is within the skill of a medical practitioner in the field and is based on general guidelines suggested here.

All concentration expressions (i.e.,% w / w) used in the present description, including concentrations in the claims, are present in terms of the total weight of the composition, unless otherwise indicated.

The term “individual” and “individuals” as used herein means members of the animal kingdom, including, but not limited to, people.

As used herein, the term “active pharmaceutical agent” means an ingredient that is useful in the treatment or prevention of a disease, disease or abnormal condition in a human or animal body, and includes glucose for the treatment of hypoglycemia.

Pharyngeal, sublingual, lingual, palatine or buccal mucosa collectively means here the “oral mucosa”. “Mucous membrane of the mouth” means any of the pharyngeal, sublingual, lingual, palatine and buccal mucous membranes.

Glucose composition

In one embodiment, the glucose composition is in liquid form. The concentration of glucose in the composition may be in the range from 100 to 800 g of glucose per liter, preferably from 300 to 800 g of glucose per liter, and more preferably about 500 g of glucose per liter. Alternatively, glucose may be present in a concentration of from 10 to 80% w / w. or from 30 to 60% wt./wt.

The present composition comprises at least one absorption enhancer for enhancing glucose transport through the membranes of the mouth. The amplifier is used to encapsulate glucose in micelles. Mixed micelles are formed when more than one absorption enhancer is used. Each absorption enhancer is present in a concentration of from 0.01 to 5, preferably from 0.01 to 2, and more preferably from 0.01 to 1% w / w. The total number of absorption enhancers is less than 10, preferably less than 5, and more preferably less than 2% w / w.

In the compositions of the present invention, any alkali metal alkyl sulfate can be used provided that compatibility problems do not arise. Preferably, the alkyl is C8-C22 alkyl, more preferably lauryl (C12). Any alkali metal can be used, with sodium being preferred. The concentration of alkali metal alkyl sulfate, if present, is preferably from 0.01 to 3, from 0.01 to 2 and from 0.01 to 1% w / w.

It will be understood that some absorption enhancers are typically the described fatty acids, bile acids, or salts thereof. A particularly preferred absorption enhancer is trihydroxycholanyl glycine and its pharmaceutically acceptable salts (e.g. sodium glycocholate). When used, sodium glycocholate is preferably present in a concentration of from 0.01 to 5, from 0.01 to 3, and from 0.01 to 1% w / w.

Glycerin is another preferred absorption enhancer. If present, then its concentration is from 0.01 to 15, from 0.01 to 10, from 0.01 to 5 and from 0.01 to 2% wt./wt.

Lecithin may be saturated or unsaturated and is preferably selected from the group consisting of phosphatidylcholine, phosphatidylserine, sphingomyelin, phosphatidylethanolamine, cephalin and lysolecithin.

Preferred salts of hyaluronic acid are alkali metal hyaluronates, in particular sodium hyaluronate, and alkaline earth metal hyaluronates and aluminum hyaluronate.

Specifically, suitable absorption enhancers include i) glycerol, sodium glycocholate and sodium lauryl sulfate, ii) glycerol, sodium glycocholate and polyoxyethylene sorbitan monooleate (sold in association with the trademark Tween 80).

The present compositions optionally contain a stabilizer, preservative and / or antioxidant. Phenolic compounds are particularly suitable for this purpose, since they not only stabilize the composition, but also protect against bacterial growth and promote absorption of the composition. A phenolic compound, as will be understood, means a compound having one or more hydroxy groups attached directly to the benzene ring. Preferred phenolic compounds of the present invention include phenol and methylphenol (also known as m-cresol), and mixtures thereof. Known sugar preservatives such as sodium benzoate can also be used successfully. Antioxidants include ascorbalpalmitate, BHA, and BHT.

It will be understood by those skilled in the art that coloring agents, flavoring agents, flavor masking agents, and amounts of other non-therapeutic compounds may also be included in the preparation. Conventional flavoring and taste masking agents include peppermint oil, menthol, synthetic flavoring agents that smell like strawberries, oranges, cherries, pomegranates, raspberries, grapes, mangoes, bananas, watermelons, chocolate, vanilla and other flavoring agents. When menthol is used as one of the absorption enhancing agents, it will obviously also add flavor to the composition. A common coloring agent that can be used is a food color (e.g., red food color).

An isotonic agent such as glycerol or dibasic sodium phosphate can also be added to the composition. The isotonic agent serves to retain micelles in the composition. When glycerin is used as one of the absorption enhancing agents, it will also function as an isotonic agent. When dibasic sodium phosphate is used as an isotonic agent, it will also serve to inhibit bacterial growth; The pH of the present glucose composition should usually be in the range of 3.5 to 7. To establish the pH of the composition, if desired, hydrochloric acid, sodium hydroxide, or another known base or acid can be used.

The compositions of the present invention can be stored at temperatures ranging from 15 ° C to 40 ° C and preferably from 15 ° C to 30 ° C.

The present glucose composition is preferably in liquid form for administration by spray. However, it can also be made in other dosage forms by altering, among other things, the pharmaceutically acceptable carrier used. For example, the present composition can be made in chewing gum, chewing gum with a liquid center, chewable tablets and lozenges. The person skilled in the art of the pharmaceutical preparation must be capable of preparing the composition of such other dosage forms. It will be understood that glucose contained in chewing gum, chewing gum with a liquid center, chewable tablets or lozenges is administered through the membranes of the mouth (preferably), and not through the membranes of the gastrointestinal tract. In order for this to happen, the composition is held in the mouth for several minutes, which can be easily determined by a simple experiment.

A method of manufacturing a glucose composition

The present invention provides a method for manufacturing the glucose composition of the present invention. The present compositions can be prepared by mixing an aqueous glucose solution with at least one absorption enhancer and other additives or ingredients. Glucose should be added in an amount effective for the desired purpose. Absorption enhancers can be added simultaneously or sequentially. Micelles will form essentially with any kind of mixing of the ingredients, but preferably with vigorous stirring at high speed, a high shear homogenizing mixer. All glucose absorption enhancers and other ingredients described above are suitable for use in the present methods.

According to one method, a composition is prepared by preparing a glucose solution, preparing an “excipient” solution, and mixing the two solutions together. An excipient solution is prepared by adding one or more absorption enhancers and any other ingredients (e.g., a preservative, flavoring agent, coloring agent, etc.) to an aqueous solvent (e.g. purified water).

Devices for introduction

According to the invention, variants of liquid glucose compositions can be administered using a number of non-aerosol mechanical spray pump devices known in the art. Such devices may administer the composition in the form of a sprayable spray or mist. The benefit of many such devices is that the potential for contamination is minimized because the devices are self-contained.

The non-aerosol dispenser may comprise a metering pump with a preset dose for delivering a predetermined amount of the glucose composition, or it may be set by the user to deliver various amounts of the glucose composition. One benefit of using a device having a metering pump (e.g., a metering dose meter) is the ability to deliver the exact amount of composition in each spraying event. Preferably, a metered dose non-aerosol dispenser is pre-set to deliver an amount that is less than the recommended dose (i.e., part of the dose) so that an individual can have more control over the amount of glucose composition that is administered in one session. For example, the dispenser may be set such that approximately 50 mg of glucose is released from the dispenser in each administration or spraying event. In this way, individuals can adjust the amount administered at 50 mg intervals. For example, an individual may carry out 3 acts of spraying in the case of a low dose or 5 acts of spraying in the case of a higher dose.

Devices can vary in size both in the volume of the container and in the size of the pump and, therefore, vary in the amount of composition introduced in the spraying act or session. The dimensions of the container can be different, the volumes are from 5 to 100 ml or from 10 to 50 ml or from 20 to 30 ml. The metering pump may be configured to deliver from 0.05 to 0.5 ml or from 0.05 to 0.3 or from 0.05 to 0.1 ml in a spraying act.

Route of administration

The glucose composition (in liquid form), according to the invention, can be administered quickly and easily by the individual or the third participant after a little training or without it (if the individual is unconscious or is not capable of coordinated action before urgent assistance). Self-introduction can be done "before exposure", i.e. the individual can continue the introduction until he feels the disappearance of symptoms. Alternatively, the administration of a certain amount of the glucose composition (for example, using a metering device with a measured dose) may be followed by a waiting period to determine if the symptoms disappear. The introduction is carried out by spraying the glucose composition in the mouth with a non-aerosol metering device. Preferably, the composition is sprayed into the oral cavity without inhalation so that droplets remain in the mouth but are not injected into the lungs and glucose is absorbed through the membranes of the mouth or mucous membrane.

According to another method, if the individual is conscious and the composition is in the form of a chewing gum (with or without a liquid center) or a tablet, a chewing gum or tablet is chewed and held in the mouth until the desired increase in blood glucose level occurs as tested to reduce or eliminate the symptoms of lowering blood sugar.

One embodiment of the composition of the present invention was prepared as follows:

Example 1: Preparation of a glucose composition according to the present invention

Solution A:

350 ml of purified USP water was heated to approximately 90 ° C. 500 g of glucose was added. The water / glucose solution was mixed until all glucose was dissolved. Then, the water / glucose solution was allowed to cool to approximately room temperature, with stirring.

Solution B:

Then, with stirring, to 100 ml of purified USP water were added: 11 g of glycerol, 2 g of sodium glycocholate, 500 mg of sodium lauryl sulfate, 500 mg of sodium benzoate, 2 g of orange flavor, 2 g of artificial cooling flavor (such as the Swedish one sold) Givaudan company). Each ingredient was added in turn and allowed to dissolve before adding the next ingredient.

Then solutions A and B were combined and purified USP water was added to a total volume of 1 L. Then, the resulting glucose composition was mixed for 5 minutes and stored at a temperature of 15 ° C to 30 ° C.

The above data on the composition of glucose are shown in the following table:

Glucose composition

Ingredient Amount (g / ml) Amount (% w / w) Glucose 0.5000 42.37 Glycerol 0.0110 0.93 Sodium glycocholate 0.0020 0.17 Sodium Lauryl Sulfate 0,0005 0.04 Sodium benzoate 0,0005 0.04 Orange flavor 0.0020 0.17 Coolant flavor 0.0020 0.17 Purified Water USP How much is required up to 1 ml How much is required up to 100

Example 2: Use of a glucose composition in a metered dose non-aerosol metering device

5 ml of the glucose composition shown in the table above in Example 1 was loaded into a non-aerosol metering device with a pump equipped with a tube immersed in liquid.

The glucose composition was sprayed from the metering device a large number of times, and the mass (and total volume) of the glucose composition sprayed per spray act was measured. It was found that the average weight is 0.084 g of the glucose composition, with a minimum weight of 0.077 g and a maximum weight of 0.088 g.

The density of the glucose composition was calculated to be 1.1532 g / ml. Thus, it was found that the average volume of the composition, metered in the spraying act, is 0.073 ml, with a minimum volume of 0.067 ml and a maximum volume of 0.076 ml.

Based on the amount of glucose in the glucose composition (500 g / l), it was calculated that the average calculated amount of glucose in the spraying act is 0.036 g, with a minimum amount of glucose of 0.033 g and a maximum amount of glucose of 0.038 g. The metering device will be actuated five times, therefore, result in the administration of 0.180 g of glucose, on average, with a minimum amount of approximately 0.165 g and a maximum amount of approximately 0.190 g.

The present method and composition causes an increase in blood glucose levels, as shown by the examples below.

Example 3: Effect of administering a glucose composition on a non-hungry individual with type II diabetes

The glucose composition of Example 1 was administered using a metered dose metering device of Example 2 to non-hungry individuals with type II diabetes and blood glucose levels were monitored.

The individual self-administered the composition into the buccal region by actuating the metering device five times, without inhalation or swallowing. Blood glucose was measured before, during and after administration using standard methods. The glucose composition was administered shortly before the time point “0”. The results are shown in table 1 and plotted in figure 1. The measurements show an increase in blood glucose levels after 5 minutes, and the peak plasma glucose concentration is reached after 17 minutes.

Table 1 The effect of administering a glucose composition on a non-hungry individual with type II diabetes Minutes after administration blood glucose level (mg / dl) -3 109 0 * 111 2 110 5 116 8 118 12 120 17 135 22 132 27 128 32 118 37 110 52 95 * measured as soon as possible after administration of the composition

Example 4: Effect of administration of a glucose composition on a hungry individual with type II diabetes

The glucose composition of Example 1 was administered using a metered dose metering device of Example 2 to a hungry individual with type II diabetes, and blood glucose was monitored. After fasting for 12 hours, the individual self-administered the composition into the buccal cavity by activating the metering device five times, without inhalation and swallowing. Blood glucose was measured before, during and after administration using standard methods. The glucose composition was administered shortly before the time point “0”. The results are shown in table 2 and plotted in the graph in figure 2. Measurements showed an almost instantaneous increase in blood glucose, with a peak plasma glucose concentration reaching 40 minutes later.

table 2 The effect of administering a glucose composition on a hungry individual with type II diabetes Minutes after administration Blood glucose level (mg / dl) -5 160 0 * 174 10 173 fifteen 183 twenty 175 25 178 Minutes after administration Blood glucose level (mg / dl) thirty 185 35 170 40 212 fifty 166 * measured as soon as possible after administration of the composition

Example 5: Effect of Glucose Composition Administration on a Healthy, Hungry Individual

The glucose composition of Example 1 was administered using a metered dose metering device of Example 2 to a healthy, non-hungry individual, and blood glucose was monitored. The individual self-administered the composition into the buccal cavity by activating the metering device five times, without inhalation or swallowing. Blood glucose was measured before, during and after administration using standard methods. The glucose composition was administered shortly before the time point “0”. The results are shown in table 3 and plotted in the graph in figure 3. Measurements showed an increase in blood glucose levels after 4 minutes, with the first peak blood glucose concentration reaching about 27 minutes and the second slightly higher peak plasma glucose concentration reaching about 65 minutes.

Table 3 The effect of administering a glucose composition on a non-hungry healthy individual Minutes after administration Blood glucose level (mg / dl) -2 104.4 one 106,2 four 113.4 6 111.6 12 113.4 21 118.8 27 112.4 34 115,2 55 117 65 124.2 75 113.4

Example 6: Effect of Administration of a Glucose Composition on a Healthy, Hungry Individual

The glucose composition of Example 1 was administered using a metered dose metering device of Example 2 to a hungry, healthy individual, and blood glucose was monitored. After fasting for 12 hours, the individual self-administered the composition into the buccal cavity by activating the metering device five times, without inhalation or swallowing. Blood glucose was measured before, during and after administration using standard methods. The glucose composition was administered shortly before the time point “0”. The results are shown in table 4 and plotted in the graph in figure 4. Measurements showed an increase in blood glucose level after 5 minutes, with the first peak plasma glucose concentration reaching 33 minutes later and the second slightly higher peak plasma glucose concentration reaching 53 minutes later.

Table 4 The effect of administering a glucose composition on a healthy, hungry individual Minutes after administration Blood glucose level (mg / dl) 0 * 99 5 104.4 10 102.6 fifteen 100.8 twenty 97.2 25 100.8 33 108 38 102.6 43 102.6 53 106,2 * measured immediately after administration of the composition

In the following Examples 7–9, all subjects starved in the evening from 8 hours in the afternoon until they were tested the next morning at 7 hours in the afternoon.

Example 7: Glucodynamics after hypoglycemia caused by insulin (subcutaneous injection (sc) of 0.11 IU / kg weight of ordinary insulin), and the introduction of 4 grams of the composition of glucose and tablets weighing 4 grams at a time point of 70 minutes

11 subjects were injected with 0.11 IU / kg of insulin body weight by subcutaneous injection at time = 0 minutes. At a time point of 70 minutes, subjects were given a commercially available glucose tablet (Dex 4 orange-flavored glucose tablets manufactured by AMG Medical Inc., Montreal, Quebec) containing 4 g of glucose. Subjects chewed and swallowed the tablet. Blood glucose levels (mg / dl) of the subjects were measured at intervals from time = -15 minutes.

On the second day, the same 11 subjects were administered 0.11 IU / kg of insulin body weight at time = 0 minutes. At a time point of 70 minutes, the subjects were given the glucose composition described above in accordance with the present invention. The glucose composition was sprayed into the oral cavity using a standard non-aerosol metering device equipped with a tube immersed in liquid, glucose was absorbed through the oral membranes, and the residual liquid was swallowed. The amount of glucose composition administered and swallowed was equivalent to 4 g of glucose. Glucose levels (mg / dl) in subjects were measured at intervals of time = -15 minutes.

To provide a comparison with placebo on the third day, 12 subjects, seven of whom took part in the above tests, did not receive the insulin, glucose tablets or glucose composition of the present invention. Their blood glucose levels were simply measured at regular intervals, starting at time = -10 minutes.

The values of blood glucose levels are given below in the text and plotted in the graph in figure 5.

Glucodynamics after insulin-induced hypoglycemia (subcutaneous injection (sc) of 0.11 IU / kg of standard insulin) and administration of 4 g of the composition of glucose and glucose tablets, 4 g, at time +70 minutes

SD = standard deviation

Figure 5 shows the results of comparing the glucose composition of the present invention with glucose tablets or the superiority in speed of a glucose tablet under these test conditions.

Example 8: Comparison of glucose tablets, 8 g, with a glucose composition, 8 g, and placebo

12 subjects were given the glucose composition described above according to the present invention. The glucose composition was sprayed into the oral cavity using a standard non-aerosol metering device equipped with a tube lowered into the liquid, glucose was absorbed through the oral membranes, and the residual liquid was swallowed. The amount of glucose composition administered and swallowed is equivalent to 8 g of glucose. Blood glucose levels (mg / dl) were measured at intervals of time = -10 minutes.

On day two, 12 subjects were given two industrially manufactured glucose tablets (orange flavored glucose tablets, Dex 4 manufactured by AMG Medical Inc., Montreal, Quebec), each containing 4 g of glucose. Subjects chewed and swallowed. Blood glucose levels (mg / dl) of the subjects were measured at intervals from time = -10 minutes.

The values of blood glucose levels are given below and plotted on the graph in Fig.6.

Comparison between glucose tablets, glucose composition, 8 g, and placebo administered to healthy volunteers

SD = standard deviation

6 shows that the glucose composition of the present invention is comparable to or better than glucose tablets as glucose tablets in function of the induced glucodynamic response.

Example 9: Comparison between glucose tablets, 4 g, glucose composition, 4 g and placebo

12 subjects were given the glucose composition described above in accordance with the present invention. The glucose composition was sprayed into the oral cavity using a standard non-aerosol metering device equipped with a tube immersed in liquid, glucose was absorbed through the oral membranes, and the residual liquid was swallowed. The amount of glucose composition administered and swallowed was equivalent to 4 g of glucose. Blood glucose levels (mg / dl) of the subject were measured at intervals from time point = -10 minutes.

On the second day, 12 subjects were given a commercially available glucose tablet (orange flavored glucose tablets, Dex 4, manufactured by AMG Medical Inc., Montreal, Quebec) containing 4 g of glucose. Subjects chewed and swallowed the tablet. Blood glucose levels (mg / dl) of the subjects were measured at intervals from time = -10 minutes.

To provide a comparison with placebo, on the third day, 12 subjects were not given glucose tablets or the glucose composition of the present invention. Their blood glucose levels were simply measured at regular intervals, starting at time = -10 minutes.

The average values of blood glucose levels are shown below and plotted in the graph in Fig.7.

Comparison between glucose tablets, 4 g glucose composition, and placebo administered to healthy volunteers

SD = standard deviation

7 shows that the glucose composition of the present invention is comparable to or better than glucose tablets as glucose tablets in function of the induced glucodynamic response.

The foregoing description is provided by way of example only and should not be construed as limiting the scope of the invention, as described further in the claims.

Claims (13)

1. Composition for the delivery of glucose through the mucous membrane of the mouth to increase the level of glucose in the blood of an individual, including:
a. effective amount of glucose
b. effective amount of sodium glycocholate,
c. an effective amount of a pharmaceutically acceptable carrier, wherein the composition is free of additional active pharmaceutical agents. 2. The composition according to claim 1, where the mucous membrane of the mouth is the mucous membrane of the cheek. 3. The composition according to claim 1 where glucose is present in a concentration of from 10 to 80 wt./wt.%. 4. The composition according to claim 1, where glucose is present in a concentration of from 20 to 70 wt./wt.%. 5. The composition according to claim 4, where glucose is present in a concentration of from 30 to 60 wt./wt.%. 6. The composition according to claim 1, where sodium glycocholate is present in a concentration of from 0.01 to 5 wt./wt.%. 7. The composition according to claim 6, where sodium glycocholate is present in a concentration of from 0.01 to 3 wt./wt.%. 8. The composition according to claim 7, where sodium glycocholate is present in a concentration of from 0.01 to 1 wt./wt.%. 9. The composition of claim 1, wherein the total concentration of sodium glycocholate is less than 10% w / w. 10. The composition according to claim 1, where the carrier is an aqueous solvent. 11. The composition according to claim 1, further comprising at least one additional ingredient selected from flavoring agents, coloring agents, preservatives and antimicrobial agents. 12. The composition according to claim 1, further comprising sodium benzoate as a preservative and antimicrobial agent. 13. The composition according to claim 1, where the carrier is the basis of chewing gum.

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