WO2024252015A1 - Use of carbohydrate-containing compositions in tablet form for treatment of hypoglycemic states - Google Patents

Abstract

The invention relates to the use of specific carbohydrate-containing compositions, in particular in tablet form, for production of agents for treatment of hypoglycemia, in particular nocturnal hypoglycemia. The compositions are easy to dose and do not leave a sweet taste in the mouth, but do release the carbohydrates present rapidly in the stomach and are therefore particularly suitable for treatment of in particular nocturnal hypoglycemia.

Description

Use of carbohydrate-containing compositions in tablet form for the treatment of hypoglycaemia

The invention relates to the use of special carbohydrate-containing compositions, in particular in tablet form, for the preparation of agents for the treatment of forms of hypoglycemia, in particular nocturnal hypoglycemia.

Diabetes mellitus is a metabolic disorder that affects the utilization of carbohydrates. It is caused in particular by a lack of insulin and can lead to chronic hyperglycemia with numerous subsequent damages.

In the digestive system, the carbohydrates ingested with food are broken down into glucose, which is transferred through the intestinal wall into the blood and distributed throughout the body. The body's own hormone insulin causes the glucose contained in the blood to enter the cells, where it is used to generate energy. The insulin required for this is mainly produced in the pancreas. If the body does not produce any insulin or does not produce enough insulin, glucose cannot be transferred into the body's cells and therefore remains in the blood. To avoid the consequences of high blood sugar levels, diabetes mellitus is usually treated with insulin. This creates the problem of correctly dosing the amount of insulin, i.e. adjusting it to the amount of carbohydrate. If too little insulin is given, too much glucose remains in the blood. If the insulin dosage is too high, hypoglycemia can occur. This type of hypoglycemia is a serious disorder that can be fatal in the worst case.

People who suffer from diabetes therefore often carry carbohydrate-containing foods with them so that they can quickly obtain carbohydrates in the event of hypoglycemia. Commonly used remedies are glucose tablets, fruit juices or bread. Hypoglycemia can also occur at night. In the case of hypoglycemia, people who suffer from diabetes wake up at night, for example, with outbreaks of sweat or are woken up by warning devices. This can happen, for example, if the person in question has eaten a meal in the evening or at night whose exact carbohydrate content is not known. The person is then dependent on estimating the carbohydrate content in order to then administer the appropriate amount of insulin. If the amount of carbohydrate is overestimated, the hypoglycemia mentioned above can then occur after insulin is administered.

Affected people often find it unpleasant to eat glucose, (sweet) fruit juices or bread, especially at night, to compensate for the hypoglycemia. In order to compensate for the sweet taste in the mouth, they would have to get up at night and brush their teeth again, for example. The task therefore arises of providing a composition that is able to specifically raise the blood sugar level in the event of hypoglycemia, is easy to dose, but at the same time does not leave an unpleasant sweet taste in the mouth, so that the affected people can continue sleeping. This task is solved by using the compositions described below.

The following publications are known from the state of the art:

The document US2014/0180224 A1 describes compositions for the treatment of nocturnal hypoglycemia. However, these are compositions that are described as "delayed and sustained release compositions". The compositions are intended to be taken before going to bed and ensure a consistent supply of carbohydrates during the night. Treatment of acute nocturnal hypoglycemia is not possible due to the delayed release.

The document CN 115226896 describes other sustained release compositions of various carbohydrates, which are also not suitable for the treatment of acute nocturnal hypoglycaemia.

The document DE 2246013 A describes a process for the production of porous carbohydrate-containing tablets which solves various production problems of Tablet formulations are intended to solve this problem. Nocturnal hypoglycemia treatment is not mentioned here.

The document WO20157148742 A1 describes compositions for producing cell cultures. These compositions are said to contain carbohydrates and are described as "sustained release" compositions. Use for the treatment of nocturnal hypoglycemia is not mentioned here.

The document CN 105963266 A describes glucose tablets that are also intended to be suitable for the treatment of hypoglycemia. Due to their composition, the tablets dissolve in the mouth and produce a sweet taste.

The present invention relates to the use of carbohydrate-containing compositions, in particular in tablet form, which only release the carbohydrates contained in the gastrointestinal tract, for the treatment of hypoglycemia, in particular nocturnal hypoglycemia.

These compositions initially contain one or more saccharides as carbohydrates, such as dextrose, lactose, maltose, trehalose, sucrose or mixtures thereof. A well-known carbohydrate mixture is, for example, maltodextrin. The carbohydrates sometimes occur in various hydrate forms, i.e. they contain different amounts of water of crystallization. Dextrose, for example, is available as a monohydrate, but also as anhydrous anhydrate. Typically, all available stable hydrate forms can be used to produce the preparations according to the invention.

The advantage of dextrose is that it works quickly, whereas other carbohydrates have a delayed onset of action but can have a longer lasting effect. Mixtures of different carbohydrates can produce a rapid initial effect, which lasts longer when more complex carbohydrates are added.

For the purpose mentioned above, the composition consists predominantly, i.e. more than 70%, of the saccharide or the saccharide mixture. In addition, only conventional agents are used to improve the processability or dissolution properties, such as stearates or cellulose. The saccharide content is up to 95%, typically around 80%. The inventive The most preferred saccharide is dextrose, especially as dextrose monohydrate.

The composition is first pressed into pellet-shaped tablet cores. The individual tablet cores have diameters between 4 and 10 mm, preferably between 6 and 8 mm, and can have the usual shapes for such compositions, such as spherical, biconvex, faceted or curved. It goes without saying that they should not have any sharp edges for the purpose of ingestion, but otherwise the shape is practically arbitrary.

According to the invention, the prefabricated tablet cores are coated with a coating that is tasteless and ensures that the tablets do not dissolve in the mouth, but that the saccharides they contain are only released in the stomach. The coating also makes the tablets easier to swallow. Such coatings are known in principle. They are usually composed on the basis of starch and modified cellulose. The decisive factor for the coating is that it does not dissolve in the mouth, but rather quickly releases the tablet core in the stomach. The following substance classes are preferably used for the coating according to the invention:

• Cellulose and cellulose derivatives, in particular carboxymethylcellulose, hydroxypropylmethylcellulose phthalate, methylcellulose, hydroxypropylmethylcellulose (hypromellose) and/or hydroxypropylcellulose

• Methacrylic acid copolymers and methacrylic acid esters

• Polyvinylpyrrolidone (PVP) and derivatives

• Polyvidone acetate

• Polyvinyl acetate phthalate

The most preferred coating agent is hydroxypropylmethylcellulose (hypromellose). The coatings can also contain colorants. Preferably, food colorants are used, such as carotenoids (E 160a), berry colorants (anthocyanins, E 163), beetroot colorants (betanin, E 162), carmine (E 120), paprika extract (E 160c) and curcumin (E 100). Particularly preferred are strongly coloring plant or fruit extracts, such as beetroot, spinach or elderberry juice and spices such as saffron and turmeric.

For practical reasons, the tablet cores are preferably coated in a single process, resulting in modified film-coated tablets (coated tablets). Alternatively, the classic coating with several layers is of course also possible.

The tablets created from the tablet cores by coating typically have a diameter of between 4 and 10 mm and a mass of between 50 and 500 mg. Preferably, the individual tablets have a diameter of 7 to 8 mm and a mass of 210 to 270 mg.

A person suffering from hypoglycemia can dose the composition according to the invention in tablet form using simple dosing devices, for example with a dosing spoon. The spoon can be designed in such a way that a total amount of tablets is taken up that corresponds to a certain amount of carbohydrates, for example a carbohydrate unit, the typical calculation unit for diabetics. Depending on requirements, one or more carbohydrate units can then be taken from a storage container and taken orally. A sip of water can be helpful in swallowing the tablets completely. As already described above, the tablets do not release any carbohydrates in the mouth within about 15 seconds, so that their sweet taste in the mouth is avoided. The tablets only dissolve in the stomach and there quickly release the saccharides they contain, which then combat hypoglycemia by raising the blood sugar level. Within one minute after swallowing, more than 80% of the carbohydrate content of the tablets is released in the empty stomach. This avoids the otherwise usual sweet taste of carbohydrate-containing compositions. At the same time, there is no need to brush your teeth afterwards to prevent caries. In the event of hypoglycemia during the night, the affected person can then go back to sleep immediately.

The properties of the tablets described also allow their use in hypoglycaemia conditions that are not caused by diabetes, eg in endurance sports. For example, marathon runners may experience so-called “hunger bouts”, which is a form of hypoglycemia that is not caused by diabetes. Another form of hypoglycemia that is not caused by diabetes can occur when people have not eaten anything for a long time or have eaten very few carbohydrates (“fastin hypoglycemia”). Taking the tablets described in a controlled dose can also overcome such hypoglycemia.

A particular advantage of the tablets described is that, when taken as described, a state of hypoglycemia can be treated without the risk of triggering sugar addiction. Experts believe that sugar addiction is promoted by the connection between the sweet taste and the immediate rise in blood sugar, as occurs when eating common sweets (e.g. chocolate bars, gummy bears). Due to the lack of the sweet taste in the mouth, the reward system in the brain is apparently not activated, so that no addictive effects occur.

examples

The following examples further explain the invention without intending to have a restrictive effect. The person skilled in the art can develop further embodiments of the invention based on the examples without having to perform an inventive step.

Example 1

Tablet core:

To produce the tablet cores, the components listed above are mixed and pressed into tablet cores. The coating is then applied using the composition listed below.

Coating: Biogrund AquaPolish F pink 040.344 or AquaPolish F pink 044.419

After drying, the tablets can be packaged.

Product description:

Tablet size: 7 or 8 mm tablet cores (curved)

Tablet core mass: 238 mg

Tablet mass (with 247 mg

coating) Example 2

Tablet core:

To produce the tablet cores, the components listed above are mixed and

Tablet cores are pressed. The coating is then applied with the composition specified below.

Coating: Biogrund AquaPolish F pink 040.344 or AquaPolish F pink 044.419

After drying, the tablets can be packaged.

Product description:

Tablet size: 7 or 8 mm tablet cores (curved)

Tablet core mass: 238 mg

Tablet mass (with 247 mg

coating)

Example 3a

Tablet core:

To produce the tablet cores, the components listed above are mixed and

Tablet cores are pressed. The coating is then applied with the composition specified below.

Coating: Biogrund AquaPolish F pink 040.344 or AquaPolish F pink 044.419

After drying, the tablets can be packaged.

Product description:

Tablet size: 7 or 8 mm tablet cores (curved)

Tablet core mass: 238 mg

Tablet mass (with 247 mg

coating)

Example 3b

Dragee core:

To produce the dragee cores, the components listed above are mixed and pressed into dragee cores. The coating is then applied using the composition listed below.

Coating: Biogrund Aquapolish F green 074.133 MS

Pantone 7425

After drying, the dragees can be packaged.

Product description:

Dragee size: 7 or 8 mm dragee cores (curved)

Tablet core mass: 238 mg

Dragee mass (with coating) 247 mg

Example 3c

Dragee core:

To produce the dragee cores, the components listed above are mixed and pressed into dragee cores. The coating is then applied using the composition listed below.

Coating: Biogrund Aquapolish F green 074.133 MS or AquaPolish F pink 044.419

After drying, the dragees can be packaged.

Product description:

Dragee size: 7 or 8 mm dragee cores (curved)

Tablet core mass: 238 mg

Dragee mass (with coating) 247 mg

Example 4

Tablet core:

To produce the tablet cores, the components listed above are mixed and pressed into tablet cores. The coating is then applied using the composition listed below.

Coating: Biogrund AquaPolish F pink 040.344

After drying, the tablets can be packaged.

Product description:

Tablet size: 7 or 8 mm tablet cores (curved)

Tablet core mass: 238 mg

Tablet mass (with 247 mg

coating)

Example 5

Tablet core:

To produce the tablet cores, the components listed above are mixed and pressed into tablet cores. The coating is then applied using the composition listed below.

Coating: Biogrund AquaPolish F pink 040.344

After drying, the tablets can be packaged.

Product description:

Tablet size: 7 or 8 mm tablet cores (curved)

Tablet core mass: 238 mg

Tablet mass (with 247 mg

coating)

Example 6a

Tablet core:

To produce the tablet cores, the components listed above are mixed and

tablet cores with a diameter of 6 mm. Example 6b

The tablet cores produced according to Example 6a will be coated with a coating, which coating has the composition given below.

Nach dem Trocknen können die Tabletten verpackt werden. Coating: Biogrund Aquapolish F green 074.133

After drying, the tablets can be packaged.

Product description:

Tablet size: Approx. 7 mm tablet cores (curved)

Tablet core mass: 117 mg

Tablet mass (with 124 mg

coating)

Example 7: Sweet Presence Binary Test to evaluate the sweetness of tablets

The question of whether a carbohydrate-containing composition produces a sweet taste in the mouth when used according to the invention can be tested by the Sweet Presence Binary Test described below.

Objective: To determine whether a tablet tastes sweet immediately after being held in the mouth for 15 seconds.

Applicability: This protocol is applicable to all types of tablets intended for oral administration and intended to be swallowed directly rather than sucked.

Materials:

- Test tablets (product to be tested)

- Water to rinse the mouth between tests

subjects:

- At least 20 test subjects (not sensory trained), preferably about 100 people

- Age between 18 and 65 years

- No known taste impairment

Method: a. Preparation:

- The test subjects are informed about the purpose of the test and give their consent to participate.

- Each test subject is instructed not to eat spicy or sweet foods before the test. b. Procedure:

- Each test subject receives a certain number of test tablets, corresponding to the usual dosage for the product being tested. - The test subjects keep the tablets in their mouth for 15 seconds before swallowing them.

- Immediately after swallowing, the test subjects indicate whether or not they perceived sweetness during the time in the mouth. c. Documentation:

- The answers are recorded in a standardized form which includes:

- test person ID

- Answer to the question whether test tablets lead to a sweet taste during the time in the mouth, (Yes/No) d. Evaluation:

- The data will be statistically evaluated to determine whether a significant number of testers perceived sweetness in the test tablets during the time in the mouth. e. Reporting:

- The results are summarized in a final report containing the following information:

- Number of test subjects who perceived sweetness in the test tablets during the time in the mouth

- Statistical analysis of the results

- Conclusions regarding the sweetness of the tested tablets f. Safety and ethical considerations:

- All test subjects are informed about possible risks and give their written consent.

- The test will be conducted under supervision to ensure compliance with protocols and provide support if needed. g. Results

When carrying out the Sweet Presence Binary Test for the compositions of Examples 1-6, more than 90% of the test subjects, and in the case of Examples 2 (n=100) and 3 (n=50) even more than 95% of the test subjects, stated that they did not perceive any sweet taste.

Claims

Claims: 1. Composition in tablet form, consisting of Tablet cores containing 70-95% dextrose, lactose, maltose, trehalose, sucrose, maltodextrin or mixtures thereof together with conventional agents to improve the processability or dissolution properties, as well as a Tablet coating selected from the following substance classes a) cellulose and cellulose derivatives, in particular carboxymethylcellulose, hydroxypropylmethylcellulose phthalate, methylcellulose, hydroxypropylmethylcellulose (hypromellose) and/or hydroxypropylcellulose, b) methacrylic acid copolymers and methacrylic acid esters c) polyvinylpyrrolidone (PVP) and derivatives d) polyvidone acetate e) polyvinyl acetate phthalate, wherein the tablets resulting from the coating from the tablet cores have a diameter of between 4 and 10 mm and a mass of between 50 and 500 mg, characterized in that the tablets do not release any carbohydrates in the mouth within 15 seconds and that the tablets release more than 80% of the carbohydrates they contain within one minute in the stomach after being swallowed. 2. Composition in tablet form according to claim 1, wherein the individual tablets have a diameter of 7 to 8 mm and a mass of 210 to 270 mg. 3. Composition in tablet form according to claim 1 or 2, wherein the tablet cores contain about 80% dextrose, lactose, maltose, trehalose, sucrose, maltodextrin or mixtures thereof. 4. A composition in tablet form according to claim 1 or 2, wherein the tablet cores contain maltodextrin. 5. A composition in tablet form according to any one of claims 1 to 4, wherein the tablet coating essentially contains hydroxypropylmethylcellulose. 6. Use of a composition in tablet form for the manufacture of an agent for the treatment of hypoglycemic conditions, the composition consisting of tablet cores containing 70-95% dextrose, lactose, maltose, trehalose, sucrose, maltodextrin or mixtures thereof together with conventional agents for improving the processability or dissolution properties, as well as a Tablet coating selected from the following substance classes a) cellulose and cellulose derivatives, in particular carboxymethylcellulose, hydroxypropylmethylcellulose phthalate, methylcellulose, hydroxypropylmethylcellulose (hypromellose) and/or hydroxypropylcellulose, b) methacrylic acid copolymers and methacrylic acid esters c) polyvinylpyrrolidone (PVP) and derivatives d) polyvidone acetate e) polyvinyl acetate phthalate, whereby the tablets produced from the tablet cores by the coating have a diameter between 4 and 10 mm and a mass between 50 and 500 mg and wherein the tablets do not release any carbohydrates within 15 seconds in the mouth and wherein the tablets release more than 80% of the carbohydrates contained in the stomach within one minute after swallowing. 7. Use of a composition in tablet form according to claim 6, wherein the individual tablets have a diameter of 7 to 8 mm and a mass of 210 to 270 mg. 8. Use of a composition in tablet form according to claim 6 or 7, wherein the tablet cores contain about 80% dextrose, lactose, maltose, trehalose, sucrose, maltodextrin or mixtures thereof. 9. Use of a composition in tablet form according to claim 6 or 7, wherein the tablet cores contain maltodextrin. 10. Use of a composition for treating hypoglycemia in tablet form according to any one of claims 6 to 9, wherein the tablet cores contain about 80% dextrose. 11.Use of a composition for treating hypoglycemia in tablet form according to at least one of claims 6 to 10, wherein the tablet coating essentially contains hydroxypropylmethylcellulose.